Drug: Arthrotec

ARTHROTEC (diclofenac sodium/misoprostol) is a combination product containing diclofenac sodium, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin E1 analog. ARTHROTEC oral tablets are white to off-white, round, biconvex, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (ARTHROTEC 50) or 75 mg (ARTHROTEC 75) diclofenac sodium surrounded by an outer mantle containing 200 mcg misoprostol. Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are: C14H10Cl2NO2Na[M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are: C22 H38O5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate. Inactive ingredients in ARTHROTEC include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate.

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Adverse Reactions Associated With ARTHROTEC Adverse reaction information for ARTHROTEC is derived from Phase III multinational controlled clinical trials in over 2,000 patients receiving ARTHROTEC 50 or ARTHROTEC 75, as well as from blinded, controlled trials of Voltaren® Delayed-Release tablets (diclofenac) and Cytotec® tablets (misoprostol). Gastrointestinal GI disorders had the highest reported incidence of adverse events for patients receiving ARTHROTEC. These events were generally minor, but led to discontinuation of therapy in 9% of patients on ARTHROTEC and 5% of patients on diclofenac. For GI ulcer rates, see Clinical Studies - Upper gastrointestinal safety. GI disorder ARTHROTEC Diclofenac Abdominal pain 21% 15% Diarrhea 19% 11% Dyspepsia 14% 11% Nausea 11% 6% Flatulence 9% 4% ARTHROTEC can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone. Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if ARTHROTEC is prescribed. The incidence of diarrhea can be minimized by administering ARTHROTEC with food and by avoiding coadministration with magnesium-containing antacids. Gynecological Gynecological disorders previously reported with misoprostol use have also been reported for women receiving ARTHROTEC (see below). Postmenopausal vaginal bleeding may be related to administration of ARTHROTEC. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology (see boxed CONTRAINDICATIONS AND WARNINGS). Elderly Overall, there were no significant differences in the safety profile of ARTHROTEC in over 500 patients 65 years of age or older compared with younger patients. Other adverse experiences reported occasionally or rarely with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are: Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis, chills, edema. Cardiovascular system: Arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased CPK, increased LDH, myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis. Central and peripheral nervous system: Coma, convulsions, dizziness, drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia, meningitis, migraine, neuralgia, paresthesia, somnolence, stroke, tremor, vertigo. Congenital, familial and genetic disorders: birth defects Digestive: Anorexia, appetite changes, constipation, dry mouth, dysphagia, enteritis, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI bleeding, GI neoplasm benign, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, peptic ulcer, stomatitis and ulcerative stomatitis, tenesmus, vomiting. Female reproductive disorders: Breast pain, dysmenorrhea, intermenstrual bleeding, leukorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage, vaginitis, uterine cramping, uterine hemorrhage. Hemic and lymphatic system: Agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, epistaxis, hemolytic anemia, leukocytosis, leukopenia, lymphadenopathy, melena, pancytopenia, pulmonary embolism, purpura, rectal bleeding, thrombocythemia, thrombocytopenia, decreased hematocrit. Hypersensitivity: Angioedema, laryngeal/pharyngeal edema, urticaria. Liver and biliary system: Abnormal hepatic function, bilirubinemia, hepatitis, jaundice, liver failure, pancreatitis. Male reproductive disorders: Impotence, perineal pain. Metabolic and nutritional: Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, BUN increased, dehydration, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, hyponatremia, periorbital edema, porphyria, weight changes, fluid retention. Musculoskeletal system: Arthralgia, myalgia. Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death. Psychiatric: Anxiety, concentration impaired, confusion, depression, disorientation, dream abnormalities, hallucinations, irritability, nervousness, paranoia, psychotic reaction. Respiratory system: Asthma, coughing, dyspnea, hyperventilation, pneumonia, respiratory depression. Skin and appendages: Acne, alopecia, bruising, eczema, erythema multiforme, exfoliative dermatitis, pemphigoid reaction, photosensitivity, pruritus, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, sweating increased, toxic epidermal necrolysis, cutaneous reactions (bullous eruption). Special senses: Hearing impairment, taste loss, taste perversion, tinnitus. Urinary system: Cystitis, dysuria, hematuria, interstitial nephritis, micturition frequency, nocturia, nephrotic syndrome, oliguria/polyuria, papillary necrosis, proteinuria, renal failure, urinary tract infection, glomerulonephritis membranous, glomerulonephritis minimal lesion. Vision: Amblyopia, blurred vision, conjunctivitis, diplopia, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal. Read the Arthrotec (diclofenac sodium, misoprostol) Side Effects Center for a complete guide to possible side effectsLearn More »

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Carefully consider the potential benefits and risks of ARTHROTEC and other treatment options before deciding to use ARTHROTEC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with ARTHROTEC, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is given below. ARTHROTEC is administered as ARTHROTEC 50 (50 mg diclofenac sodium/200 mcg misoprostol) or as ARTHROTEC 75 (75 mg diclofenac sodium/200 mcg misoprostol). Note: See Special Dosing Considerations section below. Osteoarthritis The recommended dosage for maximal GI mucosal protection is ARTHROTEC 50 tid. For patients who experience intolerance, ARTHROTEC 75 bid or ARTHROTEC 50 bid can be used, but are less effective in preventing ulcers. This fixed combination product, ARTHROTEC, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:   OA regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) ARTHROTEC 50 tid 150 600 bid 100 400 ARTHROTEC 75 bid 150 400 Rheumatoid Arthritis The recommended dosage is ARTHROTEC 50 tid or qid. For patients who experience intolerance, ARTHROTEC 75 bid or ARTHROTEC 50 bid can be used, but are less effective in preventing ulcers. This fixed combination product, ARTHROTEC, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:   RA regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) ARTHROTEC 50 qid 200 800 tid 150 600 bid 100 400 ARTHROTEC 75 bid 150 400 Special Dosing Considerations ARTHROTEC contains misoprostol, which provides protection against gastric and duodenal ulcers (see Clinical Studies). For gastric ulcer prevention, the 200 mcg qid and tid regimens are therapeutically equivalent, but more protective than the bid regimen. For duodenal ulcer prevention, the qid regimen is more protective than the tid or bid regimens. However, the qid regimen is less well tolerated than the tid regimen because of usually self-limited diarrhea related to the misoprostol dose (see ADVERSE REACTIONS - Gastrointestinal), and the bid regimen may be better tolerated than tid in some patients. Dosages may be individualized using the separate products (misoprostol and diclofenac), after which the patient may be changed to the appropriate dose of ARTHROTEC. If clinically indicated, misoprostol co-therapy with ARTHROTEC, or use of the individual components to optimize the misoprostol dose and/or frequency of administration, may be appropriate. The total dose of misoprostol should not exceed 800 mcg/day, and no more than 200 mcg of misoprostol should be administered at any one time. Doses of diclofenac higher than 150 mg/day in osteoarthritis or higher than 225 mg/day in rheumatoid arthritis are not recommended. For additional information, it may be helpful to refer to the package inserts for Cytotec® tablets and Voltaren® tablets.

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ACE-Inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Aspirin When ARTHROTEC is administered with aspirin, the protein binding of diclofenac is reduced, although the clearance of the free ARTHROTEC is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac sodium and aspirin is not generally recommended because of the potential risk of increased adverse effects. Digoxin Elevated digoxin levels have been reported in patients receiving digoxin and diclofenac sodium. Patients receiving digoxin and ARTHROTEC should be monitored for possible digoxin toxicity. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious bleeding greater than users of either drug alone. Oral Hypoglycemics Diclofenac sodium does not alter glucose metabolism in healthy people nor does it alter the effects of oral hypoglycemic agents. There are rare reports, however, from marketing experience, of changes in effects of insulin or oral hypoglycemic agents in the presence of diclofenac sodium that necessitated change in the doses of such agents. Both hypo-and hyperglycemic effects have been reported. A direct causal relationship has not been established, but physicians should consider the possibility that diclofenac sodium may alter a diabetic patient's response to insulin or oral hypoglycemic agents. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Tacrolimus Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. Cyclosporine ARTHROTEC, like other NSAID containing products, may affect renal prostaglandins and increase the toxicity of certain drugs. Ingestion of ARTHROTEC may increase cyclosporine nephrotoxicity. Patients who begin taking ARTHROTEC or who increase their dose of ARTHROTEC while taking cyclosporine may develop toxicity characteristic for cyclosporine. They should be observed closely, particularly if renal function is impaired. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Antacids Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac sodium. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. Thus, it is not recommended that ARTHROTEC be coadministered with magnesium-containing antacids. Diuretics Clinical studies, as well as postmarketing observations, have shown that ARTHROTEC can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Concomitant therapy with potassium-sparing diuretics may be associated with increased serum potassium levels. CYP2C9 Inhibitors Use caution when dosing diclofenac with CYP2C9 inhibitors (e.g. voriconazole). Concomitant use of CYP2C9 inhibitors may enhance toxicity of diclofenac due to an increase in systemic exposure to diclofenac. When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of ARTHROTEC 50 twice daily (see DOSAGE AND ADMINISTRATION). Voriconazole In a published study, single dose diclofenac (50 mg) was coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). The mean C max and AUC of diclofenac were increased by 2.1-fold and 1.8-fold respectively when coadministered with voriconazole compared to diclofenac alone. CYP2C9 Inducers Use caution when dosing diclofenac with CYP2C9 inducers (e.g. rifampin). Concomitant use of CYP2C9 inducers may lead to compromised efficacy due to a decrease in systemic exposure to diclofenac. The separate products of misoprostol and diclofenac should be used if a higher dose of diclofenac is deemed necessary (see DOSAGE AND ADMINISTRATION). Other Drugs In small groups of patients (7-10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline, or digitoxin did not significantly affect the peak levels and AUC levels of diclofenac sodium. Phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment following the initiation of diclofenac therapy. In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum. Read the Arthrotec Drug Interactions Center for a complete guide to possible interactions Learn More »

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Carefully consider the potential benefits and risks of ARTHROTEC and other treatment options before deciding to use ARTHROTEC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). ARTHROTEC is indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. See WARNINGS, Gastrointestinal Effects -Risk of Ulceration, Bleeding, and Perforation for a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications.

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See Boxed CONTRAINDICATIONS AND WARNINGS related to misoprostol. ARTHROTEC should not be taken by pregnant women. ARTHROTEC is contraindicated in patients with hypersensitivity to diclofenac or to misoprostol or other prostaglandins. ARTHROTEC should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to diclofenac sodium have been reported in such patients (see WARNINGS-Anaphylactic Reactions, and PRECAUTIONS-Preexisting Asthma). ARTHROTEC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see Boxed CONTRAINDICATIONS AND WARNINGS). ARTHROTEC is contraindicated in patients with active gastrointestinal bleeding (see WARNINGS). Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

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The toxic dose of ARTHROTEC has not been determined. However, signs of overdosage from the components of the product have been described. Diclofenac Sodium Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia. Reports of overdosage with diclofenac cover 66 cases. In approximately one-half of these reports of overdosage, concomitant medications were also taken. The highest dose of diclofenac was 5.0 g in a 17-year-old man who suffered loss of consciousness, increased intracranial pressure, and aspiration pneumonitis, and died 2 days after overdose. A 24year-old woman who took 4.0 g and the 28-and 42-year-old women, each of whom took 3.75 g, did not develop any clinically significant signs or symptoms. However, there was a report of a 17year-old woman who experienced vomiting and drowsiness after an overdose of 2.37 g of diclofenac. Animal studies show a wide range of susceptibilities to acute overdosage, with primates being more resistant to acute toxicity than rodents (LD50 in mg/kg: rats, 55; dogs, 500; monkeys, 3200). Misoprostol The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. In animals, the acute toxic effects are diarrhea, GI lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Arthrotec Symptoms of overdosage with ARTHROTEC should be treated with supportive therapy. In case of acute overdosage, gastric lavage is recommended. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol.

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ARTHROTEC (diclofenac sodium/misoprostol) is supplied as a film-coated tablet in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol. The 50 mg/200 mcg dosage strength is a round, biconvex, white to off-white tablet imprinted with four “A's” encircling a “50” in the middle on one side and “SEARLE” and “1411” on the other. The 75 mg/200 mcg dosage strength is a round, biconvex, white to off-white tablet imprinted with four “A's” encircling a “75” in the middle on one side and “SEARLE” and “1421” on the other. The dosage strengths are supplied in: Strength NDC Number Size 50/200 0025-1411-60 bottle of 60 0025-1411-90 bottle of 90 0025-1411-34 carton of 100 unit dose 75/200 0025-1421-60 bottle of 60 0025-1421-34 carton of 100 unit dose Store at or below 25°C (77°F), in a dry area. Distributed by G.D. Searle Division of Pfizer Inc., NY, NY 10017. Revised March 2015 Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

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General ARTHROTEC cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ARTHROTEC in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects See WARNINGS. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including ARTHROTEC. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ARTHROTEC, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ARTHROTEC who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ARTHROTEC should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Aseptic Meningitis As with other NSAIDs, aseptic meningitis with fever and coma has been observed on rare occasions in patients on diclofenac therapy. Although it is probably more likely to occur in patients with systemic lupus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on diclofenac, the possibility of it being related to diclofenac should be considered. Porphyria The use of ARTHROTEC in patients with hepatic porphyria should be avoided. To date, one patient has been described in whom diclofenac sodium probably triggered a clinical attack of porphyria. The postulated mechanism, demonstrated in rats, for causing such attacks by diclofenac sodium, as well as some other NSAIDs, is through stimulation of the porphyrin precursor delta-aminolevulinic acid (ALA). Information For Patients Women of childbearing potential using ARTHROTEC to treat arthritis should be told that they must not be pregnant when therapy with ARTHROTEC is initiated, and that they must use an effective contraception method while taking ARTHROTEC. See Boxed CONTRAINDICATIONS AND WARNINGS. THE PATIENT SHOULD NOT GIVE ARTHROTEC TO ANYONE ELSE. ARTHROTEC has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. SPECIAL NOTE FOR WOMEN: ARTHROTEC contains diclofenac sodium and misoprostol. Misoprostol may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
  • ARTHROTEC, like other NSAIDs, may cause serious side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
  • ARTHROTEC, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulceration and bleeding, and should ask for medical advice when observing any indicative sign or symptoms, including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects -Risk of Ulceration, Bleeding, and Perforation).
  • ARTHROTEC, like other NSAIDs, can cause serious skin side effects, such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
  • Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
  • Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical attention.
  • Patients should be informed of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactic Reactions).
  • In late pregnancy, as with other NSAIDs, ARTHROTEC should not be taken because it may cause premature closure of the ductus arteriosus.
  • Concomitant use of voriconazole increases the systemic exposure to diclofenac. When concomitant voriconazole use is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of ARTHROTEC 50 twice daily (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).
See PATIENT INFORMATION at the end of this labeling for important information to discuss with the patient. ARTHROTEC is available only as a unit-of-use package that includes a leaflet containing patient information. The patient should read the leaflet before taking ARTHROTEC and each time the prescription is renewed because the leaflet may have been revised. Keep ARTHROTEC out of the reach of children. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.), or if abnormal liver tests persist or worsen, ARTHROTEC should be discontinued. Effect on Blood Coagulation Diclofenac sodium impairs platelet aggregation but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, however, and are unlikely to be clinically important. Diclofenac sodium is a prostaglandin synthetase inhibitor, however, and all drugs that inhibit prostaglandin synthesis interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed. Misoprostol has not been shown to exacerbate the effects of diclofenac on platelet activity. Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of ARTHROTEC given alone. ARTHROTEC itself (diclofenac sodium and misoprostol combinations in 250:1 ratio) was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse micronucleus test. In a 24-month rat carcinogenicity study, oral misoprostol at doses up to 2.4 mg/kg/day (14.4 mg/m²/day, 24 times the recommended maximum human dose of 0.6 mg/m²/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, oral misoprostol at doses up to 16 mg/kg/day (48 mg/m²/day), 80 times the recommended maximum human dose based on body surface area, was not tumorigenic. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m²/day, 1 to 100 times the recommended maximum human dose based on body surface area) produced dose-related pre-and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. In a 24-month rat carcinogenicity study, oral diclofenac sodium up to 2 mg/kg/day (12 mg/m²/day) was not tumorigenic. For a 50-kg person of average height (1.46m² body surface area), this dose represents 0.08 times the recommended maximum human dose (148 mg/m²) on a body surface area basis. In a 24-month mouse carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m²/day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m²/day, 0.02 times the recommended maximum human dose based on body surface area) in females was not tumorigenic. Diclofenac sodium at oral doses up to 4 mg/kg/day (24 mg/m²/day, 0.16 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Pregnancy Category X See boxed CONTRAINDICATIONS AND WARNINGS regarding misoprostol. Non-teratogenic Effects See boxed CONTRAINDICATIONS AND WARNINGS. Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe genital bleeding, shock, fetal bradycardia, and fetal and material death have been reported. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus. Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, fetal bradycardia, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses. Additionally, because of the known effects of nonsteroidal anti-inflammatory drugs including the diclofenac sodium component of ARTHROTEC, on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Teratogenic Effects See boxed CONTRAINDICATIONS AND WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. An oral teratology study has been performed in pregnant rabbits at dose combinations (250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and has revealed no evidence of teratogenic potential for ARTHROTEC. Oral teratology studies have been performed in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m²/day, 16 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m²/day, 20 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for misoprostol. Oral teratology studies have been performed in pregnant mice at doses up to 20 mg/kg/day (60 mg/m²/day, 0.4 times the recommended maximum human dose based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m²/day, 0.4 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for diclofenac sodium. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nursing Mothers Diclofenac sodium has been found in the milk of nursing mothers. Based on limited published data from 2 studies of 22 lactating women who took a single 200-600 microgram dose of misoprostol 4-6 days postpartum, misoprostolic acid, the active metabolite of misoprostol was found in breast milk at very low levels. The highest level measured in milk was 20.9 ng/L 1 hour after dosing. These data may not reflect drug level in mature milk and in a daily dosing regimen for osteoarthritis or rheumatoid arthritis. Caution should be exercised when ARTHROTEC is administered to a nursing woman. Labor And Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Pediatric use Safety and effectiveness of ARTHROTEC in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the more than 2,100 subjects in clinical studies with ARTHROTEC, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to ARTHROTEC may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS - Renal Effects). Based on studies in the elderly, no adjustment of the dose of ARTHROTEC is necessary in the elderly for pharmacokinetic reasons (see Pharmacokinetics of ARTHROTEC - Specific populations), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

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