Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Mercury Pharma Group Ltd, Capital House, 85 King William Street, London EC4N 7BL, UK
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.
The following may exaggerate the effects of Dindevan and require a reduction of dosage:
The following may reduce the effects of Dindevan and may require the dosage to be increased:
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.
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.
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.
Patients for whom adherence may be difficult should be monitored more frequently.
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.
The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. Dindevan 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).
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease, serious heart disease, risk of falling, anaemia, malignancy, trauma, renal insufficiency, concomitant drugs (see section 4.5). 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 can indicate an overdose of Dindevan has been taken. For advice on treatment of haemorrhage see section 4.9.
Unexpected bleeding at therapeutic levels should always be investigated and INR monitored.
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.
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, Dindevan 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 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 post-operative haemorrhage. In most instances Dindevan treatment can be re-started 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.
Dindevan need not be stopped before routine dental surgery e.g. tooth extraction.
Due to a high risk of bleeding, patients with active peptic ulcers should be treated with caution. Such patients should be reviewed regularly and informed of how to recognise bleeding and what to do in the event of bleeding occurring.
Many drugs and foods interact with Dindevan and affect the prothrombin time (see section 4.5). Any change to medication, including self-medication with OTC products, warrants increased monitoring of the INR. Patients should be instructed to inform their doctor before they start to take any additional medications including over the counter medicines, herbal remedies or vitamin preparations.
Patients with hyper- or hypo-thyroidism should be closely monitored on starting Dindevan therapy.
Acquired or inherited Dindevan resistance should be suspected if larger than usual daily doses of Dindevan are required to achieve the desired anticoagulant effect.
Genetic variability particularly in relation to VKORC1 can significantly affect dose requirements for Dindevan. If a family association with this polymorphism is known extra care is warranted.
Care is required with all concomitant therapy with Dindevan. The individual product information for any new concomitant therapy should be consulted for specific guidance on Dindevan 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.
Concomitant use of drugs used in the treatment or prophylaxis of thrombosis or other drugs with adverse effects on haemostasis may increase the pharmacological effect of Dindevan, increasing the risk of bleeding.
Fibrinolytic drugs such as streptokinase and alteplase are contra-indicated in patients receiving Dindevan.
The following examples should be avoided or administered with caution with increased clinical and laboratory monitoring:
Low-dose aspirin with Dindevan may have a role in some patients but the risk of gastrointestinal bleeding is increased.
Listed below are drugs which are known to interact with Dindevan in a clinically significant way.
Examples of drugs which potentiate the effect of Dindevan:
Examples of drugs which antagonise the effect of Dindevan:
Barbiturates, Carbamazepine; Griseofulvin, Phenytoin,
Broad spectrum antibiotics may potentiate the effect of Dindevan by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyramine and sucralfate potentially decrease absorption of Dindevan. Increased INR has been reported in patients taking glucosamine and other anticoagulant (e.g. warfarin) and the potential for similar effect exists with Dindevan, accordingly this combination is not recommended.
Many herbal products have a theoretical effect on Dindevan. Patients should generally avoid taking any herbal medicines or food supplements whilst taking Dindevan and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Individual case reports suggest a possible interaction between other anticoagulant (e.g. warfarin) and cranberry juice, in most cases leading to an increase in INR or bleeding event. The possibility of similar occurrence with Dindevan may exist. Increased supervision and INR monitoring should be considered for any patient taking Dindevan and regular cranberry juice.
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 Dindevan; however most of these interactions are not proven. Patients should generally avoid taking any food supplements whilst taking Dindevan, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Heparins and danaparoid may prolong the prothrombin time, therefore a sufficient time interval should be allowed after administration before performing the test.
Oral anticoagulant therapy is contraindicated in pregnancy because of possible teratogenicity and the risk of foetal haemorrhage near term.
It is suggested that heparin, which does not cross the placenta, can be used during the first trimester and after 37 weeks of gestation. However, the use of heparin during pregnancy is not absolutely safe and specialist guidance should be obtained for patients who are pregnant and who need anticoagulant therapy.
Women of child-bearing age who are treated with Dindevan should be cautioned about the possible complications of pregnancy.
As Dindevan is distributed into breast milk, infants should not be fed with breast milk from mothers being treated with Dindevan (see section 4.3).
Dindevan has no or negligible influence on the ability to drive or use machines.
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:
Not known: Fever
Not known: leucopenia; agranulocytosis*; lymphadenopathy*; eosinophilia*; Leukocytosis*; Pancytopenia*; leukaemoid syndrome*
Not known: Hypersensitivity
Not known: Cerebral haemorrhage; cerebral subdural haematoma
Not known: Haemorrhage
Not known: Haemothorax, epistaxis
Not known: Gastrointestinal haemorrhage, rectal haemorrhage, haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena; Dysgeusia
Not known: Hepatitis, jaundice*
Not known: rash*, purpura; Blue toe syndrome; ecchymosis; alopecia*; skin necrosis*; dermatitis exfoliative*, exanthema.
Not known: Haematuria; renal damage with tubular necrosis*; albuminuria*
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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