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).
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.
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 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).
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:
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.
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.
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.
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.
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.
Read the Arthrotec (diclofenac sodium, misoprostol) Side Effects Center for a complete guide to possible side effects
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.
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.
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.
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.
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.
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.
Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
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.
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 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.
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.
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).
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 Cmax and AUC of diclofenac were increased by 2.1-fold and 1.8-fold respectively when coadministered with voriconazole compared to diclofenac alone.
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).
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
Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.
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