1. Name Of The Medicinal Product

Begrivac® 2010/2011 / suspension for injection in pre-filled syringe

Influenza vaccine (split virion, inactivated)

2. Qualitative And Quantitative Composition

Influenza virus (inactivated, split) of the following strains*:

A/California/07/2009 (H1N1) - derived strain used NYMC X-181

15 micrograms HA**

A/Perth/16/2009 (H3N2) - like strain used NYMC X-187

derived from A/Victoria/210/2009

15 micrograms HA**

B/Brisbane/60/2008 - derived strain used NYMC BX-35

15 micrograms HA**

----------------------------------------------------------------------------------------------------------------------

per 0.5 ml dose

* propagated in fertilised hen's eggs from healthy chicken flocks .

** haemagglutinin

This vaccine complies with the WHO recommendation (northern hemisphere) and EU decision for the 2010/2011 season.

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Suspension for injection in pre-filled syringe.

Slightly opalescent.

4. Clinical Particulars 4.1 Therapeutic Indications

Prophylaxis of influenza, especially in those who run an increased risk of associated complications.

The use of Begrivac 2010/2011 should be based on official recommendations.

4.2 Posology And Method Of Administration

Adults and children from 36 months: 0.5 ml.

Children from 6 months to 35 months: Clinical data are limited. Dosages of 0.25 ml or 0.5 ml have been used.

For children, who have not previously been vaccinated, a second dose should be given after an interval of at least 4 weeks.

Immunisation should be carried out by intramuscular or deep subcutaneous injection.

For instructions for preparation, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients and to residues, e.g. eggs, chicken proteins, such as ovalbumin.

The vaccine may contain residues of polymyxin B, formaldehyde, diethylether or polysorbate 80.

Immunisation shall be postponed in patients with febrile illness or acute infection.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine.

Begrivac 2010/2011 should under no circumstances be administered intravascularly.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Begrivac 2010/2011 may be given at the same time as other vaccines. Immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

The immunological response may be diminished if the patient is undergoing immuno-suppressant treatment.

Following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the false-positive ELISA test results. The transient false positive reactions could be due to the IgM response by the vaccine.

4.6 Pregnancy And Lactation

The limited data from vaccinations in pregnant women do not indicate that adverse fetal and maternal outcomes were attributable to the vaccine. The use of this vaccine may be considered from the second trimester of pregnancy. For pregnant women with medical conditions that increase their risk of complications from influenza, administration of the vaccine is recommended, irrespective of their stage of pregnancy.

Begrivac 2010/2011 may be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse reactions observed from clinical trials

The safety of trivalent inactivated influenza vaccines is assessed in open label, uncontrolled clinical trials performed as annual update requirement, including at least 50 adults aged 18 – 60 years of age and at least 50 elderly aged 61 years or older. Safety evaluation is performed during the first 3 days following vaccination.

The following undesirable effects have been observed during clinical trials with the following frequencies:

Very common (>1/10); common (

Nervous system disorders

Common:

Headache*

Skin and subcutaneous tissue disorders

Common:

Sweating*

Musculoskeletal and connective tissue disorders

Common:

Myalgia, arthralgia*

General disorders and administration site conditions

Common:

Fever, malaise, shivering, fatigue. Local reactions: redness, swelling, pain, ecchymosis, induration.*

* These reactions usually disappear within 1-2 days without treatment.

Adverse reactions reported from post-marketing surveillance

Adverse reactions reported from post-marketing surveillance are, next to the reactions which have also been observed during the clinical trials, the following:

Blood and lymphatic system disorders:

Transient thrombocytopenia, transient lymphadenopathy

Immune system disorders:

Allergic reactions, in rare cases leading to shock, angioedema

Nervous system disorders:

Neuralgia, paraesthesia, febrile convulsions, neurological disorders, such as encephalomyelitis, neuritis and Guillain Barr? syndrome

Vacsular disorders:

Vasculitis associated in very rare cases with transient renal involvement.

Skin and subcutaneous tissue disorders:

Generalised skin reactions including pruritus, urticaria or non-specific rash.

4.9 Overdose

Overdosage is unlikely to have any untoward effect.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Influenza vaccine

ATC-Code: J07BB02

Seroprotection is generally obtained within 2 to 3 weeks. The duration of postvaccinal immunity to homologous strains or to strains closely related to the vaccine strains varies but is usually 6-12 months.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Buffer solution (pH = 7.2) containing: sodium chloride, potassium chloride, magnesium chloride hexahydrate, disodium phosphate dihydrate, potassium dihydrogen phosphate and 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

1 year

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

0.5 ml suspension in pre-filled syringe (Type I glass) with plunger stopper (bromobutyl rubber) with or without needle – in pack sizes of 1, 10 or 20 (2 ? 10)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The vaccine should be allowed to reach room temperature before use.

Shake before use.

For children, when a dose of 0.25 ml is indicated, the following procedure is recommended:

Syringe without mark for the 0.25 ml dose:

The pre-filled syringe should be held in the upright position and half of the volume should be eliminated. The remaining volume should be injected.

Syringe with a mark for the 0.25 ml dose:

Discard half the contained volume up to the mark (little black line indicated on the syringe barrel below the label), before injection.

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

7. Marketing Authorisation Holder

Novartis Vaccines and Diagnostics GmbH

P.O. Box 1630

D-35006 Marburg

8. Marketing Authorisation Number(S)

national:

MRP: DE/H/125/01

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorization (national): 8. August 1996

Renewal of the authorization: 20. February 2008

10. Date Of Revision Of The Text

May 2010



Boots Soothing Eye Drops

(Cetrimide, Hamamelis Water)

Soothing & antiseptic

10 ml e

Read all of this carton for full instructions.

Uses: A soothing and antiseptic sterile solution for the relief of minor eye irritation. It can be used to soothe eyes irritated by smoke and dust. Before you use this medicine Do not use: If you are allergic to any of the ingredients If you wear soft contact lenses

You can use this medicine if you are pregnant or breastfeeding.

How to use this medicine

Check the cap seal is not broken before first use. If it is, do not use the drops.

Tilt head back and hold down lower eye lid. Squeeze the bottle to put drops into the corner (lower sac) of the eye.

For use in the eyes only.

Age: Adults and children How much: One or two drops How often: Morning and night, or when you need to

If anyone accidentally swallows some: Talk to a doctor

Possible side effects

Most people will not have problems, but some may get some of these:

Red, swollen or itchy eyes (signs of allergic reaction) – if this happens stop using the drops

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton. Throw away any unused drops 28 days after first opening.

Active ingredients

These eye drops contain Cetrimide 0.01% w/v, Hamamelis Water 5% v/v.

Also contains: purified water, boric acid, borax.

PL 00014/5237

[P]

Text prepared 11/07

Manufactured for the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

by

Hamol Limited Nottingham NG90 2DB

If you need more advice ask your pharmacist.

BTC16394 vE 28/02/08



Boots Dual Action Athlete's Foot Powder

(Chlorhexidine Hydrochloride, Tolnaftate)

Effectively treats athlete's foot

Relieves skin irritation

75 g e

Please read this label carefully. It contains important information for you. Keep this label you may need to read it again Ask your pharmacist if you need more information or advice What this medicine is for

An anti-fungal and antibacterial powder for the treatment and prevention of athlete's foot. Also effective for other skin conditions where tenderness and sweating cause skin irritation, such as dhobie itch (groin ringworm).

Before you use this medicine Do not use: If you are allergic to any of the ingredients

You can use this medicine if you are pregnant or breastfeeding.

How to use this medicine Wash and thoroughly dry the affected area Apply the powder liberally to the affected area If suffering from athlete's foot, apply the powder between the toes and also dust socks and inside of shoes with powder Adults and children:

Apply morning and night.

Continue treatment for at least one week after the condition has cleared up, to stop it coming back.

If you are treating athlete's foot it is recommended that an athlete's foot cream is used together with this product.

For use on the skin only.

Possible side effects

Most people will not have problems, but some may get some of these:

Allergic reactions (red, itchy skin) Skin irritation Contact dermatitis (redness and swelling of the skin)

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

What is in this medicine

This powder contains Chlorhexidine Hydrochloride 0.25% w/w, Tolnaftate 1% w/w.

Also contains: purified talc, maize starch, colloidal silicon dioxide.

This pack contains 75 g powder

Who makes this medicine

Manufactured by the Marketing Authorisation Holder

The Boots Company PLC Nottingham NG2 3AA

Leaflet prepared July 2007

If you would like any further information about this medicine please contact

The Boots Company PLC Nottingham NG2 3AA

Keep all medicines out of the sight and reach of children.

Use by the date on the label edge.

PL 00014/0456

The Boots Company PLC Nottingham NG2 3AA

If you need more advice ask your pharmacist.

BTC13414 vC 03-12-07



Boots Hayfever Relief Nasal Spray

(Beclometasone Dipropionate)

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to treat hayfever. However, you still need to use it carefully to get the best results from it.

Keep this leaflet, you may need to read it again Ask your pharmacist if you need more information or advice You must contact a doctor if your symptoms worsen or do not improve within 10 days What this medicine is for

This medicine contains Beclometasone Dipropionate, which belongs to a group of medicines called corticosteroids, which act to reduce swelling (inflammation) in the nose.

It can be used to treat hayfever.

Before you use this medicine

This medicine can be used by adults aged 18 years and over. However, some people should not use this medicine or should seek the advice of their pharmacist or doctor first.

Do not use: If you are allergic to any of the ingredients If you are pregnant or breastfeeding, unless your doctor tells you to Talk to your pharmacist or doctor: If you think you have a nasal infection as well as hayfever If you have recently had steroid injections or have been taking steroid tablets for a long time If you take other medicines

This medicine is not expected to affect any medicines that you may be taking.

If you are unsure about interactions with any medicines, talk to your pharmacist. This includes medicines prescribed by your doctor and medicine you have bought for yourself, including herbal and homeopathic remedies.

How to use this medicine Directions for using the spray 1. Shake the bottle gently and remove the dust cap and lock-ring (if fitted). 2. A new spray, or one which has not been used for a few days, may not work the first time. You may need to prime the bottle by pumping the spray a few times until a fine mist is produced. To do this put your forefinger and middle finger on the collar either side of the nozzle and your thumb underneath the bottle. Keeping your thumb still, press down with your fingers to pump the spray. Hold the nozzle pointing away from you while you are doing this. If the spray still doesn’t work and you think it may be blocked, clean it as described further on in the leaflet. Never try to unblock it or enlarge the tiny spray hole with a pin or other sharp object because this will destroy the spray mechanism. 3. Blow your nose gently. To use close one nostril and put the nozzle in the other nostril. Tilt your head forward slightly and keep the bottle upright. Hold the bottle as shown. 4. Start to breathe in slowly through your nose. While you are breathing in squirt a spray of fine mist into your nostril by pressing down firmly on the collar with your fingers. Breathe out through your mouth. Repeat this step to take a second spray in the same nostril. Remove the nozzle from this nostril and breath out through your mouth. 5. Repeat step 3 and 4 for the other nostril.

After using the spray, wipe the nozzle carefully with a clean tissue or handkerchief, and replace the dust cap.

To clean the spray 1. Take the dust cap off. 2. Pull upwards on the white collar to remove the nozzle. 3. Soak the nozzle and dust cap in warm water for a few minutes and then rinse under a running tap. 4. Shake off the excess water and allow to dry in a warm, not hot, place. 5. Re-fit the nozzle. 6. ‘Prime’ the bottle if necessary by pumping the spray a few times until a fine mist is produced.

Your nasal spray should be cleaned at least once a week or more often if it gets blocked.

Adults of 18 years and over: Use two sprays in each nostril, twice a day (morning and evening). Don’t use more than 8 sprays in 24 hours.



1. Name Of The Medicinal Product

BritLofex Tablets 0.2mg

2. Qualitative And Quantitative Composition

Lofexidine hydrochloride 0.2mg

3. Pharmaceutical Form

Film-coated tablet.

Peach coloured, round tablet.

4. Clinical Particulars 4.1 Therapeutic Indications

To relieve symptoms in patients undergoing opiate detoxification.

4.2 Posology And Method Of Administration

The recommended route of administration is by mouth.

ADULTS

The dosage of lofexidine should be titrated according to the patient's response. Initial dosage should be 0.8mg per day in divided doses. The dosage may be increased by increments of 0.4 to 0.8mg per day up to a maximum of 2.4mg daily. Maximum single dose should not exceed 4 x 0.2mg tablets (0.8mg). Each patient should be assessed on an individual basis; those undergoing acute detoxification will usually require the highest recommended dose and dosage increments to provide optimum relief at the time of expected peak withdrawal symptoms.

In cases where no opiate use occurs during detoxification, a duration of treatment of 7-10 days is recommended. In some cases the physician may consider longer treatment is warranted.

CHILDREN:

Safety and effectiveness in children has not been established.

ELDERLY:

There is no experience of dosing in the elderly from clinical studies. Should use in the elderly be necessary it is advised that special caution is observed in the presence of heart disease or anti-hypertensive therapy.

4.3 Contraindications

BritLofex tablets are contraindicated in patients who are allergic to lofexidine or to other imidazoline derivatives or to any excipients of BritLofex.

4.4 Special Warnings And Precautions For Use

As with other hypotensive agents, therapy with lofexidine should not be discontinued abruptly. Dosage should be reduced gradually over a period of 2-4 days or longer, to minimise blood pressure elevation and associated signs and symptoms. Lofexidine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure and in patients with bradycardia or hypotension. Blood pressure and pulse rate should be assessed frequently. Patients with a history of depression should be carefully observed during long-term therapy with lofexidine.

There have been reports of QT prolongation during lofexidine treatment. Whilst the nature of the relationship between lofexidine and these ECG changes is not yet clear, it would be prudent to avoid the use of lofexidine in patients at risk of QT prolongation i.e. those with known QT problems, metabolic disturbances, pre-existing cardiovascular disease, relevant family history or those taking other drugs known to prolong the QT interval.

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Allergic reactions may occur due to the presence of E110 (Sunset Yellow).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lofexidine may enhance the CNS depressive effects of alcohol, barbiturates and other sedatives.

Lofexidine may enhance the effects of anti-hypertensive drug therapy.

Concomitant use of tricyclic antidepressants may reduce the efficacy of lofexidine.

Concomitant use of drug which prolong the QT interval or cause electrolyte imbalance should be avoided.

4.6 Pregnancy And Lactation

Pregnancy:

The safety of lofexidine in pregnant women has not been established. High doses of lofexidine given to pregnant dogs and rabbits caused a reduction in foetal weight and increased abortions. Lofexidine should only be administered during pregnancy if the benefit outweighs the potential risk to mother and foetus.

Lactation:

It is not known whether this drug is excreted in human milk and caution should be exercised when it is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

Lofexidine may have a sedative effect. If affected, patients should be advised not to drive or operate machines.

4.8 Undesirable Effects

The adverse effects of the drug are primarily related to its central alpha-adrenergic agonist effects:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Immune system disorders:

Not known:

Allergic reactions may occur due to the presence of E110 (Sunset Yellow).

Nervous system disorders:

Very common:

Dizziness has been reported following treatment with lofexidine.

Drowsiness and related symptoms including sedation and somnolence have been reported.

Cardiac disorders:

Very common:

Bradycardia has been reported.

Not known:

There have been reports of QT prolongation during lofexidine treatment.

Vascular disorders:

Very common:

Hypotension has been reported

General disorders and administration site conditions:

Very common:

Dryness of mucous membranes especially the mouth, throat and nose has been reported.

4.9 Overdose

Overdosage may cause hypotension, bradycardia and sedation. Gastric lavage should be carried out where appropriate. In most cases, all that is required are general supportive measures.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Drugs used in opioid dependence

ATC Classification: N07BC04

Lofexidine hydrochloride is an orally active imidazoline adrenergic alpha-2-receptor agonist; and is believed to have a high affinity for 2A receptor subtypes resulting in less anti-hypertensive activity than clonidine, a non-selective alpha-2-receptor agonist. Hypotension may occur in susceptible subjects, accompanied by a decrease in heart rate.

Abrupt discontinuation of lofexidine has been, in some cases, associated with a transient increase in blood pressure to higher than pre-treatment levels.

5.2 Pharmacokinetic Properties

Lofexidine is extensively absorbed and achieves peak plasma concentration at 3 hours after administration of a single dose. The elimination half-life is 11 hours with accumulation occurring up to four days with repeat dosing. Lofexidine undergoes extensive metabolism in the liver and excretion is mainly by the kidney.

5.3 Preclinical Safety Data

Animal toxicology. Lofexidine was tolerated at high dosage in singe dose toxicity studies in animals, the LD50 being >77 mg/kg. With repeat dosing in mice, rats and dogs symptoms related to the pharmacology of the drug (ataxia, sedation, tremor, unkempt appearance and exhaustion) appeared.

Studies of mutagenicity are incomplete but lofexidine did not display mutagenicity in the Ames test. Long-term studies in rats showed no evidence of carcinogenicity.

High doses of lofexidine given to pregnant rats and rabbits caused a reduction in the foetal weight and increased abortions. No teratogenic effects were found.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose (monohydrate)

Citric acid

Povidone

Microcrystalline cellulose

Calcium stearate

Sodium lauryl sulphate

Purified water

Film Coat:

Opadry OY-S-9480 Brown

containing

Hydroxypropylmethyl cellulose

Titanium dioxide

Propylene glycol

Indigo Carmine (E132)

Sunset Yellow (E110)

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25?C. Store in original package.

6.5 Nature And Contents Of Container

Aluminium foil/aluminium foil blister strips

Aluminium foil/PVC blister strips

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Britannia Pharmaceuticals Limited

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN

United Kingdom

8. Marketing Authorisation Number(S)

PL 04483/0036

9. Date Of First Authorisation/Renewal Of The Authorisation

October 1990

10. Date Of Revision Of The Text

29 June 2010



1. Name Of The Medicinal Product

Bondronat 2 mg

Bondronat 6 mg

Concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Bondronat 2 mg

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate).

Bondronat 6 mg

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate).

Excipients: Sodium (less than 1 mmol per dose).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Bondronat is indicated in adults for

- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

- Treatment of tumour-induced hypercalcaemia with or without metastases.

4.2 Posology And Method Of Administration

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterizing the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this patient group.

Treatment of tumour-induced hypercalcaemia

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium*

* Note albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected

Serum calcium (mmol/l)

=

serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8

Or

   

Albumin-corrected

Serum calcium (mg/dl)

=

serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)]

To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

   

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

Patients with renal impairment

For patients with mild renal impairment (CLcr

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

6 mg / 15 minutes

100 ml

4 mg / 1 hour

500 ml

<30

2 mg / 1 hour

500 ml

1 Administration every 3 to 4 week

2 0.9% sodium chloride solution or 5% glucose solution

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

Elderly

No dose adjustment is required.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

Method of administration

For intravenous administration.

For single use only. Only clear solution without particles should be used.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

- Hypocalcaemia

4.4 Special Warnings And Precautions For Use

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, Bondronat has been administered concomitantly with commonly used antineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation.

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Treatment of tumour induced hypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Table 1 Adverse Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Bondronat

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Immune system disorders

       

Hypersensitivity

Metabolism and nutritional disorders

 

Hypocalcaemia**

     

Respiratory, thoracic, and mediastinal disorders

       

Bronchospasm

Skin and subcutaneous tissue disorders

       

Angioneurotic oedema

Musculoskeletal and connective tissue disorders

 

Bone pain

Myalgia

   

General disorders and administration site conditions

Pyrexia

 

Influenza-like illness**, rigors

   

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose.

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from postmarketing experience.

Table 2 Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

 

Infection

Cystitis, vaginitis, oral candidiasis

   

Neoplasms benign, malignant, and unspecified

   

Benign skin neoplasm

   

Blood and lymphatic system disorders

   

Anaemia, blood dyscrasia

   

Endocrine disorders

 

Parathyroid disorder

     

Metabolism and nutrition disorders

   

Hypophosphataemia

   

Psychiatric disorders

   

Sleep disorder, anxiety, affection lability

   

Nervous system disorders

 

Headache, dizziness, dysgeusia (taste perversion)

Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

   

Eye disorders

 

Cataract

 

Ocular inflammation†**

 

Ear and labyrinth disorders

   

Deafness

   

Cardiac disorders

 

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

   

Respiratory, thoracic, and mediastinal disorders

 

Pharyngitis

Lung oedema, stridor

   

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

   

Hepatobiliary disorders

   

Cholelithiasis

   

Skin and subcutatneous tissue disorders

 

Skin disorder, ecchymosis

Rash, alopecia

   

Musculoskeletal and connective tissue disorders

 

Osteoarthritis, myalgia, arthralgia, joint disorder

 

Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)

Osteonecrosis of jaw†**

Renal and urinary disorders

   

Urinary retention, renal cyst

   

Reproductive system and breast disorders

   

Pelvic pain

   

General disorders and administration site conditions

 

Influenza-like illness, oedema peripheral, asthenia, thirst

Hypothermia

   

Investigations

 

Gamma-GT increased, creatinine increased

Blood alkaline phosphatase increase, weight decrease

   

Injury, poisoning and procedural complications

   

Injury, injection site pain

   

**See further information below.

†Identified in postmarketing experience.

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

4.9 Overdose

Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical studies with high doses, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by intravenous administration of calcium gluconate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Drugs for treatment of bone diseases, bisphosphonate, ATC Code: M05BA06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in the treatment of tumour-induced hypercalcaemia

Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.

In the dose range recommended for treatment, the following response rates with the respective confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected serum calcium

For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 days.

Clinical studies in the prevention of skeletal events in patients with breast cancer and bone metastases

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg administered intravenously was assessed in one randomized placebo controlled phase III trial with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The results from this trial are summarised below.

Primary efficacy endpoints

The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures.

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results are summarised in Table 3.

Table 3 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

 

All Skeletal Related Events (SREs)

   

Placebo

n=158

Bondronat 6 mg

n=154

p-value

 

SMPR (per patient year)

1.48

1.19

p=0.004

Number of events (per patient)

3.64

2.65

p=0.025

SRE relative risk

-

0.60

p=0.003

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Bondronat treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 4.

Table 4 Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)

 

Placebo

n=158

Bondronat 6 mg

n=154

p-value

Bone pain *

0.21

-0.28

p<0.001

Analgesic use *

0.90

0.51

p=0.083

Quality of Life *

-45.4

-10.3

p=0.004

* Mean change from baseline to last assessment.

There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of <50ml/min.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

5.2 Pharmacokinetic Properties

After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose proportional.

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.

Biotransformation

There is no evidence that ibandronic acid is metabolized in animals or humans.

Elimination

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in special populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. For patients with mild renal impairment (CLcr

Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor that should be considered (see renal impairment section).

Paediatric population

There are no data on the use of Bondronat in patients less than 18 years old.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drug (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Acetic acid (99%)

Sodium acetate



1. Name Of The Medicinal Product

Becodisks 200 Micrograms

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate 200micrograms

3. Pharmaceutical Form

Dry Powder for Inhalation via Diskhaler Device

4. Clinical Particulars 4.1 Therapeutic Indications

Clinical Indications

Beclometasone dipropionate provides effective anti-inflammatory action in the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically. It also offers preventive treatment of asthma.

Becodisks are indicated for the following:

Adults

Prophylactic management in:

Mild asthma (PEF values greater than 80% predicted at baseline with less than 20% variability):

Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.

Moderate asthma (PEF values 60-80% predicted at baseline with 20-30% variability):

Patients requiring regular asthma medication and patients with unstable or worsening asthma on other prophylactic therapy or bronchodilator alone.

Severe asthma (PEF values less than 60% predicted at baseline with greater than 30% variability):

Patients with severe chronic asthma. On transfer to high dose inhaled beclometasone dipropionate, many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or eliminate their requirement for oral corticosteroids.

4.2 Posology And Method Of Administration

Becodisks are for administration by the inhalation route only using a Diskhaler device.

Patients should be made aware of the prophylactic nature of therapy with inhaled beclometasone dipropionate and that it should be taken regularly everyday even when they are asymptomatic.

Patients should be given a starting dose of inhaled beclometasone dipropionate which is appropriate for severity of their disease. The dose may then be adjusted until control is achieved and should be titrated to the lowest dose at which effective control of asthma is maintained.

Adults

400 microgram twice daily is the usual starting dose. One 400 microgram blister or two 200 micrograms blisters twice daily is the usual maintenance dose. Alternatively, 200 micrograms may be administered three or four times daily.

Children

100 micrograms two, three or four times a day, according to the response. Alternatively, the usual starting dose of 200 micrograms twice daily may be administered.

Special Patient Groups

There is no need to adjust the dose in elderly patients or in those with hepatic or renal impairment.

4.3 Contraindications

Hypersensitivity to Becodisks or any of its compnents is a contraindication. (See Pharmaceutical Particulars – List of Excipients).

Special care is necessary in patients with active or quiescent pulmonary tuberculosis.

4.4 Special Warnings And Precautions For Use

Patients should be instructed in the proper use of the Diskhaler to ensure that the drug reaches the target areas within the lungs. They should be made aware that Becodisks have to be used regularly everyday for optimum benefit. Patients should be made aware of the prophylactic nature of therapy with Becodisks and that they should be used regularly, even when they are asymptomatic.

Becodisks are not designed to relieve acute asthmatic symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment including lung function testing as patients are at risk of severe attacks and even death.

Increasing use of bronchodilators, in particular short-acting inhaled beta2 agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.

In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. Higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important therefore that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled beclometasone dipropionate and, if necessary, by giving a systemic steroid and/or antibiotic if there is an infection, and by use of beta-agonist therapy.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to Becodisks and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with the Diskhaler and withdrawal of systemic steroid continued, unless there are objective signs of adrenal insufficiency.

Patients weaned off oral steroids whose adrenocortical function is impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. Worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

Treatment with Becodisks should not be stopped abruptly.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions have been reported

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. 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. It should be noted, however, that the foetal changes in animals occur after relatively high systemic exposure. Because beclometasone dipropionate is delivered directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. It should be noted that the drug has been in widespread use for many years without apparent ill consequence.

No specific studies examining the transference of beclometasone dipropionate into the milk of lactating animals have been performed. It is reasonable to assume that beclometasone dipropionate is secreted in milk but at the dosages used for direct inhalation, there is low potential for significant levels in breast milk. The use of beclometasone dipropionate in mothers breast feeding their babies requires that the therapeutic benefits of the drug be weighed against the potential hazards to the mother and baby.

4.7 Effects On Ability To Drive And Use Machines

No adverse effect has been reported.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

System Organ Class

Adverse Event

Frequency

Infections & Infestations

Candidiasis of the mouth and throat.

Very Common

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

 

Rashes, urticaria, pruritis, erythema.

Uncommon

 

Oedema of the eyes, face, lips and throat

Very Rare

 

Respiratory symptoms (dyspnoea and/or bronchospasm)

Very Rare

 

Anaphylactoid/anaphylactic reactions

Very Rare

 

Endocrine Disorders

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma

Very Rare

Psychiatric Disorders

Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)

Very Rare

Depression, aggression (predominantly in children)

Not known

 

Respiratory, Thoracic & Mediastinal Disorders

Hoarseness/throat irritation

Common

Paradoxical bronchospasm

Very Rare

 

Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence of which is increased with doses greater than 400 micrograms beclometasone dipropionate per day. Patients with high blood levels of Candida precipitins, indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse out their mouth with water after using the Diskhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with beclometasone dipropionate treatment.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see 4.4 Special Warnings and Precautions for Use).

In some patients inhaled beclometasone dipropionate may cause hoarseness or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. The beclometasone dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

4.9 Overdose

Acute - inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate emergency action being taken. In these patients treatment with beclometasone dipropionate by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Chronic - use of inhaled beclometasone dipropionate in daily doses in excess of 1500 micrograms over prolonged periods may lead to adrenal suppression. Monitoring of adrenal reserve may be indicated. Treatment with inhaled beclometasone dipropionate should be continued at a dose sufficient to control asthma.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

BDP is a pro-drug with weak glucocorticoid receptor binding activity. It is hydrolysed via esterase enzymes to the active metabolite beclometasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption

When administered via inhalation (via metered dose inhaler) there is extensive conversion of BDP to the active metabolite B-17-MP within the lungs prior to systemic absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. When administered orally, in healthy male volunteers, the bioavailability of BDP is negligible but pre-systemic conversion to B-17-MP results in 41% (95% CI 27- 62 %) of the dose being available as B-17-MP.

Metabolism

BDP is cleared very rapidly from the systemic circulation, owing to extensive first pass metabolism. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone-21-monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to systemic exposure.

Distribution

The tissue distribution at steady state for BDP is moderate (20L) but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%).

Elimination

The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 120L/h) with corresponding terminal elimination half lives of 0.5h and 2.7h. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.

5.3 Preclinical Safety Data

No clinically relevant findings were observed in preclinical studies.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose(which contains milk protein)

6.2 Incompatibilities

No incompatibilities have been reported.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 30?C.

6.5 Nature And Contents Of Container

Circular double foil blister pack consisting of:

A) Lidding material (i) polyester over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 39.4 - 48.6microns or (ii) nitrocellulose over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 37.0 - 42.0microns.

B) Blister material - pvc film/aluminium foil/orientated polyamide.

Becodisks are supplied as 8 blisters per Becodisk as follows:

-Carton containing 14 disks plus a Diskhaler

-Carton containing 15 disks plus a Diskhaler

-Carton containing 5 disks plus a Diskhaler (Hospital pack)

-Refill packs of 14 disks

-Refill packs of 15 disks

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

See Patient Information Leaflet

Administrative Data 7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd.

Trading as Allen & Hanburys,

Stockley Park West,

Uxbridge

Middlesex,

UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0056

9. Date Of First Authorisation/Renewal Of The Authorisation

27 September 1993/11 December 1997

10. Date Of Revision Of The Text

23 August 2011

11. Legal Status

POM



1. Name Of The Medicinal Product

Epsom Salts (Magnesium Sulphate BP)

Boots Epsom Salts B.P.

2. Qualitative And Quantitative Composition

Magnesium Sulphate 100%

3. Pharmaceutical Form

Powder for oral solution

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic relief of occasional constipation.

4.2 Posology And Method Of Administration

Adults and children over 12 years: 1 to 4g to be taken in warm water, once daily.

Children under 12 years. Not recommended.

4.3 Contraindications

Intestinal obstruction.

4.4 Special Warnings And Precautions For Use

To be used with caution in elderly or debilitated patients and in those with renal insufficiency.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

This product may interact with tetracyclines, digoxin, vitamins and iron and may potentiate tubocurarine during anaesthesia.

4.6 Pregnancy And Lactation

The use of magnesium containing salts in the first trimester of pregnancy should be avoided.

They should only be used after medical advice if the benefits exceed potentially unknown risks of foetal exposure to magnesium. No adverse effects are anticipated in breast fed infants.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Prolonged excessive use of this product may cause alkalosis and hypermagnesaemia.

4.9 Overdose

Excessive amounts of this medicine may cause diarrhoea and dehydration. Hypermagnesaemia and hypercalcaemia may also occur, particularly if there is impaired renal function. Treatment consists of supportive and symptomatic measures with appropriate correction of fluid and electrolyte balance.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Not applicable.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Never undertaken by Abdine Limited. This product was granted a 'Licence as of Right' some 25 years ago.

6. Pharmaceutical Particulars 6.1 List Of Excipients

None.

6.2 Incompatibilities

None are recognised.

6.3 Shelf Life

As packaged for sale: Three years

As reconstituted for use: One day

After first opening the container: One month

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

A spirally wound, varnished, cardboard tub with a press-fit lid or polypropylene jar and cap containing 100g, 150g, 200g, 250g, 300g or 500g.

6.6 Special Precautions For Disposal And Other Handling

Take from 1 to 4g in warm water.

7. Marketing Authorisation Holder

Bell Sons & Co (Druggists) Ltd

Gifford House

Slaidburn Crescent

Southport

Merseyside PR9 9AL

8. Marketing Authorisation Number(S)

PL 03105/0068

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 1999

10. Date Of Revision Of The Text

29th November 2010

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)



1. Name Of The Medicinal Product

Brolene Eye Drops.

2. Qualitative And Quantitative Composition

Propamidine isetionate 0.1% w/v.

3. Pharmaceutical Form

Eye drops.

4. Clinical Particulars 4.1 Therapeutic Indications

Propamidine isetionate is an aromatic diamidine disinfectant which is active against Gram-positive non-spore forming organisms, but less active against Gram-negative bacteria and spore forming organisms. It also has antifungal properties. It may be used topically for the treatment of minor eye infections such as conjunctivitis and blepharitis.

4.2 Posology And Method Of Administration

One or two drops up to four times daily. Medical advice should be obtained if there has been no significant improvement after two days.

4.3 Contraindications

Hypersensitivity to propamidine or any other component of the preparation.

4.4 Special Warnings And Precautions For Use

If vision is disturbed or symptoms become worse during therapy, discontinue use and consult a physician.

If there is no significant improvement after two days' therapy, discontinue use and consult a physician.

The eye drops are unsuitable for use with hard or soft contact lenses.

The drops should be discarded 28 days after first opening for domiciliary use or, when used under hospital conditions, seven days after first opening.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Safety of use in pregnancy and lactation has not been established. Use during pregnancy and lactation only if considered essential by a physician.

4.7 Effects On Ability To Drive And Use Machines

May cause blurring of vision on instillation. Patients should not drive or operate hazardous machinery unless vision is clear.

4.8 Undesirable Effects

Hypersensitivity may occur.

Eye pain or irritation, usually in the form of a stinging or burning sensation, may also occur. In such cases, use should be discontinued immediately and a physician should be consulted.

4.9 Overdose

Topical overdosage not applicable. Oral ingestion of a full 10ml bottle is unlikely to cause any toxic effects.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Propamidine is a member of the aromatic diamidine group of compounds which possess bacteriostatic properties against a wide range of organisms. These diamidines exert antibacterial action against pyrogenic cocci, antibiotic resistant staphylococci and some Gram-negative bacilli, the activity of the diamidines being retained in the presence of organic matter such as tissue fluids, pus and serum.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Ammonium chloride, Sodium chloride, Benzalkonium chloride, Sodium hydroxide, Water for injections.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months

Once opened the drops should be discarded 28 days after first opening for domiciliary use or, when used under hospital conditions, 7 days after first opening.

6.4 Special Precautions For Storage

Store below 25oC.

6.5 Nature And Contents Of Container

10 ml plastic dropper bottle and tamper-proof cap.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

8. Marketing Authorisation Number(S)

PL 04425/0197

9. Date Of First Authorisation/Renewal Of The Authorisation

07 November 2002

10. Date Of Revision Of The Text

12 April 2010

LEGAL CLASSIFICATION

P



Definition of Behcet's Disease:

Behcet's disease is a rare, chronic inflammatory disorder. The cause of Behcet's disease is unknown, although there have been reports of a virus found in some individuals with the disease. Behcet's disease generally begins when individuals are in their 20s or 30s, although it can happen at any age. It tends to occur more often in men than in women. Symptoms of Behcet's disease include recurrent ulcers in the mouth (resembling canker sores) and on the genitals, and eye inflammation. The disorder may also cause various types of skin lesions, arthritis, bowel inflammation, meningitis (inflammation of the membranes of the brain and spinal cord), and cranial nerve palsies. Behcet's is a multi-system disease; it may involve all organs and affect the central nervous system, causing memory loss and impaired speech, balance, and movement.

The effects of the disease may include blindness, stroke, swelling of the spinal cord, and intestinal complications. The disease is common in Japan, Turkey and Israel, and less common in the United States.

Drugs associated with Behcet's Disease

The following drugs and medications are in some way related to, or used in the treatment of Behcet's Disease. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Learn more about Behcet's Disease

Harvard Health Guide:

Symptoms and treatment for Behcet's Disease



Boots Lip and Cold Sore Cream

Relieves cracked lips and cold sores

5 g

Read all of this carton for full instructions.

What this medicine is for

An antibacterial and protective cream for cracked lips and cold sores.

You can use this medicine if you are pregnant or breastfeeding.

How to use this medicine

Adults and children: Use a very small amount on the affected area every hour, when you need to.

Apply to the skin only.

Do not use more than the amount recommended above.

If symptoms do not go away talk to your doctor.

If anyone accidentally swallows some: Talk to a doctor.

Possible side effects

Cetostearyl alcohol may cause skin reactions (e.g. contact dermatitis).

If this becomes severe, or you notice any side effect, please tell your pharmacist or doctor.

How to store this medicine

Store below 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredients

This cream contains Cetrimide 0.5% w/w, Chlorocresol 0.1% w/w, Dimeticone 9% w/w, Urea 1% w/w.

Also contains: deionised water, liquid paraffin, cetostearyl alcohol.

PL 30306/0028

Text prepared 8/07

Manufactured for The Boots Company PLC Nottingham NG2 3AA

by

CCS Clean Chemicals Sweden AB Borl?nge SE 78173 Sweden Marketing Authorisation held by Actavis Group PTC ehf Reykjv?kurvegi 76 – 78 220 Hafnarfjorur Iceland

If you need more advice ask your pharmacist .

2787bXPil



1. Name Of The Medicinal Product

Superdrug Dual Action Diarrhoea Relief

Galpharm Dual Action Diarrhoea Relief

Diocalm Complete

Numark Diarrhoea and Dehydration Relief

Asda Dual Action Diarrhoea Relief

Tesco Dual Action Diarrhoea Relief

Boots Dual Action Diarrhoea Relief

Asda Rehydration Sachets and Anti-Diarrhoea Capsules

2. Qualitative And Quantitative Composition

The sachets contain: Glucose Monohydrate 3.58g

Sodium Chloride 0.47g

Potassium Chloride 0.30g

Sodium Citrate 0.39g

Citric Acid Anhydrous 0.128g

The capsules contain Loperamide Hydrochloride 2mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Powder for oral solution.

A white free-flowing powder mix.

Capsules, hard.

Capsules with blue cap and grey body containing a white to slightly yellow powder.

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic treatment of acute diarrhoea and replacement of associated fluid and electrolyte loss.

4.2 Posology And Method Of Administration

Adults, the elderly and children over 12 years: After the first loose motion, take two capsules followed by the contents of one or two sachets. Then after each subsequent loose motion take one capsule and a further one or two sachets. Do not take more than 6 capsules in 24 hours. Further doses of sachets can be taken after each loose motion, up to a maximum of 16 sachets in 24 hours if necessary.

Not recommended for children under 12 years of age.

Reconstitution of sachets

Reconstitute only with water and ensure the correct amount is used.

The contents of each sachet should be dissolved in 200ml (7 fluid ounces) of fresh drinking water (adults and children). Freshly boiled and cooled water should be used for infants and when fresh water is not available. The solution should be made up immediately before use and used within one hour. If refrigerated the solution may be kept for up to 24 hours.

4.3 Contraindications

The sachets are contraindicated in patients with phenylketonuria or those with hypersensitivity to any of the ingredients.

The capsules are contraindicated in patients with acute ulcerative colitis or pseudomembranous colitis, in those with abdominal distension and where ileus and constipation are present and in children under 12 years of age.

4.4 Special Warnings And Precautions For Use

Sachets: Medical supervision is necessary in the presence of renal disease, including anuria or prolonged oliguria, severe and persistent diarrhoea and vomiting, or inability to drink or retain oral fluids.

Capsules: Should be used with care in patients with severe hepatic disease.

Use should not exceed 24 hours unless advised by a doctor. A doctor should be consulted if diarrhoea is still present after 24 hours treatment. Further investigation into the cause of diarrhoea should be considered if there is no improvement within 2 days of starting treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

The combination product should not be used during pregnancy since loperamide is best avoided during pregnancy. It should be used with caution in lactating women as a small amount of loperamide is excreted in breast milk.

No safety studies on the teratogenicity of loperamide in human pregnancy have been conducted, although studies in animals have not demonstrated any teratogenic effects

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

None known to occur with the sachets. The following effects have been reported occasionally with the capsules: abdominal pain, dry mouth, dizziness, tiredness and hypersensitivity reactions including skin rashes.

4.9 Overdose

Sachets

If significant overdosage occurs, serum electrolytes should be evaluated. Corrective measures should be carried out and levels monitored until a return to normal levels is achieved.

Capsules

Overdosage of loperamide may result in constipation, paralytic ileus and central nervous depression. Gastric lavage and activated charcoal may be used in the management and if intoxication is suspected naloxone may be given as an antidote.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Rehydration sachets consist of physiological salts and glucose which are used synergistically in solution to aid rehydration. The pharmacodynamic effect is to counter the drop in the extracellular fluid volume and electrolytes in mild to moderate diarrhoea.

Loperamide is an anti-diarrhoeal agent, it inhibits peristalsis and gastro-intestinal secretions. Clinical trials undertaken in patients with acute diarrhoea have demonstrated that following a single 4 mg dose of loperamide, onset of anti-diarrhoeal action was achieved within 1 hour. Comparisons with other anti-diarrhoeal drugs have confirmed the exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic Properties

Following partial absorption in the gastro-intestinal tract, loperamide undergoes considerable first-pass metabolism in the liver and is excreted predominantly in the faeces. The elimination half-life is reported to be about 10 hours.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients Sachets: Colloidal Anhydrous Silica   Aspartame (which contains Phenylalanine)   Blackcurrant flavourings. Capsules: Lactose Monohydrate   Maize Starch   Talc   Magnesium Stearate. Capsule Shell is comprised of: Gelatin   Quinoline Yellow (E104)   Erythrosine (E127)   Patent Blue (E131)   Titanium Dioxide (E171). 6.2 Incompatibilities

None stated.

6.3 Shelf Life

Shelf life of product as packaged for sale:

2 years.

Shelf life after reconstitution according to direction:

The reconstituted solution of sachets should be discarded after 1 hour or 24 hours if stored within a refrigerator.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

Reconstituted solution: Can be stored for up to 1 hour at normal room temperature or for up to 24 hours if stored within a refrigerator.

6.5 Nature And Contents Of Container

Single dose foil laminate sachets and an aluminium/PVC blister strip or aluminium / PVC / PVdC blister strip enclosed in an outer carton.

GSL Packs contain 6 sachets and 6 capsules.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Galpharm Healthcare Limited

Hugh House

Upper Cliffe Road

Dodworth Business Park

Dodworth

Barnsley

South Yorkshire

S75 3SP

8. Marketing Authorisation Number(S)

PL 16028/0042

9. Date Of First Authorisation/Renewal Of The Authorisation

12 September 2002 / 20 February 2009

10. Date Of Revision Of The Text

February 2009 (Change to Section 9)



Boots Catarrh Pastilles

(Eucalyptus Oil, Menthol, Pumilio Pine Oil)

relieves catarrh, coughs and colds

45 g

Read all of this carton for full instructions.

What this medicine is for

This medicine contains menthol, eucalyptus and pumilio oils, which relieve chesty coughs and have antiseptic properties. It can be used to relieve the symptoms of congestion caused by catarrh, coughs and colds.

Before you take this medicine Do not take: If you are allergic to any of the ingredients If you have an intolerance to some sugars, unless your doctor tells you to (this medicine contains glucose and sucrose) Talk to your pharmacist or doctor: If you are pregnant or breastfeeding

Information about some of the ingredients: Each pastille contains a total of 0.8 g of glucose and sucrose. This should be taken into account by people with diabetes. The colour E122 in this medicine may cause allergic reactions.

How to take this medicine

Check the inner bag is not broken before use. If it is, do not use the pastilles.

Adults and children of 12 years and over: Suck one pastille when you need to.

Don’t take more than 20 pastilles in 24 hours.

Suck each pastille slowly until it dissolves.

Do not give to children under 12 years.

Do not take more than the amount recommended.

If symptoms do not go away, talk to your doctor.

If you take too many pastilles: Talk to a pharmacist or doctor straight away.

Possible side effects

Most people will not have problems, but some may get some.

If you get any of these serious side effects, stop taking the pastilles. See a doctor at once:

Difficulty in breathing, swelling of the face, neck, tongue or throat (severe allergic reactions)

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredients

Each pastille contains Eucalyptus Oil 0.02% v/w, Menthol 0.8% w/w, Pumilio Pine Oil 0.6% v/w.

Also contains: modified starch, sucrose, glucose syrup, marshmallow liquid extract, vegetable oil, beeswax, water, thymol, carmoisine (E122).

PL 00094/0009

Text prepared 8/09

Manufactured for

The Boots Company PLC Nottingham NG2 3AA

by The Marketing Authorisation holder

Ernest Jackson and Co Crediton Devon EX17 3AP

If you need more advice ask your pharmacist.



Buscopan Ampoules

20 mg/ml Solution

for Injection

(hyoscine butylbromide)

Read all of this leaflet carefully before you start taking this medicine Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What BUSCOPAN Ampoules are and what they are used for 2. Before you receive BUSCOPAN Ampoules 3. How BUSCOPAN Ampoules will be given 4. Possible side effects 5. How to store BUSCOPAN Ampoules 6. Further information What Buscopan Ampoules Are And What They Are Used For

The name of your medicine is BUSCOPAN Ampoules 20 mg/ml Solution for injection (called BUSCOPAN Ampoules in this leaflet).

BUSCOPAN Ampoules contain a medicine called ‘hyoscine butylbromide’. This belongs to a group of medicines called ‘antispasmodics’.

BUSCOPAN Ampoules are used to relieve cramps in the muscles of your:

Stomach Gut (intestine) Bladder and the tubes leading to the outside of your body (urinary system)

BUSCOPAN Ampoules can also be used in some diagnostic and therapeutic medical procedures where spasm may be a problem for example barium enema.

Before You Receive Buscopan Ampoules You should not be given BUSCOPAN Ampoules if: You are allergic (hypersensitive) to hyoscine butylbromide or any of the other ingredients (listed in Section 6) You have glaucoma (an eye problem) You have megacolon (a very enlarged bowel) You have something called ‘myasthenia gravis’ (a very rare muscle weakness problem) You have a very fast heart rate You have difficulty or pain passing water (urine) such as men with prostate problems You have gut blockage problems or a totally inactive gut You are pregnant, likely to get pregnant or are breast-feeding

You should not receive this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine.

Take special care with BUSCOPAN Ampoules

Check with your doctor or pharmacist before having this medicine if:

You have any heart problems You have a fever You have problems with your thyroid gland such as an overactive thyroid gland

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before receiving BUSCOPAN Ampoules.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because BUSCOPAN Ampoules can affect the way some other medicines work. Also some other medicines can affect the way BUSCOPAN Ampoules work.

In particular tell your doctor or pharmacist if you are taking any of the following:

Medicines for depression called ‘tricyclic antidepressants’ such as doxepin Medicines for allergies and travel sickness called ‘antihistamines’ Medicines to control your heart beat such as quinidine or disopyramide Medicines for severe mental illness such as haloperidol or fluphenazine Medicines for breathing problems such as salbutamol, ipratropium or tiotropium Amantadine - for Parkinson’s disease and flu Metoclopramide - for feeling sick (nausea)

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before receiving BUSCOPAN Ampoules.

Pregnancy and breast-feeding

You should not be given BUSCOPAN Ampoules if you are pregnant, likely to get pregnant or are breast-feeding.

Driving and using machines

Some people may have sight problems while taking this medicine. If this happens to you, wait until your sight returns to normal before driving or using any tools or machines.

Important information about some of the ingredients of BUSCOPAN Ampoules

BUSCOPAN Ampoules contain sodium chloride. The amount of sodium in a 1 ml ampoule is less than 1 mmol (23 mg), the total amount of sodium if you are given five ampoules in 24 hours is less than 1mmol (23 mg) this means that your medicine is essentially sodium free.

How Buscopan Ampoules Will Be Given

BUSCOPAN Ampoules are usually given by a doctor or nurse.

Receiving the injection

BUSCOPAN Ampoules may be given in two ways:

By being slowly injected into a vein By an injection into a muscle BUSCOPAN Ampoules may be diluted with other solutions if needed How much will you be given You will usually be given one ampoule, but you may be given a further ampoule after half an hour if required If you are being given BUSCOPAN Ampoules as part of an endoscopy your dose may need to be given more often You should not be given more than 5 ampoules in any 24-hour period

BUSCOPAN Ampoules are not recommended for children.

If you have more BUSCOPAN Ampoules than you should

It is unlikely that you will be given too much of this medicine. However, tell the doctor or nurse if you think that you have been given too much.

Buscopan Ampoules Side Effects

Like all medicines, BUSCOPAN Ampoules can cause side effects although not everybody gets them. The following side effects may happen with this medicine.

Stop taking your medicine and see a doctor straight away, if you notice any of the following serious side effects - you may need urgent medical treatment: Allergic reactions such as skin rash and itching Severe allergic reactions (anaphylaxis) such as difficulty breathing, feeling faint or dizzy (shock) Painful red eye with loss of vision Other side effects Dry mouth Dizziness Blurred vision Making less sweat than usual Increased heart rate Constipation Small blisters on hands and feet Being unable to pass water (urine) Low blood pressure, for example feeling faint Flushing

Pain at the place you had the injection may occur if you have been given BUSCOPAN Ampoules into a muscle.

Although unlikely, in certain circumstances it may be possible that BUSCOPAN may pass into the brain and cause side effects, for example confusion.

If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in this leaflet, tell your doctor or pharmacist.

How To Store Buscopan Ampoules Keep out of the reach and sight of children Store below 30°C, keep the ampoules in the outer carton in order to protect from light BUSCOPAN Ampoules should not be used after the expiry date which is printed on the carton and ampoules. The expiry date refers to the last day of that month

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

Further Information What BUSCOPAN Ampoules contain

Each ampoule contains 20 mg of the active ingredient hyoscine butylbromide. The other ingredients are sodium chloride and water for injections.

What BUSCOPAN Ampoules looks like and contents of the pack

BUSCOPAN Ampoules are clear glass ampoules containing a colourless or almost colourless, clear solution. BUSCOPAN Ampoules are supplied in cartons containing 10 x 1 ml ampoules.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisations are held by:

Boehringer Ingelheim Limited Ellesfield Avenue Bracknell Berkshire RG12 8YS United Kingdom

and the ampoules are manufactured at:

Boehringer Ingelheim Spain Tur? de can Matas Ctra. De. Rubi San Cugat del Valles Barcelona Spain

This leaflet was revised in April 2008.

© Boehringer Ingelheim Limited 2008

20080218

22C911



Address Bristol-Myers Squibb Company ,



1. Name Of The Medicinal Product

BuTrans 5 ?g/h, 10 ?g/h and 20 ?g/h transdermal patch

2. Qualitative And Quantitative Composition

5 ?g/h transdermal patch contains:

5 mg buprenorphine.

Area containing active substance: 6.25 cm2.

Nominal release rate: 5 micrograms of buprenorphine per hour (over a period of 7 days).

10 ?g/h transdermal patch contains:

10 mg buprenorphine.

Area containing active substance: 12.5 cm2.

Nominal release rate: 10 micrograms of buprenorphine per hour (over a period of 7 days).

20 ?g/h transdermal patch contains:

20 mg buprenorphine.

Area containing active substance: 25 cm2.

Nominal release rate: 20 micrograms of buprenorphine per hour (over a period of 7 days).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Transdermal patch.

Beige coloured patch with rounded corners

Square patch marked BuTrans 5 ?g/h

Rectangular patch marked BuTrans, 10 ?g/h

Square patch marked : BuTrans 20 ?g/h

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of non-malignant pain of moderate intensity when an opioid is necessary for obtaining adequate analgesia.

BuTrans is not suitable for the treatment of acute pain.

4.2 Posology And Method Of Administration

BuTrans should be administered every 7th day.

Patients aged 18 years and over:

The lowest BuTrans dose (BuTrans 5 ?g/h transdermal patch) should be used as the initial dose. Consideration should be given to the previous opioid history of the patient (see section 4.5) as well as to the current general condition and medical status of the patient.

Titration:

During initiation and titration with BuTrans, patients should use the usual recommended doses of short-acting supplemental analgesics (see section 4.5) as needed until analgesic efficacy with BuTrans is attained.

The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage increases may then be titrated based on the need for supplemental pain relief and the patient's analgesic response to the patch.

To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no more than two patches are applied at the same time, regardless of the patch strength. A new patch should not be applied to the same skin site for the subsequent 3-4 weeks (see section 5.2). Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment.

Conversion from opioids:

BuTrans can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (BuTrans 5 ?g/h transdermal patch) and continue taking short-acting supplemental analgesics (see section 4.5) during titration, as required.

Patients under 18 years of age:

As BuTrans has not been studied in patients under 18 years of age the use of BuTrans in patients below this age is not recommended.

Elderly:

No dosage adjustment of BuTrans is required in elderly patients.

Renal impairment:

No special dose adjustment of BuTrans is necessary in patients with renal impairment.

Hepatic impairment:

Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with hepatic insufficiency should be carefully monitored during treatment with BuTrans.

Patients with severe hepatic impairment may accumulate buprenorphine during BuTrans treatment. Consideration of alternate therapy should be considered, and BuTrans should be used with caution, if at all, in such patients.

Patch application:

BuTrans should be applied to non-irritated, intact skin of the upper outer arm, upper chest, upper back or the side of the chest, but not to any parts of the skin with large scars. BuTrans should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be cut with scissors, not shaven.

If the application site must be cleaned, it should be done with clean water only. Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin must be dry before the patch is applied. BuTrans should be applied immediately after removal from the sealed sachet. Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape.

The patch should be worn continuously for 7 days.

Bathing, showering, or swimming should not affect the patch. If a patch falls off, a new one should be applied.

Duration of administration:

BuTrans should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with BuTrans is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

Discontinuation:

After removal of the patch, buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with BuTrans is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of the patch. At present, only limited information is available on the starting dose of other opioids administered after discontinuation of the transdermal patch (see section 4.5).

Patients with fever or exposed to external heat:

While wearing the patch, patients should be advised to avoid exposing the application site to external heat sources, such as heating pads, electric blankets, heat lamps, sauna, hot tubs, and heated water beds, etc., as an increase in absorption of buprenorphine may occur. When treating febrile patients, one should be aware that fever may also increase absorption resulting in increased plasma concentrations of buprenorphine and thereby increased risk of opioid reactions.

4.3 Contraindications

BuTrans is contra-indicated in:

- patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients (see section 6.1)

- opioid dependent patients and for narcotic withdrawal treatment

- conditions in which the respiratory centre and function are severely impaired or may become so

- patients who are receiving MAO inhibitors or have taken them within the last two weeks (see section 4.5)

- patients suffering from myasthenia gravis

- patients suffering from delirium tremens.

4.4 Special Warnings And Precautions For Use

BuTrans should be used with particular caution in patients with convulsive disorders, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment (see section 4.2).

Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of overdose deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additional overdose deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported.

BuTrans is not recommended for analgesia in the immediate post-operative period or in other situations characterised by a narrow therapeutic index or a rapidly varying analgesic requirement.

Controlled human and animal studies indicate that buprenorphine has a lower dependence liability than pure agonist analgesics. In humans limited euphorigenic effects have been observed with buprenorphine. This may result in some abuse of the product and caution should be exercised when prescribing to patients known to have, or suspected of having, a history of drug abuse.

As with all opioids, chronic use of buprenorphine can result in the development of physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks. Withdrawal symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

BuTrans must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks (see section 4.3).

Effect of other active substances on the pharmacokinetics of buprenorphine:

Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent (about 30%) by CYP3A4 . Concomitant treatment with CYP3A4 inhibitors may lead to elevated plasma concentrations with intensified efficacy of buprenorphine.

A drug interaction study with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following BuTrans with ketoconazole as compared to BuTrans alone.

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.

Co-administration of BuTrans and enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to increased clearance which might result in reduced efficacy.

Reductions in hepatic blood flow induced by some general anaesthetics (e.g. halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.

Pharmacodynamic interactions:

BuTrans should be used cautiously with:

Benzodiazepines: This combination can potentiate respiratory depression of central origin, with risk of death (see section 4.4).

Other central nervous system depressants: other opioid derivatives (analgesics and antitussives containing e.g. morphine, dextropropoxyphene, codeine, dextromethorphan or noscapine). Certain antidepressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity.

Buprenorphine is a partial mu-receptor agonist but it is described to function as a pure mu receptor agonist at typical analgesic doses. These doses produce buprenorphine exposures comparable to or greater than those produced by BuTrans 5, 10, and 20 µg/h transdermal patches. In BuTrans clinical studies, where subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to BuTrans, there were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to BuTrans (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no data from the use of BuTrans in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for humans is unknown.

Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last three months of pregnancy may cause a withdrawal syndrome in the neonate.

Therefore BuTrans should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.

Lactation

Studies in rats have shown that buprenorphine may inhibit lactation. Excretion of buprenorphine into the milk in rats has been observed. Data on excretion into human milk are not available. Therefore the use of BuTrans during lactation should be avoided.

4.7 Effects On Ability To Drive And Use Machines

BuTrans has a major influence on the ability to drive and use machines. Even when used according to instructions, BuTrans may affect the patient's reactions to such an extent that road safety and the ability to operate machinery may be impaired. This applies particularly in the beginning of treatment and in conjunction with other centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics. An individual recommendation should be given by the physician. A general restriction is not necessary in cases where a stable dose is used.

In patients who are affected, such as during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hours after the patch has been removed.

4.8 Undesirable Effects

Serious adverse reactions that may be associated with BuTrans therapy in clinical use are similar to those observed with other opioid analgesics, including respiratory depression (especially when used with other CNS depressants) and hypotension (see section 4.4).

The following undesirable effects have occurred:

Very common (

Immune system disorders

 

Uncommon

hypersensitivity

Very rare:

anaphylactic reaction, anaphylactoid reaction

Metabolism and nutrition disorders

 

 

Common:

anorexia

Uncommon:

dehydration

 

 

 

 

Psychiatric disorders

 

Common:

confusion, depression, insomnia, nervousness,

Uncommon:

sleep disorder, restlessness, agitation, depersonalisation,

 

 

euphoric mood, affect lability, anxiety, hallucinations, nightmares

Rare:

psychotic disorder, decreased libido

Very rare:

drug dependence, mood swings

 

 

 

 

Nervous system disorders

 

Very common:

headache, dizziness, somnolence

Common:

paraesthesia

Uncommon:

sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal co-ordination, disturbance in attention

Rare:

balance disorder, speech disorder,

Very rare:

involuntary muscle contractions

 

 

 

 

Eye disorders

 

Uncommon:

dry eye, blurred vision

Rare:

visual disturbance, eyelid oedema, miosis

 

 

 

 

Ear and labyrinth disorders

 

Uncommon:

tinnitus, vertigo

Very rare:

ear pain

 

 

 

 

Cardiac/disorders

 

Uncommon:

angina pectoris, palpitations, tachycardia,

 

 

 

 

Vascular disorders

 

Common:

vasodilatation

Uncommon:

hypotension, circulatory collapse, hypertension, flushing

   

Respiratory, thoracic and mediastinal disorders

 

Common:

dyspnoea

Uncommon:

asthma aggravated, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups

Rare:

respiratory depression, respiratory failure

   

Gastrointestinal disorders

 

Very common:

constipation, dry mouth, nausea, vomiting

Common:

abdominal pain, diarrhoea, dyspepsia

Uncommon:

flatulence

Rare:

diverticulitis, dysphagia, ileus

   

Hepatobiliary disorders

 

Rare:

biliary colic

   

Skin and subcutaneous tissue disorders

     

Very common:

pruritus, erythema

Common:

rash, sweating, exanthema

Uncommon:

dry skin, face oedema, urticaria

Very rare:

pustules, vesicles

   

Musculoskeletal and connective tissue disorders

 

Uncommon:

muscle cramp, myalgia, muscular weakness, muscle spasms

Renal and urinary disorders

 

Uncommon:

urinary retention, micturition disorder

   

Reproductive system and breast disorders

 

Rare:

erectile dysfunction, sexual dysfunction

   

General disorders and administration site conditions

 

Very common:

application site pruritus, application site reaction

Common:

tiredness, asthenia, pain, peripheral oedema, application site erythema, application site rash, chest pain

Uncommon:

fatigue, influenza like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome

Rare:

application site inflammation*

   

Investigations

 

Uncommon:

alanine aminotransferase increased, weight decreased

   

Injury, poisoning and procedural complications

 

Uncommon:

accidental injury, fall

* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with BuTrans should be terminated.

Buprenorphine has a low risk of physical dependence. After discontinuation of BuTrans, withdrawal symptoms are unlikely. This may be due to the very slow dissociation of buprenorphine from the opioid receptors and to the gradual decrease of buprenorphine plasma concentrations (usually over a period of 30 hours after removal of the last patch). However, after long-term use of BuTrans, withdrawal symptoms similar to those occurring during opioid withdrawal, cannot be entirely excluded. These symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.

4.9 Overdose

Symptoms: Symptoms similar to those of other centrally acting analgesics are to be expected. These include respiratory depression, sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis.

Treatment: Remove any patches from the patient's skin. Establish and maintain a patent airway, assist or control respiration as indicated and maintain adequate body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

A specific opioid antagonist such as naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5 to 12 mg intravenously. The onset of the naloxone effect may be delayed by 30 minutes or more. Maintenance of adequate ventilation is more important than treatment with naloxone.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Analgesics, opioids; ATC code: N02 AE01

Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.

Efficacy has been demonstrated in five pivotal phase III studies of up to 12 weeks duration in patients with non-malignant pain of various aetiologies. These included patients with moderate and severe OA and back pain. BuTrans demonstrated clinically significant reductions in pain scores (approximately 3 points on the BS-11 scale) and significantly greater pain control compared with placebo.

A long term, open-label extension study (n=384) has also been performed in patients with non-malignant pain. With chronic dosing, 63% of patients were maintained in pain control for 6 months, 39% of patients for 12 months, 13% of patients for 18 months and 6% for 21 months. Approximately 17% were stabilised on the 5 mg dose, 35% on the 10 mg dose and 48% on the 20 mg dose.

5.2 Pharmacokinetic Properties

There is evidence of enterohepatic recirculation.

Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen – presumably due to biliary excretion, as enterohepatic circulation has not fully developed.

Each patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved during the first application. After removal of BuTrans, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10–24 h).

Absorption:

Following BuTrans application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for “BuTrans 10 ?g/h” to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed. Buprenorphine concentrations remain relatively constant during the 7-day patch application.

Application site:

A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by BuTrans is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26 % higher when applied to the upper back compared to the side of the chest.

In a study of healthy subjects receiving BuTrans repeatedly to the same site, an almost doubled exposure was seen with a 14 day rest period. For this reason, rotation of application sites is recommended, and a new patch should not be applied to the same skin site for 3-4 weeks.

In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26 - 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a BuTrans site immediately after patch removal did not alter absorption from the skin depot.

Distribution:

Buprenorphine is approximately 96% bound to plasma proteins.

Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was

430 l, reflecting the large volume of distribution and lipophilicity of the active substance.

Following intravenous administration, buprenorphine and its metabolites are secreted into bile, and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15% to 25% of concurrent plasma concentrations.

Biotransformation and elimination:

Buprenorphine metabolism in the skin following BuTrans application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 55l/h.

Norbuprenorphine is the only known active metabolite of buprenorphine.

Effect of buprenorphine on the pharmacokinetics of other active substances:

Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of BuTrans 20µg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

5.3 Preclinical Safety Data

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, BuTrans caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. No teratogenic effects were observed in rats or rabbits. However, perinatal mortality was reported in the literature for rats treated with buprenorphine.

A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.

In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.

Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Adhesive matrix (containing buprenorphine):

[(Z)-octadec-9-en-1-yl] (Oleyl oleate),

Povidone K90,

4-oxopentanic acid, (Levulinic Acid)

Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate] (5:15:75:5), cross-linked (DuroTak 387-2054)

Adhesive matrix (without buprenorphine):

Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl) acrylate-co-vinylacetate] (5:15:75:5), not cross-linked (DuroTak 387-2051).

Separating foil between the adhesive matrices with and without buprenorphine: Poly(Ethyleneterephthalate) – foil.

Backing layer:

Poly(Ethyleneterephthalate) – tissue.

Release liner (on the front covering the adhesive matrix containing buprenorphine) (to be removed before applying the patch):

Poly(Ethyleneterephthalate) – foil, siliconised, coated on one side with aluminium.

6.2 Incompatibilities

Not applicable

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

Sealed sachet, composed of identical top and bottom layers of heat-sealable laminate, comprising (from outside to inside) paper, LDPE, aluminium and poly(acrylic acid-co-ethylene).

Pack Sizes:

BuTrans 5 ?g/h: 2 or 4 transdermal patches

BuTrans 10 ?g/h and 20 ?g/h: 4 transdermal patches

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The patch should not be used if the seal is broken.

Disposal after use:

When changing the patch, the used patch should be removed, the adhesive layer folded inwards on itself, and the patch disposed of safely and out of sight and reach of children.

7. Marketing Authorisation Holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

8. Marketing Authorisation Number(S)

PL 16950/0136-0138

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation 10th June 2005

Date of last renewal 27th November 2008

10. Date Of Revision Of The Text

November 2008



Boots Pain Relief heat spray

(Ethyl Nicotinate 1.1% w/w, Methyl Salicylate 1.25% w/w, Racemic Camphor 0.625% w/w)

Effective relief for muscular and rheumatic pain

125 ml e

Read this can for full instructions.

Uses

A warming pain relieving spray for the relief of muscular and rheumatic pain, lumbago, fibrositis, sciatica, sprains, strains and stiffness. No massage necessary.

Before you use this medicine Do not use: If you are allergic to any of the ingredients If you are pregnant or breastfeeding, unless your doctor agrees On broken or damaged skin, or on open cuts On children under 5 years of age How to use

Keep the spray away from the eyes, face, lining of mouth, throat and nose, and other sensitive areas of the body. Do not inhale the spray.

Apply to the skin only.

Hold the can 6 inches (15 cm) away from the skin.

Adults and children of 5 years and over:

Spray the painful area with 2 or 3 short bursts of spray.

Only use a small amount of spray because using too much can irritate the skin.

If the symptoms do not go away, talk to your doctor.

If you accidentally use too much spray it will not usually cause any problems.

Possible side effects

Most people will not have problems.

If you get any of these stop using the spray. If you notice any side effect not listed here, please tell your pharmacist or doctor. Skin irritation Allergic reaction (such as itching or redness of the skin) Active ingredients

This topical spray contains Ethyl Nicotinate 1.1% w/w, Methyl Salicylate 1.25% w/w, Racemic Camphor 0.625% w/w.

Also contains: denatured ethanol, butane, isobutane, propane.

Keep all medicines out of the sight and reach of children.

Use by the date on base of the can.

PL 00014/0275

Text prepared 3/06

Manufactured for the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

by

ColepCCL UK Limited Atkinsons Way Foxhills Industrial Park Scunthorpe North Lincolnshire DN15 8QJ

Caution: Pressurised container. Protect from sunlight.

Do not expose to temperatures above 50°C.

Do not pierce or burn even when empty.

Do not use near, or place on painted or polished surfaces.

EXTREMELY FLAMMABLE

125 ml

175

Э

Do not spray on a naked flame or on incandescent material. Keep away from sources of ignition. No smoking.

If you need more advice ask your pharmacist.

BTC19928 vA 24/07/07



Boots Maximum Strength Cold & Flu Relief Direct Dose Lemon

(Paracetamol, Phenylephrine Hydrochloride)

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to treat minor conditions. However, you still need to take it carefully to get the best results from it.

Keep this leaflet, you may need to read it again Ask your pharmacist if you need more information or advice What this medicine is for

This medicine contains Paracetamol which relieves pain and reduces fever, and Phenylephrine Hydrochloride which can help relieve a blocked up nose.

It can be used to relieve the symptoms of colds and flu including aches and pains, sore throat, headache, nasal congestion and fever.

Before you take this medicine

This medicine can be taken by adults and children aged 12 years and over. However, some people should not take this medicine or should seek the advice of their pharmacist or doctor first.

Do not take: If you are allergic to any of the ingredients If you have heart problems If you have high blood pressure If you have an overactive thyroid If you are taking monoamine oxidase inhibitors (for depression) or have taken them in the last 14 days If you are pregnant or breastfeeding, unless your doctor tells you to Talk to your pharmacist or doctor: If you have Raynaud’s phenomenon (a problem with your circulation which causes cold hands and feet) If you have diabetes If you have severe kidney or liver problems (including alcoholic liver disease) Other important information

Do not drink alcohol (e.g. wine, beer, spirits) whilst taking this medicine.

Information about some of the ingredients in this medicine: Aspartame contains a source of phenylalanine. May be harmful to people with phenylketonuria.

If you take other medicines

This medicine contains paracetamol. Do not take with any other paracetamol-containing products.

Before you take this medicine, make sure that you tell your pharmacist about ANY other medicines you might be using at the same time, particularly the following:

Barbiturates, tricyclic antidepressants Medicines called beta-blockers (e.g. atenolol) for high blood pressure (your blood pressure may increase whilst you are taking this medicine) Sympathomimetic drugs such as other decongestants Vasodilators such as nifedipine (for heart problems) Domperidone or metoclopramide, for nausea and vomiting (may increase the effect of the painkiller in this medicine) Colestyramine, for lowering blood lipid levels (may reduce the effect of the painkiller in this medicine) Warfarin or other coumarins (for thinning the blood) – if you take warfarin you can take occasional doses of this medicine, but talk to your doctor first before you take it on a regular basis.

If you are unsure about interactions with any other medicines, talk to your pharmacist. This includes medicines prescribed by your doctor and medicine you have bought for yourself, including herbal and homeopathic remedies.

How to take this medicine

Check the sachet is not broken before use. If it is, do not take the medicine.

Grip the sachet firmly below the dotted line and tear along the dotted line to open. Empty the contents of the sachet into the mouth and swallow. Water is not required to take this medicine.

Adults and children of 12 years and over



1. Name Of The Medicinal Product

Beconase Hayfever Relief for Adults 0.05% Nasal Spray

2. Qualitative And Quantitative Composition

50 micrograms beclometasone dipropionate per 100 mg actuation.

For excipients, see Section 6.1.

3. Pharmaceutical Form

Nasal spray, suspension.

4. Clinical Particulars 4.1 Therapeutic Indications

Beconase Hayfever Relief for Adults is indicated for the treatment of seasonal allergic rhinitis (hayfever) in adults aged 18 and over.

4.2 Posology And Method Of Administration

Beconase Hayfever Relief for Adults is for administration by the intranasal route only.

Adults aged 18 and over: The recommended dosage is two sprays into each nostril morning and evening (400 micrograms/day). Once control has been established, it may be possible to maintain control with fewer sprays. A dosage regimen of one spray into each nostril morning and evening has been shown to be efficacious in some patients. However, should the symptoms recur, patients should revert to the recommended dosage of two sprays into each nostril morning and evening. The minimum dose should be used at which effective control of symptoms is maintained. Total daily administration should not exceed eight sprays (400 micrograms).

Beconase Hayfever Relief for Adults quickly starts to reduce inflammation and swelling in the nose. For full therapeutic benefit Beconase Hayfever Relief for Adults should be used regularly.

If symptoms have not improved after 7 days treatment, medical advice must be sought.

Beconase Hayfever Relief for Adults is not recommended for children or adolescents under 18 years of age.

4.3 Contraindications

Beconase Hayfever Relief for Adults is contra-indicated in patients with a history of hypersensitivity to any of its components.

4.4 Special Warnings And Precautions For Use

Systemic effects of nasal corticosteroids may occur, particularly at high doses when used for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Treatment with higher than recommended doses may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Medical advice should be sought before using Beconase Hayfever Relief for Adults by patients using other forms of corticosteroid treatments such as asthma medications, tablets, injections, similar nasal sprays, eye or nose drops, creams, ointments.

This product should not be used continuously for longer than 1 month without medical advice.

Infections of the nasal passages and paranasal sinuses should be appropriately treated but do not constitute a specific contra-indication to treatment with Beconase Hayfever Relief for Adults.

Although Beconase Hayfever Relief for Adults will control seasonal allergic rhinitis in most cases, an abnormally heavy challenge of summer allergens may, in certain instances, necessitate appropriate additional therapy particularly to control eye symptoms.

Medical advice should be sought before using Beconase Hayfever Relief for Adults in the case of recent injury or surgery to the nose, or problems with ulceration in the nose.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not applicable.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human fetus. It should be noted, however, that the fetal changes in animals occur after relatively high systemic exposure. Beconase Hayfever Relief for Adults delivers beclometasone dipropionate directly to the nasal mucosa and so minimises systemic exposure.

The use of beclometasone dipropionate should be avoided during pregnancy unless thought essential by the doctor.

Lactation: No specific studies examining the transference of beclometasone dipropionate into the milk of lactating animals have been performed. It is reasonable to assume that beclometasone dipropionate is secreted in milk, but at the dosages used for direct intranasal administration there is low potential for significant levels in breast milk.

Beconase Hayfever Relief for Adults should not be used during lactation without consulting a doctor.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Rare cases of nasal septal perforation have been reported following the use of intranasal corticosteroids.

As with other nasal sprays, dryness and irritation of the nose and throat, unpleasant taste and smell and epistaxis have been reported rarely.

Rare cases of raised intra-ocular pressure, glaucoma or cartaract in association with intranasal formulations of beclometasone dipropionate have been reported.

Very rare cases of hypersensitivity reactions including rashes, urticaria, pruritus and erythema, and oedema of the eyes, face, lips and throat, anaphylactoid / anaphylactic reactions, dyspnoea and/or bronchospasm have been reported.

4.9 Overdose

The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of hypothalamic-pituitary adrenal (HPA) function. No special emergency action need be taken. HPA function recovers in a day or two after discontinuation of treatment with Beconase Hayfever Relief for Adults.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Following topical administration, beclometasone 17,21-dipropionate (BDP) produces potent anti-inflammatory and vasoconstrictor effects.

BDP is a pro-drug with weak corticosteroid receptor binding affinity. It is hydrolysed via esterase enzymes to the highly active metabolite beclometasone -17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.

Beclometasone dipropionate offers a preventative background treatment for hayfever when taken prior to allergen challenge. After which, with regular use, BDP can continue to prevent allergy symptoms from reappearing.

5.2 Pharmacokinetic Properties

Absorption

Following intranasal administration of BDP in healthy males, the systemic absorption was assessed by measuring the plasma concentrations of its active metabolite B-17-MP, for which the absolute bioavailability following intranasal administration is 44% (95% CI 28%, 70%). After intranasal administration, <1% of the dose is absorbed by the nasal mucosa. The remainder, after being cleared from the nose, either by drainage or mucocilary clearance, is available for absorption from the gastrointestinal tract. Plasma B-17-MP is almost entirely due to conversion of BDP absorbed from the swallowed dose.

Following oral administration of BDP the systemic absorption was also assessed by measuring the plasma concentrations of its active metabolite B-17-MP, for which the absolute bioavailability following oral administration is 41% (95% CI 27%, 62%).

Following an oral dose, B-17-MP is absorbed slowly with peak plasma levels reached 3-5 hours after dosing.

Metabolism

BDP is cleared very rapidly from the circulation and plasma concentrations are undetectable (< 50pg/ml) following oral or intranasal dosing. There is rapid metabolism of the majority of the swallowed portion of BDP during its first passage through the liver. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone -21-monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to systemic exposure.

Distribution

The tissue distribution at steady-state for BDP is moderate (201) but more extensive for B-17-MP (4241). Plasma protein binding of BDP is moderately high (87%).

Elimination

The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 1201/h) with corresponding terminal elimination half-lives of 0.5h and 2.7h. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.

5.3 Preclinical Safety Data

None reported.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Avicel RC 591 (Microcrystalline Cellulose and Carboxymethylcellulose Sodium)

Anhydrous Dextrose for parenteral use

Benzalkonium Chloride (added as Benzalkonium Chloride solution)

Phenylethyl Alcohol

Polysorbate 80

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months. After first opening the shelf life is 3 months.

6.4 Special Precautions For Storage

Beconase Hayfever Relief for Adults should not be stored above 30°C. Keep container in the outer carton. Do not refrigerate.

6.5 Nature And Contents Of Container

Beconase Hayfever Relief for Adults is supplied in a 20ml plastic bottle fitted with a tamper resistant, metering atomising pump and nasal applicator. A combined nasal adaptor/actuator covered with a dust cap is fitted on the pump. The bottle provides 100 sprays.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Beecham Group Plc

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as

GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00079/0617

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2003

10. Date Of Revision Of The Text

05/10/2011



1. Name Of The Medicinal Product

Betadine Gargle and Mouthwash.

2. Qualitative And Quantitative Composition

Povidone Iodine USP 1% w/v (equivalent to 0.1% w/v of available iodine).

3. Pharmaceutical Form

Solution.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of acute mucosal infections of the mouth and pharynx, for example gingivitis, and mouth ulcers. For oral hygiene prior to, during and after dental and oral surgery.

4.2 Posology And Method Of Administration

For oral administration, as a gargle and mouthwash. The product should not be swallowed. Adults and children over 6 years of age: Use undiluted or diluted with an equal volume of warm water. Gargle or rinse with up to 10ml for up to 30 seconds without swallowing. Repeat up to four times daily, for up to 14 consecutive days, or as directed.

4.3 Contraindications

Not for use in children under 6 years of age and in patients with a known or suspected iodine hypersensitivity. Regular use is contraindicated in patients and users with thyroid disorders (in particular nodular colloid goitre, endemic goitre and Hashimoto's thyroiditis).

4.4 Special Warnings And Precautions For Use

Regular use should be avoided as prolonged use may lead to the absorption of a significant amount of iodine. Do not use for more than 14 days. If sores or ulcers in the mouth do not heal within 14 days, seek medical or dental advice. Regular use should be avoided in patients on concurrent lithium therapy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Absorption of iodine from povidone iodine may interfere with thyroid function tests. Contamination with povidone iodine of several types of tests for the detection of occult blood in faeces or blood in urine may produce false-positive results.

4.6 Pregnancy And Lactation

Regular use of povidone iodine should be avoided in pregnant or lactating women as absorbed iodine can cross the placental barrier and be secreted into breast milk. Although no adverse effects have been reported from limited use, caution should be recommended and therapeutic benefit must be balanced against possible effects of the absorption of iodine on foetal thyroid function and development. The use of Betadine Gargle and Mouthwash in pregnant and lactating women should be limited to a single treatment session only.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Idiosyncratic mucosal irritation and hypersensitivity reactions may occur. Excessive absorption of iodine may produce systemic effects such as metabolic acidosis, hypernatraemia and impairment of renal function.

4.9 Overdose

Excessive iodine can produce goitre and hypothyroidism or hyperthyroidism. Acute overdose may result in symptoms of metallic taste in the mouth, increased salivation, burning or pain in the throat or mouth, irritation and swelling in the eyes, difficulty in breathing due to pulmonary oedema, skin reactions, gastrointestinal upset and diarrhoea. Metabolic acidosis, hypernatraemia and renal impairment may occur. Treatment: In the cases of deliberate or accidental ingestion of large quantities of Betadine, symptomatic and supportive treatment should be provided with special attention to electrolyte balance and renal and thyroid function.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Betadine Gargle and Mouthwash contains povidone iodine, a complex of iodine which shows all the broad spectrum germicidal activity of elemental iodine. The germicidal activity is maintained in the presence of blood, pus, serum and necrotic tissue. Betadine Gargle and Mouthwash kills bacteria, viruses, fungi, spores and protozoa.

5.2 Pharmacokinetic Properties

The product is intended for topical application to the mouth and buccal cavity.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Glycerol; menthol; methyl salicylate; ethanol 96%; saccharin sodium; purified water.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months unopened.

6.4 Special Precautions For Storage

Store in a dry place below 25oC. Protect from light.

6.5 Nature And Contents Of Container

Amber soda-lime-silica glass bottle (USP Type III) fitted with an externally ribbed white urea cap, with a steran faced wad or with a wadless polypropylene cap containing 250ml of product.

6.6 Special Precautions For Disposal And Other Handling

This product should not be swallowed.

7. Marketing Authorisation Holder

Medlock Medical Limited, Tubiton House, Oldham, OL1 3HS.

8. Marketing Authorisation Number(S)

PL 21248/0006.

9. Date Of First Authorisation/Renewal Of The Authorisation

30th September 2005.

10. Date Of Revision Of The Text

September 2005.



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