Diclofenac + Misoprostol

Usage

Diclofenac + Misoprostol is prescribed for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers.

• Pharmacological Classification: Nonsteroidal anti-inflammatory drug (NSAID) combined with a prostaglandin analog.

• Mechanism of Action: Diclofenac is a non-selective inhibitor of cyclooxygenase (COX) enzymes, inhibiting both COX-1 and COX-2. This reduces prostaglandin synthesis, mitigating inflammation and pain. Misoprostol, a synthetic prostaglandin E1 analog, replaces the gastroprotective prostaglandins depleted by diclofenac, thus reducing the risk of NSAID-induced ulcers.

Alternate Names

• International/Regional Variations: Diclofenac sodium/Misoprostol
• Brand Name: Arthrotec

How It Works

• Pharmacodynamics: Diclofenac exerts its anti-inflammatory and analgesic effects through the inhibition of COX enzymes and subsequent reduction of prostaglandin synthesis. Misoprostol binds to prostaglandin E1 receptors in the gastric mucosa, stimulating mucus and bicarbonate secretion, enhancing mucosal blood flow, and reducing gastric acid secretion.

• Pharmacokinetics:

  • Absorption: Both drugs are well-absorbed orally. Diclofenac’s absorption is delayed and decreased when taken with food, while misoprostol’s absorption is not significantly affected.
  • Metabolism: Diclofenac is extensively metabolized in the liver, primarily by CYP2C9. Misoprostol undergoes rapid de-esterification to misoprostol acid, its active metabolite.
  • Elimination: Diclofenac metabolites are primarily excreted in urine, with a small amount in bile. Misoprostol acid is primarily excreted in urine, with a small amount in feces.

• Mode of Action/Receptor Binding/Enzyme Inhibition: Diclofenac inhibits COX-1 and COX-2 enzymes. Misoprostol binds to and activates prostaglandin E1 receptors.

• Elimination Pathways: Diclofenac primarily renal excretion, with some hepatic metabolism (CYP2C9). Misoprostol primarily renal excretion.

Dosage

Standard Dosage

Adults:

Osteoarthritis: 50 mg/200 mcg (Diclofenac/Misoprostol) twice or three times daily; or 75 mg/200 mcg twice daily. Rheumatoid arthritis: 50 mg/200 mcg three or four times daily; or 75 mg/200 mcg twice daily. Maximum daily dose of Misoprostol: 800 mcg.

Children:

Use and dose must be determined by a doctor. Safety and effectiveness have not been established in children under 18 years of age.

Special Cases:

• Elderly Patients: Initiate at the lowest effective dose. Close monitoring is recommended.
• Patients with Renal Impairment: Use with caution. Dosage adjustment may be needed.
• Patients with Hepatic Dysfunction: Use with caution. Dosage adjustment may be needed.
• Patients with Comorbid Conditions: Close monitoring for patients with cardiovascular disease, diabetes, or other relevant conditions.

Clinical Use Cases

Diclofenac/Misoprostol is not typically indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is for chronic conditions like osteoarthritis and rheumatoid arthritis. Other pain management strategies are typically preferred for the listed acute scenarios.

Dosage Adjustments

Dose adjustments may be necessary based on patient response, tolerability, renal function, and hepatic function.

Side Effects

Common Side Effects:

Diarrhea, abdominal pain, nausea, dyspepsia, flatulence, headache, dizziness.

Rare but Serious Side Effects:

Gastrointestinal bleeding, ulceration, perforation, myocardial infarction, stroke, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, hepatotoxicity, renal impairment.

Long-Term Effects:

Chronic kidney disease, gastrointestinal complications, cardiovascular events.

Adverse Drug Reactions (ADR):

Severe gastrointestinal bleeding or perforation, cardiovascular events, severe skin reactions, angioedema, hepatotoxicity.

Contraindications

• Hypersensitivity to diclofenac, misoprostol, or any component of the formulation.
• Active gastrointestinal bleeding.
• History of aspirin-sensitive asthma.
• Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
• Pregnancy.

Drug Interactions

• Anticoagulants (e.g., warfarin): Increased risk of bleeding.
• Antiplatelets (e.g., aspirin): Increased risk of bleeding.
• SSRIs/SNRIs: Increased risk of bleeding.
• ACE inhibitors, ARBs, Beta-blockers: May diminish antihypertensive effect.
• CYP2C9 inhibitors: Increased diclofenac exposure. Reduce diclofenac dose.
• Lithium: Increased lithium levels.
• Methotrexate: Increased methotrexate levels.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: X - Contraindicated. Misoprostol can cause miscarriage, premature birth, and birth defects. Diclofenac can cause premature closure of the ductus arteriosus.

• Breastfeeding: Misoprostol passes into breast milk. Not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Diclofenac inhibits prostaglandin synthesis. Misoprostol protects against GI ulcers.
• Side Effects: Diarrhea, abdominal pain, GI bleeding/ulceration, cardiovascular events.
• Contraindications: Pregnancy, active GI bleeding, hypersensitivity.
• Drug Interactions: Anticoagulants, antiplatelets, SSRIs/SNRIs, CYP2C9 inhibitors.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Not recommended while breastfeeding.
• Dosage: Varies based on indication and formulation. Consult guidelines.
• Monitoring Parameters: Renal function, liver function, blood pressure, signs of GI bleeding.

Popular Combinations

This medication is itself a combination. Combining it with other NSAIDs is generally not recommended due to increased risk of adverse effects. Low dose aspirin for cardiovascular prophylaxis may be an exception but requires careful consideration.

Precautions

• Evaluate renal and hepatic function before initiating therapy.
• Monitor blood pressure.
• Advise patients to report any signs of gastrointestinal bleeding.
• Avoid alcohol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Diclofenac + Misoprostol?

A: Adults: Osteoarthritis: 50 mg/200 mcg two or three times daily, or 75 mg/200 mcg twice daily. Rheumatoid arthritis: 50 mg/200 mcg three or four times daily, or 75 mg/200 mcg twice daily. Maximum daily dose of Misoprostol: 800 mcg. Pediatric use is not recommended.

Q2: How should this medication be administered?

A: Orally with food. Swallow tablets whole; do not crush or chew.

Q3: What are the most common side effects?

A: Diarrhea, abdominal pain, nausea, dyspepsia, headache.

Q4: What are the serious side effects to watch for?

A: GI bleeding/ulceration/perforation, MI, stroke, hepatic or renal dysfunction.

Q5: Can this medication be used in pregnancy?

A: No, it is contraindicated in pregnancy due to the risk of miscarriage, premature birth, and birth defects.

Q6: What are the key drug interactions?

A: Anticoagulants, antiplatelets, SSRIs/SNRIs, ACE inhibitors, ARBs, beta-blockers, CYP2C9 inhibitors, and lithium.

Q7: What should I do if a patient develops diarrhea while taking this medication?

A: Diarrhea is a common side effect. Advise the patient to maintain adequate hydration. If severe or persistent, consider dose reduction or discontinuation.

Q8: Should Diclofenac/Misoprostol be used with other NSAIDs?

A: Generally not recommended due to additive risk of adverse events. Low dose aspirin is a possible exception but requires careful consideration.

Q9: How should I monitor patients on long-term Diclofenac/Misoprostol therapy?

A: Regularly monitor renal and hepatic function, blood pressure, and be vigilant for signs and symptoms of gastrointestinal complications.

Q10: What is the role of misoprostol in this combination?

A: Misoprostol reduces the risk of NSAID-induced gastrointestinal ulcers and complications.