FDA label 9c938edd-5163-417d-e053-2a95a90aefee

BOXED WARNING SECTION CONTRAINDICATIONS AND WARNINGS DICLOFENAC SODIUM/MISOPROSTOL TABLETS CONTAIN DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS ). DICLOFENAC SODIUM/MISOPROSTOL TABLETS SHOULD NOT BE TAKEN BY PREGNANT WOMEN (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Diclofenac sodium/misoprostol tablets should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID (see WARNINGS ). In such patients, diclofenac sodium/misoprostol tablets may be prescribed if the patient: has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. is capable of complying with effective contraceptive measures. has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. will begin diclofenac sodium/misoprostol tablets only on the second or third day of the next normal menstrual period. Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, 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 (see WARNINGS ). Diclofenac sodium/misoprostol tablets are contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ). Gastrointestinal Risk 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 during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS ).

WARNINGS SECTION Regarding misoprostol: See boxed CONTRAINDICATIONS AND WARNINGS . Regarding diclofenac: See boxed CONTRAINDICATIONS AND WARNINGS . CARDIOVASCULAR EFFECTSCardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation ). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS ). Hypertension NSAIDs, including diclofenac sodium/misoprostol tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including diclofenac sodium/misoprostol tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Diclofenac sodium/misoprostol tablets should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including diclofenac sodium/misoprostol tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease Diclofenac sodium/misoprostol tablets contain diclofenac. Diclofenac metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. Therefore, treatment with diclofenac sodium/misoprostol tablets are not recommended in patients with advanced renal disease. If diclofenac sodium/misoprostol therapy must be initiated, close monitoring of the patient's renal function is advisable. Hepatic Effects In clinical trials with diclofenac sodium/misoprostol tablets, meaningful elevation of ALT (SGPT, more than 3 times the ULN [ULN = the upper limit of the normal range]) occurred in 1.6% of 2,184 patients treated with diclofenac sodium/misoprostol tablets and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with diclofenac sodium/misoprostol tablets. The misoprostol component of diclofenac sodium/misoprostol tablets does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component. Elevations of one or more liver tests may occur during therapy with diclofenac, a component of diclofenac sodium/misoprostol tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN), or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2–6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3–8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. In another clinical trial where over 17,000 patients received diclofenac for a mean of 18 months, hepatitis was rarely observed. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and usually occur within 1-6 months, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium/misoprostol tablets should be discontinued immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium/misoprostol tablets, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing diclofenac sodium/misoprostol tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur in patients without known prior exposure to diclofenac sodium/misoprostol tablets. Diclofenac sodium/misoprostol tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS—Preexisting Asthma ). Anaphylactic reactions may also occur to the misoprostol component of diclofenac sodium/misoprostol tablets. Emergency help should be sought in cases where an anaphylactic reaction occurs. Allergic reactions have been reported by less than 0.1% of patients who received diclofenac sodium/misoprostol tablets in clinical trials, and there have been rare reports of anaphylaxis in the marketed use of diclofenac sodium/misoprostol tablets outside of the United States. Skin Reactions NSAIDs, including diclofenac sodium/misoprostol tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, diclofenac sodium/misoprostol tablets should be avoided because it may cause premature closure of the ductus arteriosus.

ADVERSE REACTIONS SECTION Adverse reactions associated with diclofenac sodium/misoprostol Adverse reaction information for diclofenac sodium/misoprostol tablets is derived from Phase III multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium/misoprostol 50 or diclofenac sodium/misoprostol 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 diclofenac sodium/misoprostol tablets. These events were generally minor, but led to discontinuation of therapy in 9% of patients on diclofenac sodium/misoprostol tablets and 5% of patients on diclofenac. For GI ulcer rates, see CLINICAL STUDIES—Upper gastrointestinal safety . GI disorder Diclofenac sodium/misoprostol Diclofenac Abdominal pain 21% 15% Diarrhea 19% 11% Dyspepsia 14% 11% Nausea 11% 6% Flatulence 9% 4% Diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets are prescribed. The incidence of diarrhea can be minimized by administering diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets (see below). Postmenopausal vaginal bleeding may be related to administration of diclofenac sodium/misoprostol tablets. 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 diclofenac sodium/misoprostol tablets in over 500 patients 65 years of age or older compared with younger patients. Other adverse experiences reported occasionally or rarely with diclofenac sodium/misoprostol tablets, diclofenac or other NSAIDs, or misoprostol are: Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis, chills. 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. 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. 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. 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. Musculoskeletal system: Arthralgia, myalgia. 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. 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.

<table width="90%"> <col align="left" width="34%" valign="top"/> <col align="center" width="33%" valign="top"/> <col align="center" width="33%" valign="top"/> <thead> <tr styleCode="First Last"> <th align="left" styleCode="Lrule Rrule">GI disorder</th> <th align="center" styleCode="Rrule">Diclofenac sodium/misoprostol</th> <th align="center" styleCode="Rrule">Diclofenac</th> </tr> </thead> <tbody> <tr styleCode="Botrule First"> <td align="left" styleCode="Lrule Rrule">Abdominal pain</td> <td align="center" styleCode="Rrule">21%</td> <td align="center" styleCode="Rrule">15%</td> </tr> <tr styleCode="Botrule"> <td align="left" styleCode="Lrule Rrule">Diarrhea</td> <td align="center" styleCode="Rrule">19%</td> <td align="center" styleCode="Rrule">11%</td> </tr> <tr styleCode="Botrule"> <td align="left" styleCode="Lrule Rrule">Dyspepsia</td> <td align="center" styleCode="Rrule">14%</td> <td align="center" styleCode="Rrule">11%</td> </tr> <tr styleCode="Botrule"> <td align="left" styleCode="Lrule Rrule">Nausea</td> <td align="center" styleCode="Rrule">11%</td> <td align="center" styleCode="Rrule">6%</td> </tr> <tr> <td align="left" styleCode="Lrule Rrule">Flatulence</td> <td align="center" styleCode="Rrule">9%</td> <td align="center" styleCode="Rrule">4%</td> </tr> </tbody> </table>