Phenindione

Usage

• Phenindione is an anticoagulant medication primarily prescribed for the prevention and treatment of thromboembolic disorders. These disorders include deep vein thrombosis (DVT), pulmonary embolism (PE), and systemic embolism in patients with conditions like atrial fibrillation or rheumatic heart disease with mitral stenosis. It may also be used after a heart valve replacement.
• Pharmacological Classification: Anticoagulant (Vitamin K antagonist).
• Mechanism of Action: Phenindione inhibits the synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X) in the liver, thereby prolonging the time it takes for blood to clot.

Alternate Names

• Phenindione is the generic name.
• Brand Names: Dindevan (most common), Fenindion.

How It Works

• Pharmacodynamics: Phenindione decreases the production of vitamin K-dependent clotting factors, increasing the time taken for blood to clot. This effect is monitored by measuring the prothrombin time (PT) and calculating the International Normalized Ratio (INR).
• Pharmacokinetics:
  • Absorption: Well-absorbed orally.
  • Metabolism: Primarily hepatic metabolism.
  • Elimination: Primarily renal excretion. Phenindione has a relatively short half-life (5-6 hours), compared to warfarin, another commonly used vitamin K antagonist.
• Mode of Action: Phenindione competitively inhibits vitamin K epoxide reductase, the enzyme responsible for regenerating reduced vitamin K, a cofactor essential for the synthesis of clotting factors II, VII, IX, and X.
• Receptor Binding/Enzyme Inhibition: Vitamin K epoxide reductase inhibition.
• Elimination Pathways: Primarily renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Initial: 200 mg on day 1 (divided into two doses), followed by 100 mg on day 2.
• Maintenance: 25-200 mg daily, adjusted based on INR results. A typical maintenance dose range is 50–150 mg per day, taken once daily.
• Maximum Dosage: Doses above 200mg are generally not recommended.

Children:

• Phenindione is generally not recommended for children. Safety and efficacy have not been established in the pediatric population. If necessary, it should be prescribed by a specialist with experience in pediatric anticoagulation.

Special Cases:

• Elderly Patients: Lower initial and maintenance doses may be required due to age-related changes in drug metabolism and renal function. Close INR monitoring is essential.
• Patients with Renal Impairment: Dose reduction is necessary. Caution is advised in patients with severe renal impairment, where phenindione use may be contraindicated.
• Patients with Hepatic Dysfunction: Use with caution. Severe hepatic dysfunction is a contraindication.
• Patients with Comorbid Conditions: Dose adjustments may be required based on specific comorbidities and concomitant medications.

Clinical Use Cases

• Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations: Phenindione is not typically used in these settings due to its slower onset of action compared to other anticoagulants like heparin. It may be started concurrently with heparin but is not suitable for rapid anticoagulation or urgent reversal of anticoagulation.

Dosage Adjustments

• Dose adjustments are based on regular monitoring of INR and patient-specific factors like renal and hepatic function, concurrent medications, age, and body weight.

Side Effects

Common Side Effects:

• Bleeding (e.g., bruising, nosebleeds, bleeding gums, hematuria)
• Nausea, vomiting, diarrhea
• Skin rash, itching

Rare but Serious Side Effects:

• Severe bleeding (e.g., gastrointestinal bleeding, intracranial hemorrhage)
• Hepatotoxicity, jaundice
• Agranulocytosis, leukopenia
• Skin necrosis, exfoliative dermatitis
• Renal damage with tubular necrosis
• Hypersensitivity reactions (e.g., fever, rash, lymphadenopathy)

Long-Term Effects:

• Long-term use may increase the risk of osteoporosis.

Adverse Drug Reactions (ADR):

• Any signs of serious bleeding or hypersensitivity require immediate medical attention and discontinuation of the drug.

Contraindications

• Hypersensitivity to phenindione.
• Severe liver or kidney disease.
• Active bleeding or hemorrhagic disorders (e.g., haemorrhagic stroke, peptic ulcer).
• Bacterial endocarditis.
• Uncontrolled hypertension.
• Pregnancy and breastfeeding.
• Recent surgery or trauma.
• Within 48 hours postpartum.

Drug Interactions

• Many drugs interact with phenindione, potentially increasing or decreasing its anticoagulant effect. Some key interactions include:
  • Increased Anticoagulant Effect: NSAIDs, aspirin, amiodarone, cimetidine, many antibiotics.
  • Decreased Anticoagulant Effect: Barbiturates, carbamazepine, phenytoin, rifampicin.
  • Other Interactions: Cranberry juice, alcohol, vitamin K-rich foods can affect INR levels.
• Always consult a comprehensive drug interaction resource before co-prescribing medications with phenindione.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated. Phenindione can cross the placenta and cause fetal harm (e.g., fetal warfarin syndrome, including skeletal abnormalities, central nervous system defects, and fetal hemorrhage).
• Breastfeeding: Phenindione can be excreted in breast milk and may pose a risk to the nursing infant. Breastfeeding is contraindicated while taking this medication.

Drug Profile Summary

• Mechanism of Action: Vitamin K antagonist, inhibits synthesis of clotting factors II, VII, IX, and X.
• Side Effects: Bleeding, rash, nausea, vomiting, diarrhea; rarely, severe bleeding, hepatotoxicity, agranulocytosis, skin necrosis.
• Contraindications: Hypersensitivity, severe liver/kidney disease, active bleeding, pregnancy, breastfeeding.
• Drug Interactions: Numerous drug interactions; consult a drug interaction resource.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Initial: 200 mg day 1, then 100 mg day 2. Maintenance: 25-200 mg/day based on INR.
• Monitoring Parameters: INR (International Normalized Ratio).

Popular Combinations

• Phenindione is sometimes initially used in combination with heparin for rapid anticoagulation, followed by discontinuation of heparin once phenindione achieves therapeutic INR levels. However, warfarin has largely replaced phenindione for this purpose.

Precautions

• General Precautions: Close INR monitoring is essential. Patients should be educated about signs and symptoms of bleeding and the importance of regular blood tests.
• Specific Populations: Refer to Special Cases under Dosage section.
• Lifestyle Considerations: Alcohol intake should be limited. Patients should avoid activities that increase bleeding risk and inform all healthcare providers about their phenindione use.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Phenindione?

A: Initial: 200 mg on day 1 (divided into two doses), then 100 mg on day 2. Maintenance: 25-200 mg daily (typically 50–150 mg), adjusted based on INR results.

Q2: How is Phenindione administered?

A: Orally, as tablets, once a day.

Q3: What are the major side effects of Phenindione?

A: Bleeding (ranging from minor bruising to major hemorrhage), skin rash, nausea, vomiting, and diarrhea.

Q4: What are the contraindications for Phenindione?

A: Hypersensitivity, severe liver or kidney disease, active bleeding, pregnancy, breastfeeding, bacterial endocarditis, and uncontrolled hypertension.

Q5: How does Phenindione interact with other medications?

A: Phenindione interacts with numerous medications; consult a drug interaction resource before prescribing concurrently with other drugs. Many common medications (e.g., NSAIDs, some antibiotics) increase bleeding risk, while others (e.g., some anticonvulsants) may decrease phenindione’s effectiveness.

Q6: Can Phenindione be used during pregnancy or breastfeeding?

A: No, phenindione is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm and infant bleeding risk.

Q7: How is the effect of Phenindione monitored?

A: By regular monitoring of INR (International Normalized Ratio), which measures the clotting tendency of the blood.

Q8: What should patients be advised about while taking Phenindione?

A: Report any signs of bleeding, avoid activities that increase bleeding risk, adhere to the prescribed dosing schedule, limit alcohol intake, inform all healthcare providers (including dentists) about their phenindione use, and be aware of potential drug and food interactions (especially with cranberry juice and vitamin K rich foods).

Q9: Is there an antidote for Phenindione overdose?

A: Vitamin K1 is used to reverse the effects of phenindione. Fresh frozen plasma may be necessary in cases of severe bleeding.

Q10: Why is warfarin preferred over phenindione in most cases?

A: Phenindione carries a higher risk of serious side effects such as agranulocytosis, skin necrosis, and nephritis compared to warfarin. Warfarin’s longer half-life also allows for simpler, once-daily dosing, compared to phenindione, which may need multiple daily doses.