Apain-MS

A. Approved Indications

• Osteoarthritis (OA) in patients at high risk of developing NSAID-induced gastric ulcers.
• Rheumatoid Arthritis (RA) in patients with a history of gastrointestinal ulcers, GI bleeding, or at risk for NSAID-induced mucosal damage.

B. Clinically Accepted Off-label Uses

• Chronic Pain Management in Arthritic Conditions where NSAID therapy is required and concurrent gastric protection is warranted.
• NSAID-Induced Ulcer Prevention in patients requiring long-term NSAID therapy but with a high risk of GI complications.

Route of Administration: Oral

Recommended Dose in Adults:

• Osteoarthritis & Rheumatoid Arthritis: One tablet (containing 75 mg diclofenac sodium + 200 mcg misoprostol) twice daily.
• Alternatively: 50 mg diclofenac sodium + 200 mcg misoprostol three times daily.
• Maximum daily dose: Diclofenac 150 mg and Misoprostol 800 mcg.

Special Populations:

• Elderly:
• Start at the lower end of the dosing range.
• Monitor closely for gastrointestinal and renal side effects.
• Renal Impairment:
• Use with caution in mild-to-moderate impairment.
• Contraindicated in severe renal dysfunction.
• Hepatic Impairment:
• Use with caution.
• Monitor liver enzymes regularly.
• Pediatrics:
• Safety and efficacy not established; not recommended in pediatric patients.

Administration Notes:

• Take with food to reduce GI side effects.
• Swallow whole; do not crush or chew.

Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), leading to decreased prostaglandin synthesis and thereby reducing inflammation, pain, and swelling in arthritic conditions.
Misoprostol is a synthetic prostaglandin E1 analog that exerts gastroprotective effects by increasing gastric mucus and bicarbonate secretion and enhancing mucosal blood flow. It counteracts the ulcerogenic potential of diclofenac, especially in patients at risk for NSAID-induced gastrointestinal complications. Together, the combination offers anti-inflammatory effects while minimizing GI damage.

• Absorption:
• Diclofenac Sodium: Rapid and complete absorption; peak plasma levels in ~2 hours.
• Misoprostol: Rapid absorption; peak plasma concentration in ~30 minutes.
• Bioavailability:
• Diclofenac: ~50% (due to first-pass metabolism)
• Misoprostol: ~80–90%
• Distribution:
• Both extensively bound to plasma proteins; diclofenac >99%, misoprostol ~85%.
• Metabolism:
• Diclofenac: Hepatically metabolized by CYP2C9 to inactive metabolites.
• Misoprostol: Rapidly de-esterified to misoprostol acid (active form).
• Elimination:
• Primarily renal excretion of metabolites.
• Half-life:
• Diclofenac: ~1–2 hours
• Misoprostol acid: ~20–40 minutes

• Pregnancy:
• Misoprostol is contraindicated during pregnancy due to its abortifacient properties and risk of uterine rupture, miscarriage, or birth defects.
• FDA Pregnancy Category: X
• Lactation:
• Diclofenac: Present in breast milk in trace amounts.
• Misoprostol: Excreted in breast milk; may cause diarrhea in breastfed infants.
• Caution advised; avoid use unless benefits outweigh risks.

• Primary Class: NSAID with Gastroprotective Agent
• Subclasses:
• NSAID: Non-selective COX inhibitor (Diclofenac Sodium)
• Prostaglandin Analog: Gastrointestinal mucosal protector (Misoprostol)

• Known hypersensitivity to diclofenac, misoprostol, other NSAIDs, or prostaglandins
• Pregnancy (due to uterotonic effect of misoprostol)
• Active gastrointestinal bleeding, ulceration, or perforation
• Severe hepatic or renal impairment
• Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
• History of NSAID-induced asthma, angioedema, or anaphylaxis
• Women of childbearing potential not using effective contraception

• Pregnancy Risk: Misoprostol may cause miscarriage, uterine rupture, and birth defects.
• Gastrointestinal Risk: Despite protection from misoprostol, GI bleeding and ulceration can still occur, especially in elderly or high-risk patients.
• Cardiovascular Risk: NSAIDs may increase risk of serious thrombotic events, MI, or stroke.
• Renal & Hepatic Monitoring: Use with caution and regular monitoring in patients with liver or kidney disease.
• Diarrhea Risk: Misoprostol may cause dose-dependent diarrhea, especially during initial days of therapy.
• Electrolyte Abnormalities: Risk of dehydration from diarrhea in elderly or debilitated patients.

Common:

• Gastrointestinal: Diarrhea, abdominal pain, flatulence, nausea, dyspepsia
• Neurologic: Headache, dizziness
• Dermatologic: Rash

Less Common:

• Vomiting
• Constipation
• GI bleeding (less frequent than diclofenac monotherapy)
• Abnormal liver enzymes

Serious / Rare:

• Peptic ulcer perforation
• Gastrointestinal hemorrhage
• Myocardial infarction or stroke
• Anaphylaxis or severe hypersensitivity
• Uterine rupture (if used during pregnancy)

• Antacids (especially magnesium-containing): May worsen misoprostol-induced diarrhea.
• Anticoagulants/Antiplatelets (e.g., warfarin, aspirin): Increased bleeding risk.
• Other NSAIDs or corticosteroids: Increased risk of GI toxicity.
• Methotrexate and Cyclosporine: Elevated toxicity risk due to reduced renal clearance.
• Diuretics, ACE inhibitors, ARBs: Increased risk of renal impairment.
• CYP2C9 inhibitors/inducers: May alter diclofenac metabolism and plasma levels.
• Alcohol: Increases gastrointestinal bleeding risk.

• FDA has reaffirmed the requirement for a boxed warning regarding the abortifacient effect of misoprostol and cardiovascular/GI risks associated with diclofenac.
• EMA continues to recommend this combination for patients requiring long-term NSAIDs with GI protection.
• NICE recommends gastroprotective agents like misoprostol when prescribing NSAIDs in high-risk populations (e.g., elderly, history of ulcers).
• No new indication or dosage changes reported in recent clinical guideline updates.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Humidity: Store in a dry place; protect from excessive moisture
• Light: Keep in original container; protect from light
• Handling Precautions:
• Keep out of reach of children
• Do not crush or split tablets
• Misoprostol is sensitive to moisture; close container tightly after use
• Shelf-life: Use before expiration date on packaging; discard unused tablets if damaged or exposed to air