SULINDAC

1. Drug Name

• Generic Name: Sulindac

• Brand Names: Clinoril, Sulindac

2. Drug Classification

• Class: Nonsteroidal Anti-Inflammatory Drug (NSAID)

• Subclass: Indene derivative

3. Mechanism of Action

• Sulindac works by inhibiting cyclooxygenase (COX) enzymes, both COX-1 and COX-2, which results in reduced production of prostaglandins that mediate pain, inflammation, and fever.

• Its mechanism is similar to other NSAIDs, though sulindac is a prodrug that is metabolized to its active sulfide form, which exerts the pharmacologic effects.

• Sulindac also has some effects on leukocyte migration and lysosomal membrane stabilization, contributing to its anti-inflammatory activity.

4. Pharmacokinetics

• Absorption: Well absorbed orally, with a bioavailability of approximately 50-60%. Peak plasma concentration is reached in about 2-4 hours after oral administration.

• Distribution: Volume of distribution (Vd) is about 0.15 L/kg, and the drug is highly protein-bound (99%) to plasma proteins.

• Metabolism: Sulindac is a prodrug that is metabolized in the liver to its active sulfide form via CYP450 enzymes (particularly CYP2C9).

• Excretion: The half-life (t½) of the active metabolite is approximately 7-16 hours. Excretion occurs primarily through the kidneys and to a lesser extent through the feces.

• Special Considerations: Patients with renal impairment may experience prolonged drug elimination, requiring dose adjustments.

5. Indications

• Primary Indications:

  • Acute and chronic treatment of pain and inflammation associated with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

  • Management of acute gouty arthritis.

• Off-Label Uses:

  • Treatment of bursitis and tendinitis.

  • Used in the management of Familial Adenomatous Polyposis (FAP) for chemoprevention of colorectal cancer.

• Specific Populations: Primarily used in adults; not recommended in pediatric patients unless specifically advised by a healthcare provider.

6. Dosage and Administration

• Adults:

  • Osteoarthritis/Rheumatoid Arthritis: 150-200 mg daily in one or two divided doses. If necessary, the dose may be increased up to 400 mg per day.

  • Acute Gout: 200 mg twice daily for 7-14 days.

• Pediatric: Safety and efficacy in children under 18 years have not been well established for most indications.

• Route: Oral administration.

• Dosing Adjustments:

  • In cases of renal impairment, the dose may need to be reduced, and renal function should be monitored.

• Maximum Safe Dose: 400 mg per day.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to sulindac or any component of the formulation.

  • Active peptic ulcer disease or history of GI bleeding.

  • Severe hepatic or renal impairment.

  • Pregnancy (especially in the third trimester) due to risks of fetal harm, including premature closure of the ductus arteriosus.

• Relative Contraindications:

  • Asthma or a history of aspirin-exacerbated respiratory disease.

  • Cardiovascular disease and high risk of thrombotic events.

  • Congestive heart failure, as NSAIDs may exacerbate fluid retention and worsen the condition.

8. Warnings and Precautions

• Black Box Warnings:

  • Increased risk of serious cardiovascular events (e.g., myocardial infarction, stroke) associated with long-term NSAID use, especially in patients with preexisting cardiovascular conditions.

  • GI bleeding, ulceration, and perforation are serious risks, which may be fatal.

• Special Warnings:

  • Renal Function: Use with caution in patients with renal dysfunction as sulindac can cause or worsen renal impairment.

  • Elderly Patients: Higher risk of adverse gastrointestinal and renal effects; dose reduction may be required.

  • Liver Disease: May cause hepatic toxicity, so liver function should be monitored in patients with existing liver disease.

• Monitoring Parameters:

  • Monitor liver enzymes, renal function, and blood pressure, particularly with long-term therapy.

9. Adverse Effects

• Common Adverse Effects (≥10%): GI discomfort (nausea, abdominal pain, indigestion), headache, dizziness.

• Less Common but Clinically Significant: Edema, elevated liver enzymes, skin rash.

• Rare/Serious Adverse Reactions:

  • Gastrointestinal: Severe GI bleeding, ulcers, and perforation.

  • Hepatotoxicity: Risk of liver damage, including hepatitis and liver failure.

  • Renal Toxicity: Can lead to acute renal failure, particularly in patients with predisposing conditions (e.g., dehydration, renal insufficiency).

  • Severe allergic reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis.

10. Drug Interactions

• Major Drug Interactions:

  • Anticoagulants (e.g., warfarin): Increases the risk of bleeding due to synergistic effects.

  • Lithium: May increase plasma lithium levels, leading to toxicity.

  • ACE inhibitors/ARBs: Increased risk of renal dysfunction.

  • Methotrexate: Increases methotrexate toxicity, especially with high doses.

• Food-Drug Interactions: Food may delay absorption, but it does not significantly alter the extent of absorption.

• Interactions with Lab Tests: May cause mild elevations in liver enzymes, renal function markers (creatinine, BUN), and prolong bleeding time.

11. Clinical Pharmacology

• Sulindac’s pharmacodynamics involve the inhibition of COX-1 and COX-2, leading to a reduction in the synthesis of prostaglandins. By reducing inflammation and pain, it is effective for long-term management of osteoarthritis and rheumatoid arthritis.

• Due to its prodrug nature, sulindac’s active sulfide metabolite is responsible for its therapeutic effects, and it has a moderate half-life, enabling once- or twice-daily dosing.

12. Special Populations

• Pregnancy: Contraindicated, particularly in the third trimester due to risks of fetal harm, including premature closure of the ductus arteriosus.

• Lactation: It is not known whether sulindac is excreted in breast milk, but caution is advised in breastfeeding mothers.

• Geriatrics: Elderly patients are more prone to adverse GI and renal effects. Lower doses and close monitoring are recommended.

• Renal/Hepatic Dysfunction: Use with caution in patients with impaired renal or hepatic function. Dose reductions may be necessary, and these patients should be closely monitored.

13. Therapeutic Uses

• First-Line Therapy: Sulindac is used for the treatment of inflammatory arthritis (e.g., osteoarthritis, rheumatoid arthritis) and acute pain management in conditions like gout.

• Second-Line Therapy: Can be used as an adjunct to other analgesics for pain management, especially when other NSAIDs are not well tolerated.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Periodic liver function tests, renal function tests, and complete blood counts during long-term therapy.

• Patient-Reported Symptom Checklists: Monitor for GI symptoms such as abdominal pain, bleeding, or dyspepsia.

• Monitoring of Therapeutic and Toxic Levels: Careful monitoring for signs of GI bleeding, renal toxicity, and liver dysfunction.

15. Overdose Management

• Symptoms of Overdose: Nausea, vomiting, abdominal pain, dizziness, and drowsiness. Severe overdose can lead to renal failure, hypotension, or coma.

• Treatment Protocols:

  • Activated charcoal if overdose occurred within 1-2 hours of ingestion.

  • Supportive care, including IV fluids and symptomatic treatment.

  • Hemodialysis is not typically effective, as sulindac is highly protein-bound.

16. Patient Counseling Information

• Advise patients to take sulindac with food to reduce gastrointestinal irritation.

• Instruct patients to be aware of signs of GI bleeding (e.g., black stools, hematemesis), liver issues (e.g., jaundice, dark urine), and renal toxicity (e.g., decreased urination, swelling).

• Inform patients to avoid alcohol and to limit other NSAIDs to reduce the risk of side effects.