1. Name Of The Medicinal Product

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

2. Qualitative And Quantitative Composition

2.1 General description

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

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

2.2 Qualitative and quantitative composition

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

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

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

Solvent: water for injections.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Powder: dry white to slightly yellow powder or cake.

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

The reconstituted medicinal product is a clear and colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

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

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

4.2 Posology And Method Of Administration

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

Posology

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

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

 

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

2 ? administered IU

body weight (kg)

On demand treatment

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

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

Degree of haemorrhage/ Type of surgical procedure

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

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

Haemorrhage

Early haemarthrosis, muscle bleed or oral bleed

 

20 - 40

 

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

More extensive haemarthrosis, muscle bleed or haematoma

30 - 60

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

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

60 - 100

Repeat infusion every 8 to 24 hours until threat is resolved

Surgery

Minor

including tooth extraction

 

30 - 60

 

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

Major

80 - 100

(pre- and postoperative)

a) By bolus infusions

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

b) By continuous infusion

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

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

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

Continuous Infusion

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

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

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

Prophylaxis

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

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

Paediatric population

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

Patients with inhibitors

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

Method of administration

For intravenous use.

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

Continuous infusion

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

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

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

 

Desired plasma FVIII level

Infusion rate

IU/h/kg

Infusion rate for 75 kg patient

ml/h

   

Clearance: 3 ml/h/kg

   

Concentrations of rFVIII solution

         

100 IU/ml

200 IU/ml

400 IU/ml

 

100 % (1 IU/ml)

3.0

2.25

1.125

0.56

 

60 % (0.6 IU/ml)

1.8

1.35

0.68

0.34

 

40 % (0.4 IU/ml)

1.2

0.9

0.45

0.225

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

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

clearance = infusion rate/actual FVIII level.

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

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

4.3 Contraindications

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

- Known allergic reactions to mouse or hamster protein.

4.4 Special Warnings And Precautions For Use

Hypersensitivity reactions

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

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

Antibodies (inhibitors)

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

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

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

Continuous infusion

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

Registration

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

Sodium content

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with KOGENATE Bayer.

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

There are no fertility data available.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

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

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

MedDRA Standard

System Organ Class

Common

Uncommon

Rare

Blood and the Lymphatic System Disorders

Inhibitor Formation to FVIII

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

Inhibitor Formation to FVIII

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

 

General Disorders and Administration Site Conditions

Infusion site reaction

 

Infusion related febrile reaction (pyrexia)

Immune System Disorders

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

 

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

* see section below

Description of selected adverse reactions

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

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

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

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

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

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

4.9 Overdose

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

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

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

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

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

5.2 Pharmacokinetic Properties

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

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

5.3 Preclinical Safety Data

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

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

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

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder

Glycine

Sodium chloride

Calcium chloride

Histidine

Polysorbate 80

Sucrose

Solvent

Water for injections

6.2 Incompatibilities

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

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

6.3 Shelf Life

30 months.

After reconstitution, the product should be used immediately.

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

Do not refrigerate after reconstitution.

6.4 Special Precautions For Storage

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

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

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

6.5 Nature And Contents Of Container

Each package of KOGENATE Bayer contains:

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

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

• syringe plunger rod

• vial adapter

• one venipuncture set

• two sterile alcohol swabs for single use

• two dry swabs

• two plasters

6.6 Special Precautions For Disposal And Other Handling

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

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

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

Use the provided venipuncture set for intravenous injection.

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

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

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

7. Marketing Authorisation Holder

Bayer Pharma AG

13342 Berlin

Germany

8. Marketing Authorisation Number(S)

EU/1/00/143/007

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

10. Date Of Revision Of The Text

1 July 2011

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



Pronunciation: KEE-toe-PROE-fen



Pronunciation: LAK-tyoo-lose



Address Kyowa Pharmaceutical, Inc. ,



Pronunciation: TRY-am-SIN-oh-lone ah-SEE-toe-nide



potassium chloride



Generic Name: echinacea purpurea, plantago major, ferrum phosphoricum, potassium sulfate, magnesium phosphate, dibasic trihydrate and bryonia alba root granule



Generic Name: antihemophilic factor (factor VIII) (injection) (an TEE hee moe FIH lick FAC tor)



Pronunciation: KEE-toe-ROLE-ak



Definition of Keratoconjunctivitis: Inflammation of the cornea and conjunctiva.

Drugs associated with Keratoconjunctivitis

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







kee-toe-ROLE-ak

Nasal route(Spray)

For short term use only (up to 5 days in adults). Not for use in pediatric patients and not indicated for minor or chronic pain. Contraindicated in patients with peptic ulcer disease, history of gastrointestinal (GI) bleeding or perforation, peri-operative pain in the setting of CABG surgery, advanced renal impairment, risk of renal failure due to volume depletion, cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis, and high risk of bleeding. Use caution with elderly patients due to high risk of GI adverse events and in patients with cardiovascular disease or risk factors for cardiovascular disease .

Commonly used brand name(s)

In the U.S.

Sprix

Available Dosage Forms:

Spray

Pharmacologic Class: NSAID

Chemical Class: Acetic Acid (class)

Uses For ketorolac

Ketorolac nasal spray is used to relieve moderate to moderately severe pain, such as pain that occurs after an operation or other painful procedure. It is a nonsteroidal anti-inflammatory drug (NSAID) that will reduce pain and inflammation.

Ketorolac has side effects that can be very dangerous. The risk of having a serious side effect increases with the amount that is used and the length of time it is used. Ketorolac should not be used for more than 5 days in a row. Before using ketorolac, you should discuss with your doctor the good that ketorolac can do as well as the risks of using it.

ketorolac is available only with your doctor's prescription.

Before Using ketorolac

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For ketorolac, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to ketorolac or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ketorolac nasal spray in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ketorolac nasal spray in the elderly. However, because of ketorolac's toxicity, it should be used with caution in the elderly, after less toxic alternatives have been considered or found ineffective. Recommended doses should not be exceeded, and the patient should be carefully monitored during treatment. In addition, elderly patients are more likely to have age-related heart, kidney, liver, stomach, or bowel problems, which may require caution and an adjustment in the dose for patients receiving ketorolac nasal spray.

Pregnancy Pregnancy Category Explanation 1st Trimester C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. 2nd Trimester C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. 3rd Trimester D Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking ketorolac, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ketorolac with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Aceclofenac Acemetacin Alclofenac Apazone Aspirin Benoxaprofen Bufexamac Carprofen Clometacin Clonixin Dexketoprofen Diclofenac Diflunisal Dipyrone Droxicam Etodolac Etofenamate Felbinac Fenbufen Fenoprofen Fentiazac Floctafenine Flufenamic Acid Flurbiprofen Ibuprofen Indomethacin Indoprofen Isoxicam Ketoprofen Lornoxicam Meclofenamate Mefenamic Acid Meloxicam Nabumetone Naproxen Niflumic Acid Nimesulide Oxaprozin Oxyphenbutazone Pentoxifylline Phenylbutazone Pirazolac Piroxicam Pirprofen Probenecid Propyphenazone Proquazone Sulindac Suprofen Tenidap Tenoxicam Tiaprofenic Acid Tolmetin Zomepirac

Using ketorolac with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Abciximab Ardeparin Argatroban Beclamide Beta Glucan Bivalirudin Caramiphen Carbamazepine Certoparin Chlormethiazole Cilostazol Citalopram Clopidogrel Clovoxamine Dabigatran Etexilate Dalteparin Danaparoid Desirudin Diazepam Dipyridamole Enoxaparin Escitalopram Ethotoin Felbamate Femoxetine Flesinoxan Fluoxetine Fluvoxamine Fondaparinux Fosphenytoin Gabapentin Ginkgo Heparin Lacosamide Lepirudin Levetiracetam Mephenytoin Mephobarbital Methotrexate Nadroparin Nefazodone Oxcarbazepine Paraldehyde Paramethadione Parnaparin Paroxetine Pemetrexed Phenacemide Phenobarbital Phenytoin Piracetam Pregabalin Protein C Reviparin Rivaroxaban Rufinamide Sertraline Sibutramine Stiripentol Tacrolimus Tiagabine Ticlopidine Tinzaparin Tirofiban Topiramate Trimethadione Valproic Acid Vigabatrin Vilazodone Zimeldine Zonisamide

Using ketorolac with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acebutolol Acetohexamide Alacepril Alprenolol Amiloride Arotinolol Atenolol Azilsartan Medoxomil Azosemide Befunolol Bemetizide Benazepril Bendroflumethiazide Benzthiazide Betaxolol Bevantolol Bisoprolol Bopindolol Bucindolol Bumetanide Bupranolol Buthiazide Candesartan Cilexetil Canrenoate Captopril Carteolol Carvedilol Celiprolol Chlorothiazide Chlorpropamide Chlorthalidone Cilazapril Clopamide Cyclopenthiazide Cyclosporine Delapril Desvenlafaxine Dilevalol Duloxetine Enalaprilat Enalapril Maleate Eprosartan Esmolol Ethacrynic Acid Fosinopril Furosemide Gliclazide Glimepiride Glipizide Gliquidone Glyburide Hydrochlorothiazide Hydroflumethiazide Imidapril Indapamide Irbesartan Labetalol Landiolol Levobetaxolol Levobunolol Lisinopril Lithium Losartan Mepindolol Methyclothiazide Metipranolol Metolazone Metoprolol Milnacipran Moexipril Nadolol Nebivolol Nipradilol Olmesartan Medoxomil Oxprenolol Penbutolol Pentopril Perindopril Pindolol Piretanide Polythiazide Propranolol Quinapril Ramipril Sotalol Spirapril Spironolactone Talinolol Tasosartan Telmisartan Temocapril Tertatolol Timolol Tolazamide Tolbutamide Torsemide Trandolapril Triamterene Trichlormethiazide Valsartan Venlafaxine Xipamide Zofenopril Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of ketorolac. Make sure you tell your doctor if you have any other medical problems, especially:

Anemia or Congestive heart failure or Crohn's disease, history of or Edema (fluid retention or body swelling) or Heart attack, history of or Heart disease or Hypertension (high blood pressure) or Kidney disease, or history of or Liver disease, or history of or Stroke, history of or Ulcerative colitis, history of—Use with caution. May make these conditions worse. Aspirin-sensitive asthma, history of or Aspirin sensitivity, history of or Bleeding problems or Kidney disease, severe or Major surgery, prior to or Stomach ulcers or bleeding, or history of—Should not be used in patients with these conditions. Heart surgery (e.g., coronary artery bypass graft [CABG])—Should not be used to relieve pain right before or after the surgery. Proper Use of ketorolac

Take ketorolac only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Do not use it for more than 5 days in a row. The total number of days also includes any doses of ketorolac that may be given in a hospital or clinic setting. Using too much of ketorolac increases the chance of side effects, especially in elderly patients.

ketorolac should come with a medication guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

ketorolac is only used in the nose. Do not get any of it in your eyes. If it does get in the eyes, rinse them with water right away and call your doctor.

Drink extra fluids while you are using ketorolac. This will keep your kidneys working well and help prevent kidney problems.

To use:

If you are using the nasal spray for the first time, you will need to prime the spray. To do this, pump the bottle five times until some of the medicine sprays out. Now it is ready to use. Gently blow your nose to clear the nostrils. Sit or stand up straight and tilt your head slightly forward. Insert the tip of the bottle into your right nostril. Point the bottle away from the center of your nose. Spray once into your right nostril. If your dose is 2 sprays, spray once into your left nostril the same way. After using the spray, wipe the tip of the bottle with a clean tissue and put the clear plastic cover back on. Do not use the bottle for more than 24 hours after your first dose. Throw the bottle away after 24 hours even if it still has liquid in it. Dosing

The dose of ketorolac will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ketorolac. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For nasal dosage form (spray): For pain: Adults weighing 50 kilograms (kg) or more—31.5 milligrams (mg) or 1 spray in each nostril every 6 to 8 hours. Your doctor may adjust your dose if needed. However, the dose is usually not more than 126 mg (a total of 8 sprays) per day. Older adults and adults weighing less than 50 kg—15.75 mg or 1 spray in only one nostril every 6 to 8 hours. However, the dose is usually not more than 63 mg (a total of 4 sprays) per day. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of ketorolac, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep the unopened bottle in the refrigerator. Protect it from light and freezing. Once opened, store the bottle at room temperature, away from heat and direct sunlight. Throw away any unused medicine 24 hours after you opened the bottle and used your first dose.

Precautions While Using ketorolac

It is very important that your doctor check your progress while you are using ketorolac. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to use it.

Do not use any other form of ketorolac (such as injection or tablets) or other NSAIDs unless your doctor says it is okay. Some examples of NSAIDs are aspirin, diclofenac, ibuprofen, naproxen, Advil®, Aleve®, Celebrex®, Ecotrin®, Motrin®, or Voltaren®. Also, you should not use ketorolac together with pentoxifylline (Trental®) or probenecid (Benemid®).

Ketorolac may cause bleeding in your stomach or intestines. This problem can happen without warning signs. This is more likely if you have had a stomach ulcer in the past, if you smoke or drink alcohol regularly, if you are over 60 years of age, are in poor health, or are using certain other medicines (such as steroids or a blood thinner). Stop using ketorolac and call your doctor right away if you have bloody or black, tarry stools; severe stomach pain or heartburn; or vomiting of blood or material that looks like coffee grounds.

ketorolac may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using ketorolac.

Ketorolac may increase your risk of having a heart attack. This is more likely in people who already have heart disease. Stop using ketorolac and call your doctor right away if you have chest pain or discomfort; an irregular or fast heart beat; severe indigestion or heartburn; nausea; sweating; or troubled breathing with exertion.

Serious skin reactions can occur during treatment with ketorolac. Stop using ketorolac and check with your doctor right away if you have any of the following symptoms while you are using ketorolac: blistering, peeling, loosening of the skin; chills; cough; diarrhea; fever; itching; joint or muscle pain; red skin lesions; sore throat; sores, ulcers, or white spots in the mouth or on the lips; or unusual tiredness or weakness.

Check with your doctor right away if you have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

ketorolac Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Abdominal or stomach pain, cramping, or burning bloody or black, tarry stools blurred vision constipation diarrhea dizziness fast, irregular, pounding, or racing heartbeat or pulse headache heartburn indigestion nausea nervousness pale skin pounding in the ears severe stomach pain sweating unusual bleeding or bruising unusual tiredness or weakness vomiting of blood or material that looks like coffee grounds Less common Burning feeling in the chest or stomach chest pain or discomfort decrease in amount or frequency of urine difficult or labored breathing frequent urge to urinate frequent urination increased amount of pale, dilute urine lightheadedness, dizziness, or fainting rapid, shallow breathing shortness of breath troubled breathing with exertion Rare Bleeding gums bloody or cloudy urine blue lips and fingernails chills clay-colored stools confusion cough or hoarseness coughing that sometimes produces a pink frothy sputum dark urine difficult, burning, or painful urination difficulty with swallowing dilated neck veins extreme fatigue general tiredness and weakness increased blood pressure increased sweating increased thirst itching or hives light-colored stools lower back or side pain nosebleeds pain or burning in the throat pinpoint red spots on the skin rash rectal bleeding sores, ulcers, or white spots on the lips or tongue or inside the mouth stomach upset swelling of the face, fingers, feet, or lower legs swollen glands tenderness in the stomach area tightness in the chest unpleasant breath odor upper right abdominal pain vomiting weight gain or loss wheezing yellow eyes or skin Incidence not known Blistering, peeling, or loosening of the skin bloating change in consciousness convulsions difficulty with moving dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position feeling of warmth feeling that others are watching you or controlling your behavior feeling, seeing, or hearing things that are not there fever with or without chills general body swelling joint or muscle pain large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs loss of consciousness muscle aching or cramping muscle pains or stiffness pain or discomfort in the arms, jaw, back, or neck pains in the stomach, side, or abdomen, possibly radiating to the back pale or blue lips, fingernails, or skin puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue red skin lesions, often with a purple center red, irritated eyes redness of the face, neck, arms, and occasionally, upper chest redness, soreness, or itching skin severe mood or mental changes sneezing sores, welting, or blisters swollen joints swollen, painful, or tender lymph glands in the neck, armpit, or groin weakness or heaviness of the legs

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Acid or sour stomach belching continuing ringing or buzzing or other unexplained noise in the ears drowsiness excess air or gas in the stomach or intestines full feeling hearing loss nasal discomfort passing gas swelling or inflammation of the mouth Less common Runny nose stuffy nose watering of the eyes Rare Abnormal dreams abnormal taste appetite changes bloody nose bruising burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings decreased awareness or responsiveness delusions dementia difficulty with speaking drooling excessive thirst false or unusual sense of well-being feeling of constant movement of self or surroundings feeling sad or empty general feeling of discomfort or illness inability to concentrate increase in body movements irritability lack or loss of strength large, flat, blue, or purplish patches in the skin loss of balance control loss of interest or pleasure muscle trembling, jerking, or stiffness redness, swelling, or soreness of the tongue restlessness seeing, hearing, or feeling things that are not there sensation of spinning shakiness in the legs, arms, hands, or feet shuffling walk sleepiness or unusual drowsiness sleeplessness tiredness trouble concentrating trouble sleeping uncontrolled movements, especially of the face, neck, and back weight loss Incidence not known Burning, dry, or itching eyes eye discharge or excessive tearing flushed, dry skin fruit-like breath odor increased hunger increased urination redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid stiff neck or back unexplained weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

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More ketorolac Nasal resources Ketorolac Nasal Use in Pregnancy & Breastfeeding Drug Images Ketorolac Nasal Drug Interactions Ketorolac Nasal Support Group 74 Reviews for Ketorolac Nasal - Add your own review/rating Compare ketorolac Nasal with other medications Pain Postoperative Pain





Generic Name: pegloticase (peg LOE ti kase)



Generic Name: salicylic acid and urea topical (sal ih SILL ik AH sid and you REE ah)



1. Name Of The Medicinal Product

Ketorolac Trometamol 30mg/ml Injection Solution

2. Qualitative And Quantitative Composition

Each 1ml ampoule contains 30 mg Ketorolac trometamol

For excipients please see section 6.1

3. Pharmaceutical Form

Solution for Injection

Colourless or slightly yellowish solution in amber glass ampoules.

4. Clinical Particulars 4.1 Therapeutic Indications

Ketorolac Injection is indicated for the short-term management of moderate to severe acute post-operative pain.

4.2 Posology And Method Of Administration

Ketorolac Injection is for administration by intramuscular or bolus intravenous injection. Bolus intravenous doses should be given over at least 15 seconds. Ketorolac Injection should not be used for epidural or spinal administration.

The time to onset of analgesic effect following both IV and IM administration is similar and is approximately 30 minutes, maximum analgesia occurs within one to two hours. Analgesia normally lasts for four to six hours.

Dosage should be adjusted according to the severity of the pain and the patient response. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

The administration of continuous multiple daily doses of ketorolac intramuscularly or intravenously should not exceed two days because adverse events may increase with prolonged usage. There has been limited experience with dosing for longer periods since the vast majority of patients have transferred to oral medication or no longer require analgesic therapy after this time.

Adults

The recommended initial dose of Ketorolac Injection is 10mg followed by 10 to 30mg every four to six hours as required. In the initial post-operative period, Ketorolac Injection may be given as often as every two hours if needed. The lowest effective dose should be given. A total daily dose of 90mg for non-elderly and 60mg for the elderly, patients with renal impairment and patients less than 50kg should not be exceeded. The maximum duration of treatment should not exceed two days.

The dosage in patients under 50kg should be reduced.

Opioid analgesics (e.g. morphine, pethidine) may be used concomitantly, and may be required for optimal analgesic effect in the early post-operative period when pain is most severe. Ketorolac does not interfere with opioid binding and does not exacerbate opioid-related respiratory depression or sedation. When used in association with Ketorolac Injection, the daily dose of opioid is usually less than that normally required. However, opioid side-effects should still be considered, especially in day-case surgery.

Patients receiving Ketorolac Injection, and who are converted to oral Ketorolac, should receive a total combined daily dose not exceeding 90mg (60mg for the elderly, patients with renal impairment and patients less than 50kg). The oral component should not exceed 40mg on the day the change of formulation is made. Patients should be converted to oral treatment as soon as possible.

Elderly

For patients over 65 years, the lower end of the dosage range is recommended and a total daily dose of 60mg should not be exceeded (see section 4.4 Special warnings and special precautions for use).

Children

Safety and efficacy in children have not been established. Therefore, Ketorolac Injection is not recommended for use in children under 16 years of age.

Renal impairment

Ketorolac Injection should not be used in moderate to severe renal impairment and a reduced dosage given in lesser impairment (not exceeding 60mg/day IV or IM) (see section 4.3 Contra-indications).

4.3 Contraindications

• Active or previous peptic ulcer. History of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy.

• suspected or confirmed cerebrovascular bleeding

• haemorrhagic diatheses, including coagulation disorders

• hypersensitivity to ketorolac trometamol or other NSAIDs and those patients in whom aspirin or other prostaglandin synthesis inhibitors induce allergic reactions (severe anaphylactic-like reactions have been observed in such patients)

• the complete or partial syndrome of nasal polyps, angioedema or bronchospasm

• concurrent treatment with other NSAIDs including cyclooxygenase 2 specific inhibitors, oxpentifylline, probenecid or lithium salts

• hypovolaemia from any cause or dehydration

• moderate or severe renal impairment (serum creatinine > 160 micromol/l)

• a history of asthma

• severe heart failure

• patients who have had operations with a high risk of haemorrhage or incomplete haemostasis

• patients on anti-coagulants including low dose heparin (2500 - 5000 units twelve hourly)

• during pregnancy, labour, delivery or lactation

• children under 16 years of age

• Ketorolac is contra-indicated as prophylactic analgesia before surgery due to inhibition of platelet aggregation and is contra-indicated intra-operatively because of the increased risk of bleeding

• patients currently receiving aspirin

4.4 Special Warnings And Precautions For Use

Physicians should be aware that in some patients pain relief might not occur until 30 minutes or more after IV or IM administration.

Use in the elderly: in common with other NSAIDs, patients over the age of 65 years may be at an increased risk of experiencing adverse events compared to younger patients. The elderly have an increased plasma half-life and reduced plasma clearance of ketorolac, therefore a total daily dose of greater than 60mg ketorolac is not recommended.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

Gastro-intestinal effects: ketorolac can cause gastro-intestinal irritation, ulcers or bleeding in patients with or without a history of previous symptoms. Elderly and debilitated patients are more prone to develop these reactions. The incidence increases with dose and duration of treatment.

A study has shown increased rates of clinically serious GI bleeding in patients < 65 years of age who received an average daily dose of > 90mg ketorolac IM as compared to those patients receiving parenteral opioids.

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5).

Where GI bleeding or ulceration occurs in patients receiving Ketorolac, the treatment should be withdrawn.

Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particulary at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Ketorolac.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Ketorolac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Respiratory effects: bronchospasm may be precipitated in patients with a history of asthma.

Renal effects: drugs that inhibit prostaglandin biosynthesis (including non-steroidal anti-inflammatory drugs) have been reported to cause nephrotoxicity including but not limited to: glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. In patients with renal, cardiac or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration of renal function.

As with other drugs that inhibit prostaglandin synthesis, elevations of serum urea, creatinine and potassium have been reported with ketorolac and may occur after one dose.

Patients with impaired renal function: since ketorolac and its metabolites are excreted primarily by the kidney, patients with moderate to severe impairment of renal function (serum creatinine greater than 160 micromol/l) should not receive Ketorolac Injection. Patients with lesser renal impairment should receive a reduced dose of ketorolac (not exceeding 60mg/day IM or IV) and their renal status should be closely monitored.

Female fertility: the use of Ketorolac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation for infertility, withdrawal of Ketorolac should be considered.

Caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal failure. Patients at greatest risk of this reaction are those who are volume depleted because of blood loss or severe dehydration, patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics. Discontinuation of NSAID therapy is typically followed by recovery to the pre-treatment state. Inadequate fluid/blood replacement during surgery, leading to hypovolaemia, may lead to renal dysfunction, which could be exacerbated when ketorolac is administered. Therefore, volume depletion should be corrected and close monitoring of serum urea and creatinine and urine output is recommended until the patient is normovolaemic. In patients on renal dialysis, ketorolac clearance was reduced to approximately half the normal rate and terminal half-life increased approximately three-fold.

Fluid retention and oedema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac clearance or terminal half-life.

Borderline elevations of one or more liver function tests may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued therapy. Meaningful elevations (greater than three times normal) of serum glutamate pyruvate transaminase (SGPT/ALT) or serum glutamate oxaloacetate transaminase (SGOT/AST) occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, ketorolac should be discontinued.

Haematological effects: patients with coagulation disorders should not receive ketorolac. Patients on anti-coagulation therapy may be at increased risk of bleeding if given ketorolac concurrently. The concomitant use of ketorolac and prophylactic low-dose heparin (2500 - 5000 units twelve hourly) has not been studied extensively and may also be associated with an increased risk of bleeding. Patients already on anti-coagulants or who require low-dose heparin should not receive ketorolac. Patients who are receiving other drug therapy that interferes with haemostasis should be carefully observed if ketorolac is administered. In controlled clinical studies, the incidence of clinically significant post-operative bleeding was less than 1%.

Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding times were raised, but not outside the normal range of two to eleven minutes. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued.

Post-operative wound haemorrhage has been reported in association with the immediate peri-operative use of ketorolac. Therefore, ketorolac should not be used in patients who have had operations with a high risk of haemorrhage or incomplete haemostasis. Caution should be used where strict haemostasis is critical, e.g. in cosmetic or day-case surgery. Haematomata and other signs of wound haemorrhage and epistaxis have been reported with the use of ketorolac. Physicians should be aware of the pharmacological similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibit cyclo-oxygenase and the risk of bleeding, particularly in the elderly.

The risk of clinically serious gastro-intestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose greater than 60mg/day of ketorolac.

Ketorolac is not an anaesthetic agent and possesses no sedative or anxiolytic properties; therefore it is not recommended as a pre-operative medication for the support of anaesthesia when these effects are required.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ketorolac should not be used with other NSAIDs or in patients receiving aspirin because of the potential for additive side-effects.

Ketorolac is highly bound to human plasma protein (mean 99.2%) and binding is concentration-independent.

Ketorolac did not alter digoxin protein binding. In vitro studies indicated that at therapeutic concentrations of salicylate (300?g/ml) and above, the binding of ketorolac was reduced from approximately 99.2% to 97.5%. Therapeutic concentrations of digoxin, warfarin, paracetamol, phenytoin and tolbutamide did not alter ketorolac protein binding. Because ketorolac is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein-bound drugs significantly.

Care should be taken when administering ketorolac with anti-coagulants since co-administration may cause an enhanced anti-coagulant effect.

There is no evidence in animal or human studies that ketorolac induces or inhibits the hepatic enzymes capable of metabolising itself or other drugs. Hence ketorolac would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.

In normovolaemic healthy subjects, ketorolac reduces the diuretic response to frusemide by approximately 20%, so particular care should be taken in patients with cardiac decompensation.

Ketorolac and other non-steroidal anti-inflammatory drugs can reduce the anti-hypertensive effect of beta-blockers and may increase the risk of renal impairment when administered concurrently with ACE inhibitors, particularly in volume depleted patients.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.

Caution is advised when methotrexate is administered concurrently, since some prostaglandin synthesis inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.

Probenecid should not be administered concurrently with ketorolac because of increases in ketorolac plasma level and half-life.

As with all NSAIDs caution is advised when cyclosporin is co-administered because of the increased risk of nephrotoxicity.

NSAIDs should not be used for eight to twelve days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.

As with all NSAIDs, caution should be taken when co-administering with cortico-steroids because of the increased risk of gastro-intestinal bleeding.

Patients taking quinolones may have an increased risk of developing convulsions.

Co-administration with diuretics can lead to a reduced diuretic effect, and increase the risk of nephrotoxicity of NSAIDs.

Because of an increased tendency to bleeding when oxpentifylline is administered concurrently, this combination should be avoided.

In patients receiving lithium there is a possible inhibition of renal lithium clearance, increased plasma lithium concentration and potential lithium toxicity. (See section 4.3 Contra-indications).

4.6 Pregnancy And Lactation

There is no evidence of teratogenicity in rats or rabbits studied at maternally-toxic doses of ketorolac. Prolongation of the gestation period and/or delayed parturition was seen in the rat. Ketorolac and its metabolites have been shown to pass into the foetus and milk of animals. Ketorolac has been detected in human milk at low levels. Safety in human pregnancy has not been established. Congenital abnormalities have been reported in association with NSAID administration in man, however these are low in frequency and do not follow any discernible pattern. Ketorolac is therefore contra-indicated during pregnancy, labour or delivery, or in mothers who are breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Some patients may experience dizziness, drowsiness, visual disturbances, headaches, vertigo, insomnia or depression with the use of ketorolac. If patients experience these, or other similar undesirable effects, they should not drive or operate machinery.

4.8 Undesirable Effects

The following side-effects have been reported.

Gastro-intestinal:

Nausea, dyspepsia, gastro-intestinal pain, gastro-intestinal bleeding, abdominal discomfort, haematemesis, gastritis, oesophagitis, diarrhoea, eructation, constipation, flatulence, fullness, melaena, peptic ulcer, non-peptic gastro-intestinal ulceration, rectal bleeding, ulcerative stomatitis, vomiting, haemorrhage, perforation, pancreatitis. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4).

Central nervous/musculoskeletal systems:

Anxiety, drowsiness, dizziness, headache, sweating, dry mouth, nervousness, paraesthesia, functional disorders, abnormal thinking, depression, euphoria, convulsions, excessive thirst, inability to concentrate, insomnia, malaise, fatigue, stimulation, vertigo, abnormal taste and vision, optic neuritis, myalgia, abnormal dreams, hallucinations, hyperkinesia, hearing loss, tinnitus, aseptic meningitis, psychotic reactions.

Renal:

Nephrotoxicity including increased urinary frequency, oliguria, acute renal failure, hyponatraemia, hyperkalaemia, haemolytic uraemic syndrome, flank pain (with or without haematuria), raised serum urea and creatinine, interstitial nephritis, urinary retention, nephrotic syndrome.

Cardiovascular/haematological:

Flushing, bradycardia, pallor, purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, hypertension, palpitations, chest pain.

Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high does and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Respiratory:

Dyspnoea, asthma, pulmonary oedema.

Dermatological:

Pruritus, urticaria, skin photosensitivity, Lyell's syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash.

Hypersensitivity reactions:

Anaphylaxis, bronchospasm, laryngeal oedema, hypotension, flushing and rash. Such reactions may occur in patients with or without known sensitivity to ketorolac or other non-steroidal anti-inflammatory drugs.

These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma and nasal polyps). Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome (see section 4.3 Contra-indications).

Bleeding:

Post-operative wound haemorrhage, haematomata, epistaxis, increased bleeding time.

Reproductive, female:

Infertility

Other:

Asthenia, oedema, weight gain, abnormalities of liver function tests, hepatitis, liver failure, jaundice, fever. Injection site pain has been reported in some patients.

4.9 Overdose

Doses of 360mg given intramuscularly over an eight hour interval for five consecutive days have caused abdominal pain and peptic ulcers that have healed after discontinuation of dosing. Two patients recovered from unsuccessful suicide attempts. One patient experienced nausea after 210mg ketorolac, and the other hyperventilation after 300mg ketorolac.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC code M01A

Ketorolac is a potent analgesic agent of the non-steroidal, anti-inflammatory class (NSAID). It is not an opioid and has no known effects on opioid receptors. Its mode of action is to inhibit the cyclo-oxygenase enzyme system and hence prostaglandin synthesis and it demonstrates a minimal anti-inflammatory effect at its analgesic dose.

5.2 Pharmacokinetic Properties

Intramuscular

Following intramuscular administration, ketorolac was rapidly and completely absorbed. A mean peak plasma concentration of 2.2?g/ml occurred an average of 50 minutes after a single 30mg dose. Age, kidney and liver function affect terminal plasma half-life and mean total clearance as outlined in the table below (estimated from a single 30mg IM dose of ketorolac).

Type of subjects

Total clearance (l/hr/kg) mean (range)

Terminal half-life (hrs) mean (range)

Normal subjects (n = 54)

 

0.023 (0.010 - 0.046)

 

5.3 (3.5 - 9.2)

 

Patients with hepatic dysfunction (n = 7)

 

0.029 (0.013 - 0.066)

 

5.4 (2.2 - 6.9)

 

Patients with renal impairment (n = 25) (serum creatinine 160 - 430 micromol/l)

 

0.016 (0.005 - 0.043)

 

10.3 (5.9 - 19.2)

 

Renal dialysis patients (n = 9)

 

0.016 (0.003 - 0.036)

 

13.6 (8.0 - 39.1)

 

Healthy elderly subjects (n = 13)

(mean age 72)

 

0.019 (0.013 - 0.034)

 

7.0 (4.7 - 8.6)

 

Intravenous

Intravenous administration of a single 10mg dose of ketorolac resulted in a mean peak plasma concentration of 2.4?g/ml at an average of 5.4 minutes after dosing. The terminal plasma elimination half-life was 5.1 hours, average volume of distribution 0.15 l/kg, and total plasma clearance 0.35ml/min/kg.

The pharmacokinetics of ketorolac in man following single or multiple doses are linear. Steady-state plasma levels are achieved after dosing every six hours for one day. No changes in clearance occurred with chronic dosing. The primary route of excretion of ketorolac and its metabolites is renal: 91.4% (mean) of a given dose being found in the urine and 6.1% (mean) in the faeces.

More than 99% of the ketorolac in plasma is protein-bound over a wide concentration range.

5.3 Preclinical Safety Data

An 18-month study in mice with oral doses of ketorolac trometamol at 2mg/kg/day (0.9 times human systemic exposure at the recommended IM or IV dose of 30mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5mg/kg/day (0.5 times the human AUC), showed no evidence of tumourigenicity.

Ketorolac trometamol was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac trometamol did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590?g/ml and at higher concentrations, ketorolac trometamol increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.

Impairment of fertility did not occur in male or female rats at oral doses of 9mg/kg (0.9 times the human AUC) and 16mg/kg (1.6 times the human AUC) of ketorolac trometamol, respectively.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Ethanol, sodium chloride, sodium hydroxide and water for injections

6.2 Incompatibilities

Ketorolac Injection should not be mixed in a small volume (e.g. in a syringe) with morphine sulphate, pethidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride, as precipitation of ketorolac will occur.

It is compatible with normal saline, 5% dextrose, Ringer's, lactated Ringer's or Plasmacyte solutions. Compatibility of Ketorolac Injection with other drugs is unknown.

6.3 Shelf Life

Two years

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage time sand conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8oC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not store above 30°C. Keep container in the outer carton and protect from light.

6.5 Nature And Contents Of Container

Ampoules, amber type I glass. In cartons containing either 6 or 100 ampoules.

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions.

7. Marketing Authorisation Holder

Beacon Pharmaceutical Ltd

Tunbridge Wells

Kent TN1 1YG

8. Marketing Authorisation Number(S)

PL 18157/0012

9. Date Of First Authorisation/Renewal Of The Authorisation

30/04/2007

10. Date Of Revision Of The Text

30/04/2007



Pronunciation: poe-TASS-ee-uhm GLOO-coe-nate





Generic Name: anakinra (Subcutaneous route)

an-a-KIN-ra

Commonly used brand name(s)

In the U.S.

Kineret

Available Dosage Forms:

Solution

Therapeutic Class: Immunological Agent

Pharmacologic Class: Interleukin-1 Inhibitor

Uses For Kineret

Anakinra is used to treat moderate to severe symptoms of rheumatoid arthritis. It may relieve redness, pain, tenderness, and warmth in hands, feet, wrists, shoulders, elbows, and ankles. This medicine is used in patients 18 years of age or older. Anakinra will not cure the disease, but will help with the symptoms as long as you continue to take it.

This medicine is available only with your doctor's prescription.

Before Using Kineret

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of anakinra in children with use in other age groups.

Geriatric

This medicine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy Pregnancy Category Explanation All Trimesters B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Abatacept Adalimumab Certolizumab Pegol Etanercept Golimumab Infliximab Rilonacept Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Active infections—May be worsened by anakinra Asthma—Patients with asthma may be at higher risk of getting a serious infection when taking anakinra. Immunosuppression—Anakinra has not been studied in patients who have immune system problems. The effects of the medicine in these patients is not known Kidney disease—Higher blood levels of anakinra may occur Proper Use of Kineret

Your health care professional will teach you or your caregiver how to give the injection. You must demonstrate the procedure so that your health care professional knows you understand. Before taking the injection, check the medicine to make sure it is clear and doesn't have any particles in it. If it looks cloudy or discolored, or has any particles floating in it, you should throw it away. Do not shake the syringe. Give the entire dose and then throw away the syringe. Your health care professional will tell you how to dispose of your syringes. Do not reuse syringes. Do not keep part of a dose for later use. Take the medicine at the same time each day. If you have questions or problems with the procedure, call your health care professional.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For injection dosage form For rheumatoid arthritis: Adults—100 milligrams (mg) a day injected under the skin. Children—Use and dose must be determined by your doctor. Anakinra is not usually recommended for use in children. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Kineret

It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

Your body's ability to fight infection may be reduced while you are being treated with anakinra, it is very important that you call your doctor at the first signs of any infection (for example, if you get a fever or chills).

While you are being treated with anakinra, do not have any immunizations (vaccinations) without your doctor's approval.

Kineret Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Chest pain cough diarrhea fever or chills general feeling of discomfort or illness headache itching, pain, redness, swelling, tenderness or warmth on skin joint pain loss of appetite muscle aches and pains nausea pain or tenderness around eyes and cheekbones redness, bruising pain at the injection site runny nose shivering shortness of breath sneezing sore throat sweating tightness in chest trouble sleeping unusual tiredness or weakness vomiting wheezing Less common or rare Black, sticky stools difficulty in swallowing itching lower back pain or side pain painful or difficult urination pale skin rash; hives; swelling of face or lips ulcers, sores or white spots in mouth unusual bruising or bleeding

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Abdominal or stomach pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

See also: Kineret side effects (in more detail)

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More Kineret resources Kineret Side Effects (in more detail) Kineret Use in Pregnancy & Breastfeeding Kineret Drug Interactions Kineret Support Group 4 Reviews for Kineret - Add your own review/rating Kineret Prescribing Information (FDA) Kineret Consumer Overview Kineret Monograph (AHFS DI) Kineret MedFacts Consumer Leaflet (Wolters Kluwer) Anakinra Professional Patient Advice (Wolters Kluwer) Compare Kineret with other medications Rheumatoid Arthritis Schnitzler Syndrome Still's Disease



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