DICLOFENAC SODIUM AND MISOPROSTOL
Clinical safety rating: avoid
No significant drug interactions Contraindicated in pregnancy due to abortifacient properties.
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis. Misoprostol is a synthetic prostaglandin E1 analog that replaces protective prostaglandins in the gastric mucosa, reducing gastric acid secretion and increasing mucus and bicarbonate production.
| Metabolism | Diclofenac is primarily metabolized by cytochrome P450 CYP2C9, with minor contributions from CYP3A4. Misoprostol is rapidly de-esterified to its active metabolite, misoprostol acid, which undergoes further beta-oxidation and reduction. |
| Excretion | Diclofenac: ~65% renal (primarily as glucuronide conjugates, with <1% unchanged), ~35% biliary/fecal. Misoprostol: >80% renal as inactive metabolites. |
| Half-life | Diclofenac: Terminal t1/2 ~1-2 h (short, requiring frequent dosing). Misoprostol: Terminal t1/2 ~20-40 min (rapidly de-esterified to active misoprostol acid, with acid t1/2 ~20-30 min). |
| Protein binding | Diclofenac: >99% bound to albumin. Misoprostol acid: ~80-90% bound to albumin. |
| Volume of Distribution | Diclofenac: Vd ~1.3 L/kg (extensive tissue distribution). Misoprostol: Vd not well defined for acid; parent drug rapidly hydrolyzed. |
| Bioavailability | Diclofenac: Oral ~50-60% (first-pass metabolism). Misoprostol: Oral ~70-80% (rapidly absorbed and de-esterified to active acid). |
| Onset of Action | Oral: Diclofenac analgesia within ~30 min; misoprostol gastric protection (cytoprotective) within 30 min; combined product for dysmenorrhea relief in 1-2 h. |
| Duration of Action | Diclofenac: Analgesic effect ~4-8 h (dose-dependent). Misoprostol: Duration of gastric protection ~4-6 h; for combined product, clinical effect persists for dosing interval (usually 8-12 h). |
| Molecular Weight | Diclofenac sodium: 318.13 Da; Misoprostol: 382.54 Da |
Diclofenac sodium 50 mg/misoprostol 200 mcg orally twice daily with food for osteoarthritis and rheumatoid arthritis; diclofenac sodium 75 mg/misoprostol 200 mcg orally twice daily for rheumatoid arthritis.
| Dosage form | TABLET, DELAYED RELEASE |
| Renal impairment | GFR < 30 mL/min: contraindicated. GFR 30-59 mL/min: use with caution, no specific dose adjustment; monitor renal function. GFR >= 60 mL/min: no adjustment. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: use with caution, reduce dose or increase interval; not recommended. Child-Pugh Class C: contraindicated. |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established. No standard weight-based dosing. |
| Geriatric use | Initiate at lowest effective dose; consider renal function (age-related decline); avoid if GFR < 30 mL/min; increased risk of GI bleeding, renal impairment, and hypotension. |
| 1st trimester | Avoid; risk of miscarriage and malformations (primarily due to misoprostol component: uterine contractions, bleeding; diclofenac: NSAID-associated risks including oligohydramnios, premature ductus arteriosus closure). |
| 2nd trimester | Avoid; NSAIDs can cause oligohydramnios, premature ductus arteriosus constriction; misoprostol may induce uterine contractions. |
| 3rd trimester | Contraindicated; NSAIDs cause premature closure of ductus arteriosus, oligohydramnios; misoprostol can induce labor, uterine rupture. |
Clinical note
No significant drug interactions Contraindicated in pregnancy due to abortifacient properties.
| FDA category | Contraindicated |
| Placental transfer | Both diclofenac and misoprostol cross the placenta; diclofenac binding >99%; misoprostol acid crosses and can cause uterine contractions. |
■ FDA Black Box Warning
NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Diclofenac is contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk.
| Common Effects | Diarrhea |
| Serious Effects |
Pregnancy (especially third trimester, risk of premature ductus arteriosus closure, uterine rupture)Hypersensitivity to diclofenac, misoprostol, or any componentActive peptic ulcer disease or gastrointestinal bleedingSevere renal impairment (CrCl <30 mL/min)Severe hepatic impairmentHistory of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDsCoronary artery bypass graft (CABG) surgery (perioperative pain)
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| Breastfeeding | Diclofenac and misoprostol (active metabolite misoprostol acid) are excreted into breast milk in low levels; NSAIDs are generally considered compatible, but misoprostol may cause diarrhea in infants. Caution with large doses or for prolonged periods. |
| Lactation Rating | L3 (Moderately Safe; limited data suggests low risk, but potential for adverse effects in infant). |
| Teratogenic Risk | Diclofenac: Risk category C in first and second trimesters; category D in third trimester. Avoid in third trimester due to premature closure of ductus arteriosus and oligohydramnios. Misoprostol: Contraindicated in pregnancy as it stimulates uterine contractions and can cause miscarriage, premature labor, and birth defects (e.g., Möbius syndrome). High risk of fetal harm throughout pregnancy. |
| Fetal Monitoring | Ultrasound monitoring for oligohydramnios or ductus arteriosus constriction if diclofenac used in third trimester. Fetal heart rate monitoring if misoprostol exposure occurs. Monitor maternal gastrointestinal bleeding and renal function, especially with prolonged use. |
| Fertility Effects | Diclofenac may impair female fertility through inhibition of prostaglandin synthesis affecting ovulation; reversible upon discontinuation. Misoprostol does not directly affect fertility, but its use during pregnancy is contraindicated due to risk of pregnancy loss. |
| Precautions |
| Cardiovascular risk; gastrointestinal risk; hypertension; fluid retention; renal toxicity; hepatic toxicity; anaphylactoid reactions; skin reactions; hematologic toxicity; use in pregnancy (misoprostol can cause uterine contractions, abortion, or fetal harm); avoidance with aspirin or other NSAIDs; elderly patients; pre-existing asthma. |
| Food/Dietary | Avoid alcohol and high-fat meals as they may increase GI irritation. Take with food or milk to reduce dyspepsia. No specific food restrictions other than avoiding known GI irritants. |
| Clinical Pearls | Diclofenac sodium/misoprostol is contraindicated in pregnancy (misoprostol is abortifacient). Use lowest effective dose; misoprostol component mitigates NSAID-induced GI injury but not cardiovascular risk. Avoid in patients with active GI bleed or inflammatory bowel disease. Renal function monitoring is essential, especially in elderly or volume-depleted patients. Misoprostol may cause diarrhea and uterine cramping. |
| Patient Advice | Do not take if pregnant or planning pregnancy; misoprostol can cause miscarriage. · Take with food to reduce stomach upset; avoid alcohol. · Report severe abdominal pain, black/tarry stools, or vomiting blood immediately. · Do not take other NSAIDs or aspirin unless prescribed. · Notify healthcare provider if diarrhea persists or becomes severe. |