Cytomis

1 INDICATIONS AND USAGE Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions ( 5.3 )] . Diclofenac sodium and misoprostol delayed-release tablets are a combination of diclofenac sodium, a non-steroidal anti-inflammatory drug, and misoprostol, a prostaglandin-1 (PGE1) analog, indicated for the treatment of signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. ( 1 )

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Osteoarthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three times daily. A dosage of diclofenac higher than 150 mg/day is not recommended. ( 2.2 ) Rheumatoid Arthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three or four times daily. A dosage of diclofenac higher than 200 mg/day is not recommended. ( 2.3 ) For dosage modifications due to intolerance, see the full Prescribing Information. ( 2.2 , 2.3 ) 2.1 Important Dosage Information Carefully consider the potential benefits and risks of diclofenac sodium and misoprostol delayed-release tablets and other treatment options before deciding to use diclofenac sodium and misoprostol delayed-release tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . After observing the response to initial therapy with diclofenac sodium and misoprostol delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. Diclofenac sodium and misoprostol delayed-release tablets are not recommended for patients who would not receive the appropriate dosage of both active ingredients. Diclofenac sodium and misoprostol delayed-release tablets, a fixed combination product, is administered as diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg (50 mg diclofenac sodium and 200 mcg misoprostol) or diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg (75 mg diclofenac sodium and 200 mcg misoprostol). 2.2 Recommended Dosage in Patients with Osteoarthritis The recommended dosage for the treatment of osteoarthritis for maximal GI mucosal protection is diclofenac…

12.1 Mechanism of Action Diclofenac sodium and misoprostol delayed-release tablets are a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin (PG) synthesis in vitro . Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Misoprostol Misoprostol is a synthetic PGE1 analog with gastric antisecretory and mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs. Misoprostol can increase bicarbonate and mucus production, but it has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to differentiate whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both. In vitro studies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other…

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 ( 5.2 )] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Hypertension [see Warnings and Precautions ( 5.5 )] Heart Failure and Edema [see Warnings and Precautions ( 5.6 )] Renal Toxicity and Hyperkalemia [see Warnings and Precautions ( 5.7 )] Anaphylactic Reactions [see Warnings and Precautions ( 5.8 )] Serious Skin Reactions [see Warnings and Precautions ( 5.10 )] Hematologic Toxicity [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (>2%) are: abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, alanine aminotransferase increased, hematocrit decreased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 diclofenac sodium and misoprostol delayed-release tablets is derived from multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg or diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets. Gastrointestinal GI disorders had the highest reported incidence of adverse reactions for patients receiving diclofenac sodium and misoprostol delayed-release tablets. These events were generally minor, but led…

4 CONTRAINDICATIONS Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients: Pregnancy. Use of misoprostol, a component of diclofenac sodium and misoprostol delayed-release tablets, during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions ( 5.2 )] Active gastrointestinal bleeding [see Warnings and Precautions ( 5.3 )] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions ( 5.8 , 5.9 )] Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions ( 5.8 , 5.10 )] Pregnancy ( 4 ) In the setting of CABG surgery ( 4 ) Active gastrointestinal bleeding ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) Known hypersensitivity to diclofenac sodium, misoprostol, or any components of the drug product ( 4 )

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity with NSAIDs : Use of NSAIDs, including diclofenac in women at about 20 weeks gestation and later in pregnancy may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 4 , 5.1 , 8.1 ) Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.4 ) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.5 , 7 ) Heart Failure and Edema: Avoid in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.6 ) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.7 ) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. ( 5.8 ) Exacerbation of Asthma Related to Aspirin Sensitivity: Contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.9 ) Serious Skin Reactions: Discontinue at first appearance of skin rash or other signs of hypersensitivity. ( 5.10 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. ( 5.11 ) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. ( 5.12 , 7 ) 5.1 Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs Misoprostol Administration of misoprostol, a component of diclofenac sodium and misoprostol delayed-release tablets, to pregnant women can cause uterine rupture, abortion, premature birth, or birth…

7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with diclofenac and misoprostol. Table 1: Clinically Significant Drug Interactions with Diclofenac and Misoprostol Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac sodium and misoprostol delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions ( 5.12 )] . Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.3 )] . Intervention: Concomitant use of diclofenac sodium and misoprostol delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.12 )] . Diclofenac sodium and misoprostol delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol).…