Heamawarin 5 mg Tablets

Heamawarin is indicated for:

• the prevention and management of deep vein thrombosis.
• the prevention and management of pulmonary embolism.
• the prevention of thromboembolism in:
• atrial fibrillation.
• prosthetic heart valves.
• post myocardial infarction.
• the treatment of transient ischaemic attacks.

Posology

The administration and dosage of Heamawarin 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 u2013 2,5 (PT ratio 1,3 u2013 1,5) Prophylaxis of deep vein thrombosis (DVT), including surgery in high risk patients.

INR 2,0 u2013 3,0 (PT ratio 1,3 u2013 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 u2013 4,5 (PT ratio 1,5 u2013 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.

• Known hypersensitivity to warfarin or to any of the excipients listed in section 6.1;
• Haemorrhagic states;
• Haemorrhagic stroke (see section 4.4);
• Clinically significant bleeding;
• Within 72 hours of major surgery with risk of severe bleeding (see section 4.4);
• Peptic ulceration or other gastrointestinal disorders involving bleeding;
• Conditions involving bleeding from respiratory or genito-urinary tract;
• Severe wounds (including surgical);
• Prosthetic heart valves;
• Infective endocarditis;
• Impaired liver function;
• Impaired kidney function;
• Hypertension;
• Cerebrovascular haemorrhage;
• Aneurysm (cerebral or aortic);
• Pericarditis, pericardial effusion;
• Neuro- or ophthalmic surgery - recent or contemplated;
• Surgery involving large exposed raw surfaces;
• Within 48 hours postpartum;
• Polyarthritis;
• Vitamin C deficiency;
• Major regional block anaesthesia;
• Inadequate laboratory facilities or lack of patient co-operation;
• Threatened abortion;
• 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);
• Pregnancy and lactation (see section 4.6).

Most adverse events reported with warfarin 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.

Patient monitoring

Dosage should be individualised for each patient and periodic determinations of prothrombin time should be done (see section 4.2). Patients should be given a patient information leaflet and informed of symptoms for which they should seek medical attention. Patients should be given detailed instructions concerning their medicine, the importance of compliance and advice concerning modification of their lifestyle if necessary. The possibility of interactions-should be explained. Patients should carry an anticoagulant card or other proof that they are on anticoagulants. Patients for whom adherence may be difficult should be monitored more frequently.

Commencement of therapy

When therapy with Heamawarin is started using a standard dosing regimen the 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).

Thrombophilia

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

Cessation of therapy

Abrupt cessation of anticoagulant therapy is not recommended. The dose should be tapered over three to four weeks.

Haemorrhage

The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. Heamawarin 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) (see section 4.3).

Risk factors for bleeding include high intensity of anticoagulation (INR >4,0), age u226565, 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 Heamawarin should have 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 report immediately to medical practitionersu2019 signs and symptoms of bleeding.

Checking the INR and reducing or omitting doses depending on INR level is essential. If the INR is found to be too high, reduce dose or stop warfarin treatment; sometimes it will be necessary to reverse anticoagulation. INR should be checked within 2u20133 days to ensure that it is falling.

Any concomitant anti-platelet medicines should be used with caution due to an increased risk of bleeding. Unexpected bleeding at therapeutic levels should always be investigated and INR monitored (see section 4.3).

Special populations

Special care is required in the elderly, in patients with Vitamin K deficiency and in patients with hyperthyroidism. The rate of warfarin metabolism depends on thyroid status. Therefore, patients with hyper- or hypothyroidism should be closely monitored on starting treatment with Heamawarin. INR should be monitored more frequently in patients at an increased risk of over coagulation e.g., patients with severe hypertension, liver or renal disease.

Heamawarin should be used with caution in patients with:

• Prolonged dietary deficiency;
• Infectious diseases or disturbances of intestinal flora, sprue, antibiotic therapy;
• Polycythaemia vera, vasculitis, severe diabetes, allergic or anaphylactic disorders.

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 Heamawarin is beneficial, but the risk of early recurrent embolism is low and therefore a break in treatment after ischaemic stroke is justified. Heamawarin 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.

Calciphylaxis

Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking warfarin, also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with Heamawarin.

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, Heamawarin should be stopped 3 days prior to surgery. Where it is necessary to continue anticoagulation e.g., risk of life-threatening thromboembolism, the INR should be reduced to <2.5 and heparin therapy should be started. If surgery is required and Heamawarin cannot be stopped 3 days beforehand, anticoagulation should be reversed with low-dose vitamin K. The timing for re-instating Heamawarin therapy depends on the risk of post-operative haemorrhage. In most instances Heamawarin treatment can be re-started as soon as the patient has an oral intake. The need for modification of therapy before elective operative procedures or in women contemplating pregnancy should be discussed.

Dental Surgery

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 or Heamawarin need not be stopped before routine dental surgery, e.g., tooth extraction.

Active peptic ulceration

Due to a high risk of bleeding, patients with active peptic ulcers should not be treated with Heamawarin (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. Heamawarin 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 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 Heamawarin or vitamin K;
• Additional anticoagulant effects by medicines that inhibit platelet function.

Pharmacodynamic interactions

Medicines that 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 Heamawarin, increasing the risk of bleeding. Fibrinolytic medicines such as streptokinase and alteplase are contraindicated in patients receiving Heamawarin (see section 4.3).

Medicines which should be avoided if possible

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

• Clopidogrel.
• Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cox-2 specific NSAIDS.
• Sulfinpyrazone.
• Thrombin inhibitors such as bivalirudin, dabigatran.
• Dipyridamole.
• 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 (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants.
• Other medicines which inhibit haemostasis, clotting or platelet action.

Dipyridamole and aspirin can cause bleeding when given to patients taking anticoagulants, but without any alteration in INR. Low-dose aspirin with Heamawarin may the risk of gastrointestinal bleeding. Heamawarin may initially be given in conjunction with a 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 Heamawarin dosage 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, Heamawarin dosage may need to be increased and the level of monitoring increased. There is a small subset of medicines for which interactions are known; however, the 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).

Listed below are medicines which are known to interact with warfarin in a clinically significant way.

Medicines which potentiate the effect of warfarin

allopurinol, capecitabine, erlotinib, disulfiram, azole antifungals (ketoconazole, fluconazole, miconazole) omeprazole, paracetamol (prolonged regular use), propafenone, amiodarone, tamoxifen, methylphenidate zafirlukast, fibrates, statins (not pravastatin; predominantly associated with fluvastatin) erythromycin, telithromycin, co-trimoxazole, metronidazole, chloramphenicol, cimetidine, clofibrate, danazol, glucagon, quinidine, dextropropoxyphene, vitamin E, thyroid hormones, diazoxide, aminoglycosides, alcohol, triclofos, chloral hydrate, sulphonamides, sulphonylurea-type antidiabetic medicines, phenylbutazone and other pyrazolones, anabolic steroids, sulphinpyrazone, aspirin and other NSAIDS, and amiodarone.

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 Heamawarin therapy, hyperlipaemia and hypothyroidism.

Other interactions

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

Interactions with herbal products

Herbal preparations containing St John's Wort (Hypericum perforatum) must not be used whilst taking Heamawarin, due to a proven risk of decreased plasma concentrations and reduced clinical effects of warfarin. Many other herbal products have a theoretical effect on Heamawarin; however, most of these interactions are not proven. Patients should generally avoid taking any herbal medicines or food supplements whilst taking Heamawarin 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 warfarin.

Interactions with food and food supplements

A possible interaction between Heamawarin and cranberry juice may occur and, 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 Heamawarin and regular cranberry juice. Grapefruit juice may cause a modest rise in INR in some patients taking Heamawarin. 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 Heamawarin; however, most of these interactions are not proven. Patients should generally avoid taking any food supplements whilst taking Heamawarin 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 prothrombin time, therefore a sufficient time interval should be allowed after administration before performing the test.

Women of childbearing potential

Women of childbearing age who are taking Heamawarin should use effective contraception during treatment and for at least 1 month after the final dose of Heamawarin.

Pregnancy

Warfarin is a recognised teratogen. Treatment with Heamawarin during pregnancy should be avoided (see section 4.3).

Breastfeeding

Treatment with Heamawarin during breastfeeding should be avoided (see section 4.3).

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

MedDRA System organ class Frequency Undesirable effect

Infections and infestations frequency not known Fever

Blood and lymphatic system disorders less frequent Leukopenia, granulocytosis

Immune system disorders frequency not known Hypersensitivity

Metabolism and nutrition disorders less frequent Inhibits vitamin K synthesis, lipid emboli, including systemic athero-emboli and cholesterol emboli

Nervous system disorders frequency not known Cerebral haemorrhage; Cerebral subdural haematoma

Vascular disorders frequency not known Haemorrhage with consequent effects of haematomas and anaemia

Respiratory, thoracic and mediastinal disorders frequency not known Haemothorax, epistaxis

Gastrointestinal disorders less frequent Diarrhoea; nausea; vomiting; bloated stomach or gas; loss of appetite; stomach cramps or pain; melaena frequency not known Gastrointestinal haemorrhage, rectal haemorrhage, haematemesis; pancreatitis

Hepato-biliary disorders frequency not known Jaundice; hepatic dysfunction; hepatotoxicity, usually asymptomatic and seen on laboratory results, dark urine

Skin and subcutaneous tissue disorders frequency not known Rash; alopecia; purpura; u2018purple toesu2019 syndrome; erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis, calciphylaxis, precipitating venous limb gangrene syndrome, sores, ulcers or white spots in the mouth or throat

Musculoskeletal and connective tissue disorders less frequent Increased risk of osteoporotic fracture due to vitamin K deficiency. Patients on long-term Heamawarin treatment may be at increased risk

Renal and urinary disorders less frequent Haematuria, renal damage with resultant oedema and proteinuria, with difficulty in urination

Investigations frequency not known Unexplained drop in haematocrit; haemoglobin decreased

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/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 patient's 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 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, no bleeding or minor bleeding - stop warfarin, and give phytomenadione (vitamin K 1) 0,5 to 1 mg for adults, 0,015u20130,030 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 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 reaches appropriate target levels.
• INR <6,0 but more than 0,5 units above target value - reduce dose or stop warfarin, restart when INR reaches appropriate target levels.

For patients NOT on long-term anticoagulants without major haemorrhage

Measure the INR (prothrombin time) 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 prothrombin time is already significantly prolonged (INR >4,0). The adult dose of vitamin K 1 is 10 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.