ARTHROTEC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ARTHROTEC (ARTHROTEC).
Arthrotec is a combination of diclofenac, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX-1 and COX-2) enzymes, reducing prostaglandin synthesis, and misoprostol, a synthetic prostaglandin E1 analog that protects the gastric mucosa by increasing mucus and bicarbonate secretion, enhancing mucosal blood flow, and promoting epithelial repair.
| Metabolism | Diclofenac is primarily metabolized by CYP2C9 (major) and CYP3A4 (minor) via hydroxylation and glucuronidation, followed by renal excretion. Misoprostol is rapidly de-esterified to misoprostol acid, the active metabolite, which undergoes further oxidation and glucuronidation, with renal excretion. |
| Excretion | Renal: ~95% as metabolites (diclofenac: ~65% as glucuronide conjugates; misoprostol: ~80% as inactive metabolites). Biliary/fecal: <5%. |
| Half-life | Diclofenac: ~2 hours (range 1-4 h); misoprostol: 20-40 minutes (acid metabolite 1.5 h). No accumulation with repeated dosing. |
| Protein binding | Diclofenac: >99.5% (primarily albumin); misoprostol: 80-90% (albumin). |
| Volume of Distribution | Diclofenac: 0.17-0.55 L/kg (widely distributed, crosses placenta); misoprostol: not well characterized (estimated 2-3 L/kg). |
| Bioavailability | Diclofenac: ~50% (oral, immediate-release); misoprostol: 70-80% (oral, extensively metabolized). |
| Onset of Action | Oral: diclofenac analgesia within 1 h; misoprostol cytoprotection within 30 min. |
| Duration of Action | Diclofenac: 6-8 h (immediate-release); misoprostol: 3-6 h (gastric protection lasts up to 6 h). |
| Molecular Weight | Diclofenac: 296.15 Da; Misoprostol: 382.54 Da |
One tablet (diclofenac 50 mg / misoprostol 200 mcg) orally twice daily with food.
| Dosage form | TABLET, DELAYED RELEASE |
| Renal impairment | GFR 30-59 mL/min: no adjustment; GFR <30 mL/min: contraindicated. |
| Liver impairment | Child-Pugh class A: no adjustment; class B or C: use with caution, consider dose reduction of diclofenac; not recommended in severe hepatic impairment. |
| Pediatric use | Not recommended for pediatric patients; safety and efficacy not established. |
| Geriatric use | Initiate at lowest effective dose; monitor renal function and gastrointestinal bleeding risk; start with one tablet daily if required. |
| 1st trimester | Avoid: Use of NSAIDs in the first trimester is associated with increased risk of miscarriage and congenital malformations (e.g., cardiac defects, gastroschisis). Diclofenac is contraindicated after 30 weeks' gestation due to risk of premature ductus arteriosus closure; misoprostol is contraindicated throughout pregnancy due to uterotonic effects and risk of uterine rupture, abortion, and fetal harm. |
| 2nd trimester | Avoid: NSAID use in the second trimester may be associated with oligohydramnios and fetal renal dysfunction. Misoprostol is contraindicated due to risk of uterine contractions and fetal harm. |
| 3rd trimester | Contraindicated: NSAIDs after 30 weeks' gestation cause premature closure of the ductus arteriosus and oligohydramnios. Misoprostol is contraindicated due to risk of uterine rupture and fetal harm. |
Clinical note
Comprehensive clinical and safety monograph for ARTHROTEC (ARTHROTEC).
| Placental transfer | Both components cross the placenta. Diclofenac crosses in animal studies; human data limited. Misoprostol is known to cross the placenta and can induce uterine contractions. Substantial transfer of misoprostol occurs after oral administration. |
■ 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. Arthrotec 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 (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk.
| Serious Effects |
Pregnancy (especially third trimester)History of hypersensitivity to diclofenac, misoprostol, other NSAIDs, or prostaglandinsActive gastrointestinal bleeding or ulcerationSevere heart failure (NYHA III-IV)Cytopenias (e.g., thrombocytopenia, leukopenia)Severe hepatic impairmentSevere renal impairment (CrCl <30 mL/min)Cerebrovascular or other active bleedingInflammatory bowel disease (unless directed by physician)
| Precautions | Cardiovascular: increased risk of thromboembolic events, myocardial infarction, and stroke; avoid in patients with recent CABG., Gastrointestinal: serious GI adverse events including bleeding, ulceration, and perforation; use with caution in patients at risk., Renal: may cause renal toxicity; avoid in patients with advanced renal disease., Hepatic: may cause elevations in liver enzymes and liver injury; monitor LFTs., Fetal toxicity: misoprostol can induce labor and cause fetal harm; contraindicated in pregnancy., Hypertension: can worsen or induce hypertension., Anaphylactoid reactions: may occur; avoid in patients with aspirin allergy., Hematologic: may cause anemia; monitor hemoglobin. |
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| Breastfeeding | Diclofenac and misoprostol are excreted into breast milk in low amounts. Diclofenac is considered compatible with breastfeeding due to low transfer; however, misoprostol may cause diarrhea in infants. Use caution and monitor infant for adverse effects. The benefits of therapy should be weighed against potential risks. |
| Lactation Rating | L3 |
| Teratogenic Risk | ARTHROTEC contains diclofenac (NSAID) and misoprostol. Misoprostol is a known abortifacient and teratogen. First trimester: Risk of Möbius syndrome, cranial nerve palsy, and limb defects. Second/third trimester: Misoprostol can cause uterine rupture, premature labor, and fetal death. NSAIDs may cause premature ductus arteriosus closure and oligohydramnios. Pregnancy category X - contraindicated in pregnancy. |
| Fetal Monitoring | If exposure occurs, monitor for uterine contractions, fetal heart rate, amniotic fluid index (oligohydramnios), and ductus arteriosus patency (fetal echocardiography after 32 weeks). Assess for maternal gastrointestinal bleeding or uterine hyperstimulation. |
| Fertility Effects | NSAIDs may impair female fertility by inhibiting prostaglandin synthesis, affecting ovulation and implantation. Misoprostol can cause uterine contractions and cervical softening, potentially interfering with implantation. Reversible upon discontinuation. |
| Food/Dietary | Take with food or milk to minimize gastrointestinal irritation. Avoid alcohol as it increases risk of GI bleeding. |
| Clinical Pearls | ARTHROTEC is a fixed-dose combination of diclofenac (NSAID) and misoprostol (PGE1 analog) indicated for osteoarthritis and rheumatoid arthritis in patients at high risk for NSAID-induced gastric ulcers. Misoprostol reduces gastric acid secretion and increases mucus and bicarbonate production, but can cause diarrhea, abdominal cramps, and uterine contractions. Contraindicated in pregnancy due to abortifacient properties. Use lowest effective dose; monitor renal function, blood pressure, and signs of GI bleeding. |
| Patient Advice | Take with food to reduce GI upset. · Avoid alcohol and other NSAIDs (e.g., ibuprofen, naproxen) while taking this medication. · Inform all healthcare providers you are taking Arthrotec. · Do not use if pregnant or planning pregnancy; misoprostol can cause miscarriage. Use effective contraception. · Report black/tarry stools, severe abdominal pain, vomiting blood, or chest pain immediately. · This medication can cause diarrhea, especially at start of therapy; stay hydrated. |