6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
- GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
- Hepatotoxicity [see Warnings and Precautions (5.3)]
- Hypertension [see Warnings and Precautions (5.4)]
- Heart Failure and Edema [see Warnings and Precautions (5.5)]
- Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
- Anaphylactic Reactions [see Warnings and Precautions (5.7)]
- Serious Skin Reactions [see Warnings and Precautions (5.9)]
- Hematologic Toxicity [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 diclofenac delayed-release tablets and misoprostol tablets.
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 (14)].
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 Warnings, Contraindications (4) and Warnings and Precautions (5)].
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 with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are:
Body as a whole: asthenia, fatigue, malaise.
Central and peripheral nervous system: dizziness, drowsiness, headache, insomnia, paresthesia, vertigo.
Digestive: anorexia, appetite changes, constipation, dry mouth, dysphagia, esophageal ulceration, oesophagitis, eructation, gastritis, gastroesophageal reflux, GI neoplasm benign, peptic ulcer, tenesmus, vomiting.
Female reproductive disorders: breast pain, dysmenorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.
Hemic and lymphatic system: epistaxis, leukopenia, melena, purpura, decreased hematocrit.
Metabolic and nutritional: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, dehydration, hyponatremia.
Musculoskeletal system: arthralgia, myalgia.
Psychiatric: anxiety, concentration impaired, depression, irritability.
Respiratory system: asthma, coughing, hyperventilation.
Skin and appendages: alopecia,eczema, pemphigoid reaction, photosensitivity, sweating increased, pruritus.
Special senses: taste perversion, tinnitus.
Renal and urinary disorders: dysuria, nocturia, polyuria, proteinuria, urinary tract infection.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval of ARTHROTEC, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.
Body as a whole: death, fever, infection, 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, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.
Congenital, familial and genetic disorders: birth defects.
Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.
Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.
Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.
Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria.
Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.
Male reproductive disorders: impotence, perineal pain.
Metabolic and nutritional: BUN increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, 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: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.
Reproductive system and breast disorders: female fertility decreased.
Respiratory system: dyspnea, pneumonia, respiratory depression.
Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous reactions (bullous eruption).
Special senses: hearing impairment, taste loss.
Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulohephritis.
Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.