Aspen Warfarin 5mg Tablets

ASPEN WARFARIN 5 mg is indicated for:

Prevention and management of deep venous thrombosis and pulmonary embolism.

Prevention of thromboembolism in:

• atrial fibrillation.
• prosthetic heart valves.
• post myocardial infarction.
• the treatment of transient ischaemic attacks.

Posology

Adults

The administration and dosage of ASPEN WARFARIN 5 mg must be individualised for each patient according to the patientu2019s sensitivity as indicated by the International Normalised Ratio (INR). INR measurements should be carried out before treatment, on the 2nd and 3rd days of treatment and then on alternate days until the maintenance dose is established. Thereafter the patient should be monitored monthly.

Satisfactory levels of INR for maintenance, vary with the condition treated and the risk of thromboembolism.

INR 2,0 to 2,5 (PT ratio 1,3 to 1,5)

Prophylaxis of DVT including surgery in high-risk patients.

INR 2,0 to 3,0 (PT ratio 1,3 to 1,5)

Prophylaxis of DVT in hip surgery and fractured femur operations. Prevention of thromboembolism in myocardial infarction, mitral stenosis with embolism, atrial fibrillation, tissue prosthetic heart valves. Treatment of DVT, pulmonary embolism, transient ischaemic attacks, systemic embolism.

INR 3,0 to 4,5 (PT ratio 1,5 to 2,0)

Recurrent DVT and pulmonary embolism. Arterial disease including myocardial infarction. Prosthetic heart valves. The correlation between the INR and the PT ratio is based on thromboplastin with an international sensitivity index of 2,3.

Treatment should be commenced with a 5 mg dose once daily. The dose should be titrated according to INR results, to the desired INR, according to the condition. Maintenance doses usually range from 2,5 to 10 mg daily. Doses should be given at the same time each day.

Method of administration

For oral administration.

ASPEN WARFARIN 5 mg is contraindicated in:

• Hypersensitivity to warfarin or any of the excipients in the formulation (see section 6.1).
• Haemorrhagic stroke.
• Clinically significant bleeding.
• Within 72 hours of major surgery with risk of severe bleeding (see section 4.4).
• Peptic ulcers or other gastrointestinal disease involving bleeding.
• Conditions involving bleeding from respiratory or genito-urinary tract.
• Severe wounds (including surgical).
• Infective endocarditis.
• Impaired liver function.
• Impaired kidney function.
• Hypertension.
• Cerebrovascular haemorrhage.
• Aneurysm - cerebral, aortic.
• Pericarditis, pericardial effusion.
• Neuro- or ophthalmic surgery - recent or contemplated.
• Surgery involving large exposed raw surfaces.
• Within 48 hours postpartum (see section 4.6).
• Polyarthritis.
• Vitamin C deficiency.
• Major regional block anaesthesia.
• Inadequate laboratory facilities or lack of patient co-operation.
• Threatened abortion (see section 4.6).
• Safety in children younger than 18 years has not been established.
• Medicines where interactions may lead to a significantly increased risk of bleeding (see section 4.5).
• Fibrinolytic medicines (see section 4.5).
• Patients using over-the-counter miconazole oral gel (see section 4.5).
• Pregnancy and lactation (see section 4.6).

Most adverse events reported with ASPEN WARFARIN 5 mg are a result of over-anticoagulation. Therefore, it is important that the need for therapy is reviewed on a regular basis and therapy discontinued when no longer required.

Commencement of therapy

Monitoring

When therapy with ASPEN WARFARIN 5 mg is started using a standard dosing regimen, the international normalisation ratio (INR) should be determined daily or on alternate days in the early days of treatment. Once the INR has stabilised in the target range the INR can be determined at longer intervals (see section 4.2) INR should be monitored more frequently in patients at an increased risk of over-coagulation, e.g. patients with severe hypertension and liver or renal disease (see section 4.3). Patients for whom adherence may be difficult should be monitored more frequently.

Cessation of therapy

Abrupt cessation of ASPEN WARFARIN 5 mg therapy is not recommended except when bleeding occurs. The dose should be tapered over three to four weeks.

Thrombophilia

Patients with protein C-deficiency are at risk of developing skin necrosis when starting ASPEN WARFARIN 5 mg treatment. In patients with protein C-deficiency, therapy should be introduced without a loading dose of ASPEN WARFARIN 5 mg even if heparin is given. Patients with protein S-deficiency may also be at risk and it is advisable to introduce ASPEN WARFARIN 5 mg therapy slowly in these circumstances.

Risk of haemorrhage

The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. ASPEN WARFARIN 5 mg should be given with caution to patients where there is a risk of serious haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding and severe wounds including surgical wounds) (see section 4.3)

Risk factors for bleeding include high intensity of anticoagulation (INR > 4,0), age u2265 65, highly variable INRs, history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease, serious heart disease, risk of falling, anaemia, malignancy, trauma, renal insufficiency, concomitant medicines (see section 4.5).

All patients treated with ASPEN WARFARIN 5 mg should have their INR monitored regularly.

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed on measures to minimise risk of bleeding and to immediately report signs and symptoms of bleeding to medical practitioners. Checking the INR and reducing or omitting doses depending on INR level is essential, following consultation with anticoagulation services if necessary. If the INR is found to be too high, reduce dose or stop ASPEN WARFARIN 5 mg treatment. It will be sometimes necessary to reverse anticoagulation. INR should be checked within 2 to 3 days to ensure that it is falling.

Any concomitant anti-platelet medicines should be used with caution due to an increased risk of bleeding.

Haemorrhage

Haemorrhage can indicate an overdose of ASPEN WARFARIN 5 mg has been taken (see section 4.9). Unexpected bleeding at therapeutic levels should always be investigated and INR should be monitored (see section 4.3).

Ischaemic stroke

Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the infarcted brain. In patients with atrial fibrillation long-term treatment with ASPEN WARFARIN 5 mg is beneficial, but there is a risk of early recurrent embolism and therefore a break in treatment after ischaemic stroke is justified. ASPEN WARFARIN 5 mg treatment should be re-started 2 to 14 days following ischaemic stroke, depending on the size of the infarct and blood pressure.

In patients with large embolic strokes or uncontrolled hypertension, warfarin treatment should be stopped for 14 days.

Surgery

For surgery where there is no risk of severe bleeding, surgery can be performed with an INR of < 2,5. For surgery where there is a risk of severe bleeding, ASPEN WARFARIN 5 mg should be stopped 3 days prior to surgery to provide for an appropriate INR (u00b1 2) to be attained. Where it is necessary to continue anticoagulation e.g. risk of life-threatening thromboembolism, ASPEN WARFARIN 5 mg should be stopped and when the INR is reduced to < 2,5 and heparin therapy should be started. If surgery is required and ASPEN WARFARIN 5 mg cannot be stopped 3 days beforehand, anticoagulation should be reversed with vitamin K to an appropriate INR of u02c2 2. The timing for re-instating ASPEN WARFARIN 5 mg therapy depends on the risk of post-operative haemorrhage. In most instances ASPEN WARFARIN 5 mg treatment can be re-started as soon as the patient is able to take oral medicine.

Dental surgery

ASPEN WARFARIN 5 mg need not be stopped before routine dental surgery, e.g. tooth extraction. The management of patients who undergo dental or any surgical procedures requires close liaison between doctors, surgeons and dentists. An adjustment of dosage may be necessary.

Active peptic ulceration

Due to a high risk of bleeding, patients with active peptic ulcers should not be treated with ASPEN WARFARIN 5 mg (see section 4.3).

A wide variety of interactions may occur, increasing or diminishing the anticoagulant response with different mechanisms involved. Not all interactions have been identified, and some interacting medicines do so by more than one mechanism therefore the nett effect may be unpredictable. ASPEN WARFARIN 5 mg has a narrow therapeutic range and care is required with all concomitant therapy. The individual product information for any new concomitant therapy should be consulted for specific guidance on warfarin dose adjustment and therapeutic monitoring. If no information is provided the possibility of an interaction should still be considered.

Increased monitoring should be considered when commencing any new therapy if there is any doubt as to the extent of interaction.

Mechanisms of interaction include:

• Displacement from albumin binding sites;
• Altering metabolism of medicines by inhibition or induction of hepatic microsomal enzymes;
• Interference with absorption or metabolism of ASPEN WARFARIN 5 mg or vitamin K;
• Additional anticoagulant effects by medicines that inhibit platelet function.

Pharmacodynamic interactions

Medicines which are contraindicated

Concomitant use of medicines used in the treatment or prophylaxis of thrombosis, or other medicines with adverse effects on haemostasis may increase the pharmacological effect of ASPEN WARFARIN 5 mg, increasing the risk of bleeding, including asparaginase and some contrast media. Fibrinolytic medicines such as streptokinase, urokinase and alteplase are contraindicated in patients receiving ASPEN WARFARIN 5 mg (see section 4.3). Over-the-counter miconazole oral gel is contraindicated in patients receiving ASPEN WARFARIN 5 mg (see section 4.3). Some interacting medicines do not produce predictable effects. There have been reports of increased as well as decreased anticoagulant activity with disopyramide, phenytoin, quinidine and oral contraceptives.

Dipyridamole and aspirin can cause bleeding when given to patients taking anticoagulants, but without any alteration in INR.

Medicines which should be avoided

The following medicines should be avoided, or administered with caution with increased clinical and laboratory monitoring:

• Clopidogrel.
• Non-steroidal anti-inflammatory drugs (NSAIDs), including cox-2 specific NSAIDs.
• Sulfinpyrazone.
• Thrombin inhibitors such as dabigatran, bivalirudin.
• Unfractionated heparins and heparin derivatives, low molecular weight heparins.
• Fondaparinux, rivaroxaban.
• Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab.
• Prostacyclin.
• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants.
• Other medicines which inhibit haemostasis, clotting or platelet action.

A low-dose aspirin with ASPEN WARFARIN 5 mg may have a role in some patients, but the risk of gastrointestinal bleeding is increased. ASPEN WARFARIN 5 mg may initially be given with heparin in the initial treatment of thrombosis, until the INR is in the correct range.

Metabolic interactions

Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered. Medicines that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR, potentially increasing the risk of bleeding. When these medicines are co-administered, the dosage of ASPEN WARFARIN 5 mg may need to be reduced and the level of monitoring increased. Conversely, medicines which induce these metabolic pathways may decrease warfarin plasma concentrations and INR, potentially leading to reduced efficacy. When these medicines are co-administered, the dosage of ASPEN WARFARIN 5 mg may need to be increased and the level of monitoring increased. There is a small subset of medicines for which interactions are known, however their clinical effect on the INR is variable. In these cases, increased monitoring on starting and stopping therapy is advised. Care should also be taken when stopping or reducing the dose of a metabolic inhibitor or inducer, once patients are stable on this combination (offset effect).

Medicines which potentiate the effect of warfarin

Allopurinol, capecitabine, erlotinib, disulfiram, azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole), omeprazole, paracetamol (prolonged regular use), propafenone, amiodarone, tamoxifen, methylphenidate, zafirlukast, fibrates, statins (predominantly associated with fluvastatin), erythromycin, telithromycin, co-trimoxazole (sulfamethoxazole), metronidazole, chloramphenicol, cimetidine, clofibrate, danazol, glucagon, quinidine, thyroid hormones, tramadol, dextropropoxyphene, vitamin E, diazoxide, aminoglycosides, alcohol, triclofos, chloral hydrate, sulphonamides, sulphonylurea-type antidiabetic medicines, phenylbutazone and other pyrazolones, anabolic steroids, sulphinpyrazone, aspirin and other NSAIDS.

Medicines which antagonise the effect of warfarin

Barbiturates, primidone, carbamazepine, griseofulvin, oral contraceptives, rifampicin, azathioprine, phenytoin, phytomenadione, glutethimide, vitamin K, glucocorticoids and cholestyramine.

Medicines with variable effect

Corticosteroids, nevirapine, ritonavir.

The following factors may be responsible for an increase in prothrombin time

Carcinoma, collagen disease, congestive heart failure, diarrhoea, elevated temperature, hepatic disorders, infectious hepatitis, jaundice and a poor nutritional state.

The following factors may be responsible for a decrease in prothrombin time

Diabetes mellitus, oedema, hereditary resistance to ASPEN WARFARIN 5 mg therapy, hyperlipaemia and hypothyroidism.

Other medicine interactions

Broad spectrum antibiotics may potentiate the effect of ASPEN WARFARIN 5 mg by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyramine and sucralfate potentially decrease absorption of ASPEN WARFARIN 5 mg. Increased INR has been reported in patients taking glucosamine and ASPEN WARFARIN 5 mg. This combination is not recommended.

Interactions with herbal products

Herbal preparations containing St. Johnu2019s wort (Hypericum perforatum) must not be used whilst taking ASPEN WARFARIN 5 mg due to a proven risk of decreased plasma concentrations and reduced clinical effects of warfarin. Many other herbal products have a theoretical effect on ASPEN WARFARIN 5 mg, however most of these interactions are not proven. Patients should generally avoid taking any herbal medicines or food supplements whilst taking ASPEN WARFARIN 5 mg and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.

Alcohol

Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of ASPEN WARFARIN 5 mg.

Interactions with food and food supplements

Case reports suggest an interaction between ASPEN WARFARIN 5 mg and cranberry juice, in most cases leading to an increase in INR or bleeding event. Patients should be advised to avoid cranberry products. Increased supervision and INR monitoring should be considered for any patient taking ASPEN WARFARIN 5 mg and regular cranberry juice. Limited evidence suggests that grapefruit juice may cause a modest rise in INR in some patients taking ASPEN WARFARIN 5 mg.

Certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet. Many other food supplements have a theoretical effect on ASPEN WARFARIN 5 mg; however most of these interactions are not proven. Patients should generally avoid taking any food supplements whilst taking ASPEN WARFARIN 5 mg and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.

Laboratory tests

Heparins and danaparoid may prolong the INR, therefore a sufficient time interval should be allowed after administration before performing the test.

ASPEN WARFARIN 5 mg is contraindicated in pregnancy and lactation as ASPEN WARFARIN 5 mg is teratogenic in animals and humans (see section 4.3).

Women of childbearing potential / Contraception in males and females

Females of childbearing potential must be advised to use effective contraception during treatment, and for at least 1 month after the final dose of ASPEN WARFARIN 5 mg.

Pregnancy

Warfarin is a recognised teratogen. Based on human experience warfarin causes congenital malformations, foetal warfarin syndrome (warfarin embryopathy) characterised by bone stippling (chondrodysplasia punctata) and nasal hypoplasia when administered in the first trimester of pregnancy. CNS abnormalities may develop after use in any trimester, but appear most likely when used in the second or third trimester. The use in the late stages of pregnancy is associated with foetal haemorrhage. ASPEN WARFARIN 5 mg has also been associated with an increased rate of abortion and foetal death. Women of child-bearing age who are taking ASPEN WARFARIN 5 mg should use effective contraception during treatment. Treatment with ASPEN WARFARIN 5 mg during pregnancy should be avoided (see section 4.3).

Lactation

Warfarin is excreted in breast milk in small amounts. Women on ASPEN WARFARIN 5 mg should not breastfeed (see section 4.3).

Patients should not drive, use machinery or perform any tasks that require concentration until they are certain that ASPEN WARFARIN 5 mg does not adversely affect their ability to do so safely (see section 4.8).

a) Tabulated list of adverse reactions

System organ class Frequent Less frequent Frequency unknown (cannot be estimated from the available data)

Infections and infestations Fever

Blood and the lymphatic system disorders Anaemia, leukopenia, granulocytosis

Immune system disorders Hypersensitivity reactions

Metabolism and nutrition disorders Inhibition of vitamin K synthesis, lipid emboli, including systemic athero- emboli and cholesterol emboli

Nervous system disorders Cerebral haemorrhage

Vascular disorders Haemorrhage from almost any organ of the body with the consequent effects of haematomas. Intracranial haemorrhage, including cerebral subdural haematoma, haemothorax, epistaxis, gastrointestinal haemorrhage, rectal haemorrhage, haematemesis.

Gastrointestinal disorders Pancreatitis, diarrhoea, nausea, vomiting, melaena, bloated stomach or gas, loss of appetite, stomach cramps or pain.

Hepatobiliary disorders Jaundice, hepatic dysfunction. Hepatotoxicity, usually asymptomatic and seen on laboratory results, dark urine.

Skin and subcutaneous tissue disorders Rash, alopecia, purpura, purple toe syndrome, erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis, skin reactions. Calciphylaxis, precipitating venous limb gangrene syndrome, sores, ulcers or white spots in the mouth or throat.

Musculoskeletal and connective tissue disorders Osteoporosis, increased risk of osteoporotic fracture due to vitamin K deficiency, patients on long-term ASPEN WARFARIN 5 mg treatment may be at increased risk.

Renal and urinary disorders Haematuria, renal damage with resultant oedema and Anticoagulant-related nephropathy (see section 4.4).

Reproductive system and breast disorders Priapism.

Investigations Unexplained drop in haematocrit, decreased haemoglobin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088/+27 (0)11 239-6200

See section 4.8.

Symptoms

Excessive bleeding may occur.

Treatment

The benefit of gastric decontamination is uncertain. If the patient presents within 1 hour of ingestion of more than 0,25 mg/kg or more than the patientu2019s therapeutic dose, consider activated charcoal (50 g for adults; 1 g/kg for children).

In cases of life-threatening haemorrhage

Stop warfarin treatment, give prothrombin complex concentrate (Factors II, VII, IX, and X) 30 to 50 units/kg or (if no concentrate available) fresh frozen plasma 15 ml/kg.

Non-life-threatening haemorrhage

Where anticoagulation can be suspended, give slow intravenous injection of phytomenadione (vitamin K 1) 10 mg to 20 mg for adults (250 micrograms/kg for a child). Where rapid re-anticoagulation is desirable (e.g. valve replacements) give prothrombin complex concentrate (Factors II, VII, IX, and X) 30 to 50 units/kg or (if no concentrate available) fresh frozen plasma 15 ml/kg. Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post overdose.

For patients on long-term warfarin therapy without major haemorrhage

• INR > 8,0 with no bleeding or minor bleeding - stop warfarin, and give phytomenadione (vitamin K 1) 0,5 mg to 1 mg for adults, 0,015 to 0,030 mg/kg (15 to 30 micrograms/kg) for children by slow intravenous injection or 5 mg by mouth (for partial reversal of anticoagulation give smaller oral doses of phytomenadione e.g. 0,5 mg to 2,5 mg using the intravenous preparation orally); repeat dose of phytomenadione if INR still too high after 24 hours. Large doses of phytomenadione may completely reverse the effects of warfarin and make re-establishment of anticoagulation difficult.
• INR 6,0 to 8,0, no bleeding or minor bleeding - stop warfarin, restart when INR is below appropriate target value.
• INR < 6,0 but more than 0,5 units above target value - reduce dose or stop warfarin, restart when INR is below target value.

For patients not on long-term anticoagulants without major haemorrhage

Measure the INR at presentation and sequentially every 24 to 48 hours after ingestion depending on the initial dose and initial INR.

If the INR remains normal for 24 to 48 hours and there is no evidence of bleeding, there should be no further monitoring necessary.

Give vitamin K 1 (phytomenadione) if:

a) there is no active bleeding and the patient has ingested more than 0,25 mg/kg or b) the INR is already significantly prolonged (INR > 4,0). The adult dose of vitamin K 1 is 10 mg to 20 mg orally (250 micrograms/kg body weight for a child). Delay oral vitamin K 1 at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K 1.