PHENINDIONE

Posology:

Adults: Initial loading dose of 200mg, followed on the second day by a dose of 100mg. Dosage must be adjusted from the third day, dependent on the results of the appropriate coagulation tests such as prothrombin time, reported as international normalised ratio (INR).

Note:

Concomitant heparin therapy affects the results of INR control tests, and heparin should be discontinued at least 6 hours before the first INR control test is undertaken. Control tests must be undertaken at regular intervals and the dosage adjusted according to the results of the INR tests.

A maintenance dose of 50-150mg/day is satisfactory in most patients, but a "resistant" patient may need 200mg/day or more. A "sensitive" patient may need less than 50mg/day. Method of administration Oral

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data) The following undesirable effects have been reported: System organ class database Frequency Adverse reactions Infections and infestations Not known Fever Blood and lymphatic system disorders Not known leucopenia; agranulocytosis*; lymphadenopathy*; eosinophilia*; Leukocytosis*; Pancytopenia*; leukaemoid syndrome* Immune system disorders Not known Hypersensitivity Nervous system disorders Not known Cerebral haemorrhage; cerebral subdural haematoma Vascular disorders Not known Haemorrhage Respiratory, thoracic and mediastinal disorders Not known Haemothorax, epistaxis Gastrointestinal disorders Not known Gastrointestinal haemorrhage, rectal haemorrhage, haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena; Dysgeusia Hepatobiliary disorders Not known Hepatitis, jaundice* Skin and subcutaneous tissue disorders Not known Rash*, purpura; Blue toe syndrome; ecchymosis; alopecia*; skin necrosis*; dermatitis exfoliative*, exanthema.

Renal and Urinary disorders Not known Haematuria; renal damage with tubular necrosis*; albuminuria* Investigations Not known Haematocrit decreased; haemoglobin decreased *These events have been reported in relation to hypersensitivity reactions.

If any of the above effects are found, Dindevan therapy should be stopped immediately, and a full investigation of blood, liver and renal function should be undertaken. Possible sensitivity to other drugs should be considered. Other anticoagulants, such as warfarin, are tolerated usually by patients sensitive to Dindevan.

An episode of bleeding during anticoagulant therapy must be investigated fully and not regarded automatically as a manifestation of overdosage. The metabolites of Dindevan often colour the urine pink or orange. This effect may be distinguished from discoloration caused by haemoglobin by the addition of a few drops of dilute acetic acid to the urine.

If the discoloration is due to Dindevan, the discoloration will disappear immediately. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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Most adverse events reported with Dindevan are a result of allergic reactions or over anticoagulation therefore it is important that the need for therapy is reviewed on a regular basis and therapy discontinued when no longer required.

Patients should be made aware of the symptoms of allergic reactions and told to seek medical advice if they experience any signs of allergic reactions. Patients should be given a patient-held information booklet (‘anticoagulant card’) and informed of symptoms for which they should seek medical attention.

5) 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 vitamin K antagonists, 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 Dindevan.

Monitoring When Dindevan 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 stabilized in the target range, the INR can be determined at longer intervals.

g. patients with severe hypertension, liver or renal disease. Patients for whom adherence may be difficult should be monitored more frequently. Thrombophilia Patients with protein C deficiency are at risk of developing skin necrosis when starting Dindevan treatment.

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

Risk of haemorrhage The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding). 5). All patients treated with Dindevan 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 minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding.

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 Dindevan treatment; sometimes it will be necessary to reverse anticoagulation.

INR should be checked within 2–3 days to ensure that it is falling. Any concomitant anti-platelet drugs should be used with caution due an increased risk of bleeding. Haemorrhage Haemorrhage can indicate an overdose of Dindevan has been taken.

9. Unexpected bleeding at therapeutic levels should always be investigated and INR monitored. Ischemic 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 Dindevan is beneficial, but the risk of early recurrent embolism is low and therefore a break in treatment after ischaemic stroke is justified.

Dindevan treatment should be re-started 2–14 days following ischaemic stroke, depending on the size of the infarct and blood pressure. In patients with large embolic strokes or uncontrolled hypertension, Dindevan treatment should be stopped for 14 days.

5. For surgery where there is a risk of severe bleeding, Dindevan should be stopped 3 days prior to surgery. g. 5 and heparin therapy should be started. If surgery is required and Dindevan cannot be stopped 3 days beforehand, anticoagulation should be reversed with low-dose vitamin K.

The timing for re-instating Dindevan therapy depends on the risk of postoperative haemorrhage. In most instances Dindevan treatment can be restarted as soon as the patient has an oral intake. Administration of Vitamin K can lead to resistance to the action of Dindevan for some days.

For this reason, fresh-frozen plasma should be administrated to patients with prosthetic heart valves when haemorrhage has occurred. g. tooth extraction. Active peptic ulceration Due to a high risk of bleeding, patients with active peptic ulcers should be treated with caution.

Such patients should be reviewed […]

1. 6) • Lactation: Infants should not be fed with breast milk from mothers being treated with Dindevan. 5) • Dindevan should not be given to patients with severe renal or hepatic disease, bacterial endocarditis, actual or potential haemorrhagic conditions, or to patients with uncontrolled hypertension