Phenindione

Phenindione is an anticoagulant agent belonging to Vitamin K Antagonist.

Phenindione is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post-myocardial infarction.

Phenindione is absorbed slowly from the gastrointestinal tract. Time to peak plasma concentration: 1-3 hours. Phenindione crosses the placenta and enters breast milk. The plasma protein binding of Phenindione is approximately 88 %. Pre-systemic metabolism is noted to be 3% ±2. Renal Excretion accounts for exclusive and plasma half-life is 5 - 6 hours.

Phenindione shows common side effects like Bleeding, skin rash, fever, diarrhea, vomiting, sore throat, skin necrosis, bruising, liver inflammation, a blood disorder, dark stools, blood, and pink or orange coloration of urine.

Phenindione is available in the form of an Oral tablet.

Phenindione is available in India, Canada, Malaysia, Germany, and Australia.

Phenindione belonging to the Vitamin K Antagonist acts as an anticoagulant agent.

Phenindione inhibits vitamin K reductase, resulting in the depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

The onset of action of Phenindione occurs within 36-48 hours.

The Duration of Action for Phenindione in the body is approximately 48-72 hours.

Phenindione is available in the form of an Oral Tablet.

Phenindione Tablet is taken orally.

Phenindione is an anticoagulant, prescribed for thromboembolic (blood clot) disorders such as deep vein thrombosis and pulmonary embolism.

Phenindione is an anticoagulant agent belonging to Vitamin K Antagonist.

Phenindione antagonizes the effects of vitamin K and interferes w/ the formation of clotting factors II, VII, IX, and X.

Phenindione is approved for use in the following clinical indications

• Prophylaxis or treatment of thromboembolic disorders

For the treatment of pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, mural thrombosis, and thrombophilia.

• Prophylaxis or treatment of thromboembolic disorders

Adult:

Initial: 200 mg in 2 equal doses on day 1, then 100 mg on day 2. Maintenance: 50-150 mg/day.

Phenindione is available in various strengths as 10mg and 25mg.

Phenindione is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

Severe: Contraindicated.

• Dosage Adjustment in Hepatic impairment Patient

Severe: Contraindicated.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include ginseng, ginkgo, ginger, and garlic.

Phenindione is Contraindicated in patients with severe liver or kidney diseases, infection of heart valves, actual or potential bleeding conditions, patients with uncontrolled high blood pressure, hypersensitivity, and pregnancy.

• Thrombophilia

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 S deficiency may also be at risk and it is advisable to introduce Phenindione therapy slowly in these circumstances.

• Risk of hemorrhage

The most frequently reported adverse effect of all oral anticoagulants is hemorrhage. Phenindione should be given with caution to patients where there is a risk of serious hemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal Bleeding). Risk factors for Bleeding include the 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, anemia, malignancy, trauma, renal insufficiency, concomitant drugs. All patients treated with Phenindione 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 the risk of Bleeding and to report immediately to physicians signs and symptoms of Bleeding. Checking the INR and reducing or omitting doses depending on the INR level is essential, following consultation with anticoagulation services if necessary. If the INR is found to be too high, reduce the dose or stop Phenindione 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 to an increased risk of Bleeding.

• Hemorrhage

Hemorrhage can indicate an overdose of Phenindione has been taken. For advice on the treatment of hemorrhage. Unexpected Bleeding at therapeutic levels should always be investigated and INR monitored.

• Ischemic stroke

Anticoagulation following an ischaemic stroke increases the risk of secondary hemorrhage 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 blood pressure. In patients with large embolic strokes or uncontrolled hypertension, Phenindione 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, Phenindione 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 Phenindione cannot be stopped 3 days beforehand, anticoagulation should be reversed with low-dose vitamin K. The timing for re-instating Phenindione therapy depends on the risk of postoperative hemorrhage. In most instances, Phenindione 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 Phenindione for some days. For this reason, fresh-frozen plasma should be administrated to patients with prosthetic heart valves when a hemorrhage has occurred.

• Dental Surgery

Phenindione 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 be treated with caution. Such patients should be reviewed regularly and informed of how to recognize bleeding and what to do in the event of Bleeding occurring.

As Phenindione is distributed into breast milk, infants should not be fed with breast milk from mothers being treated with Phenindione.

Oral anticoagulant therapy is contraindicated in pregnancy because of possible teratogenicity and the risk of fetal hemorrhage 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 childbearing age who are treated with Phenindione should be cautioned about the possible complications of pregnancy.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include ginseng, ginkgo, ginger, and garlic.

• Common Adverse effects

Hypersensitivity reactions (including fever, lymphadenopathy, agranulocytosis, eosinophilia, leukocytosis, pancytopenia, leukemoid syndrome, diarrhea, vomiting, jaundice, rash, alopecia, skin necrosis, exfoliative dermatitis, renal damage w/ tubular necrosis, albuminuria), hemorrhage. Rarely, calciphylaxis. Cerebral hemorrhage, cerebral subdural hematoma, Haemorrhage, GI hemorrhage, rectal hemorrhage, haematemesis, pancreatitis, dysgeusia, nausea, melaena, Haemothorax, epistaxis, Hepatitis, Pink- or orange-colored urine, haematuria, decreased hematocrit, decreased Hb, leucopenia, Purpura, blue toe syndrome, ecchymosis, exanthema.

The following drugs should be avoided or taken with caution while taking Phenindione

• Clopidogrel
• 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
• SSRI and SNRI antidepressants
• Clofibrate
• Miconazole
• Antineoplastics
• Other drugs inhibit hemostasis, clotting, or platelet action.
• Low-dose aspirin with Phenindione may have a role in some patients, but the risk of gastrointestinal Bleeding is increased.

Examples of drugs that potentiate the effect of Phenindione

• ACTH, allopurinol, amitriptyline/nortriptyline, Cimetidine, Dextropropoxyphene, Glucagon, Hepato-toxic drugs, Phenformin, Thyroid compounds, Tolbutamide
• Disulfiram, amiodarone, propafenone, anabolic steroids, corticosteroids, oral contraceptives, and zafirlukast.

Examples of drugs that antagonize the effect of Phenindione

• Barbiturates, Carbamazepine; Griseofulvin, Phenytoin

The common side effects of Phenindione include the following

• Common

Bleeding, skin rash, fever, diarrhea, vomiting, sore throat, skin necrosis, bruising, liver inflammation, a blood disorder, dark stools, blood, and pink or orange coloration of urine.

• Rare

Hypersensitivity reactions.

• Pregnancy

Pregnancy Category

Oral anticoagulant therapy is contraindicated in pregnancy because of possible teratogenicity and the risk of fetal hemorrhage 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 childbearing age who are treated with Phenindione should be cautioned about the possible complications of pregnancy.

• Nursing Mothers

As Phenindione is distributed into breast milk, infants should not be fed with breast milk from mothers being treated with Phenindione.

• Symptoms: Spontaneous bruising, hematomas, haematuria, rectal Bleeding, hemorrhage into any internal organ.
• Management: Give activated charcoal if ingestion is recent (w/in 1 hr) and the ingested amount is >0.25 mg/kg or more than the patient's therapeutic dose. If prothrombin time is prolonged w/ no active bleeding, give vit K 0.5-1 mg by slow IV infusion. If w/ active Bleeding, give fresh frozen plasma and vit K 1 mg by slow IV infusion. If w/ life threatening hemorrhage, give fresh frozen plasma or factor concentrate.

Pharmacodynamic

Phenindione thins the blood by antagonizing vitamin K which is required to produce clotting factors in the liver. Anticoagulants such as Phenindione have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage (damage caused by an inadequate blood supply to an organ or part of the body). However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae. Phenindione has actions similar to warfarin, but it is now rarely employed because of its higher incidence of severe adverse effects.

Pharmacokinetics

• Absorption

Phenindione is absorbed slowly from the gastrointestinal tract. Time to peak plasma concentration: 1-3 hours.

• Distribution

Phenindione crosses the placenta and enters breast milk. The plasma protein binding of Phenindione is approximately 88 %.

• Metabolism and Excretion

Pre-systemic metabolism is noted to be 3% ±2. Renal Excretion accounts for exclusive and plasma half-life is 5 - 6 hours.

• https://go.drugbank.com/drugs/DB00498
• https://www.mims.com/philippines/drug/info/phenindione?mtype=generic
• https://www.medindia.net/doctors/drug_information/phenindione.htm#Prescription
• https://www.druginfosys.com//drug.aspx?drugCode=560&type=1#Kinetics