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Precautions and Warnings

Most adverse reactions to phenindione 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 advised 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 effects of phenindione may be increased and a dosage reduction may be required in the following:
Weight loss
Elderly
Acute illness
Mild to moderate renal impairment
Decreased dietary intake of vitamin K

The effects of phenindione may be reduced and an increase in dosage may be required in the following:
Weight gain
Diarrhoea
Vomiting
Increased intake of vitamin K, fats or oils

When phenindione 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.

The INR should be monitored more frequently in patients at an increased risk of over anticoagulation e.g. patients with severe hypertension, liver or renal disease, and in patients for whom adherence may be difficult.

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

Phenindione should be used with caution in patients with a risk of serious haemorrhage, e.g. concomitant NSAIDs, recent ischaemic stroke, peptic ulcer or previous gastrointestinal bleeding.

Risk factors for bleeding include high intensity of anticoagulation (INR greater than 4, age greater than or equal to 65, highly variable INRs, cerebrovascular disease, serious heart disease, risk of falling, anaemia, malignancy, trauma.

Patients should be instructed in measures to minimise risk of bleeding and to report immediately any signs or symptoms of bleeding.

Monitoring the INR and reducing or omitting doses depending in the INR result is essential, following consultation with anticoagulant services if necessary. If the INR is found to be too high, reduce dose or stop phenindione therapy. Sometimes it may be necessary to reverse anticoagulation. The INR should be checked within 2-3days to ensure that it is falling.

Haemorrhage can indicate an overdose of phenindione. 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 phenindione is beneficial, but the risk of early recurrent embolism is low and therefore a break in treatment after ischaemic stroke is justified. Phenindione treatment should be re-started 2-14 days following ischaemic stroke, depending on the size of the infarct and the blood pressure. In patients with large embolic strokes, or uncontrolled hypertension, phenindione treatment should be stopped for 14 days.

For surgery where there is no risk of bleeding, surgery can be performed with an INR below 2.5. For surgery where there is a risk of severe bleeding, phenindione should be stopped 3 days prior to surgery.

Where it is necessary to continue anticoagulation, the INR should be reduced to below 2.5 and heparin therapy should be started.

If surgery is required and phenindione cannot be stopped 3 days beforehand, anticoagulation should be reversed with low dose vitamin K.

Administration of vitamin K can lead to resistance to the action of phenindione for some days. For this reason, fresh-frozen plasma should be administered to patients with prosthetic heart valves when haemorrhage has occurred.

Phenindione need not be stopped before routine dental surgery.

Use with caution in patients with mild to moderate hepatic impairment.

Patients with hyper or hypothyroidism should be closely monitored on starting phenindione therapy.

Acquired or inherited phenindione resistance should be suspected if larger than usual daily doses of phenindione therapy are required to achieve the desired anticoagulant effect.

Genetic variability particularly in relation to VKORC1 can significantly affect dose requirements for phenindione. If a family association with this polymorphism is known extra care is warranted.

The metabolites of phenindione may cause a pink/orange discolouration of urine. To distinguish this effect from the presence of haemoglobin in the urine, add a few drops of dilute acetic acid to the urine. The discolouration will disappear immediately if caused by phenindione.

If any side effects occur, phenindione therapy should be discontinued immediately and blood, hepatic and renal function should be tested.

Women of child bearing age should be warned of the possible complications of pregnancy during phenindione administration.

Patients should be advised to avoid glucosamine, herbal medicines and food supplements as these may have an effect on phenindione. Patients should inform their physician if they are taking any of these as increased monitoring may be required. Increased supervision and INR monitoring should be considered for any patient taking phenindione and regular cranberry juice.

Certain foods 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.

Contains lactose. Use with caution in patients with glucose-galactose malabsorption syndrome and lactose intolerance.

Pregnancy and Lactation

Pregnancy

Contraindicated during pregnancy because of possible teratogenicity and the risk of foetal haemorrhage near term. There is limited information about the use of phenindione during pregnancy and therefore other agents with more evidence of safety during pregnancy may be preferred.

Women of child bearing age should be warned of the possible complications of pregnancy during phenindione administration.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Recommended for use in pregnancy? - No

Known human teratogen? - Yes

Lactation

Contraindicated during breastfeeding. There is little information on the use of phenindione during breastfeeding. Phenindione is approximately 70% protein bound and a higher transfer with a therapeutic dosage for an infant has been shown. There has been a report of a breastfed infant with pathological coagulation parameters and haematomas during the mother's treatment. There has also been a report of phenindione use in a breastfeeding woman which resulted in a massive scrotal haematoma and wound oozing in a 1.5 month old breastfed infant shortly after a herniotomy was performed.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug excreted in breast milk? - Yes

Considered suitable or recommended by manufacturer? - No

UK Drugs in Lactation Advisory Service classification - Contraindicated

Drug substance licensed in infants? - No

Presentation

Tablets containing 10mg phenindione
Tablets containing 25mg phenindione
Tablets containing 50mg phenindione

Drugs List

phenindione 10mg tablets

phenindione 25mg tablets

phenindione 50mg tablets

Therapeutic Indications

Uses

Anticoagulant therapy in the prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation.

Prophylaxis after insertion of prosthetic heart valves.

Prophylaxis and treatment of venous thrombosis and pulmonary embolism.

Dosage

Phenindione is a synthetic anticoagulant that interferes with the formation of factors II, VII, IX and X. An effect is produced 36 to 48 hours after the initial dose. The effect declines 48 to 72 hours following the cessation of phenindione therapy.

Adults

Initial loading dose of 200mg, followed on the second day by a dose of 100mg. From the third day, the dosage should be adjusted according to the results of the appropriate coagulation tests.

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

Maintenance doses of 50-150mg per day are sufficient in most patients. However, some patients may require doses of less than 50mg per day or more than 200mg per day.

Elderly

Use with caution in patients over 65 years as they may be at an increased risk of bleeding.

A dosage reduction may be required in elderly patients.

Children

Contraindicated. No information available on its use in children under 18 years.

Patients with Renal Impairment

Mild to moderate renal impairment

The effects of phenindione may be increased and a dosage reduction may be required.

Severe renal impairment

Contraindicated in these patients.

Patients with Hepatic Impairment

Mild to moderate hepatic impairment

Use with caution.

Severe hepatic impairment

Contraindicated in these patients.

Contraindications

Severe hepatic impairment
Severe renal impairment
Bacterial endocarditis
Actual or potential haemorrhagic conditions
Uncontrolled hypertension
Haemorrhagic stroke
Within 72hours of major surgery with risk of severe bleeding
Within 48hours postpartum
Children under 18 years
Pregnancy - see Pregnancy section
Breastfeeding - see Lactation section
Galactosaemia