FAMVIR 750 mg Tablets (Novartis Pharmaceuticals UK Ltd)


1. Name Of The Medicinal Product

FAMVIR® 750 mg Tablets

2. Qualitative And Quantitative Composition

Famciclovir 750 mg

3. Pharmaceutical Form

White, oval, film-coated 'Tiltab' tablets containing 750 mg famciclovir for oral administration.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of herpes zoster (shingles) infections.

4.2 Posology And Method Of Administration

Dosage:

Adults:

Herpes Zoster Infections

One 750 mg tablet once daily for seven days. The tablet should be taken at approximately the same time each day. Treatment should be initiated as early as possible in the course of the disease, promptly after diagnosis.

Elderly:

Dosage modification is not required unless renal function is impaired.

Renally Impaired:

As reduced clearance of penciclovir is related to reduced renal function, special attention should be given to dosage in patients with impaired renal function. The following modifications are recommended:

For the treatment of herpes zoster infections:

Creatinine clearance (ml/min/1.73m2 )

Dosage

30-59

250 mg twice daily

10-29

250 mg once daily

When only serum creatinine is available a nomogram or the following formula (Cockcroft and Gault) should be used to estimate creatinine clearance.

Creatinine clearance (ml/min/1.73m2) =

Renally impaired patients on haemodialysis:

For a patient on haemodialysis, a dosage interval of 48 hours is recommended for periods between dialysis. Since four hours' haemodialysis results in approximately 75% reduction in plasma concentrations of penciclovir, the full dose of famciclovir should be administered immediately following dialysis.

Hepatically Impaired:

Dosage modification is not required for patients with well compensated chronic liver disease. There is no information on patients with overtly decompensated chronic liver disease; accordingly no precise dose recommendations can be made for this group of patients.

Children:

There are currently insufficient data on the safety and efficacy of FAMVIR in children and therefore its use in children is not recommended.

Administration:

Oral.

4.3 Contraindications

FAMVIR is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of FAMVIR . It is also contraindicated in those patients who have shown hypersensitivity to penciclovir.

4.4 Special Warnings And Precautions For Use

Special attention should be paid to patients with impaired renal function as dosage adjustment may be necessary. (see sections 4.2 and 4.9) No special precautions are required for hepatically impaired or elderly patients.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant pharmacokinetic interactions have been identified. Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir.

4.6 Pregnancy And Lactation

Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir, the safety of FAMVIR in human pregnancy has not been established. FAMVIR should, therefore , not be used during pregnancy or in nursing mothers unless the potential benefits of treatment outweigh any possible risk.

Studies in rats show that penciclovir is excreted in the breast milk of lactating females given oral famciclovir. There is no information on excretion in human milk.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence that famciclovir (FAMVIR) will affect the ability of a patient to drive or to use machines.

4.8 Undesirable Effects

Famciclovir has been well tolerated in human studies. Headache and nausea have been reported in clinical trials. These were generally mild or moderate in nature and occurred at a similar incidence in patients receiving placebo treatment.

In post-marketing experience, in addition to the above, vomiting, dizziness and skin rash, and confusion which was predominantly in the elderly, have been reported rarely. Hallucinations have been reported very rarely.

4.9 Overdose

Overdose experience with famciclovir is limited. A report of accidental acute overdosage (10.5g) was asymptomatic. In a report of chronic use (10g/day for two years), famciclovir was well tolerated . In the event of an overdose supportive and symptomatic therapy should be given as appropriate.

Acute renal failure has been reported rarely in patients with underlying renal disease where the FAMVIR dosage has not been appropriately reduced for the level of renal function.

Penciclovir is dialysable and plasma concentrations are reduced by approximately 75% following four hours' haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Famciclovir is the oral form of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vivo and in vitro activity against human herpes viruses including Varicella zoster virus and Herpes simplex types 1 and 2.

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models, this effect is due to in vivo conversion to penciclovir. In virus-infected cells penciclovir is rapidly and efficiently converted into the triphosphate (mediated via virus-induced thymidine kinase).

Penciclovir triphosphate persists in infected cells for more than 12 hours where it inhibits replication of viral DNA and has a half-life of nine, 10 and 20 hours in cells infected with Varicella zoster, Herpes simplex virus type 1 and herpes simplex virus type 2 respectively. In uninfected cells treated with penciclovir, concentrations of penciclovir-triphosphate are only barely detectable. Accordingly, uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.

Penciclovir has been shown to be active against a recently isolated acyclovir-resistant Herpes simplex virus strain which has an altered DNA polymerase.

5.2 Pharmacokinetic Properties

General characteristics

Following oral administration, famciclovir is rapidly and extensively absorbed and rapidly converted to the active compound, penciclovir. Bioavailability of penciclovir after oral FAMVIR is 77%. Mean peak plasma concentration of penciclovir, following 750 mg oral dose of famciclovir, was 4.9 micrograms/ml and occurred at a median time of 50 minutes post-dose. Plasma concentration-time curves of penciclovir are similar following single and repeat (t.i.d.) dosing. The terminal plasma half-life of penciclovir after both single and repeat dosing with famciclovir is approximately 2.0 hours. There is no accumulation of penciclovir on repeated dosing with famciclovir. Penciclovir and its 6-deoxy precursor are poorly (<20%) bound to plasma proteins.

Famciclovir is eliminated principally as penciclovir and its 6-deoxy precursor which are excreted in urine unchanged. FAMVIR has not been detected in urine. Tubular secretion contributes to the renal elimination of the compound.

Characteristics in patients

Uncomplicated herpes zoster infection does not significantly alter the pharmacokinetics of penciclovir measured after oral administration of FAMVIR.

5.3 Preclinical Safety Data

Famciclovir has no significant effects on spermatogenesis or sperm morphology and motility in man. At doses greatly in excess of those used therapeutically impaired fertility was observed in male rats - no such effects being observed in female rats.

At a dose level approximately 50 times the normal therapeutic dose there was an increased incidence of mammary adenocarcinoma in female rats. No such effect was seen in male rats or mice of either sex.

Additionally famciclovir was not found to be genotoxic in a comprehensive battery of in vivo and in vitro tests designed to detect gene mutation, chromosomal damage and repairable damage to DNA. Penciclovir, in common with other drugs of this class, has been shown to cause chromosomal damage, but did not induce gene mutation in bacterial or mammalian cell systems, nor was there evidence of increased DNA repair in vitro.

The findings are not considered to have any clinical significance.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Hydroxypropyl Cellulose EP

Sodium Starch Glycollate BP

Magnesium Stearate EP

Hydroxypropyl Methyl Cellulose EP

Titanium Dioxide EP

Polyethelene Glycol NF

6.2 Incompatibilities

No specific incompatibilities.

6.3 Shelf Life

Famciclovir tablets have a shelf-life of three years.

6.4 Special Precautions For Storage

Store at or below 30°C in a dry place.

6.5 Nature And Contents Of Container

FAMVIR is supplied as a starter pack containing one tablet and as a shingles patient pack in original blister packs containing seven tablets and a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

SmithKline Beecham plc

SB House

Great West Road

Brentford

Middlesex TW8 9BD

Trading as:

SmithKline Beecham Pharmaceuticals

Mundells

Welwyn Garden City

Hertfordshire AL7 1EY

8. Marketing Authorisation Number(S)

PL 10592/0084

9. Date Of First Authorisation/Renewal Of The Authorisation

August 1996.

10. Date Of Revision Of The Text

March 2000

Legal Category:

POM


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Emadine


emedastine difumarate
Dosage Form: ophthalmic solution
Emadine®
(emedastine difumarate ophthalmic solution) 0.05% DESCRIPTION

Emadine® (emedastine difumarate ophthalmic solution) 0.05% is a sterile ophthalmic solution containing emedastine, a relatively selective, H1-receptor antagonist for topical administration to the eyes. Emedastine difumarate is a white, crystalline, water-soluble fine powder with a molecular weight of 534.57. The chemical structure is presented below:

Structural Formula:

Chemical Name:

1H-benzimidazole,1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl),(E)-2-butenedioate (1:2)

Each mL of Emadine contains: Active: 0.884 mg emedastine difumarate equivalent to 0.5 mg emedastine. Preservative: benzalkonium chloride 0.01%. Inactives: tromethamine; sodium chloride; hypromellose; hydrochloric acid/sodium hydroxide (adjust pH); and purified water. It has a pH of approximately 7.4 and an osmolality of approximately 300 mOsm/kg.

CLINICAL PHARMACOLOGY

Emedastine is a relatively selective, histamine H1 antagonist. In vitro examinations of emedastine's affinity for histamine receptors (H1: Ki=1.3 nM, H2: Ki=49,067 nM, and H3: Ki=12,430 nM) demonstrate relative selectivity for the H1 histamine receptor. In vivo studies have shown concentration-dependent inhibition of histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Emedastine appears to be devoid of effects on adrenergic, dopaminergic and serotonin receptors.

Following topical administration in man, emedastine was shown to have low systemic exposure. In a study involving 10 normal volunteers dosed bilaterally twice daily for 15 days with emedastine ophthalmic solution 0.05%, plasma concentrations of the parent compound were generally below the quantitation limit of the assay (<0.3 ng/mL). Samples in which emedastine was quantifiable ranged from 0.30 to 0.49 ng/mL. The elimination half-life of oral emedastine in plasma is 3-4 hours. Approximately 44% of the oral dose is recovered in the urine over 24 hours with only 3.6% of the dose excreted as parent drug. Two primary metabolites, 5- and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. The 5'-oxoanalogs of 5- and 6-hydroxyemedastine and the N-oxide are also formed as minor metabolites. In an environmental study, patients with allergic conjunctivitis were treated with Emadine® (emedastine difumarate ophthalmic solution) 0.05% for six weeks. The results demonstrated that Emadine® (emedastine difumarate ophthalmic solution) 0.05% provides relief of the signs and symptoms of allergic conjunctivitis. In conjunctival antigen challenge studies, in which subjects were challenged with antigen both initially and up to four hours after dosing, Emadine® (emedastine difumarate ophthalmic solution) 0.05% was demonstrated to be significantly more effective than placebo in preventing ocular itching associated with allergic conjunctivitis.

INDICATIONS AND USAGE

Emadine® (emedastine difumarate ophthalmic solution) 0.05% is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis.

CONTRAINDICATIONS

Emadine® (emedastine difumarate ophthalmic solution) is contraindicated in persons with a known hypersensitivity to emedastine difumarate or any of its components.

WARNINGS

FOR TOPICAL OPHTHALMIC USE ONLY - NOT FOR INJECTION OR ORAL USE.

PRECAUTIONS Information for Patients:

To prevent contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep the bottle tightly closed when not in use. Do not use if the solution has become discolored.

Patients should be advised not to wear a contact lens if their eye is red. Emadine® (emedastine difumarate ophthalmic solution) 0.05% should not be used to treat contact lens related irritation. The preservative in Emadine® (emedastine difumarate ophthalmic solution) 0.05%, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red, should be instructed to wait at least ten minutes after instilling Emadine® (emedastine difumarate ophthalmic solution) 0.05% before they insert their contact lenses.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Emedastine difumarate demonstrated no carcinogenicity effects in lifetime studies in mice and rats at dietary doses more than 80,000 times and more than 26,000 times the maximum recommended ocular human use level of 0.002 mg/kg/day for a 50 kg adult, respectively. Higher dose levels were not tested. Emedastine difumarate was determined to be nonmutagenic in an in vitro bacterial reverse mutation (Ames) test, an in vitro modification of the Ames test, an in vitro mammalian chromosome aberration test, an in vitro mammalian forward mutation test, an in vitro mammalian DNA repair synthesis test, an in vivo mammalian sister chromatid exchange test and an in vivo mouse micronucleus test. There was no evidence of impaired fertility or reproductive capacity in rats at 15,000 times the maximum recommended ocular human use level.

Pregnancy: Pregnancy Category B.

Teratology and peri- and post-natal studies have been conducted with emedastine difumarate in rats and rabbits. At 15,000 times the maximum recommended ocular human use level, emedastine difumarate was shown not to be teratogenic in rats and rabbits and no effects on peri/post-natal development were observed in rats. However, at 70,000 times the maximum recommended ocular human use level, emedastine difumarate was shown to increase the incidence of external, visceral and skeletal anomalies in rats. There are, however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:

Emedastine has been identified in breast milk in rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when Emadine® (emedastine difumarate ophthalmic solution) 0.05% is administered to a nursing mother.

Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 3 years have not been established.

Geriatric Use:

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

ADVERSE REACTIONS

In controlled clinical studies of Emadine® (emedastine difumarate ophthalmic solution) 0.05% lasting for 42 days, the most frequent adverse reaction was headache 11%. The following adverse experiences were reported in less than 5% of patients: Abnormal dreams, asthenia, bad taste, blurred vision, burning or stinging, corneal infiltrates, corneal staining, dermatitis, discomfort, dry eye, foreign body sensation, hyperemia, keratitis, pruritus, rhinitis, sinusitis and tearing. Some of these events were similar to the underlying disease being studied.

OVERDOSAGE

Somnolence and malaise have been reported following daily oral administration. Oral ingestion of the contents of a 15 mL DROP-TAINER® dispenser would be equivalent to 7.5 mg. In case of overdosage, treatment is symptomatic and supportive.

DOSAGE AND ADMINISTRATION

The recommended dose is one drop in the affected eye up to four times daily.

HOW SUPPLIED

Emadine® (emedastine difumarate ophthalmic solution) 0.05% is supplied as follows:

5 mL in opaque, plastic DROP-TAINER® dispenser.

5 mL: NDC 0065-0325-05

STORAGE: Store at 4° - 30°C (39° - 86°F).

Rx Only

U.S. Patents Nos. 5,441,958.

Revised: May 2009

ALCON LABORATORIES, INC.

6201 South Freeway

Fort Worth, Texas 76134 USA

1-800-757-9195

MedInfo@AlconLabs.com

Printed in USA

©2002, 2003, 2009 Alcon, Inc.

340326-0509

PRINCIPLE DISPLAY PANEL

NDC 0065-0325-05

Alcon®

Emadine®

(emedastine

Difumarate

Ophthalmic

solution) 0.05%

5 mL Sterile


Emadine 
emedastine difumarate  solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0065-0325 Route of Administration OPHTHALMIC DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EMEDASTINE DIFUMARATE (EMEDASTINE) EMEDASTINE DIFUMARATE 0.884 mg  in 1 mL Inactive Ingredients Ingredient Name Strength TROMETHAMINE   SODIUM CHLORIDE   HYDROCHLORIC ACID   SODIUM HYDROXIDE   WATER   HYPROMELLOSES   BENZALKONIUM CHLORIDE   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0065-0325-05 5 mL In 1 BOTTLE, PLASTIC None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020706 02/15/1998
Labeler - Alcon Laboratories, Inc. (008018525) Registrant - Alcon Laboratories, Inc. (008018525) Establishment Name Address ID/FEI Operations Alcon Laboratories, Inc. 008018525 MANUFACTURE Revised: 07/2011Alcon Laboratories, Inc. More Emadine resources Emadine Side Effects (in more detail) Emadine Dosage Emadine Use in Pregnancy & Breastfeeding Emadine Support Group 0 Reviews for Emadine - Add your own review/rating Emadine Concise Consumer Information (Cerner Multum) Emadine Monograph (AHFS DI) Emadine Advanced Consumer (Micromedex) - Includes Dosage Information Emadine Drops MedFacts Consumer Leaflet (Wolters Kluwer) Compare Emadine with other medications Conjunctivitis, Allergic
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Disprin


1. Name Of The Medicinal Product

Disprin

2. Qualitative And Quantitative Composition

Active Ingredient

mg/Tablet

Specification

Aspirin

300.00

Ph Eur

3. Pharmaceutical Form

Dispersible tablet

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of mild to moderate pain in headaches, including migraine headaches, toothache, neuralgia, sciatica, period pains and sore throats.

Reduction of temperature in feverishness, influenza and colds.

Reduction of inflammation in rheumatism and lumbago.

4.2 Posology And Method Of Administration

Oral administration after dissolution in water.

Adults (including children 16 years and over): Two to three tablets every 4 hours. Do not exceed 13 tablets in 24 hours.

Do not give to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

There is no indication that dosage need be modified in the elderly.

4.3 Contraindications

Should not be given to patients suffering from a previous history of peptic ulceration or active peptic ulceration or haemophilia.

4.4 Special Warnings And Precautions For Use

The product labelling will include:

Do not give to children under 16 years unless on the advice of a doctor.

Keep out of reach of children.

If you are receiving regular medical treatment, are asthmatic, allergic to aspirin or have or have had a stomach ulcer, seek your doctor's advice before taking this product.

There is a possible association between aspirin and Reye's Syndrome when given to children. Reye's Syndrome is a very rare disease which affects the brain and liver and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aspirin may enhance the effects of anticoagulants and inhibit the effects of uricosurics.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

4.6 Pregnancy And Lactation

There is clinical and epidemiological evidence of the safety of aspirin in human pregnancy, but it may prolong labour and contribute to maternal and neonatal bleeding and is best avoided at term and during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

May precipitate bronchospasm and induce attacks of asthma or hypersensitivity in susceptible subjects. May also induce gastrointestinal haemorrhage, occasionally major.

4.9 Overdose

Salicylate poisoning is usually associated with plasma concentrations>350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of four years. In children aged four years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations>700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under ten years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Aspirin:

Aspirin inhibits the cyclo-oxygenase enzyme involved in conversion of phospholipids to prostaglandins and its effects on the body are believed to result primarily from prevention of prostaglandin production. These effects include peripheral analgesia, fever reduction, reduction in inflammation and inhibition of platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Aspirin is rapidly absorbed from the stomach and upper gastrointestinal tract with peak levels after around 20-30 minutes following dissolution. It is subject to first-pass metabolism with an overall bioavailability of around 70%. Metabolism is by conversion to salicylic acid and then by further conversion to other metabolites. These are excreted by the kidneys in both free and conjugated form. The plasma half-life of aspirin is around 15-20 minutes and that of salicylic acid is 2-3 hours.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Calcium carbonate, maize starch, citric acid, talc, sodium lauryl sulphate, saccharin, crospovidone and lime flavour.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

Cardboard carton containing tablets in strips of aluminium foil with vinyl heat seal. Pack sizes: 6, 8, 12, 16, 24, 32, 48, 96 and 500 tablets. (Those pack sizes printed in bold are currently sold).

6.6 Special Precautions For Disposal And Other Handling

Oral administration after dissolution in water.

7. Marketing Authorisation Holder

Reckitt Benekiser Healthcare (UK) Limited

Dansom Lane

Hull

HU8 7DS

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00063/0017.

9. Date Of First Authorisation/Renewal Of The Authorisation

24/04/1995 / 23/02/2004

10. Date Of Revision Of The Text

26/01/2009


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LMX4 Lidocaine 4% w / w Cream


1. Name Of The Medicinal Product

LMX 4

Lidocaine 4%w/w Cream

2. Qualitative And Quantitative Composition

Lidocaine 4%w/w

For excipients, see 6.1

3. Pharmaceutical Form

Cream

A white to off-white yellowish cream

4. Clinical Particulars 4.1 Therapeutic Indications

Local anaesthetic for topical use to produce surface anaesthesia of the skin prior to venous cannulation or venipuncture.

4.2 Posology And Method Of Administration

For cutaneous use only.

Adults, including elderly, and children over one month of age.

Apply 1g to 2.5g of cream onto the skin to cover a 2.5cm x 2.5cm (6.25cm2) area where venous cannulation or venipuncture will occur. No more than 1g of cream should be applied to infants below the age of 1 year. 1g of cream equates to approximately 5cm of cream squeezed from the 5g tube or 3.5cm from the 30g tube.

The cream should remain undisturbed and the area can be covered with an occlusive dressing to prevent disturbance or interference by the patient or other external factors. Adequate anaesthesia should be obtained after 30 minutes, but the LMX4 Cream may be applied for up to 5 hours under a dressing. Prior to starting the procedure, the LMX 4 Cream should be removed using a clean gauze swab and the site for venous cannulation or venipuncture prepared in the usual manner. The procedure should be initiated approximately 5 minutes after the cream has been removed. Maximum application time for 1 month upto 3 month infant should not exceed 60 minutes. Maximum application time for 3 month upto 12 month infant should not exceed 4 hours. Maximum application for 12 month infant – adult should not exceed 5 hours.

4.3 Contraindications

Hypersensitivity to the active substance, or any of the amide-type local anaesthetics, or any of the excipients.

4.4 Special Warnings And Precautions For Use

For external use only.

Avoid contact with eyes.

Do not apply to irritated skin or if excessive irritation develops. If condition worsens, or if symptoms persist unaltered for more than seven days or clear up and occur again within only a few days, discontinue use of this product and consult a doctor.

Do not use in large quantities, particularly over raw or blistered areas.

LMX 4 contains propylene glycol which may cause skin irritation.

LMX 4 has not been applied to wounds, mucous membranes or in areas of atopic dermatitis as there are no clinical data in relation to these.

Anaesthetic efficacy during the heel lancing of neonates has not been studied.

Application of lidocaine to larger areas or for longer times than those recommended could result in sufficient absorption of lidocaine resulting in serious adverse effects.

Studies in laboratory animals (guinea pigs) have shown that lidocaine has an ototoxic effect when instilled into the middle ear. In these same studies, animals exposed to lidocaine in the external auditory canal only showed no abnormality. Lidocaine should not be used in any clinical situation in which its penetration or migration beyond the tympanic membrane into the middle ear is possible.

Dermal application of lidocaine may cause transient local blanching followed by transient erythema.

PRECAUTIONS

General: Repeated doses of lidocaine may increase blood levels of lidocaine. Lidocaine should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine including acutely ill, debilitated, or elderly patients.

Lidocaine coming in contact with the eye should be avoided because animal studies have demonstrated severe eye irritation. Also the loss of protective reflexes can permit corneal irritation and potential abrasion. Absorption of lidocaine in conjunctival tissues has not been determined. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine; however, lidocaine should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. Patients with severe hepatic disease, because of their inability to metabolize local anaesthetics normally, are at greater risk of developing toxic plasma concentrations of lidocaine.

When lidocaine is used, the patient should be aware that the production of dermal analgesia may be accompanied by the block of all sensations in the treated skin. For this reason, the patient should avoid inadvertent trauma to the treated area by scratching, rubbing, or exposure to extreme hot or cold temperatures until complete sensation has returned.

Lidocaine has bactericidal and antiviral properties in concentrations above 0.5%. For this reason, the results of intra-cutaneous injections of live vaccines (such as BCG vaccination) should be monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lidocaine should be used with caution in patients receiving Class I anti-arrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and generally synergistic.

The risk of additional systemic toxicity should be considered when large doses of LMX 4 are applied to patients already using other local anaesthetics.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, lidocaine should be used during pregnancy only if clearly needed.

Lidocaine is not contraindicated in labour and delivery. Should LMX 4 be used concomitantly with other products containing lidocaine, total doses contributed by all formulations must be considered.

Lidocaine can cross the placental barrier.

Lidocaine is excreted in human milk. Therefore, caution should be exercised when LMX 4 is administered to a nursing mother since the milk:plasma ratio of lidocaine is 0.4.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Common side effects (>1/100) can include irritation, redness, itching, or rash.

In rare cases local anaesthetics have been associated with allergic reactions including anaphylactic shock.

Corneal irritation after accidental eye exposure.

4.9 Overdose

Overdose with LMX 4 cream is unlikely but signs of systemic toxicity would be consistent with those of lidocaine.

An indication of systemic toxicity may include blurred vision, dizziness or drowsiness, difficulty breathing, trembling, chest pain, or irregular heartbeat.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Anaesthetics for topical use, lidocaine, ATC Code: D04A B 01

Lidocaine applied to intact skin provides dermal analgesia by a release of lidocaine from the cream into the epidermal and dermal layers of the skin, and by the accumulation of lidocaine in the vicinity of pain receptors and nerve endings. Lidocaine is an amide-type local anaesthetic agent which stabilises neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anaesthetic action. The onset, depth and duration of dermal analgesia provided by lidocaine depend primarily on the duration of application. LMX 4 may cause transient peripheral vasoconstriction followed by transient vasodilation at the application site.

5.2 Pharmacokinetic Properties

The amount of lidocaine systemically absorbed is directly related to both the duration of application and to the area over which it is applied. It is not known if it is metabolized into the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent to that of lidocaine. The metabolite, 2,6-xylidine, has unknown pharmacologic activity but is carcinogenic in rats. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of concentrations, respectively. The half-life of lidocaine elimination from the plasma following IV administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). This half-life may be increased in cardiac or hepatic dysfunction. More than 98% of an absorbed dose of can be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg (mean 13, ±3 SD, n=13).

When applied topically to intact skin, the absorption of lidocaine is very low. Increased absorption is therefore to be expected when applied to mucosa or previously damaged skin.

The maximum plasma level of active ingredient was very low (0.3 µg/ml or less) in a study investigating the application of LMX 4 in children of different ages. It was well below the toxically effective plasma level of ingredients.

5.3 Preclinical Safety Data

The mutagenic potential of lidocaine HCl has been tested in the Ames Salmonella/mammalian microsome test and by analysis of structural chromosome aberrations in human lymphocytes in vitro, and by mouse micronucleus test in vivo. There was no indication in these tests of any mutagenic effects. The mutagenicity of 2,6-xylidine, a metabolite of lidocaine, has been studied in different tests with mixed results. The compound was found to be weakly mutagenic in the Ames test only under metabolic activation conditions. In addition, 2,6-xylidine was observed to be mutagenic at the thymidine kinase locus, with or without activation, and induced chromosome aberrations and sister chromatic exchanges at concentrations at which the drug precipitated out of the solution (1.2 mg/ml). No evidence of genotoxicity was found in the in vivo assays measuring unscheduled DNA synthesis in rat hepatocytes, chromosome damage in polychromatic erythrocytes or preferential killing of DNA repair-deficient bacteria in liver, lung, kidney, testes and blood extracts from mice. However, covalent binding studies of DNA from liver and ethmoid turbinates in rats indicate that 2,6-xylidine may be genotoxic under certain conditions in vivo.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzyl Alcohol

Carbomers

Cholesterol

Phospholipon 80H (Hydrogenated Soy Lecithin)

Polysorbate 80 (Tween 80)

Propylene Glycol

Trolamine

Vitamin E Acetate

Purified Water

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

Unopened:

Two years

Opened:

3 months

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

The pack sizes are 5g and 30g.

Both packs comprise of an aluminium tube with an epoxyphenolic internal lacquer, fitted with a polypropylene cap.

The following packaging options are approved but not all of these packaging options may be marketed:

1) A carton containing one 5g tube.

2) A carton containing five 5g tubes.

3) A carton containing one 5g tube with two Tegaderm® occlusive dressings.

4) A carton containing five 5g tubes with ten Tegaderm® occlusive dressings.

5) A carton containing one 30g tube.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Ferndale Pharmaceuticals Ltd

12 York Place

Leeds

LS1 2DS

United Kingdom

8. Marketing Authorisation Number(S)

PL 20685/0034

9. Date Of First Authorisation/Renewal Of The Authorisation

20/11/2007

10. Date Of Revision Of The Text

15/03/2011


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Arava


Generic Name: leflunomide
Dosage Form: tablet, film coated
Arava® Tablets
(leflunomide)
10 mg, 20 mg, 100 mg CONTRAINDICATIONS AND WARNINGS Pregnancy

Pregnancy must be excluded before the start of treatment with Arava. Arava is contraindicated in pregnant women, or women of childbearing potential who are not using reliable contraception. (see CONTRAINDICATIONS and WARNINGS.) Pregnancy must be avoided during Arava treatment or prior to the completion of the drug elimination procedure after Arava treatment.

Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in some patients treated with Arava. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2?ULN before initiating treatment, should not be treated with Arava. Use caution when Arava is given with other potentially hepatotoxic drugs.

Monitoring of ALT levels is recommended at least monthly for six months after starting Arava, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt Arava therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of Arava therapy may be considered. (SEE WARNINGS – HEPATOTOXICITY).

Arava Description

Arava® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:

Arava is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).

Arava - Clinical Pharmacology Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

Pharmacokinetics

Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite.

Absorption

Following oral administration, peak levels of the active metabolite, M1, occurred between 6 – 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.

Table 1. Pharmacokinetic Parameters for M1 after Administration of Leflunomide at Doses of 5, 10, and 25 mg/day for 24 Weeks to Patients (n=54) with Rheumatoid Arthritis (Mean ± SD) (Study YU204) Maintenance (Loading) Dose Parameter 5 mg (50 mg) 10 mg (100 mg) 25 mg (100 mg) * Concentration at 24 hours after loading dose † Concentration at 24 hours after maintenance doses at steady state C24 (Day 1) (µg/mL)* 4.0 ± 0.6 8.4 ± 2.1 8.5 ± 2.2 C24 (ss) (µg/mL)† 8.8 ± 2.9 18 ± 9.6 63 ± 36 t1/2(DAYS) 15 ± 3 14 ± 5 18 ± 9

Relative to an oral solution, Arava tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.

Distribution

M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.

Metabolism

Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.

Elimination

The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.

In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day. (See PRECAUTIONS - General - Need for Drug Elimination). Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.

Special Populations Gender

Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.

Age

Age has been shown to cause a change in the in vivo pharmacokinetics of M1 (see CLINICAL PHARMACOLOGY – Special Populations - Pediatrics).

Smoking

A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Chronic Renal Insufficiency

In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when Arava is administered to these patients.

Hepatic Insufficiency

Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended.

Pediatrics

The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ?40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients.

Table 2: Population Pharmacokinetic Estimate of M1 Clearance Following Oral Administration of Leflunomide in Pediatric Patients with Polyarticular Course JRA Mean ±SD [Range] N Body Weight (kg) CL (mL/h) 10 <20 18 ± 9.8 [6.8–37] 30 20–40 18 ± 9.5 [4.2–43] 33 >40 26 ± 16 [9.7–93.6] Drug Interactions

In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.

In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 – 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. (See PRECAUTIONS – Drug Interactions).

Methotrexate

Coadministration, in 30 patients, of Arava (100 mg/day ? 2 days followed by 10 – 20 mg/day) with methotrexate (10 – 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity (see PRECAUTIONS – Drug Interactions – Hepatotoxic Drugs).

Rifampin

Following concomitant administration of a single dose of Arava to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when Arava was given alone. Because of the potential for Arava levels to continue to increase with multiple dosing, caution should be used if patients are to receive both Arava and rifampin.

Clinical Studies A. ADULTS

The efficacy of Arava in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function.

1. Reduction of signs and symptoms

Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR)20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ? 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study.

2. Inhibition of structural damage

Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233–241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.

3. Improvement in physical function

Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).

In all Arava monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter.

US301 Clinical Trial in Adults

Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. Primary analysis was at 52 weeks with blinded treatment to 104 weeks.

Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.

The rate and reason for withdrawal is summarized in Table 3.

Table 3: Withdrawals in US301 n(%) patients Leflunomide
190 Placebo
128 Methotrexate
190 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. Withdrawals in Year-1   Lack of efficacy 33 (17.4) 70 (54.7) 50 (26.3)   Safety 44 (23.2) 12 (9.4) 22 (11.6)   Other*     15 (7.9)         10 (7.8)         17 (9.0)       Total 92 (48.4) 92 (71.9) 89 (46.8)  Patients entering Year 2 98 36 101 Withdrawals in Year-2   Lack of efficacy 4 (4.1) 1 (2.8) 4 (4.0)   Safety 8 (8.2) 0 (0.0) 10 (9.9)   Other*     3 (3.1)         8 (22.2)         7 (6.9)       Total 15 (15.3) 9 (25.0) 21 (20.8) MN301/303/305 Clinical Trial in Adults

Study MN301 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303).

Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.

Patient withdrawal data in MN301/303/305 is summarized in Table 4.

Table 4: Withdrawals in study MN301/303/305 n(%) patients Leflunomide
133 Placebo
92 Sulfasalazine
133 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. Withdrawals in MN301 (Mo 0–6)   Lack of efficacy 10 (7.5) 29 (31.5) 14 (10.5)   Safety 19 (14.3) 6 (6.5) 25 (18.8)   Other*     8 (6.0)         6 (6.5)         11 (8.3)       Total 37 (27.8) 41 (44.6) 50 (37.6)   Patients entering MN303 80 76 Withdrawals in MN303 (Mo 7–12)   Lack of efficacy 4 (5.0) 2 (2.6)   Safety 2 (2.5) 5 (6.6)   Other*     3 (3.8)         1 (1.3)       Total 9 (11.3) 8 (10.5)   Patients entering MN305 60 60 Withdrawals in MN305 (Mo 13–24)   Lack of efficacy 0 (0.0) 3 (5.0)   Safety 6 (10.0) 8 (13.3)   Other*     1 (1.7)         2 (3.3)       Total 7 (11.7) 13 (21.7) MN302/304 Clinical Trial in Adults

Study MN302 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.

Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.

Patient withdrawal data in MN302/304 is summarized in Table 5.

Table 5: Withdrawals in MN302/304 n(%) patients Leflunomide
501 Methotrexate
498 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. Withdrawals in MN302 (Year-1)   Lack of efficacy 37 (7.4) 15 (3.0)   Safety 98 (19.6) 79 (15.9)   Other*     17 (3.4)         17 (3.4)       Total 152 (30.3) 111 (22.3)   Patients entering MN304 292 320 Withdrawals in MN304 (Year-2)   Lack of efficacy 13 (4.5) 9 (2.8)   Safety 11 (3.8) 22 (6.9)   Other*     12 (4.1)         12 (3.8)       Total 36 (12.3) 43 (13.4) Clinical Trial Data 1. Signs and symptoms Rheumatoid Arthritis

The ACR20 Responder at Endpoint rates are shown in Figure 1. Arava was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with Arava treatment were consistent across the 6 and 12 month studies (41 – 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. Arava treatment effect was evident by 1 month, stabilized by 3 – 6 months, and continued throughout the course of treatment as shown in Figure 2.

Figure 1

Comparisons 95%Confidence Interval p Value US301 Leflunomide vs. Placebo (12, 32) <0.0001 Methotrexate vs. Placebo (8, 30) <0.0001 Leflunomide vs. Methotrexate (-4, 16) NS MN301 Leflunomide vs. Placebo (7, 33) 0.0026 Sulfasalazine vs. Placebo (4, 29) 0.0121 Leflunomide vs. Sulfasalazine (-8, 16) NS MN302 Leflunomide vs. Methotrexate (-19, -7) <0.0001

Figure 2

*Last Observation Carried Forward.

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7.

Table 6. Summary of ACR Response Rates* Study and Treatment Group ACR20 ACR50 ACR70 * Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early. † N is the number of ITT patients for whom adequate data were available to calculate the indicated rates. ‡ p<0.001 leflunomide vs placebo § p<0.02 leflunomide vs placebo Placebo-Controlled Studies US301 (12 months) Leflunomide (n=178)† 52.2‡ 34.3‡ 20.2‡ Placebo (n=118)† 26.3 7.6 4.2 Methotrexate (n=180)† 45.6 22.8 9.4 MN301(6 months) Leflunomide (n=130)† 54.6‡ 33.1‡ 10.0§ Placebo (n=91)† 28.6 14.3 2.2 Sulfasalazine (n=132)† 56.8 30.3 7.6 Non-Placebo Active-Controlled Studies MN302 (12 months) Leflunomide (n=495)† 51.1 31.1 9.9 Methotrexate (n=489)† 65.2 43.8 16.4

Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Arava was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. In addition, Arava was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between Arava and the active comparators.

Table 7. Mean Change in the Components of the ACR Responder Index* Components Placebo-Controlled Studies Non-placebo Controlled Study US301
(12 months) MN301 Non-US
(6 months) MN302 Non-US
(12 months) Leflunomide Methotrexate Placebo Leflunomide Sulfasalazine Placebo Leflunomide Methotrexate * Last Observation Carried Forward; Negative Change Indicates Improvement † Based on 28 joint count ‡ Visual Analog Scale - 0=Best; 10=Worst Tender joint count† -7.7 -6.6 -3.0 -9.7 -8.1 -4.3 -8.3 -9.7 Swollen joint count† -5.7 -5.4 -2.9 -7.2 -6.2 -3.4 -6.8 -9.0 Patient global assessment‡ -2.1 -1.5 0.1 -2.8 -2.6 -0.9 -2.3 -3.0 Physician global assessment‡ -2.8 -2.4 -1.0 -2.7 -2.5 -0.8 -2.3 -3.1 Physical function/disability (MHAQ/HAQ) -0.29 -0.15 0.07 -0.50 -0.29 -0.04 -0.37 -0.44 Pain intensity‡ -2.2 -1.7 -0.5 -2.7 -2.0 -0.9 -2.1 -2.9 Erythrocyte Sedimentation rate -6.26 -6.48 2.56 -7.48 -16.56 3.44 -10.12 -22.18 C-reactive protein -0.62 -0.50 0.47 -2.26 -1.19 0.16 -1.86 -2.45 Not included in the ACR Responder Index Morning Stiffness (min) -101.4 -88.7 14.7 -93.0 -42.4 -6.8 -63.7 -86.6 2. Maintenance of effect

After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment.

Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of Arava treatment in all three trials.

3. Inhibition of structural damage

The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. Arava was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine.

Figure 3

L= Leflunomide; M=methotrexate; S=sulfasalazine; P=placebo

Comparisons 95% Confidence Interval p Value US301 Leflunomide vs. Placebo (-4.0, -1.1) 0.0007 Methotrexate vs. Placebo (-2.6, -0.2) 0.0196 Leflunomide vs. Methotrexate (-2.3, 0.0) 0.0499 MN301 Leflunomide vs. Placebo (-6.2, -1.8) 0.0004 Sulfasalazine vs. Placebo (-6.9, 0.0) 0.0484 Leflunomide vs. Sulfasalazine (-3.3, 1.2) NS MN302 Leflunomide vs. Methotrexate (-2.2, 7.4) NS 4. Improvement in physical function

The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Arava was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.

The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In US301, at 12 months, Arava provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.

Figure 4

Comparisons 95% Confidence Interval p Value US301 Leflunomide vs. Placebo (-0.58, -0.29) 0.0001 Leflunomide vs. Methotrexate (-0.34, -0.07) 0.0026 MN301 Leflunomide vs. Placebo (-0.67, -0.36) <0.0001 Leflunomide vs. Sulfasalazine (-0.33, -0.03) 0.0163 MN302 Leflunomide vs. Methotrexate (0.01, 0.16) 0.0221 Maintenance of effect

The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.

B. PEDIATRICS Clinical Trials in Pediatrics

Arava was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving Arava, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ? 30 % responder endpoint. In this trial, the loading dose and maintenance dose of Arava was based on three weight categories: <20 kg, 20–40kg, and >40 kg. The response rate to Arava in pediatric patients ?40 kg was less robust than in pediatric patients >40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious pla


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Leflunomide



Leflunomide Tablets, USP
10 mg and 20 mg

CONTRAINDICATIONS AND WARNINGS

Pregnancy

Pregnancy must be excluded before the start of treatment with Leflunomide. Leflunomide tablets are contraindicated in pregnant women, or women of childbearing potential who are not using reliable contraception. (see CONTRAINDICATIONS and WARNINGS.) Pregnancy must be avoided during Leflunomide treatment or prior to the completion of the drug elimination procedure after Leflunomide treatment.

Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in some patients treated with Leflunomide. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, should not be treated with Leflunomide. Use caution when Leflunomide tablets are given with other potentially hepatotoxic drugs.

Monitoring of ALT levels is recommended at least monthly for six months after starting Leflunomide tablets, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt Leflunomide therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely Leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If Leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of Leflunomide therapy may be considered. (see WARNINGS: Hepatotoxicity).

Leflunomide Description

Leflunomide tablets, USP are pyrimidine synthesis inhibitors. The chemical name for Leflunomide is N-(4’-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:

Each Leflunomide tablet, USP for oral administration, contains 10 mg or 20 mg of Leflunomide. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, and titanium dioxide.

Meets USP Dissolution Test 2.

Leflunomide - Clinical Pharmacology Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

Pharmacokinetics

Following oral administration, Leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of Leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of Leflunomide have primarily examined the plasma concentrations of this active metabolite.

Absorption

Following oral administration, peak levels of the active metabolite, M1, occurred between 6 to 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.


Table 1. Pharmacokinetic Parameters for M1 after Administration of Leflunomide at Doses of 5, 10, and 25 mg/day for 24 Weeks to Patients (n=54) with Rheumatoid Arthritis (Mean ± SD) (Study YU204) * Concentration at 24 hours after loading dose † Concentration at 24 hours after maintenance doses at steady state Maintenance (Loading) Dose Parameter

5 mg

(50 mg)

10 mg

(100 mg)

25 mg

(100 mg) C24 (Day 1) (mcg/mL)* 4.0 ± 0.6 8.4 ± 2.1 8.5 ± 2.2 C24 (ss) (mcg/mL)† 8.8 ± 2.9 18 ± 9.6 63 ± 36 T1/2 (DAYS) 15 ± 3 14 ± 5 18 ± 9

Relative to an oral solution, Leflunomide tablets are 80% bioavailable. Co-administration of Leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.

Distribution

M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.

Metabolism

Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of Leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for Leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.

Elimination

The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be Leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.

In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day (see PRECAUTIONS: General: Need for Drug Elimination). Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.

Special Populations Gender

Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.

Age

Age has been shown to cause a change in the in vivo pharmacokinetics of M1 (see CLINICAL PHARMACOLOGY: Special Populations: Pediatrics).

Smoking

A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Chronic Renal Insufficiency

In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of Leflunomide use in subjects with renal insufficiency, caution should be used when Leflunomide is administered to these patients.

Hepatic Insufficiency

Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize Leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of Leflunomide in patients with hepatic insufficiency is not recommended.

Pediatrics

The pharmacokinetics of M1 following oral administration of Leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ?40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients.


Table 2. Population Pharmacokinetic Estimate of M1 Clearance Following Oral Administration of Leflunomide in Pediatric Patients with Polyarticular Course JRA Mean ±SD [Range] N Body Weight (kg) CL (mL/h) 10 <20 18 ± 9.8 [6.8-37] 30 20-40 18 ± 9.5 [4.2-43] 33 >40 26 ± 16 [9.7-93.6] Drug Interactions

In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between Leflunomide and tri-phasic oral contraceptives, and cimetidine.

In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4’-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed (see PRECAUTIONS: Drug Interactions).

Methotrexate

Co-administration, in 30 patients, of Leflunomide (100 mg/day x 2 days followed by 10 to 20 mg/day) with methotrexate (10 to 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity (see PRECAUTIONS: Drug Interactions: Hepatotoxic Drugs).

Rifampin

Following concomitant administration of a single dose of Leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~ 40%) over those seen when Leflunomide was given alone. Because of the potential for Leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to receive both Leflunomide and rifampin.

Clinical Studies A. Adults

The efficacy of Leflunomide in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function.

1. Reduction of signs and symptoms

Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR)20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An “ACR20 Responder” is a patient who had ?20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An “ACR20 Responder at Endpoint” is a patient who completed the study and was an ACR20 Responder at the completion of the study.

2. Inhibition of structural damage

Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233-241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.

3. Improvement in physical function

Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).

In all Leflunomide monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter.

US301 Clinical Trial in Adults

Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to Leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg b.i.d. Primary analysis was at 52 weeks with blinded treatment to 104 weeks.

Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 Leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 Leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.

The rate and reason for withdrawal is summarized in Table 3.


Table 3. Withdrawals in US301 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. n (%) patients

Leflunomide

190

Placebo

128

Methotrexate

190 Withdrawals in Year-1 Lack of efficacy 33 (17.4) 70 (54.7) 50 (26.3) Safety 44 (23.2) 12 (9.4) 22 (11.6) Other* 15 (7.9) 10 (7.8) 17 (9.0) Total 92 (48.4) 92 (71.9) 89 (46.8) Patients entering Year 2 98 36 101 Withdrawals in Year-2 Lack of efficacy 4 (4.1) 1 (2.8) 4 (4.0) Safety 8 (8.2) 0 (0.0) 10 (9.9) Other* 3 (3.1) 8 (22.2) 7 (6.9) Total 15 (15.3) 9 (25.0) 21 (20.8) MN301/303/305 Clinical Trial in Adults

Study MN301 randomized 358 patients with active RA to Leflunomide 20 mg/day (n=133), sulfasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of Leflunomide and sulfasalazine (study MN303).

Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 Leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of Leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 Leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.

Patient withdrawal data in MN301/303/305 is summarized in Table 4.


Table 4. Withdrawals in Study MN301/303/305 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. n (%) patients

Leflunomide

133

Placebo

92

Sulfasalazine

133

Withdrawals in

MN301 (Mo 0-6) Lack of efficacy 10 (7.5) 29 (31.5) 14 (10.5) Safety 19 (14.3) 6 (6.5) 25 (18.8) Other* 8 (6.0) 6 (6.5) 11 (8.3) Total 37 (27.8) 41 (44.6) 50 (37.6) Patients entering MN303 80 76

Withdrawals in

MN303 (Mo 7-12) Lack of efficacy 4 (5.0) 2 (2.6) Safety 2 (2.5) 5 (6.6) Other* 3 (3.8) 1 (1.3) Total 9 (11.3) 8 (10.5) Patients entering MN305 60 60

Withdrawals in

MN305 (Mo 13-24) Lack of efficacy 0 (0.0) 3 (5.0) Safety 6 (10.0) 8 (13.3) Other* 1 (1.7) 2 (3.3) Total 7 (11.7) 13 (21.7) MN302/304 Clinical Trial in Adults

Study MN302 randomized 999 patients with active RA to Leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.

Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 Leflunomide, 320 methotrexate). Patients continued on the same daily dosage of Leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 Leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.

Patient withdrawal data in MN302/304 is summarized in Table 5.


Table 5. Withdrawals in MN302/304 * Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. n (%) patients

Leflunomide

501

Methotrexate

498

Withdrawals in

MN302 (Year-1) Lack of efficacy 37 (7.4) 15 (3.0) Safety 98 (19.6) 79 (15.9) Other* 17 (3.4) 17 (3.4) Total 152 (30.3) 111 (22.3) Patients entering MN304 292 320

Withdrawals in

MN304 (Year-2) Lack of efficacy 13 (4.5) 9 (2.8) Safety 11 (3.8) 22 (6.9) Other* 12 (4.1) 12 (3.8) Total 36 (12.3) 43 (13.4) Clinical Trial Data 1. Signs and symptoms Rheumatoid Arthritis

The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflunomide was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with Leflunomide treatment were consistent across the 6 and 12 month studies (41 to 49%). No consistent differences were demonstrated between Leflunomide and methotrexate or between Leflunomide and sulfasalazine. Leflunomide treatment effect was evident by 1 month, stabilized by 3 to 6 months, and continued throughout the course of treatment as shown in Figure 2.

Figure 1

 

 

Comparisons

95%

Confidence

Interval

 

 

p Value US301 Leflunomide vs. Placebo (12, 32) <0.0001 Methotrexate vs. Placebo (8, 30) <0.0001 Leflunomide vs. Methotrexate (-4, 16) NS MN301 Leflunomide vs. Placebo (7, 33) 0.0026 Sulfasalazine vs. Placebo (4, 29) 0.0121 Leflunomide vs. Sulfasalazine (-8, 16) NS MN302 Leflunomide vs. Methotrexate (-19, -7) <0.0001

Figure 2

*Last Observation Carried Forward.

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7.

Table 6. Summary of ACR Response Rates* * Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early. † N is the number of ITT patients for whom adequate data were available to calculate the indicated rates. ‡ p<0.001 Leflunomide vs placebo § p<0.02 Leflunomide vs placebo

Study and

Treatment Group

 

ACR20

 

ACR50

 

ACR70 Placebo-Controlled Studies US301 (12 months) Leflunomide (n=178)† 52.2‡ 34.3‡ 20.2‡ Placebo (n=118)† 26.3 7.6 4.2 Methotrexate (n=180)† 45.6 22.8 9.4 MN301 (6 months) Leflunomide (n=130)† 54.6‡ 33.1‡ 10.0§ Placebo (n=91)† 28.6 14.3 2.2 Sulfasalazine (n=132)† 56.8 30.3 7.6 Non-Placebo Active-Controlled Studies MN302 (12 months) Leflunomide (n=495)† 51.1 31.1 9.9 Methotrexate (n=489)† 65.2 43.8 16.4

Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Leflunomide was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. In addition, Leflunomide was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between Leflunomide and the active comparators.


Table 7. Mean Change in the Components of the ACR Responder Index* * Last Observation Carried Forward; Negative Change Indicates Improvement † Based on 28 joint count ‡ Visual Analog Scale – 0=Best; 10=Worst   Placebo-Controlled Studies Non-placebo Controlled Study   US301 (12 Months) MN301 Non-US (6 Months) MN302 Non-US (12 Months) Components Leflunomide Methotrexate Placebo Leflunomide Sulfasalazine Placebo Leflunomide Methotrexate Tender joint count† -7.7 -6.6 -3.0 -9.7 -8.1 -4.3 -8.3 -9.7 Swollen joint count† -5.7 -5.4 -2.9 -7.2 -6.2 -3.4 -6.8 -9.0 Patient global assessment‡ -2.1 -1.5 0.1 -2.8 -2.6 -0.9 -2.3 -3.0 Physician global assessment‡ -2.8 -2.4 -1.0 -2.7 -2.5 -0.8 -2.3 -3.1 Physical function/disability (MHAQ/HAQ) -0.29 -0.15 0.07 -0.50 -0.29 -0.04 -0.37 -0.44 Pain intensity‡ -2.2 -1.7
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VIDENE ALCOHOLIC TINCTURE (Ecolab)


1. Name Of The Medicinal Product

VIDENE ALCOHOLIC TINCTURE

2. Qualitative And Quantitative Composition

Povidone-iodine 10% w/w

3. Pharmaceutical Form

Topical Solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Videne Alcoholic Tincture is a broad-spectrum antiseptic for topical application. It is indicated for quick-drying pre-operative skin disinfection, particularly in orthopaedic surgery.

4.2 Posology And Method Of Administration

Videne Alcoholic Tincture is applied undiluted to the area to be incised and painted on thoroughly using a gauze swab. The solution may be allowed to dry to form a protective film or may be removed using a sterile gauze swab.

There are no special dosage recommendations for children or elderly patients.

4.3 Contraindications

Videne Alcoholic Tincture must never be administered orally.

4.4 Special Warnings And Precautions For Use

Care should be taken with known iodine-sensitive subjects, although such people do not normally react to povidone-iodine.

Videne Alcoholic Tincture must not be used on broken skin because of the intense stinging caused by the alcohol present.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Videne Alcoholic Tincture is not recommended for use during pregnancy because of the possibility of absorption through broken skin and subsequent interference with tests of neonatal thyroid function.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

In very rare instances Videne Alcoholic Tincture may produce skin reactions in iodine-sensitive subjects. These reactions subside on cessation of treatment.

4.9 Overdose

In cases where Videne Alcoholic Tincture has been taken orally, gastric lavage with dilute starch mucilage or a 1% solution of sodium thiosulphate must be administered. The electrolyte balance must be corrected and lost fluids replaced.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Povidone-iodine has antiseptic activity and is used mainly for the treatment of contaminated wounds and preparation of pre-operative skin and mucous membranes. It is considered to be less irritant than iodine.

5.2 Pharmacokinetic Properties

Povidone-iodine is slightly absorbed when applied to the skin. Iodides are excreted mainly in the urine, with smaller amounts appearing in the faeces, saliva and sweat.

5.3 Preclinical Safety Data

Povidone-iodine had a low acute toxicity in both dogs and rats following either oral or intraperitoneal administration. Absorption of iodine through intact skin is low following the application of solutions of povidone-iodine although systemic absorption of iodine is greatly increased if the solutions are applied to broken skin, mucous membranes or are introduced into cavities of the body. At subcutaneous dose levels of up to 75mg/kg/day, povidone-iodine was non-teratogenic in rabbits following administration to pregnant animals during the period of organogenesis.

Some early in vitro studies indicated a possible mutagenic action for povidone-iodine. However, a number of later studies, using in vitro and in vivo test systems, do not indicate a significant level of mutagenic/genotoxic activity for povidone-iodine. Although conflicting data have been published, there is no convincing evidence to suggest that povidone-iodine adversely affects wound healing. Concentration of 0.05 and 0.5% povidone-iodine did not cause significant ocular damage when administered into the vitreous cavities of rabbits' eyes. There is some evidence to suggest that povidone-iodine-containing solutions applied to the round window of the chinchilla ear could result in high frequency hearing loss.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Alkyl Phenol Ether Sulphate (ammonium salt)

Industrial Methylated Spirit 95%

Citric Acid

Di-sodium Phosphate, Anhydrous

Purified Water

6.2 Incompatibilities

None stated

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store below 20°C in a dry place, protected from light.

6.5 Nature And Contents Of Container

Videne Alcoholic Tincture is packaged in a 500 ml HDPE bottle sealed with a plastic screw cap.

6.6 Special Precautions For Disposal And Other Handling

None stated

7. Marketing Authorisation Holder

Ecolab Ltd, Lotherton Way, Garforth, Leeds, LS25 2JY.

8. Marketing Authorisation Number(S)

PL 04509/0040

9. Date Of First Authorisation/Renewal Of The Authorisation

1 March 2003

10. Date Of Revision Of The Text

August 2006


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Heparin sodium 10 IU / ml I.V. flush solution (Leo Laboratories Ltd)


1. Name Of The Medicinal Product

Heparin sodium 10 IU/ml I.V. flush solution

2. Qualitative And Quantitative Composition

Heparin Sodium Ph. Eur. 10 IU/ml

3. Pharmaceutical Form

Solution for Injection.

4. Clinical Particulars 4.1 Therapeutic Indications

To maintain the patency of in-dwelling intravenous lines. It is not recommended for therapeutic use.

4.2 Posology And Method Of Administration

For injection into the catheter/cannula.

For routine use, 1

4.3 Contraindications

Known hypersensitivity to constituents.

Current or history of heparin-induced thrombocytopenia.

4.4 Special Warnings And Precautions For Use

As there is a risk of antibody-mediated heparin-induced thrombocytopenia, platelet counts should be measured in patients receiving regular and repeated use of heparin flush solutions for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.

Heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Heparin Sodium 10 IU/ml i.v. flush solution should be used with caution in patients with hypersensitivity to low molecular weight heparin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

For incompatibilities with other medicinal products see Section 6.2.

When an indwelling device is used for repeated withdrawal of blood samples for laboratory analyses and the presence of heparin or saline is likely to interfere with or alter the results of the tests, the in situ heparin flush solution should be cleared from the device by aspirating and discarding a volume of solution equivalent to that of the indwelling venipuncture device before the desired blood sample is taken.

4.6 Pregnancy And Lactation

The dose of heparin used would not be expected to constitute a hazard.

Heparin does not cross the placental barrier and is not excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Heparin has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable Effects

When used as recommended, the low dose of heparin reaching the blood is unlikely to have any systemic effects. However, heparin may cause thrombocytopenia and hypersensitivity reactions.

Local irritation may occur if inadvertently injected subcutaneously.

4.9 Overdose

An overdose is unlikely to occur. Bleeding is the main sign of overdose with heparin. As heparin is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages. In case of severe haemorrhages heparin may be neutralised with protamine sulphate injected slowly intravenously. One mg of protamine sulphate neutralises approximately 100 IU of heparin. Nevertheless, the required protamine sulphate dose varies according to the time of heparin administration and the dose administered.

It is important to avoid overdosage of protamine sulphate because protamine sulphate itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50 mg. Intravenous injection of protamine sulphate may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Heparin is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Water for Injections

6.2 Incompatibilities

This product is compatible with normal saline. Heparin has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and antihistamines.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

10 x 5 ml ampoules

Ph Eur Type 1 glass ampoules.

6.6 Special Precautions For Disposal And Other Handling

Any portion of the contents not used at once should be discarded.

7. Marketing Authorisation Holder

LEO Laboratories Limited

Longwick Road

Princes Risborough

Bucks HP27 9RR

8. Marketing Authorisation Number(S)

PL 0043/0092

9. Date Of First Authorisation/Renewal Of The Authorisation

8 March 1984/21 May 1995.

10. Date Of Revision Of The Text

November 2007

LEGAL CATEGORY

POM


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Patanol


Generic Name: Olopatadine Hydrochloride
Class: Antiallergic Agents
ATC Class: S01GX09
VA Class: OP900
Chemical Name: 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride
Molecular Formula: C21H23NO3•HCl
CAS Number: 140462-76-6

Introduction

Relatively selective histamine H1-receptor antagonist1 2 3 4 5 6 and mast-cell stabilizer.1 2 3 4 5 6 b

Uses for Patanol Allergic Conjunctivitis

Temporary prevention of ocular itching associated with allergic conjunctivitis.1 2 13

Patanol Dosage and Administration Administration Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution.1 Not for injection or oral use.1

If more than one topical ophthalmic drug is used, administer the drugs at least 5 minutes apart.12

Avoid contamination of the solution container.1

Dosage

Available as olopatadine hydrochloride; dosage expressed in terms of olopatadine.1

Pediatric Patients Allergic Conjunctivitis Ophthalmic

Children ?3 years of age: 1 or 2 drops of a 0.1% solution in the affected eye(s) twice daily (at an interval of 6–8 hours).1

Once symptomatic improvement is established, continue therapy for as long as necessary to sustain improvement.12

Adults Allergic Conjunctivitis Ophthalmic

1 or 2 drops of a 0.1% solution in the affected eye(s) twice daily (at an interval of 6–8 hours).1

Once symptomatic improvement is established, continue therapy for as long as necessary to sustain improvement.12

Cautions for Patanol Contraindications

Known hypersensitivity to olopatadine or any ingredient in the formulation.1

Warnings/Precautions Specific Populations Pregnancy

Category C.1

Lactation

Distributed into milk in rats following oral administration;1 not known whether distributed into human milk following topical application to the eye.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in children <3 years of age.1

Appears to be well-tolerated in children 3–16 years of age.11 13

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.a

Common Adverse Effects

Headache.1 2 13

Interactions for Patanol

No formal drug interaction studies to date.12

Patanol Pharmacokinetics Absorption Bioavailability

Limited systemic exposure following topical application to the eye;1 plasma concentrations usually are undetectable.1 12 13

Onset

Rapid onset;3 13 14 15 symptomatic relief of itching generally occurs within 30 minutes.12 13 15

Duration

Long duration (?8 hours).3 13 14 15

Distribution Extent

Distribution into human ocular tissues and fluids not characterized.1

Elimination Metabolism

Metabolized in the liver to monodesmethyl olopatadine and olopatadine N-oxide following topical application to the eyes.1 12

Elimination Route

Eliminated principally by renal excretion; 60–70% of systemically absorbed dose excreted in urine as parent drug.1 12

Half-life

Approximately 3 hours following topical application to the eyes.1

Stability Storage Ophthalmic Solution

4–25°C.1

ActionsActions

Inhibits type I immediate hypersensitivity reactions in vitro and in vivo.1 3

Suppresses the release of inflammatory mediators (e.g., histamine, prostaglandin D2, tryptase) in response to antigenic stimulation of human conjunctival mast cells in a dose-dependent manner.5 13

Inhibits histamine-stimulated conjunctival vascular permeability response in a concentration-dependent manner.3

Potency is comparable to that of levocabastine and exceeds that of pheniramine or antazoline.3 13

Advice to Patients

Importance of learning and adhering to proper administration techniques to avoid contamination of the solution container.1 12

Importance of removing soft contact lenses prior to administration of each dose.1 Delay reinsertion for 10 minutes after administration if eyes are not red; do not wear contact lenses if eye(s) are red.1 12 Not indicated for contact lens-related irritation.1

Importance of administering different topical ophthalmic preparations at least 5 minutes apart.12

Importance of patients informing clinicians of exisiting or contemplated therapy, including prescription and OTC drugs.

Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.a

Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Olopatadine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.1% (of olopatadine)

Patanol (with benzalkonium chloride)

Alcon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Pataday 0.2% Solution (ALCON VISION): 2/$119.99 or 7/$334.98

Patanol 0.1% Solution (ALCON VISION): 5/$125.99 or 15/$359.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2004. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Alcon Laboratories. Patanol (olopatadine hydrochloride) ophthalmic solution 0.1% prescribing information. Fort Worth, TX; 1996 Dec.

2. Anon. Olopatadine for allergic conjunctivitis. Med Lett Drugs Ther. 1997; 39:108-9. [PubMed 9398823]

3. Yanni JM, Stephens DJ, Miller ST et al. The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther. 1996; 12:389-400. [PubMed 8951675]

4. Sharif NA, Xu SX, Yanni JM. Olopatadine (AL-4943A): ligand binding and functional studies on a novel, long acting H1-selective histamine antagonist and anti-allergic agent for use in allergic conjunctivitis. J Ocul Pharmacol Ther. 1996; 12:401-7. [PubMed 8951676]

5. Sharif NA, Xu SX, Miller ST et al. Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases. J Pharmacol Exp Ther. 1996; 278:1252-61. [PubMed 8819509]

6. Kamei C, Sugimoto Y, Nakamura S et al. Effect of (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride on experimental allergic conjunctivitis and rhinitis in rats and guinea pigs. Arzneimittelforschung. 1995; 45:1005-8. [PubMed 7488300]

7. Ciprandi G, Buscaglia S, Cerqueti PM et al. Drug treatment of allergic conjunctivitis: a review of the evidence. Drugs. 1992; 43:154-76. [IDIS 360840] [PubMed 1372215]

8. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician. 1998; 57:735-46. [IDIS 418448] [PubMed 9490996]

9. Titi MJ. A critical look at ocular allergy drugs. Am Fam Physician. 1996; 53:2637-42. [IDIS 367250] [PubMed 8644576]

10. Galindez OA, Kaufman HE. Coping with the itchy-burnies: the management of allergic conjunctivitis. Ophthalmology. 1996; 103:1335-6. [IDIS 373485] [PubMed 8841290]

11. Reviewers’ comments (personal observations).

12. Alcon Laboratories; Fort Worth, TX: Personal communication.

13. Alcon Laboratories. Patanol (olopatadine hydrochloride) ophthalmic solution 0.1% product monograph. Fort Worth, TX: (not dated).

14. Abelson MB, Spitalny L. Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am J Ophthalmol. 1998; 125:797-804. [IDIS 409293] [PubMed 9645717]

15. Abelson MB. Evaluation of olopatadine, a new ophthalmic antiallergic agent with dual activity, using the conjunctival allergen challenge model. Ann Allergy Asthma Immunol. 1998; 81:211-8. [IDIS 415165] [PubMed 9759796]

a. Alcon Laboratories. Patanol (olopatadine hydrochloride) ophthalmic solution 0.1% prescribing information. Fort Worth, TX; 2003 Dec.

b. Anon. New drugs for allergic conjunctivitis. Med Lett Drugs Ther. 2000; 42:39-40. [PubMed 10825920]

More Patanol resources Patanol Side Effects (in more detail) Patanol Use in Pregnancy & Breastfeeding Patanol Support Group 8 Reviews for Patanol - Add your own review/rating Patanol Prescribing Information (FDA) Patanol Consumer Overview Patanol Advanced Consumer (Micromedex) - Includes Dosage Information Patanol Drops MedFacts Consumer Leaflet (Wolters Kluwer) Pataday Prescribing Information (FDA) Compare Patanol with other medications Seasonal Allergic Conjunctivitis
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VIDENE SURGICAL SCRUB (Ecolab)


1. Name Of The Medicinal Product

VIDENE SURGICAL SCRUB

2. Qualitative And Quantitative Composition

Povidone-iodine 7.5% w/w

3. Pharmaceutical Form

Topical solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Videne Surgical Scrub is a broad-spectrum antiseptic for topical use. It is indicated for pre-operative hand disinfection by the surgical team, or for disinfecting the site of incision prior to elective surgery.

4.2 Posology And Method Of Administration

Pre-operative surgical scrub - after first wetting the hands and arms with water, approximately 3.5 ml of Videne Surgical Scrub is applied and rubbed thoroughly on to these areas. A brush may be used to scrub the nails. A little water is added to develop a lather and finally this is rinsed off with running water.

Pre-operative skin preparation - the site of incision should be washed with Videne Surgical Scrub two or three times a day for at least two days prior to the operation. Immediately before surgery the skin should be moistened with water, Videne Surgical Scrub applied and rubbed thoroughly into the area for several minutes. A sterile gauze swab is used to develop a lather which is finally rinsed off with water.

Only water should be used to dilute Videne Surgical Scrub.

There are no special dosage recommendations for children or elderly patients.

4.3 Contraindications

Videne Surgical Scrub must never be administered orally.

4.4 Special Warnings And Precautions For Use

Care should be taken when Videne Surgical Scrub is used on known iodine-sensitive subjects, although such people do not normally react to povidone-iodine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Videne Surgical Scrub is not recommended for use during pregnancy because of the possibility of absorption through broken skin and subsequent interference with tests of neonatal thyroid function.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

In very rare instances Videne Surgical Scrub may produce skin reactions in iodine-sensitive subjects. These reactions subside on cessation of treatment.

4.9 Overdose

In cases where Videne Surgical Scrub has been taken orally, gastric lavage with dilute starch mucilage or a 1% solution of sodium thiosulphate must be administered. The electrolyte balance must be corrected and lost fluids replaced.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Povidone-iodine has antiseptic activity and is used mainly for the treatment of contaminated wounds and pre-operative preparation of skin and mucous membranes. It is considered to be less irritant than iodine.

5.2 Pharmacokinetic Properties

Povidone-iodine is slightly absorbed when applied to the skin. Iodides are excreted mainly in the urine, with smaller amounts appearing in the faeces, saliva and sweat.

5.3 Preclinical Safety Data

Povidone-iodine had a low acute toxicity in both dogs and cats following either oral or intraperitoneal administration. Absorption of iodine through intact skin is low following the application of solutions of povidone-iodine although systemic absorption of iodine is greatly increased if the solutions are applied to broken skin, mucous membranes or are introduced into cavities of the body. At subcutaneous dose levels of up to 75mg/Kg/day, povidone-iodine was non-teratogenic in rabbits following administration to pregnant animals during the period of organogenesis.

Some early in vitro studies indicated a possible mutagenic action for povidone-iodine. However, a number of later studies, using in vitro and in vivo test systems, do not indicate a significant level of mutagenic/genotoxic activity for povidone-iodine. Although conflicting data have been published, there is no convincing evidence to suggest that povidone-iodine adversely affects wound healing. Concentration of 0.05 and 0.5% povidone-iodine did not cause significant ocular damage when administered into the vitreous cavities of rabbits' eyes. There is some evidence to suggest that povidone-iodine-containing solutions applied to the round window of the chinchilla ear could result in high frequency hearing loss.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Alkyl Phenol Ether Sulphate (Ammonium Salt)

Polyethylene glycol 400

Cocoamide DEA

Glycerol

PVP K90

Citric acid

Di-sodium phosphate, anhydrous

Purified Water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store below 30°C in a dry place, protected from light.

6.5 Nature And Contents Of Container

Videne Surgical Scrub is packaged in a 500 ml HDPE bottle sealed with a plastic screw cap.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Ecolab Ltd, Lotherton Way, Garforth, Leeds, LS25 2JY.

8. Marketing Authorisation Number(S)

PL 04509/0042

9. Date Of First Authorisation/Renewal Of The Authorisation

1 March 2003

10. Date Of Revision Of The Text

August 2006


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Virgan (Spectrum Thea Pharmaceuticals Limited)


1. Name Of The Medicinal Product

VIRGAN eye gel.

2. Qualitative And Quantitative Composition

Active Ingredient.

Ganciclovir 0.15%.

3. Pharmaceutical Form

Eye gel.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of acute herpetic keratitis (dendritic and geographic ulcers).

4.2 Posology And Method Of Administration

Instil one drop of gel in the inferior conjunctival sac of the eye to be treated, 5 times a day until complete corneal re-epithelialisation. Then 3 instillations a day for 7 days after healing. The treatment does not usually exceed 21 days.

Use in the elderly:

The dosage in the elderly is the same as in adults (see above). There is no need to adjust the dosage in the elderly as in clinical trials patients up to the age of 85 years have been treated and no specific health concerns were observed.

Use in children:

VIRGAN eye gel is not recommended for use in children.

Only limited clinical trial data are available (7 children, range 2-14 years).

4.3 Contraindications

Hypersensitivity to ganciclovir or acyclovir or to any other ingredients of the product.

4.4 Special Warnings And Precautions For Use

The following special warnings and precautions for use should be borne in mind, although systemic effects after ocular instillation are very unlikely. In preclinical testing ganciclovir given systemically caused aspermatogenesis, mutagenicity, teratogenicity, carcinogenicity and suppression of female fertility. These effects in animal studies have been observed at plasma concentrations far exceeding those being seen in humans after therapeutic use of Virgan Eye Gel (see also 5.3). However, ganciclovir should be considered a potential carcinogen and teratogen in humans.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In case of any additional local ocular treatment there should be an application interval of at least 5 minutes between the two medications. VIRGAN Eye Gel should be the last medication instilled.

Although the quantities of ganciclovir passing into the general circulation after ophthalmic use are small, the risk of drug interactions cannot be ruled out.

Interactions with ganciclovir administered systemically have been observed:

Binding of ganciclovir to plasma proteins is only about 1-2% and drug interactions involving binding site displacement are not anticipated.

It is possible that drugs which inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa might have combined additive toxic effects when used concomitantly with, before or after ganciclovir. Because of the possibility of additive toxicity with co-administration of drugs such as dapsone, pentamidine, flucystosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations or other nucleoside analogues, combination with ganciclovir therapy should be used only if the potential benefits outweigh the risks.

Since both zidovudine and ganciclovir can result in neutropenia, it is recommended that these two drugs should not be given concomitantly during induction treatment with ganciclovir. Maintenance ganciclovir treatment plus zidovudine at the recommended dose resulted in severe neutropenia in most patients studied to date.

Generalised seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly.

It is also possible that probenecid, as well as other drugs which inhibit renal tubular secretion or resorption, may reduce renal clearance of ganciclovir and could increase the plasma half-life of ganciclovir.

4.6 Pregnancy And Lactation

Teratogenicity has been observed in animal studies with systemic ganciclovir. There is no experience regarding the safety of VIRGAN eye gel in human pregnancy or lactation. Administration during pregnancy and lactation is therefore not recommended, except for compelling reasons.

4.7 Effects On Ability To Drive And Use Machines

Patients should refrain from driving a vehicle or operating machines on the occurrence of any visual disturbance or other visual symptomatology.

4.8 Undesirable Effects

In some cases, adverse events which did not result in a treatment interruption were observed in relation to the use of VIRGAN eye gel: burning sensations or brief tingling sensations, superficial punctate keratitis, visual disturbance on application.

4.9 Overdose

There is practically no risk of adverse events due to accidental oral ingestion since a tube of 5g contains 7.5mg ganciclovir compared to the daily adult i.v. dose of 500-1000mg.

In the unlikely event of overdose, dialysis and hydration may be of benefit in reducing drug plasma levels.

Toxic manifestations seen in animals given very high single intravenous doses of ganciclovir (500mg/kg) included emesis, hypersalivation, anorexia, bloody diarrhoea, inactivity, cytopenia, abnormal liver function tests and BUN, testicular atrophy and death.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

VIRGAN® is a formulation of 0.15% ganciclovir in a transparent aqueous gel with a hydrophilic polymer base.

Ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl)guanine or DHPG, is a broadspectrum virustatic agent which inhibits the replication of viruses, including viruses of the herpes group, both in vivo and in vitro: herpes simplex types 1 and 2 (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes zoster (HZV).

The mean effective dose (ED50) in vitro of ganciclovir on ocular clinical isolates of the herpes simplex virus is on average 0.23 µg/ml (0.06 - 0.50).

Ganciclovir inhibits in vitro the replication of various adenovirus serotypes.

The ED50 is 1.8 to 4.0 µg/ml for Ad 8 and Ad 19, those most frequently seen in ophthalmology.

Herpetic viruses induce one or more cellular kinases in the host cells, which phosphorylise the ganciclovir into its triphosphate derivative. This phosphorylation is carried out mainly in infected cells, as the concentrations of ganciclovir-triphosphate in non-infected cells are 10 times lower.

Ganciclovir-triphosphate works as an antiviral agent by inhibiting the synthesis of viral DNA in two ways: competitive inhibition of viral DNA polymerases and direct incorporation into viral DNA which has the effect of stopping its elongation.

5.2 Pharmacokinetic Properties

Studies of ocular pharmacokinetics in rabbits have shown a rapid and relevant penetration of ganciclovir into the cornea and the anterior segment of the eye, allowing concentrations higher than the effective antiviral concentrations over several hours. In fact, after instillation of one drop of ganciclovir gel, the concentrations (Cmax) of ganciclovir measured in the cornea (17µg/g), the conjunctiva (160µg/g), the aqueous humour (1µg/g) and the iris/ciliary body (4µg/g), are higher than the inhibitory concentrations for herpes simplex viruses 1 and 2 (< 0.5µg/ml) over more than 4 hours.

The repeated instillation 4 times a day for 12 days in rabbits with herpetickeratitis does not result in an accumulation of ganciclovir in the plasma.

In man, after daily ocular instillations repeated 5 times a day for 11 to 15 days in the course of treatment of superficial herpetic keratitis, plasma levels determined by means of a precise analytical method (quantification limit: 0.005µg/ml) are very low: on average 0.013µg/ml (0 - 0.037) which is 640 times lower than levels following a one hour iv infusion of 5mg/kg (Cmax = 8.0 µg/ml). The oral bioavailability of ganciclovir is approximately 6% when taken with food. Ganciclovir has a half life of 2.9 hours, the systemic clearance is 3.64 ml/min/kg and the major route of excretion of ganciclovir is via glomerular filtration of unchanged drug.

5.3 Preclinical Safety Data

Animal data indicate that a side-effect of systemic ganciclovir is inhibition of spermatogenesis which is reversible at lower doses and irreversible at higher doses. Animal data have also indicated that permanent suppression of fertility in women may occur.

Ganciclovir had no effect on developing mouse foetuses at daily intravenous doses of 36mg/kg, but caused maternal/foetal toxicity and embryo death at daily doses of 108mg/kg. In rabbits, ganciclovir had no effect on developing foetuses at daily intravenous doses of 6mg/kg, but caused foetal growth retardation, embryo death, teratogenicity and/or maternal toxicity at daily doses of 20 or 60mg/kg.

Ganciclovir did not cause point mutations in bacterial or yeast cells or dominant lethality in mice, but caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. Ganciclovir was positive in these tests at thousands of times the concentration in plasma of patients undergoing therapy with VIRGAN eye gel.

Ganciclovir was carcinogenic in the mouse after daily oral doses of 20 and 1000mg/kg/day. No carcinogenic effect occurred at the dose of 1mg/kg/day.

Tumour incidence was slightly increased at plasma levels of ganciclovir approximately 50 times human levels following VIRGAN eye gel treatment.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzalkonium chloride

Carbomer 974P

Sorbitol

Sodium hydroxide

Purified water

6.2 Incompatibilities

None known to date.

6.3 Shelf Life

In the unopened container: 3 years.

In the opened container: 4 weeks.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

5g tube (polyethylene-aluminium) with dropper nozzle (polyethylene) and screw cap (polyethylene) fitted with a detachable plastic base. This base allows the tube to be placed vertically, with the dropper nozzle pointing downwards, thus avoiding an accumulation of air around the opening, which would inhibit the correct formation of drops.

6.6 Special Precautions For Disposal And Other Handling

The package remains sterile until the original closure is broken. Do not use VIRGAN eye gel for more than 28 days after first opening.

7. Marketing Authorisation Holder

LABORATOIRES THEA

12RUE LOUIS-BLERIOT

Z.I. DU BREZET

63017 CLERMONT FERRAND CEDEX 2

FRANCE

8. Marketing Authorisation Number(S)

PL 20162/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

21st July 2000

10. Date Of Revision Of The Text

February 2002

February 2003


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Heparin sodium 100 IU / ml I.V. flush solution (Leo Laboratories Ltd)


1. Name Of The Medicinal Product

HEPARIN SODIUM 100 IU/ml I.V. FLUSH SOLUTION

2. Qualitative And Quantitative Composition

Heparin sodium Ph. Eur. 100 IU/ml

3. Pharmaceutical Form

Solution for Injection.

4. Clinical Particulars 4.1 Therapeutic Indications

To maintain the patency of in-dwelling intravenous lines. It is not recommended for therapeutic use.

4.2 Posology And Method Of Administration

For routine use, 2 ml containing 200 IU of heparin should be administered into the catheter/cannula every 4-8 hours or as required.

4.3 Contraindications

Known hypersensitivity to constituents.

Current or history of heparin induced thrombocytopenia.

Heparin Sodium 100 IU/ml i.v. flush solution contains 10 mg/ml of the preservative benzyl alcohol. This formulation must not be given to premature babies or neonates.

4.4 Special Warnings And Precautions For Use

As there is a risk of antibody-mediated heparin-induced thrombocytopenia, platelet counts should be measured in patients receiving regular and repeated use of heparin flush solutions for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.

Heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Heparin Sodium 100 IU/ml i.v. flush solution should be used with caution in patients with hypersensitivity to low molecular weight heparin.

Heparin Sodium 100 IU/ml i.v. flush solution contains the preservative benzyl alcohol 10mg/ml. This product should be administered with caution to infants and children up to 3 years old, as there is a risk that benzyl alcohol may cause toxic and allergic reactions (anaphylactoid) in this age group (see also section 4.3 for premature babies or neonates).

Heparin Sodium 100 IU/ml i.v. flush solution contains esters of parahydroxybenzoates as a preservative system. These may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

For incompatibilities with other medicinal products see Section 6.2.

When an indwelling device is used for repeated withdrawal of blood samples for laboratory analyses and the presence of heparin or saline is likely to interfere with or alter the results of the tests, the in situ heparin flush solution should be cleared from the device by aspirating and discarding a volume of solution equivalent to that of the indwelling venipuncture device before the desired blood sample is taken.

4.6 Pregnancy And Lactation

The dose of heparin used would not be expected to constitute a hazard. However, as benzyl alcohol may cross the placenta, the use of Heparin Sodium 100 IU/ml i.v. flush solution containing benzyl alcohol should be avoided during pregnancy.

Heparin does not cross the placental barrier and is not excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Heparin has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable Effects

When used as recommended, the low dose of heparin reaching the blood is unlikely to have any systemic effects. However, heparin may cause thrombocytopenia and hypersensitivity reactions.

Local irritation may occur if inadvertently injected subcutaneously.

4.9 Overdose

An overdose is unlikely to occur. Bleeding is the main sign of overdose with heparin. As heparin is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages. In case of severe haemorrhages heparin may be neutralised with protamine sulphate injected slowly intravenously. One mg of protamine sulphate neutralises approximately 100 IU of heparin. Nevertheless, the required protamine sulphate dose varies according to the time of heparin administration and the dose administered.

It is important to avoid overdosage of protamine sulphate because protamine sulphate itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50 mg. Intravenous injection of protamine sulphate may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Heparin is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzyl alcohol,

Methylparahydroxybenzoate,

Propylparahydroxybenzoate,

Sodium citrate,

Sodium chloride,

Water for Injections.

6.2 Incompatibilities

This product is compatible with normal saline. Heparin has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and antihistamines.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

10 x 2 ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

LEO Laboratories Limited

Longwick Road

Princes Risborough

Bucks HP27 9RR

8. Marketing Authorisation Number(S)

PL 0043/0057

9. Date Of First Authorisation/Renewal Of The Authorisation

23 October 1978/16 January 1995

10. Date Of Revision Of The Text

November 2007

LEGAL CATEGORY

POM


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Locoid Scalp Lotion


1. Name Of The Medicinal Product

LOCOID SCALP LOTION

2. Qualitative And Quantitative Composition

Contains 0.1% w/v hydrocortisone butyrate.

For excipients, see 6.1

3. Pharmaceutical Form

Cutaneous solution.

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

The product is recommended for clinical use in the treatment of scalp conditions responsive to topical corticosteroids e.g. eczema, dermatitis and psoriasis.

Topical corticosteroids are not generally indicated in psoriasis but may be acceptable in psoriasis excluding widespread plaque psoriasis provided warnings are given; see section 4.4 Special warnings and special precautions for use.

4.2 Posology And Method Of Administration

For topical application to the scalp.

Dosage: To be applied evenly and sparingly no more than twice daily

Adults and the Elderly: The same dose is used for adults and the elderly, as clinical evidence would indicate that no special dosage regimen is necessary in the elderly.

Children: Long term treatment should be avoided where possible.

Infants: Therapy should be limited if possible to a maximum of seven days.

4.3 Contraindications

Hypersensitivity to hydrocortisone or to any of the ingredients of the lotion.

This preparation is contraindicated in the presence of untreated viral or fungal infections, tubercular or syphilitic lesions, peri-oral dermatitis, acne vulgaris and rosacea and in bacterial infections unless used in connection with appropriate chemotherapy.

4.4 Special Warnings And Precautions For Use

Although generally regarded as safe, even for long-term administration in adults, there is a potential for adverse effects if over used in infancy. Extreme caution is required in dermatoses of infancy. In such patients courses of treatment should not normally exceed 7 days.

As with all corticosteroids, application to the face, flexures and other areas of thin skin may cause skin atrophy and increased absorption and should be avoided.

Topical corticosteroids may be hazardous in psoriasis for a number of reasons including rebound relapses following development of tolerance, risk of generalised pustular psoriasis and local and systemic toxicity due to impaired barrier function of the skin. Steroids may have a place in psoriasis of the scalp and chronic plaque psoriasis of the hands and feet. Careful patient supervision is important.

Keep away from eyes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human foetus.

Theoretically, there is the possibility that if maternal systemic absorption occurred the infant's adrenal function could be affected.

The use of topical corticosteroids during lactation is unlikely to present a hazard to infants being breast-fed.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

System Organ Class

Rare

>/10,000,<1/1000

Very rare

</10,000

Not known

Immune system disorders

 

 

 

 

Hypersensitivity

Endocrine disorders

 

 

Adrenal suppression

 

 

Skin and subcutaneous tissue disorders

Skin atropy, often irreversible, with thinning of the epidermis

Telangiectasia

Skin striae

Pustular acne

Perioral dermatitis

Rebound effect

Skin depigmentation

Dermatitis and eczema, including contact dermatitis

 

 

 

 

4.9 Overdose

Excessive use under occlusive dressings may produce adrenal suppression. No special procedures or antidote. Treat any adverse effects symptomatically.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Hydrocortisone butyrate is a potent topical corticosteroid.

5.2 Pharmacokinetic Properties

The topical activity has been demonstrated in vivo using the McKenzie-Stoughton test.

5.3 Preclinical Safety Data

No preclinical safety data have been generated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Isopropyl alcohol, glycerol (85%), Povidone K90, anhydrous citric acid, anhydrous sodium citrate, purified water.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Plastic, dropper-necked screw cap vial.

Pack sizes: 30 ml and 100 ml.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Astellas Pharma Ltd

Lovett House

Lovett Road

Staines

TW18 3AZ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00166/0060R

9. Date Of First Authorisation/Renewal Of The Authorisation

First authorised 28 September 1973; renewed 19 December 2003.

10. Date Of Revision Of The Text

15 July 2009

11. LEGAL CATEGORY

POM.


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Gynoxin 200 mg vaginal capsules


1. Name Of The Medicinal Product

Gynoxin 200 mg Vaginal Capsules

2. Qualitative And Quantitative Composition

Each vaginal capsule contains 200 mg of the active ingredient fenticonazole nitrate.

For excipients, see 6.1

3. Pharmaceutical Form

Vaginal capsule, soft

Ivory white, opaque, soft gelatin capsules

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of vulvovaginal candidiasis.

4.2 Posology And Method Of Administration

Route of Administration:

Intravaginal

Adults:

One 200 mg vaginal capsule at bedtime for 3 days

The capsule must be introduced deeply into the vagina.

Gynoxin is not greasy, does not soil and can easily be removed with water.

Children:

The use of Gynoxin in children is not recommended.

4.3 Contraindications

Ascertained hypersensitive to the product and to other imidazole derivatives.

4.4 Special Warnings And Precautions For Use

The product should not be used in conjunction with barrier contraceptives.

In the event of a hypersensitivity reaction or development of resistant organisms, treatment should be discontinued and the physician consulted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not investigated. Since systemic absorption of fenticonazole after application is low, interactions with other drugs are unlikely.

4.6 Pregnancy And Lactation

Oral administration of fenticonazole in rats has been reported to produce prolonged gestation and embryotoxic effects after doses above 40mg/kg/day. Fenticonazole does not interfere with the function of male and female gonads and does not modify the first phases of reproduction.

Fenticonazole has shown no teratogenic effects in rats and rabbits. Fenticonazole or its metabolites cross the placental barrier in pregnant rats and rabbits after vaginal application and are excreted in milk of lactating rats.

Since there is no experience of use during pregnancy or lactation, Gynoxin should not be used unless the physician considers it essential to the welfare of the patient.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

After intravaginal administration slight transient burning, which usually disappears rapidly, may occasionally occur.

Prolonged topical application may cause sensitisation reactions.

4.9 Overdose

Because of the low systemic absorption after vaginal application, overdosage is unlikely. In case of a suspected accidental oral ingestion emesis should be induced or gastric lavage may be attempted. Irrespective of success in inducing emesis the patient should be made to drink water or lemonade with active charcoal and a laxative. Symptomatic therapy may be administered if indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC code: G01A F12

Fenticonazole is a broad-spectrum antimycotic agent.

• In vitro: high fungistatic and fungicidal activity against Candida albicans

• In vivo: healing of vaginal mycoses due to Candida within 5 days in mice.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies in humans have shown that systemic absorption of fenticonazole nitrate after vaginal administration is minimal.

5.3 Preclinical Safety Data

LD50 mice: oral>3000mg/kg; i.p 1276mg/kg (M), 1265mg/kg (F)

LD50 rats: oral>3000mg/kg; s.c>750mg/kg; i.p. 440mg/kg (M), 309mg/kg (F)

Chronic toxicity: following oral administration of 40-80-160mg/kg/day for 6 months in rats and dogs, fenticonazole was well tolerated, although some evidence of light and moderate general toxicity occurred (increase in liver weight at 160mg/kg without histopathological alterations in rats, and a transient increase in serum SGPT at 80 and 160mg/kg, together with an increase in liver weight in dogs).

Fenticonazole does not interfere with the function of male and female gonads, and does not modify the first phases of reproduction. Studies in reproductive toxicology revealed, as for other imidazole derivatives, an embryolethal effect at high dosages (>20mg/kg). Fenticonazole has shown no teratogenic effects in rats and rabbits and has revealed no mutagenic potential in six mutagenicity tests.

Satisfactory results were obtained in tolerability tests performed in guinea pigs, rabbits as well as in mini-pigs, the skin of which is similar to that of humans, as far as morphology, functionality and sensitivity to irritating agents are concerned.

Fenticonazole has shown no evidence of sensitisation, phototoxicity and photoallergy.

Pharmacokinetic studies have revealed no transcutaneous absorption either in man or in animals and a very low vaginal absorption.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Medium chain triglycerides

Colloidal anhydrous silica

Shell constituents:

Gelatin

Glycerol

Titanium dioxide

Ethyl parahydroxybenzoate sodium (E215)

Sodium propyl parahydroxybenzoate (E217)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C. Do not refrigerate or freeze. Store in the original package.

6.5 Nature And Contents Of Container

Blister pack of PVC/PVdC + aluminium foil, in packs of 3.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data 7. Marketing Authorisation Holder

Recordati Industria Chimica e Farmaceutica SpA

Via Matteo Civitali

1-20148 Milano

Italy

8. Marketing Authorisation Number(S)

PL 04595/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

22/09/99

10. Date Of Revision Of The Text

14/12/2009

POM


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Nu-Seals 75


1. Name Of The Medicinal Product

Nu-Seals 75, Aspirin 75mg Gastro-resistant Tablets, PostMI 75EC, Nu-Seals Cardio 75

2. Qualitative And Quantitative Composition

Acetylsalicylic Acid 75mg

3. Pharmaceutical Form

White, gastro-resistant tablets, coded “75” or “GP”.

4. Clinical Particulars 4.1 Therapeutic Indications

For the secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery (see below).

Aspirin has an antithrombotic action, mediated through inhibition of platelet activation, which has been shown to be useful in secondary prophylaxis following myocardial infarction and in patients with unstable angina or ischaemic stroke including cerebral transient attacks.

Nu-Seals 75 is indicated when prolonged dosage of aspirin is required. The special coating resists dissolution in gastric juice, but will dissolve readily in the relatively less acid environment of the duodenum. Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 75 is unsuitable for the short-term relief of pain.

4.2 Posology And Method Of Administration

Nu-Seals 75 is for oral administration to adults only.

Patients should seek the advice of a doctor before commencing therapy for the first time.

The usual dosage, for long-term use, is 75-150mg once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 300mg a day may be used on the advice of a doctor.

Antithrombotic action: 150mg at diagnosis and 75mg daily thereafter. Tablets taken at diagnosis should be chewed in order to gain rapid absorption.

The elderly: The risk-benefit ratio of the antithrombotic action of aspirin has not been fully established.

Children:

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki's disease). See 'Special warnings and precautions for use'.

4.3 Contraindications

Hypersensitivity to aspirin. Hypoprothrombinaemia, haemophilia and active peptic ulceration or a history of peptic ulceration.

4.4 Special Warnings And Precautions For Use

There is a possible association between aspirin and Reye's syndrome when given to children. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

Before commencing long-term aspirin therapy for the management of cerebrovascular or cardiovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.

Aspirin decreases platelet adhesiveness and increases bleeding time. Haematological and haemorrhagic effects can occur, and may be severe. Patients should report any unusual bleeding symptoms to their physician.

Salicylates should be used with caution in patients with a history of peptic ulceration or coagulation abnormalities. They may also induce gastro-intestinal haemorrhage, occasionally major.

They may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Aspirin should be used with caution in patients with impaired renal or hepatic function (avoid if severe), or in patients who are dehydrated.

Patients with hypertension should be carefully monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Salicylates may enhance the effect of oral hypoglycaemic agents, phenytoin and sodium valproate. They inhibit the uricosuric effect of probenecid and may increase the toxicity of sulphonamides.

Aspirin may potentiate the effect of heparin and increases the risk of bleeding with oral anticoagulants, antiplatelet agents and fibrinolytics.

Plasma salicylate concentrations may be reduced by concurrent use of corticosteroids, and salicylate toxicity may occur following withdrawal of the corticosteroids. The risk of gastrointestinal ulceration and bleeding may be increased when aspirin and corticosteroids are co-administered.

Concurrent use of aspirin and other NSAIDs should be avoided. Use of two or more NSAID preparations increases the risk of serious gastrointestinal haemorrhage.

Concurrent administration of carbonic anhydrase inhibitors such as acetazolamide and salicylates may result in severe acidosis and increased central nervous system toxicity.

In large doses, salicylates may also decrease insulin requirements.

Patients using gastro-resistant aspirin should be advised against ingesting antacids simultaneously to avoid premature drug release.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

4.6 Pregnancy And Lactation

Pregnancy: Although clinical and epidemiological evidence suggests the safety of aspirin for use in pregnancy, caution should be exercised when considering use in pregnant patients. Aspirin has the ability to alter platelet function and there may be a risk of haemorrhage in infants whose mothers have consumed aspirin during pregnancy. Prolonged pregnancy and labour, with increased bleeding before and after delivery, decreased birth weight and increased rate of stillbirth have been reported with high blood salicylate levels. With high doses there may be premature closure of the ductus arteriosus and possible persistent pulmonary hypertension in the newborn. Analgesic doses of aspirin should be avoided during the last trimester of pregnancy.

Lactation: As aspirin is excreted in breast milk, Nu-Seals should not be taken by patients who are breast-feeding, as there is a risk of Reye's syndrome in the infant. High maternal doses may impair platelet function in the infant.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Gastrointestinal irritation is common in patients taking aspirin preparations, and nausea, vomiting, dyspepsia, gastritis, gastrointestinal erosions and ulceration have been reported. Anaemia may occur following chronic gastrointestinal blood loss or acute haemorrhage.

Aspirin prolongs bleeding time, and bleeding disorders, such as epistaxis, haematuria, purpura, ecchymoses, haemoptysis, gastrointestinal bleeding, haematoma and cerebral haemorrhage have occasionally been reported. Fatalities have occurred.

Hypersensitivity reactions include skin rashes, urticaria, angioedema, asthma, bronchospasm and rarely, anaphylaxis.

Other side effects: urate kidney stones and tinnitus.

4.9 Overdose

Salicylate poisoning is usually associated with plasma concentrations>350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiogenic pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations>700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years and over 70 have increased risk of salicylate toxicity, and may require dialysis at an earlier stage.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Aspirin has analgesic, antipyretic and anti-inflammatory actions.

It also has antithrombotic action which is mediated through inhibition of platelet activation.

Nu-Seals 75 tablets have a gastro-resistant coat sandwiched between a sealing coat and a top coat. The gastro-resistant coat is intended to resist gastric fluid whilst allowing disintegration in the intestinal fluid.

Owing to the delay that the coating imposes on the release of the active ingredient, Nu-Seals 75 is unsuitable for the short-term relief of pain.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

In a bioequivalence study comparing the pharmacokinetics of the 300mg product with 4 x 75mg presentation in human volunteers, measures such as terminal phase half-life, area-under-the curve and peak plasma concentrations were recorded on days 1 and 4. On day 1 salicylate reached a peak plasma concentration of between 10.34 and 31.57 mcg/ml and between 11.76 and 27.47mcg/ml for the 300mg and 75mg tablets respectively. Time to peak concentration ranged from 4 to 8 hours and from 3 to 6 hours respectively. AUC ranged from 54.0 to 131.2 and from 64.3 to 137.6 h.mcg/ml respectively. The terminal phase half-life ranged from 1.33 to 2.63 hours and from 1.47 to 2.59 hours respectively. On day 4 Cmax varied from 15.01 to 48.97 mcg/ml for the 300mg tablet and from 11.26 to 60.21 mcg/ml for 4 x 75mg tablets. Tmax ranged from 4 to 8 hours and from 3 to 8 hours, whilst AUC ranged from 89.8 to 297.4 h.mcg/ml and from 61.5 to 293.4 h.mcg/ml respectively.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber in addition to that summarised in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maize Starch

Hypromellose

Talc

Methacrylic acid – ethyl acrylate (1:1) copolymer dispersion 30 per cent

Polyethylene Glycol 3350

Propylene Glycol

Benzyl Alcohol

Emulsion silicone

Edible Printing Ink - containing either: E124 Red and Shellac or: E172 Black, Shellac and E322 Lecithin

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep containers tightly closed.

6.5 Nature And Contents Of Container

Blisters comprising of UPVC on one side and aluminium foil on the other containing 14, 28, 56 or 84 tablets. HDPE bottles with screw caps containing 500 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0062

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 21 April 1994

Date of last renewal of authorisation: 12 May 2006

10. Date Of Revision Of The Text

10th August 2010


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Magnevist 2mmol / l solution for injection


1. Name Of The Medicinal Product

Magnevist® 2 mmol/l solution for injection

2. Qualitative And Quantitative Composition

1ml aqueous solution contains 1.876 mg gadopentetic acid, dimeglumine salt as active ingredient (equivalent to 0.002 mmol gadopentetic acid, dimeglumine, containing 0.32 mg gadolinium).

For excipients see section 6.1.

3. Pharmaceutical Form

Solution for injection.

4. Clinical Particulars 4.1 Therapeutic Indications

For contrast enhancement in direct magnetic resonance arthrography.

4.2 Posology And Method Of Administration

This medicinal product is for diagnostic use by intraarticular administration only.

The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferro-magnetic objects including vascular clips etc) must be observed.

The dose required is administered via intraarticular injection under strict aseptic technique and according to the instructions provided in section 6.6. 'Instructions for use and handling'. Contrast-enhanced MRI can be commenced immediately afterwards.

The recommendations for the use of Magnevist 2 mmol/l apply to a field strength between 0.2 Tesla and 1.5 Tesla.

Intraarticular administrations of contrast agents are to be given with the patient lying or sitting. After the end of the injection, the patient should be kept under supervision for at least half an hour.

Adults:

In general, for all joints the administration of up to 20 ml (knee joint up to 50 ml) Magnevist 2 mmol/l is sufficient for good opacification and to answer all the relevant clinical questions. A volume leading to a slight distension of the joint capsule should be injected. Only so much contrast medium should be injected until discrete resistance is felt and/or the patient experiences a mild feeling of pressure.

Guidelines on volumes to be administered:

Joint

Volume required

Shoulder

15-20 ml

Elbow

~ 10 ml

Wrist

4 ml

Finger joint

1-2 ml

Hip

10-20 ml

Knee

25-50 ml

Ankle

12-20 ml

Children:

The product is not recommended in the paediatric age group until further data become available.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Strict aseptic technique is required to prevent infection.

Fluoroscopic control should be used to ensure proper needle placement and prevent extracapsular injection. Undue pressure should not be exerted during injection.

Intraarticular injections of Magnevist 2 mmol/l should be avoided in infected joints.

• Hypersensitivity

Severe systemic hypersensitivity reactions cannot be totally excluded (see section 4.8).

Mild angioedema, conjunctivitis, coughing, pruritus, rhinitis, sneezing and urticaria, which can occur irrespective of the amount administered and the mode of administration, may be the first signs of incipient state of shock.

As with other contrast agents, delayed reactions may occur (hours later or up to several days).

As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended.

Medication for the treatment of hypersensitivity reactions as well as readiness for institution of emergency measures are necessary. Appropriate drugs and instruments (e.g. endotracheal tube and ventilator) must be readily available.

The risk of hypersensitivity reactions is higher in case of;

- previous reaction to contrast media,

- history of bronchial asthma,

- history of allergic disorders

The decision to use Magnevist 2 mmol/l must be made after particularly careful evaluation of the risk-benefit-ratio in patients with an allergic disposition.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As for all other gadolinium containing contrast media, no interactions with other medicaments have been observed. Formal drug interaction studies have not been carried out. See also section 6.2 Incompatibilities.

Magnevist should be administered without the addition of iodinated contrast media as iodinated contrast media reduce the level of contrast achievable with Magnevist (see Section 6.6 Instructions for use and handling).

4.6 Pregnancy And Lactation

• Pregnancy

For gadopentetic acid, dimeglumine no clinical study data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal / foetal development (see section 5.3).

Caution should be exercised using Magnevist 2mmol/l in pregnant women.

• Lactation

No data exist concerning intra-articular administration in lactating women. After intravascular use minimal amounts of gadopentetic acid, dimeglumine salt (a maximum of 0.04%) of the intravenously administered dose enters the breast milk. From experience gained so far, harm to the breast-fed infant is considered unlikely.

4.7 Effects On Ability To Drive And Use Machines

No effects of Magnevist 2 mmol/l on driving ability and use of machinery can be expected. However, joint effusion may affect the ability to drive due to a limited joint mobility.

4.8 Undesirable Effects

Frequency of adverse reactions from clinical trial data

Based on experience in more than 4,900 patients, the undesirable effects listed below have been observed and classified by investigators as drug-related.

Adverse reactions with the use of Magnevist 2 mmol are usually of mild to moderate intensity.

The most frequently reported reactions were local injection site reactions, i.e. injection site pain and joint pressure sensations which are mainly related to the procedure itself.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).

System Organ Class

Common

(

Uncommon

(

Rare

(

Nervous system disorders

 

 

Headache

Dizziness

 

 

Vascular disorders

 

 

 

 

Vasovagal reaction

Gastrointestinal disorders

 

 

Nausea

Vomiting

General disorders and administration site conditions

Injection site pain/

Injection site (joint) pressure sensation

 

 

 

 

The most appropriate MedDRA term is used to describe a reaction and its synonyms and related conditions.

• Immune system disorders/Hypersensitivity/Allergic reaction

Systemic hypersensitivity may occur rarely in the form of skin reactions. The possibility of a severe hypersensitivity reaction cannot be totally excluded (see section 4.4).

• General disorders and administration site conditions

Injection of Magnevist 2 mmol/l into the joint is commonly associated with transient discomfort, e.g. pressure and pain due to the injected volume. Severe pain may often result from undue use of pressure or the injection of large volumes.

Other adverse reactions commonly known from intravenous injection of gadolinium chelates were so far not observed with Magnevist 2 mmol/l, due to the low dose and the topical administration.

4.9 Overdose

No signs of intoxication secondary to an overdose have so far been observed or reported on clinical use.

On the basis of the results of the acute toxicity studies with higher concentrated solutions of gadopentetic acid, dimeglumine, a risk of acute intoxication is highly unlikely after intraarticular injection of Magnevist 2 mmol/l.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Magnevist 2 mmol/l is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by the di-N-methylglucamine salt of gadopentetic acid, dimeglumine - the gadolinium complex of pentetic acid (diethylene triamine pentaacetic acid = DTPA). When a suitable scanning sequence (e.g. T1-weighted spin-echo technique) is used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

Gadopentetic acid, dimeglumine is a highly paramagnetic compound which leads to distinct shortening of relaxation times, even in low concentrations. The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons) is 3.67 in water and about 4.95 l/mmol/sec in plasma, and displays only slight dependency on the strength of the magnetic field.

The concentration of Magnevist 2 mmol/l corresponds to 1/250 of the concentration used for i.v. administration. This concentration is sufficient to allow adequate imaging efficacy even after further dilution with joint effusion. If the joint cavity is filled with gadolinium-containing fluid, the signal in the cavity increases on use of T1-weighted sequences, i.e. it becomes bright and contrasts clearly with all structures with a weak or intermediate signal (i.e. all intraarticular structures: hyaline and fibrous cartilage, all ligaments, tendons and the joint capsule). While normal, or even increased, joint fluid does not differ in its signal behaviour in T1-weighted images from all the other anatomical structures apart from fibrocartilage, the intraarticular administration of Magnevist 2 mmol/l leads to distinctly improved contrast situations.

DTPA forms a firm complex with the paramagnetic gadolinium ion with extremely high in vivo and in vitro stability (log K = 22 - 23). The dimeglumine salt of gadopentetic acid, dimeglumine is a highly water-soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. The substance does not display any particular protein binding or inhibitory interaction with enzymes (e.g. myocardial Na+ and K+ ATPase). Magnevist 2 mmol/l does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.

Based on clinical experience, impairment of hepatic, renal or cardiovascular function is not expected.

The physico-chemical properties of Magnevist 2 mmol/l listed below are:

Magnevist 2 mmol/l

 

 

Contrast medium concentration

(mg/ml)

1.88

Osmolality (Osm/kg H2 O) At 37°C

0.29

Viscosity (mPa·s)

At 20°C

At 37°C

 

1.03

0.71

Density (g/ml)

At 20°C

At 37°C

 

 

1.01

1.00

 

pH-value

 

4.8-8.0

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of gadopentetic acid, dimeglumine have been extensively studied after intravenous and oral administration in doses exceeding the amount injected intraarticularly.

After intraarticular injection the compound distributes in the synovial fluid and diffuses into the interstitial space. Marginal uptake into the cartilage is completely reversible.

After distribution in the extracellular space primarily through diffusion controlled processes, the gadopentetic acid, dimeglumine is eliminated unmetabolised via the kidneys by glomerular filtration.

5.3 Preclinical Safety Data

• Systemic toxicity

Animal systemic tolerance studies following repeated daily intravenous administration, after doses much higher than that given intraarticularly, produced no findings which object to a single diagnostic administration of Magnevist 2 mmol/l to humans.

• Genotoxicity, tumorigenicity

Animal studies into genotoxic effects (gene, chromosomal and genome mutation tests) of gadopentetic acid, dimeglumine in vivo and in vitro gave no indication of a mutagenic potential.

In a tumorigenicity study with gadopentetic acid, dimeglumine in rats no compound-related tumours could be observed. Due to this fact, the absence of genotoxic effects and taking into account the pharmacokinetics and the absence of indications of toxic effects on fast-growing tissues, as well as the fact that Magnevist 2 mmol/l is clinically only administered once, there is no evident risk of a tumorigenic effect on humans.

• Local tolerance and contact-sensitising potential

Local tolerance studies with Magnevist 2 mmol/l following single intraarticular administration in animals gave no indication that adverse local effects can be expected in joints of humans.

Local tolerance studies with gadopentetic acid, dimeglumine following single subcutaneous and intramuscular administration in animals indicated that slight local intolerance reactions could occur at the injection site after inadvertent administration.

No indication of a contact-sensitising potential of gadopentetic acid, dimeglumine was observed during animal sensitisation studies.

6. Pharmaceutical Particulars 6.1 List Of Excipients

pentetic acid

meglumine

sodium chloride

water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

Prefilled syringe of 20ml

Glass barrel: glass type I, colourless

Plunger stopper: chlorinated butyl rubber

Tip cap: chlorinated butyl rubber

Luer Lock Adaptor: polysulphone

6.6 Special Precautions For Disposal And Other Handling

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination and injected under sterile conditions.

The tip cap should be removed from the prefilled syringe immediately before use.

Any contrast medium solution not used in one examination must be discarded.

Mixture of Magnevist 2 mmol/l with X-ray contrast media before injection is not recommended as it may reduce efficacy. The minimal amount of X-ray contrast medium required for control of the needle position in the joint may be separately injected prior to the administration of Magnevist 2 mmol/l (0.5 ml to a maximum of 1.0 ml).

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG 14 1JA

Trading as Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0544

9. Date Of First Authorisation/Renewal Of The Authorisation

01 May 2008

10. Date Of Revision Of The Text

11 August 2008

Legal category: POM


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Paromomycin



Dosage Form: capsules
Paromomycin Sulfate Capsules, USP
Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Paromomycin Sulfate Capsules, USP, and other antibacterial drugs, Paromomycin Sulfate Capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Paromomycin sulfate is a broad spectrum antibiotic produced by Streptomycesriomosus var. Paromomycinus. It is a white, amorphous, stable, water-soluble product. Paromomycin sulfate is designated chemically as 0-2, 6-Diamino-2, 6 - dideoxy - ? - L - idopyranosyl - (1?3) - 0 - ? - D - ribofuranosyl - (1?5) - 0 - [2 - amino - 2 - deoxy - ? - D - glucopyranosyl - (1?4)] - 2 - deoxystreptamine sulfate (salt). The molecular formula is C23H45N5O14•xH2SO4, with a molecular weight of 615.64 (base). Its structural formula is:

Each capsule, for oral administration, contains Paromomycin sulfate equivalent to 250mg Paromomycin. Each capsule also contains the following inactive ingredients: FD&C Blue # 1, D&C Red # 28, FD&C Red # 40, gelatin and titanium dioxide.

The imprinting ink for the 250 mg capsule contains D&C yellow #10, FD&C blue # 1, FD&C blue # 2, FD&C red # 40, iron oxide black, pharmaceutical shellac glaze, and propylene glycol.

CLINICAL PHARMACOLOGY

The in-vitro and in-vivo antibacterial action of Paromomycin closely parallels that of neomycin. It is poorly absorbed after oral administration, with almost 100% of the drug recoverable in the stool.

INDICATIONS AND USAGE

Paromomycin sulfate is indicated for intestinal amebiasis–acute and chronic (NOTE-It is not effective in extraintestinal amebiasis); management of hepatic coma–as adjunctive therapy.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Paromomycin Sulfate Capsules and other antibacterial drugs, Paromomycin Sulfate Capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

Paromomycin sulfate is contraindicated in individuals with a history of previous hypersensitivity reactions to it. It is also contraindicated in intestinal obstruction.

PRECAUTIONS

Prescribing Paromomycin Sulfate Capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. The use of this antibiotic, as with other antibiotics, may result in an overgrowth of nonsusceptible organisms, including fungi. Constant observation of the patient is essential. If new infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken. The drug should be used with caution in individuals with ulcerative lesions of the bowel to avoid renal toxicity through inadvertent absorption.

Information for Patients

Patients should be counseled that antibacterial drugs including Paromomycin Sulfate Capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Paromomycin Sulfate Capsules is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Paromomycin Sulfate Capsules or other antibacterial drugs in the future.

PEDIATRIC USE

See DOSAGE AND ADMINISTRATION section.

Adverse Reactions

Nausea, abdominal cramps, and diarrhea have been reported in patients on doses over 3 g daily.

DOSAGE AND ADMINISTRATION

Intestinal amebiasis: Adults and Pediatric Patients: Usual dose—25 to 35 mg/kg body weight daily, administered in three doses with meals, for five to ten days.
Management of hepatic coma: Adults: Usual dose—4 g daily in divided doses, given at regular intervals for five to six days.

HOW SUPPLIED

Paromomycin Sulfate Capsules, USP each contain Paromomycin sulfate equivalent to 250 mg Paromomycin, are supplied as follows:

NDC 23155-038-01: Bottles of 100

The capsule is Dark Blue Opaque / White Opaque, imprinted with “HP 38” in black ink on the cap and on the body.

STORAGE

Store at 20°-25°C (68°-77°F)
[See USP controlled Room Temperature]
Protect from moisture.
Preserve in tight containers as defined in the USP.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured for:
Heritage Pharmaceuticals Inc.
Edison, NJ 08837

1.866.901.DRUG (3784)

Heritage®

Iss. 09/09

BOTTLE LABEL – PRINCIPAL DISPLAY PANEL

NDC 23155-038-01

Paromomycin Sulfate
Capsules USP

250 mg

100 Capsules              Rx only

Heritage


Paromomycin SULFATE 
Paromomycin sulfate  capsule Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 23155-038 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Paromomycin sulfate (Paromomycin) Paromomycin sulfate 250 mg Inactive Ingredients Ingredient Name Strength FD&C Blue No. 1   D&C Red No. 28   FD&C Red No. 40   gelatin   titanium dioxide   D&C yellow No. 10   FD&C blue No. 2   ferrosoferric oxide   shellac   propylene glycol   Product Characteristics Color BLUE (Dark Blue Opaque) , WHITE (White Opaque) Score no score Shape CAPSULE (CAPSULE) Size 19mm Flavor Imprint Code HP;38;HP;38 Contains          Packaging # NDC Package Description Multilevel Packaging 1 23155-038-01 100 CAPSULE In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065173 10/22/2009
Labeler - Heritage Pharmaceuticals Inc (780779901) Revised: 09/2009Heritage Pharmaceuticals Inc More Paromomycin resources Paromomycin Side Effects (in more detail) Paromomycin Dosage Paromomycin Use in Pregnancy & Breastfeeding Drug Images Paromomycin Drug Interactions Paromomycin Support Group 1 Review for Paromomycin - Add your own review/rating Paromomycin MedFacts Consumer Leaflet (Wolters Kluwer) paromomycin Advanced Consumer (Micromedex) - Includes Dosage Information paromomycin Concise Consumer Information (Cerner Multum) Humatin Concise Consumer Information (Cerner Multum) Paromomycin Sulfate Monograph (AHFS DI) Compare Paromomycin with other medications Amebiasis Cryptosporidiosis Dientamoeba fragilis Dog Tapeworm Fish Tapeworm Infection Giardiasis Hepatic Coma Hymenolepis nana, Dwarf Tapeworm Taenia saginata, beef tapeworm Taenia solium, pork tapeworm
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CNL8



Dosage Form: nail lacquer
CNL8 (ciclopirox topical solution 8%)Nail Lacquer CNL8 Description

CNL8 (ciclopirox topical solution, 8%) nail lacquer.

For use on fingernails and toenails and immediately adjacent skin only.

Not for use in eyes.

CNL8 (ciclopirox topical solution, 8%) nail lacquer contains a synthetic antifungal agent, ciclopirox. It is intended for topical use on fingernails and toenails and immediately adjacent skin.

Each gram of CNL8 (ciclopirox topical solution, 8%) nail lacquer contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, NF; isopropyl alcohol, USP; and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.

CNL8 (ciclopirox topical solution, 8%) nail lacquer is a clear, colorless to slightly yellowish solution.

The chemical name for ciclopirox is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, with the molecular formula C12H17NO2 and a molecular weight of 207.27. The CAS Registry Number is 29342-05-0. The chemical structure is:








CNL8 - Clinical Pharmacology Microbiology Mechanism of Action: The mechanism of action of ciclopirox has been investigated using various in vitro and in vivo infection models. One in vitro study suggested that ciclopirox acts by chelation of polyvalent cations (Fe+3 or Al+3) resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. The clinical significance of this observation is not known.
Activity in vitro and ex vivo:  In vitro methodologies employing various broth or solid media with and without additional nutrients have been utilized to determine ciclopirox minimum inhibitory concentration (MIC) values for the dermatophytic molds.(1-2) As a consequence, a broad range of MIC values, 1-20 mcg/mL were obtained for Trichophyton rubrum and Trichophyton mentagrophytes species. Correlation between in vitro MIC results and clinical outcome has yet to be established for ciclopirox.
One ex vivo study was conducted evaluating 8% ciclopirox against new and established Trichophyton rubrum and Trichophyton mentagrophytes infections in ovine hoof material.(3) After 10 days of treatment the growth of T. rubrum and T. mentagrophytes in the established infection model was very minimally affected. Elimination of the molds from hoof material was not achieved in either the new or established for infection models.
Susceptibility testing for Trichophyton rubrum species: In vitro susceptibility testing methods for determining ciclopirox MIC values against the dermatophytic molds, including Trichophyton rubrum species, have not been standardized or validated. Ciclopirox MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of Trichophyton rubrum are susceptible or resistant to ciclopirox have not been established.
Resistance Studies: have not been conducted to evaluate drug resistance development in T. rubrum species exposed to 8% ciclopirox topical solution. Studies assessing crossresistance to ciclopirox and other known antifungal agents have not been performed.
Antifungal Drug Interaction: No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis is not recommended
PHARMACOKINETICS

As demonstrated in pharmacokinetic studies in animals and man, ciclopirox olamine is rapidly absorbed after oral administration and completely eliminated in all species via feces and urine. Most of the compound is excreted either unchanged or as glucuronide. After oral administration of 10 mg of radiolabeled drug (14Cciclopirox) to healthy volunteers, approximately 96% of the radioactivity was excreted renally within 12 hours of administration. Ninety four percent of the renally excreted radioactivity was in the form of glucuronides. Thus, glucuronidation is the main metabolic pathway of this compound.


Systemic absorption of ciclopirox was determined in 5 patients with dermatophytic onychomycoses, after application of CNL8 (ciclopirox topical solution, 8%) nail lacquer to all 20 digits and adjacent 5 mm of skin once daily for six months.  Random serum concentrations and 24 hour urinary excretion of ciclopirox were determined at two weeks and at 1,2, 4 and 6 months after initiation of treatment and 4 weeks post-treatment.  In this study, ciclopirox serum levels ranged from 12-80 ng/mL. Based on urinary data, mean absorption of ciclopirox from the dosage form was less than 5% of the applied dose. One month after cessation of treatment, serum and urine levels of ciclopirox were below the limit of detection.
In two vehicle-controlled trials, patients applied CNL8 (ciclopirox topical solution, 8%) nail lacquer to all toenails and affected fingernails. Out of a total of 66 randomly selected patients on active treatment, 24 had detectable serum ciclopirox concentrations at some point during the dosing interval (range 10.0-24.6 ng/mL). It should be noted that eleven of these 24 patients took concomitant medication containing ciclopirox as ciclopirox olamine (Loprox® Cream, 0.77%).
The penetration of the CNL8 (ciclopirox topical solution, 8%) nail lacquer was evaluated in an in vitro investigation. Radiolabeled ciclopirox applied once to onychomycotic toenails that were avulsed demonstrated penetration up to a depth of approximately 0.4 mm. As expected, nail plate concentrations decreased as a function of nail depth. The clinical significance of these findings in nail plates is unknown. Nail bed concentrations were not determined.
INDICATIONS & USAGE

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.)

CNL8 (ciclopirox topical solution,8%) nail lacquer as a component of a comprehensive management program, is indicated as topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Tricho-phyto rubrum. The comprehensive management program includes removal of the unattached, infected nails as frequently as monthly, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures.

No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis, is not recommended.
CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used only under medical supervision as described above. 
The effectiveness and safety of CNL8 (ciclopirox topical solution, 8%) nail lacquer in the following populations have not been studied. The clinical trials with use of CNL8 (ciclopirox topical solution, 8%) nail lacquer excluded patients who: were pregnant or nursing, planned to become pregnant, had a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of derma-tomycoses, extensive seborrheic dermatitis, recent or recurring herpes zoster, or persistent herpes simplex), were HIV seropositive, received organ transplant, required medication to control epilepsy, were insulin dependent diabetics or had diabetic neuropathy. Patients with severe plantar (moccasin) tinea pedis were also excluded.
The safety and efficacy of using CNL8 (ciclopirox topical solution, 8%) nail lacquer daily for greater than 48 weeks have not been established.
Clinical Studies

The results of use of CNL8 (ciclopirox topical solution, 8%) nail lacquer in treatment of onychomycosis of the toenail without lunula involvement were obtained from two double-blind, placebo-controlled studies conducted in the US. In these studies, patients with onychomycosis of the great toenails without lunula involvement were treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer in conjunction with monthly removal of the unattached, infected toenail by the investigator.  CNL8 (ciclopirox topical solution, 8%) nail lacquer was applied for 48 weeks. At baseline, patients had 20-65% involvement of the target great toenail plate. Statistical significance was demonstrated in one of two studies for the endpoint “complete cure” (clear nail and negative mycology), and in two studies for the endpoint “almost clear” (10% nail involvement and negative mycology) at the end of study. These results are presented below.

At Week 48 (plus Last Observation Carried Forward for the Intent-to-Treat (ITT) Population
                                                            Study 312                                Study 313
                                                            Active              Vehicle             Active                 Vehicle
Complete Cure*                                     6/110 (5.5%)     1/109 (0.9%)     10/118 (8.5%)      0/117 (0%)
Almost Clear**                                      7/107 (6.5%)      1/108 (0.9%)     14/116 (12%)       1/115 (0%)
Negative Mycology Alone ***                  30/105 (29%)     12/106 (11%)    41/115 (36%)       10/114 (9%)
*Clear nail and negative Mycology
** Less than or equal to 10% nail involvement and negative mycology
The summary of reported patient outcomes for the ITT population at 12 weeks following the end of treatment are presented below. Note that post-treatment efficacy assessments were scheduled only for patients who achieved a complete cure.
Post-treatment Week 12 Data for Patients Who Achieved Complete Cure at Week 48
                                                                                    Study 312                             Study 313
                                                                                    Active         Vehicle               Active             Vehicle
Number of Treated Patients                                            112             111                     119                 118
Completed Cure at Week 48                                           6                 1                         10                  1
Post-treatment Week 12 Outcomes:
   Patients Missing all Week 12 Assessments                  2                 0                         2                     0
   Patients with Week 12 Assessments                            4                 1                         8                     0
       Complete Cure                                                        3                 1                         4                     0
       Almost Clear                                                           2*                1                         1*                    0
       Negative Mycology                                                  3                 1                          5                    0


* Four patients (from studies 312 and 313) who were completely cured did not have post-treatment Week 12 planimetry data.


Contraindications CNL8 (ciclopirox topical solution, 8%) nail lacquer is contraindicated in individuals who have shown hypersensitivity to any of its components. Warnings

CNL8 (ciclopirox topical solution, 8%) nail lacquer is not for ophthalmic, oral, or intravaginal use. For use on nails and immediately adjacent skin only.

Precautions

If a reaction suggesting sensitivity or chemical irritation should occur with the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer treatment should be discontinued and appropriate therapy instituted. So far there is no relevant clinical experience with patients with insulin dependent diabetes or who have diabetic neuropathy. The risk of removal of the unattached, infected nail, by the health care professional and trimming by the patient should be carefully considered before prescribing to patients with a history of insulin dependent diabetes mellitus or diabetic neuropathy.

INFORMATION FOR PATIENTS

Patients should have detailed instruction regarding the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product.

The patient should be told to:

1. Use CNL8 (ciclopirox topical solution, 8%) nail lacquer as directed by a health care professional. Avoid contact witheyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. CNL8 (ciclopirox topical solution, 8%) nail lacquer is for external use only.
2.CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis). Contact with the surrounding skin may produce mild, transient irritation (redness).
3.  Removal of the unattached,infected nail, as frequently as monthly, by a health care professional is needed with the use of this medication. Inform a health care professional if you have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program.
4.  Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing).
5.  Up to 48 weeks of daily applications with CNL8 (ciclopirox topical solution, 8%) nail lacquer and professional removal of the unattached,infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement).
6.  Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.
7.  A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail.
8.  Do not use the medication for any disorder other than that for which it is prescribed. Do not use nail polish or other nail cosmetic products on the treated nails.
9. Avoid use near heat or open flame, because product is flammable.
CARCINOGENESIS, MUTAGENESIS and IMPAIRMENT OF FERTILITY

No carcinogenicity study was conducted with CNL8 (ciclopirox topical solution, 8%) nail lacquer formulation. A carcinogenicity study of ciclopirox (1% and 5% solutions in polyethylene glycol 400) in female mice dosed topically twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application sites.

In human systemic tolerability studies following daily application (~340 mg of CNL8 (ciclopirox topical solution, 8%) nail lacquer) in subjects with distal subungual onychomycosis, the average maximal serum level of ciclopirox was 31±28 ng/mL after two months of once daily applications. This level was 159 times lower than the lowest toxic dose and 115 times lower than the highest nontoxic dose in rats and dogs fed 7.7 and 23.1 mg ciclopirox (as ciclopirox olamine)/kg/day.

The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene mutation in Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Chinese hamster lung fibroblasts, with and without metabolic activation (positive); gene mutation assay in HGPRT-test with V79 Chinese hamster lung fibroblasts (negative); unscheduled DNA synthesis in human A549 cells (negative); and BALB/c3T3 cell transformation assay (negative). In an in vivo Chinese hamster bone marrow cytogenetic assay, ciclopirox was negative for chromosome aberrations at 5,000 mg/kg.

Oral reproduction studies in rats at doses up to 3.85 mg ciclopirox (as ciclopirox olamine)/kg/day [equivalent to approximately 1.4 times the potential exposure at the maximum recommended human topical dose (MRHTD)] did not reveal any specific effects on fertility or other reproductive parameters. MRHTD (mg/m2) is based on the assumption of 100% systemic absorption of 27.12 mg ciclopirox (~340 mg CNL8 (ciclopirox topical solution, 8%) nail lacquer that will cover all the fingernails and toenails including 5 mm proximal and lateral fold area plus onycholysis to a maximal extent of 50%.
PREGNANCY Teratogenic effects: Pregnancy Category B Teratology studies in mice, rats, rabbits, and monkeys at oral doses of up to 77, 23, 23, or 38.5 mg, respectively, of ciclopirox as ciclopirox olamine/kg/day (14, 8, 17, and 28 times MRHTD), or in rats and rabbits receiving topical doses of up to 92.4 and 77 mg/kg/day, respectively (33 and 55 times MRHTD), did not indicate any significant fetal malformations. There are no adequate or well controlled studies of topically applied ciclopirox in pregnant women. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. NURSING MONTHERS It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when CNL8
(ciclopirox topical solution, 8%) nail lacquer is administered to a nursing woman. PEDIATRIC USE Based on the safety profile in adults, CNL8 (ciclopirox topical solution, 8%) nail lacquer is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population. GERIATRIC USE Based on the safety profile in adults, CNL8 (ciclopirox topical solution, 8%) nail lacquer is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population. ADVERSE REATIONS

In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer and 7% (23/328) of patients treated with vehicle reported treatment- emergent adverse events (TEAE) considered by the investigator to be causally related to the test material. The incidence of these adverse events, within each body system, was similar between the treatment groups except for Skin and Appendages: 8% (27/327) and 4% (14/328) of subjects in the ciclopirox and vehicle groups reported at least one adverse event, respectively. The most common were rash-related adverse
events: periungual erythema and erythema of the proximal nail fold were reported more frequently in patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer (5% [16/327]) than in patients treated with vehicle (1% [3/328]). Other TEAEs thought to be causally related included nail disorders such as shape change, irritation, ingrown toenail, and discoloration.

The incidence of nail disorders was similar between the treatment groups (2% [6/327] in the CNL8 (ciclopirox topical solution, 8%) nail lacquer group and 2% [7/328] in the vehicle group). Moreover, application site reactions and/or burning of the skin occurred in 1% of patients in 1% of patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer (3/327) and vehicle (4/328).  A 21-Day Cumulative Irritancy study was conducted under conditions of semi-occlusion.  Mild reactions were seen in 46% of patients with CNL8 (ciclopirox topical solution, 8%) nail lacquer 32% with the vehicle and 2% with the negative control, but all were reactions of mild transient erythema.  There was no evidence of allergic contact sensitization for either the CNL8 (ciclopirox topical solution, 8%) nail lacquer or the vehicle base. In a separate study of the photosensitization potential of CNL8 (ciclopirox topical solution, 8%) nail lacquer in a maximized test design that included the occluded application of sodium lauryl sulfate, no photoallergic reactions were noted. In
four subjects localized allergic contact reactions were observed.  In the vehicle-controlled studies, one patient treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer discontinued treatment due to a rash, localized to the palm (causal relation to test material undetermined).
Use of CNL8 (ciclopirox topical solution, 8%) nail lacquer for 48 additional weeks was evaluated in an open-label extension study conducted in patients previously treated in the  vehicle-controlled studies. Threecpercent (9/281) of subjects treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer experienced at least one TEAE that the investigator thought was causally related to the test material. Mild rash in the form of periungual erythema (1% [2/281]) and nail disorders (1% [4/281]) were the most frequently reported. Four patients discontinued because of TEAEs. Two of the four had events considered to be related to test material: one patient’s great toenail “broke away” and another had an elevated creatine phosphokinase level on Day 1 (after 48 weeks of treatment with vehicle in the previous vehicle-controlled study).
To report SUSPECTED ADVERSE REACTIONS contact JSJ Pharmaceuticals at 800-499-4468.
DOSAGE and ADMINISTRATION CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used as a component of a comprehensive management program for onychomycosis.  Removal of the unattached, infected nail, as frequently as monthly, by a health care professional, weekly trimming by the patient, and daily application of the medication are all integral parts of this therapy. Careful consideration of the appropriate nail management program should be given to patients with diabetes (see PRECAUTIONS).
Nail Care By Health Care Professionals:  Removal of the unattached, infected nail, as frequently as monthly, trimming of onycholytic nail, and filing of excess horny material should be performed by professionals trained in treatment of nail disorders.
Nail Care By Patient:  Patients should file away (with emery board) loose nail material and trim nails, as required, or as directed by the health care professional, every seven days after CNL8 (ciclopirox topical solution, 8%) nail lacquer is removed with alcohol. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied once daily (preferably at bedtime or eight hours before washing) to all affected nails with the applicator brush provided. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate.
If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis).
CNL8 (ciclopirox topical solution, 8%) nail lacquer should not be removed on a daily basis. Daily applications should be made over the previous coat and removed with alcohol every seven days. This cycle should be repeated throughout the duration of therapy.
How is CNL8 Supplied

CNL8 nail kit (ciclopirox topical solution, 8%), Swabplus nail lacquer remover, emery board – which contains 3 - 5 ml bottles of CNL8 (ciclopirox topical solution, 8%) nail lacquer (glass bottles with screw caps which are fitted with brushes), 25 - 0.15 ml nail lacquer remover swabs and 1 emery board (NDC 68712-027-01).

CNL8 (ciclopirox topical solution, 8%) nail lacquer, single count 5 ml bottle (NDC 68712-027-03).

Protect from light (e.g., store the bottle in the carton after every use).

CNL8 (ciclopirox topical solution, 8%) nail lacquer should be stored at room temperature between 59° and 86° F (15° and 30° C).


INFORMATION FOR PATIENTS Patients should have detailed instruction regarding the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product.
The patient should be told to:
1. Use CNL8 (ciclopirox topical solution, 8%) nail lacquer as directed by a health care professional.  Avoid contact with eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. CNL8 (ciclopirox topical solution, 8%) nail lacquer is for external use only.
2. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis). Contact with the surrounding skin may produce mild, transient irritation (redness).
3. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional is needed with the use of this medication. Inform a health care professional if you have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program.
4.  Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing).
5.  Up to 48 weeks of daily applications with CNL8 (ciclopirox topical solution, 8%) nail lacquer and professional removal of the unattached, infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement).
6.  Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.
7.  A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail.
8.  Do not use the medication for any disorder other than that for which it is prescribed.
9.  Do not use nail polish or other nail cosmetic productson the treated nails.
10. Avoid use near heat or open flame, because product is flammable.
Manufactured for:
Innocutis Holdings LLC
Charleston, SC 29401
1-800-499-4468
CNL8nails.com
REFERENCES
References:
1. Dittmar W., Lohaus G. 1973. HOE296, A new antimycotic compound with a broad antimicrobial spectrum. Arzneim- Forsch./Drug Res. 23:670-674.
2. Niewerth et al., 1998. Antimicrobial susceptibility testing of dermatophytes: Comparison of the agar macrodilution and broth micro dilution tests. Chemotherapy. 44:31-35.
3. Yang et al., 1997. A new simulation model for studying in vitro topical penetration of antifungaldrugs into hard keratin.  J. Mycol. Med. 7:195-98.  Gantrez is a registered trademark of GAF Corporation
Rev. 419:00 12/07


CNL8  
ciclopirox   solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68712-027 Route of Administration TOPICAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CICLOPIROX (CICLOPIROX) CICLOPIROX 2.28 g  in 1 mL Inactive Ingredients Ingredient Name Strength ETHYL ACETATE   ISOPROPYL ALCOHOL   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 68712-027-01 3 BOTTLE In 1 CARTON contains a BOTTLE, GLASS (68712-027-03) 1 68712-027-03 5 mL In 1 BOTTLE, GLASS This package is contained within the CARTON (68712-027-01) 2 68712-027-03 5 mL In 1 BOTTLE, GLASS None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078270 10/31/2008
Labeler - Innocutis Holdings LLC (071501252) Revised: 12/2011Innocutis Holdings LLC

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ProHance Injection


gadoteridol
Dosage Form: injection, solution
ProHance®
(Gadoteridol) Injection, 279.3 mg/mL WARNING: NEPHROGENIC SYSTEMIC FIBROSIS

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.

The risk for NSF appears highest among patients with: chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.  For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration (see WARNINGS). ProHance Injection Description

ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection.

Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula:

Each mL of ProHance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative.

ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:

PARAMETER Osmolality (mOsmol/kg water)   @ 37° C 630 Viscosity (cP) @ 20° C 2.0   @ 37° C 1.3 Specific Gravity   @ 25° C 1.140 Density (g/mL) @ 25° C 1.137 Octanol: H2O coefficient -3.68 ± 0.02

ProHance has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use.

ProHance Injection - Clinical Pharmacology Pharmacokinetics

The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively.

Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo.

The renal and plasma clearance rates (1.41 ± 0.33 mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 ± 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration.

It is unknown if protein binding of ProHance occurs in vivo.

Pharmacodynamics

Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.

In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known.

CLINICAL TRIALS

ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated.

ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans.

Indications and Usage for ProHance Injection Central Nervous System

ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues.

Extracranial/Extraspinal Tissues

ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck.

Contraindications

None known.

Warnings Nephrogenic Systemic Fibrosis (NSF)

 Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance administration to Bracco Diagnostics (1-800-257-8151) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).

 Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.

 Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle erythrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied.

Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis.

Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. (See PRECAUTIONS-General).

Precautions General

Gadoteridol is cleared from the body by glomerular filtration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHance®. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment.

In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHance® is unknown.

The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders.

Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.

When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syringe, the solution should be used immediately.

Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See Pharmacokinetics under CLINICAL PHARMACOLOGY and Central Nervous System under DOSAGE AND ADMINISTRATION).

Information for patients:

Patients scheduled to receive ProHance should be instructed to inform their physician if the patient;

is pregnant or breast feeding has anemia or diseases that affect the red blood cells has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases.  has recently received a GBCA.

 GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:

 Describe the clinical manifestations of NSF  Describe procedures to screen for the detection of renal impairment

 Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY

No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility.

ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg.

Pregnancy Category C

ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation.

There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman.

Pediatric Use

Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections)

Adverse Reactions

The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2-17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported.

The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity.

The following additional adverse events occurred in fewer than 1% of the patients:

Body as a Whole: Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Laryngismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) Cardiovascular: Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm Digestive: Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting Nervous System: Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Arm; Staring Episode; Seizure; Syncope Respiratory System: Dyspnea; Rhinitis; Cough Skin and Appendages: Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits Special Senses: Tinnitus

The following adverse drug reactions have also been reported:

Body as a Whole: Generalized Edema; Laryngeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death) Cardiovascular: Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders Digestive: Increased Salivation; Dysphagia Nervous System: Stupor; Tremor; Loss of Consciousness Respiratory: Apnea; Wheezing Skin and Appendages: Sweating; and Cyanosis Special Senses: Voice Alteration; Transitory Deafness Urogenital: Urinary Incontinence Overdosage

Clinical consequences of overdose with ProHance have not been reported.

ProHance Injection Dosage and Administration Central Nervous System

ADULTS: The recommended dose of ProHance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose.

CHILDREN (2-18 years): The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied.

Extracranial/Extraspinal Tissues

ADULTS: The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min).

CHILDREN: Safety and efficacy for extracranial/extra-spinal tissues has not been established.
Dose adjustments in renal and liver impairment have not been studied.

To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of ProHance (Gadoteridol) Injection.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials.

How is ProHance Injection Supplied

ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of:

Five 5 mL fills in single dose 15 mL vials (NDC 0270-1111-04) Five 10 mL fills in single dose 30 mL vials (NDC 0270-1111-01) Five 15 mL fills in single dose 30 mL vials (NDC 0270-1111-02) Five 20 mL fills in single dose 30 mL vials (NDC 0270-1111-03) Five 10 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-16) Five 17 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-45) STORAGE

ProHance (Gadoteridol) Injection should be stored at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. Frozen syringes should be discarded.

Directions for Use of the ProHance® (Gadoteridol) Injection single dose syringe*

1) Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel.
2) Holding syringe erect, aseptically remove the rubber cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. 3) Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. 4) Properly dispose of the syringe and any other materials used.

*The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson.

This product is covered by one or more of:

U.S. Patent No. 4,885,363; U.S. Patent No. 4,963,344; U.S. Patent No. 5,474,756; U.S. Patent No. 5,846,519; and U.S. Patent No. 6,143,274.

Manufactured for
Bracco Diagnostics Inc.
Princeton, NJ 08543
by BIPSO GmbH
78224 Singen (Germany)

F.1/6058056
Revised July 2011

 

Prohance 5mL Vial label
NDC 0270-1111-04

Prohance 5mL Vial Box

 

Prohance 5x 10mL Syringe label
NDC 0270-1111-16

Prohance 10mL Syringe label


PROHANCE 
gadoteridol  injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0270-1111 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength gadoteridol (gadoteridol) gadoteridol 279.3 mg  in 1 mL Inactive Ingredients Ingredient Name Strength calteridol calcium .23 mg  in 1 mL tromethamine 1.21 mg  in 1 mL Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0270-1111-04 5  In 1 BOX contains a VIAL, SINGLE-DOSE 1 5 mL In 1 VIAL, SINGLE-DOSE This package is contained within the BOX (0270-1111-04) 2 0270-1111-01 5  In 1 BOX contains a VIAL, SINGLE-DOSE 2 10 mL In 1 VIAL, SINGLE-DOSE This package is contained within the BOX (0270-1111-01) 3 0270-1111-02 5  In 1 BOX contains a VIAL, SINGLE-DOSE 3 15 mL In 1 VIAL, SINGLE-DOSE This package is contained within the BOX (0270-1111-02) 4 0270-1111-03 5  In 1 BOX contains a VIAL, SINGLE-DOSE 4 20 mL In 1 VIAL, SINGLE-DOSE This package is contained within the BOX (0270-1111-03) 5 0270-1111-16 5  In 1 BOX contains a SYRINGE, GLASS 5 10 mL In 1 SYRINGE, GLASS This package is contained within the BOX (0270-1111-16) 6 0270-1111-45 5  In 1 BOX contains a SYRINGE, GLASS 6 17 mL In 1 SYRINGE, GLASS This package is contained within the BOX (0270-1111-45)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020131 11/16/1992
Labeler - BRACCO DIAGNOSTICS INC. (849234661) Registrant - BRACCO DIAGNOSTICS INC. (849234661) Establishment Name Address ID/FEI Operations BRACCO IMAGING SPA 543024777 API MANUFACTURE Establishment Name Address ID/FEI Operations BIPSO GmbH 342104149 MANUFACTURE Revised: 09/2011BRACCO DIAGNOSTICS INC. More ProHance Injection resources ProHance Injection Side Effects (in more detail) ProHance Injection Dosage ProHance Injection Use in Pregnancy & Breastfeeding ProHance Injection Drug Interactions ProHance Injection Support Group 0 Reviews for ProHance Injection - Add your own review/rating Compare ProHance Injection with other medications CNS Magnetic Resonance Imaging
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KOGENATE Bayer 250 IU Powder and solvent for solution for injection (Medimop)


1. Name Of The Medicinal Product

KOGENATE Bayer 250 IU powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

2.1 General description

Each vial contains nominally 250 IU human coagulation factor VIII (octocog alfa).

Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster kidney cells containing the human factor VIII gene.

2.2 Qualitative and quantitative composition

One ml of KOGENATE Bayer 250 IU contains approximately 100 IU (250 IU / 2.5 ml) of human coagulation factor VIII (octocog alfa) after reconstitution.

The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard which was calibrated against WHO standard in International Units (IU).

The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.

Solvent: water for injections.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Powder: dry white to slightly yellow powder or cake.

Solvent: water for injection, a clear, colourless solution.

The reconstituted medicinal product is a clear and colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand's disease.

4.2 Posology And Method Of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

Posology

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal activity. The required dose is determined using the following formulae:

I. Required IU = body weight (kg) ? desired factor VIII rise (% of normal) ? 0.5

 

II. Expected factor VIII rise (% of normal) =

2 ? administered IU

body weight (kg)

On demand treatment

The dose, frequency and duration of the substitution therapy must be individualised according to the patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the bleeding, the presence of inhibitors, and the factor VIII level desired).

The following table provides a guide for factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period:

Degree of haemorrhage/ Type of surgical procedure

Factor VIII level required (%) (IU/dl)

Frequency of doses (hours)/ Duration of therapy (days)

Haemorrhage

Early haemarthrosis, muscle bleed or oral bleed

 

20 - 40

 

Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive haemarthrosis, muscle bleed or haematoma

30 - 60

Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and disability are resolved.

Life threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed

60 - 100

Repeat infusion every 8 to 24 hours until threat is resolved

Surgery

Minor

including tooth extraction

 

30 - 60

 

Every 24 hours, at least 1 day, until healing is achieved.

Major

80 - 100

(pre- and postoperative)

a) By bolus infusions

Repeat infusion every 8 - 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60%

b) By continuous infusion

Raise factor VIII activity pre-surgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/Kg/h) adjusting according to patient's daily clearance and desired factor VIII levels for at least 7 days.

The amount to be administered and the frequency of administration should always be adapted according to the clinical effectiveness in the individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.

During the course of treatment, appropriate determination of factor VIII levels is advised in order to guide the dose to be administered and the frequency at which to repeat the infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

Continuous Infusion

It has been shown in a clinical study performed with adult haemophilia A patients who undergo a major surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, during and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions. For the calculation of the initial infusion rate, clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average population value (3.0-3.5 ml/h/kg) and then adjust accordingly.

Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) ? desired factor VIII level (in IU/ml)

For continuous infusion, clinical and in vitro stability has been demonstrated using ambulatory pumps with a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC) materials. This should be considered for a continuous infusion administration.

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of KOGENATE Bayer per kg body weight at intervals of 2 to 3 days.

In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

Paediatric population

Data have been obtained from clinical studies in 61 children under 6 years of age and non-interventional studies in children of all ages.

Patients with inhibitors

Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with KOGENATE Bayer. However, in the presence of an inhibitor the doses required are variable and must be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia.

Method of administration

For intravenous use.

KOGENATE Bayer should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level (maximal rate of infusion: 2 ml/min).

Continuous infusion

KOGENATE Bayer can be infused by continuous infusion. The infusion rate should be calculated based on the clearance and the desired FVIII level.

Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg bw/concentration of solution (IU/ml).

Example for calculation of infusion rate for continuous infusion after initial bolus injection

 

Desired plasma FVIII level

Infusion rate

IU/h/kg

Infusion rate for 75 kg patient

ml/h

   

Clearance: 3 ml/h/kg

   

Concentrations of rFVIII solution

         

100 IU/ml

200 IU/ml

400 IU/ml

 

100 % (1 IU/ml)

3.0

2.25

1.125

0.56

 

60 % (0.6 IU/ml)

1.8

1.35

0.68

0.34

 

40 % (0.4 IU/ml)

1.2

0.9

0.45

0.225

Higher infusion rates may be required in conditions with accelerated clearance during major bleedings or extensive tissue damage during surgical interventions.

After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using the steady state equation with the measured FVIII level and the rate of infusion using the following equation:

clearance = infusion rate/actual FVIII level.

During continuous infusion, infusion bags should be changed every 24 hours.

For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the package leaflet.

4.3 Contraindications

- Known hypersensitivity to the active substance or to any of the excipients.

- Known allergic reactions to mouse or hamster protein.

4.4 Special Warnings And Precautions For Use

Hypersensitivity reactions

As with any intravenous protein product, allergic type hypersensitivity reactions are possible.

Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild hypotension and nausea during infusion can constitute an early warning for hypersensitivity and anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately and patient should contact their physician. In case of shock, the current medical standards for shock treatment should be observed.

Antibodies (inhibitors)

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units (BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development.

Patients treated with recombinant coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. (See also section 4.8)

Continuous infusion

In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.

Registration

In the interest of the patients, it is recommended that, whenever possible, every time that KOGENATE Bayer is administered to them, the name and the batch number of the product is registered.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of KOGENATE Bayer with other medicinal products are known.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with KOGENATE Bayer.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE Bayer should be used during pregnancy and breast-feeding only if clearly indicated.

There are no fertility data available.

4.7 Effects On Ability To Drive And Use Machines

KOGENATE Bayer has no influence on the ability to drive or to use machines.

4.8 Undesirable Effects

The most commonly reported adverse drug reaction occurring is the formation of neutralising antibodies (prevalent in previously untreated or minimally treated patients).

The frequencies of adverse reactions reported with KOGENATE Bayer are summarized in the table below. Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (

MedDRA Standard

System Organ Class

Common

Uncommon

Rare

Blood and the Lymphatic System Disorders

Inhibitor Formation to FVIII

(Reported in PUP and minimally treated patients in clinical trials)*

Inhibitor Formation to FVIII

(Reported in PTP in clinical trials and Post Marketing Studies)*

 

General Disorders and Administration Site Conditions

Infusion site reaction

 

Infusion related febrile reaction (pyrexia)

Immune System Disorders

Skin associated hypersensitivity reactions, (pruritus, urticaria and rash)

 

Systemic Hypersensitivity reactions (including one anaphylactic reaction, nausea, blood pressure abnormal and, dizziness)

* see section below

Description of selected adverse reactions

The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

In clinical studies, KOGENATE Bayer has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with KOGENATE Bayer developed inhibitors: Overall, 9 out of 60 (15%) developed inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3 - 18 days).

The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.

In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

In extensive post-registration studies with KOGENATE Bayer, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.

During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients (see sections 4.3 and 4.4).

4.9 Overdose

No case of overdose with recombinant coagulation factor VIII has been reported.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to vWF in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay method for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and duration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to that achieved with plasma-derived factor VIII.

5.2 Pharmacokinetic Properties

The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for factor VIII derived from human plasma.

After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional pharmacokinetic parameters for KOGENATE Bayer for bolus injection are: mean residence time [MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0 ml/h/kg (range 1.6-4.6 ml/h/kg).

5.3 Preclinical Safety Data

Even doses several fold higher than the recommended clinical dose (related to body weight) failed to demonstrate any acute or subacute toxic effects for KOGENATE Bayer in laboratory animals (mouse, rat, rabbit, and dog).

Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with octocog alfa due to the immune response to heterologous proteins in all non-human mammalian species.

No studies were performed on the mutagenic potential of KOGENATE Bayer, since no mutagenic potential could be detected in vitro or in vivo for the predecessor product of KOGENATE Bayer.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder

Glycine

Sodium chloride

Calcium chloride

Histidine

Polysorbate 80

Sucrose

Solvent

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6..

Only the provided components (powder vial, pre-filled syringe containing solvent, vial adapter and venipuncture set) should be used for reconstitution and injection because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf Life

30 months.

After reconstitution, the product should be used immediately.

However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 30°C in PVC bags for continuous infusion.

Do not refrigerate after reconstitution.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light.

The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the product expires at the end of this 12-month period; the new expiry date must be noted on the outer carton.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Each package of KOGENATE Bayer contains:

• one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber blend stopper and aluminium seal)

• one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey bromobutyl rubber blend stopper)

• syringe plunger rod

• vial adapter

• one venipuncture set

• two sterile alcohol swabs for single use

• two dry swabs

• two plasters

6.6 Special Precautions For Disposal And Other Handling

Detailed instructions for preparation and administration are contained in the package leaflet provided with KOGENATE Bayer.

KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for injections) in the prefilled syringe and the vial adapter. Reconstitution should be performed in accordance with good practices rules, particularly with attention to asepsis. Gently rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use KOGENATE Bayer if you notice visible particulate matter or turbidity.

After reconstitution, the solution is drawn back into the syringe.

Use the provided venipuncture set for intravenous injection.

For continuous infusion, the product must be prepared under aseptic conditions.

For single use only. Any unused solution must be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Bayer Pharma AG

13342 Berlin

Germany

8. Marketing Authorisation Number(S)

EU/1/00/143/007

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

10. Date Of Revision Of The Text

1 July 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.


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