Misoprostol

12.1 Mechanism of Action Diclofenac sodium/misoprostol is 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 unrelated compounds, such as hi

1 INDICATIONS AND USAGE Diclofenac sodium/misoprostol is 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/misoprostol is 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/misoprostol and other treatment options before deciding to use diclofenac sodium/misoprostol. 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/misoprostol, the dose and frequency should be adjusted to suit an individual patient’s needs. Diclofenac sodium/misoprostol is not recommended for patients who would not receive the appropriate dosage of both active ingredients. Diclofenac sodium/misoprostol, a fixed combination product, is administered as diclofenac sodium/misoprostol 50 (50 mg diclofenac sodium and 200 mcg misoprostol) or as diclofenac sodium/misoprostol 75 (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 sodium/misoprostol 50 three times a day. For patients who experience intolerance, diclofenac sodium/misoprostol 75 two times a day or diclofenac sodium/misoprostol 50 two times a day can be used, but these dosages are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 150 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Osteoarthritis Regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) Diclofenac sodium/misoprostol 50 three times a day two times a day For patients who experience intolerance; these dosages are less effective in preventing ulcers 150 100 600 400 Diclofenac sodium/misoprostol 75 two times a day 150 400 2.3 Recommended Dosage in Patients with Rheumatoid Arthritis The recommended dosage for the treatment of rheumatoid arthritis is diclofenac sodium/misoprostol 50 three or four times a day. For patients who experience intolerance, diclofenac sodium/misoprostol 75 two times a day or diclofenac sodium/misoprostol 50 two times a day can be used, but are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 200 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Rheumatoid Arthritis Regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) Diclofenac sodium/misoprostol 50 four times a day three times a day two times a day For patients who experience intolerance; these dosages are less effective in preventing ulcers 200 150 100 800 600 400 Diclofenac sodium/misoprostol 75 two times a day 150 400 2.4 Additional Dosage Recommendations Diclofenac sodium/misoprostol contains misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies (14) ] . For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose [see Adverse Reactions (6.1) ] , and the two times a day regimen may be better tolerated than three times a day in some patients. Dosages may be individualized using the separate products (misoprostol and diclofenac sodium), after which the patient may be switched to the appropriate diclofenac sodium/misoprostol dosage. If clinically indicated, misoprostol co-therapy with diclofenac sodium/misoprostol to optimize the misoprostol dose and/or frequency of administration, may be appropriate. Do not exceed a total misoprostol dose of 800 mcg/day and do not administer more than 200 mcg of misoprostol at any one time. When concomitant use of CYP2C9 inhibitors is necessary, the maximum total daily dose of diclofenac is 100 mg per day. Do not exceed a dosage of diclofenac sodium/misoprostol 50 mg twice daily [see Drug Interactions (7) ] . For additional information, refer to the Prescribing Information for the individual products of diclofenac sodium and misoprostol.

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 Pfizer Inc. at 1-800-438-1985 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/misoprostol is derived from 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 diclofenac sodium delayed-release tablets and misoprostol tablets Gastrointestinal GI disorders had the highest reported incidence of adverse reactions for patients receiving diclofenac sodium/misoprostol. These events were generally minor, but led to discontinuation of therapy in 9% of patients on diclofenac sodium/misoprostol and 5% of patients on diclofenac sodium. For GI ulcer rates, [see Clinical Studies (14) ]. GI disorder Diclofenac sodium/misoprostol Diclofenac Sodium Abdominal pain 21% 15% Diarrhea 19% 11% Dyspepsia 14% 11% Nausea 11% 6% Flatulence 9% 4% Diclofenac sodium/misoprostol 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 is prescribed. The incidence of diarrhea can be minimized by administering diclofenac sodium/misoprostol 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 (see below). Postmenopausal vaginal bleeding may be related to administration of diclofenac sodium/misoprostol. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology [see Boxed Warnings , Contraindications (4) and Warnings and Precautions (5) ] . Other adverse experiences reported occasionally with diclofenac sodium/misoprostol, 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, esophagitis, 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. Vision: diplopia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval of diclofenac sodium/misoprostol, 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 t

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/misoprostol 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/misoprostol and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12) ] . Diclofenac sodium/misoprostol is 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). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. During concomitant use of diclofenac sodium/misoprostol and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium/misoprostol and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7) ]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium/misoprostol with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7) ] . Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac sodium/misoprostol and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium/misoprostol and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac sodium/misoprostol and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac sodium/misoprostol and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Preca