DICLOFENAC SODIUM AND MISOPROSTOL- diclofenac sodium and misoprostol_tablet, film coated

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. 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 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 histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. Misoprostol, over the range of 50 mcg to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal- stimulated secretion. Misoprostol also produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output. The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination (diclofenac sodium/misoprostol 50 or 75) are similar to the profiles when the two drugs are administered as separate tablets (see Table 2 Table 2: Pharmacokinetic Parameters of Diclofenac and Misoprostol Acid Following Single Oral Doses of Diclofenac Sodium/Misoprostol or Separate Products in Healthy Subjects SD: Standard deviation of the mean; AUC: Area under the curve; C max max MISOPROSTOL ACID Mean (SD) Treatment (n=36) C max T max AUC( 0en dash4h (pg·hr/mL) Diclofenac sodium/misoprostol 50 441 (137) 0. 13) 266 (95) Misoprostol 478 (201) 0. 10) 295 (143) Diclofenac sodium/misoprostol 75 304 (110) 0. 09) 177 (49) Misoprostol 290 (130) 0. 12) 176 (58) DICLOFENAC Mean (SD) Treatment (n=36) C max T max AUC (0en dash12h) (ng·hr/mL) Diclofenac sodium/misoprostol 50 1207 (364) 2. 0) 1380 (272) Diclofenac Sodium 1298 (441) 2. 0) 1357 (290) Diclofenac sodium/misoprostol 75 2025 (2005) 2. 4) 2773 (1347) Diclofenac Sodium 2367 (1318) 1. 7) 2609 (1185) Diclofenac Misoprostol Food decreases the multiple-dose bioavailability profile of diclofenac sodium/misoprostol 50 and diclofenac sodium/misoprostol 75. Diclofenac Misoprostol After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7. 6 pg/mL (CV 37%) and 20. 9 pg/mL (CV 77%) after single 200 mcg and 600 mcg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to <1 pg/mL at 5 hours post-dose. These data may not reflect drug level in mature milk and in a daily dosing regimen for osteoarthritis or rheumatoid arthritis. Metabolism Diclofenac Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac. Misoprostol Diclofenac Conjugates of unchanged diclofenac account for 5% to 10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20% to 30% of the dose excreted in the urine and for 10% to 20% of the dose excreted in the bile. Conjugates of three other metabolites together account for 10% to 20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1. 4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity. Misoprostol Geriatric Patients No differences in the pharmacokinetics of diclofenac were observed in geriatric subjects (66 to 81 years; N=10) compared to younger adult subjects (26 to 46 years; N=10) following administration of diclofenac 50 mg twice daily for 4 weeks. Though the mean AUC value of misoprostol acid for elderly subjects was 41% higher in geriatric healthy subjects (mean age, 69. 6 years, N=24) compared to younger adult healthy subjects (mean age, 25. 2 years, N=24) following single dose of misoprostol 400 µg, the increase in exposure is not clinically meaningful. In a multiple-dose crossover study of diclofenac sodium/misoprostol administered twice daily to 24 subjects aged 65 years of age and older, misoprostol did not affect the pharmacokinetics of diclofenac [see Use in Specific Populations (8. 5) Racial or Ethnic Groups Pharmacokinetic differences due to race have not been identified. Patients with Renal Impairment In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min) following intravenous administration of 50 mg diclofenac, AUC values and elimination rates were comparable to those in healthy subjects. Pharmacokinetic studies with misoprostol in patients with severe renal impairment requiring hemodialysis (n=8, mean creatinine clearance 6. 73m 2 max [see Use in Specific Populations (8. 6) Patients with Hepatic Impairment In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubin, N=10), diclofenac concentrations and urinary elimination values following administration of 100 mg oral solution were comparable to those in healthy subjects. In a study of subjects with mild to moderate hepatic impairment, mean misoprostol acid AUC and C max max Diclofenac Aspirin: Table 1 [see Drug Interactions (7) Voriconazole max [see Drug Interactions (7) 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. Other drugs max Misoprostol Diazepam Other drugs.

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.

3 [see Warnings and Precautions (5) 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 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 Diclofenac sodium/misoprostol contains misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies (14) [see Adverse Reactions (6. 1) 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 10) [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 1-877-446-3679 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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) Warnings and Precautions (5) Other adverse experiences reported occasionally with diclofenac sodium/misoprostol, diclofenac or other NSAIDs, or misoprostol are: Body as a whole: Central and peripheral nervous system: Digestive: Female reproductive disorders: Hemic and lymphatic system: Metabolic and nutritional: Musculoskeletal system: Psychiatric: Respiratory system: Skin and appendages: Special senses: Renal and urinary disorders: Vision: 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 to drug exposure. Body as a whole: Cardiovascular system: Central and peripheral nervous system: Congenital, familial and genetic disorders: Digestive: Female reproductive disorders: Hemic and lymphatic system: Hypersensitivity: Liver and biliary system: Male reproductive disorders: Metabolic and nutritional: Pregnancy, puerperium and perinatal conditions Psychiatric: Reproductive system and breast disorders: Respiratory system: Skin and appendages: Special senses: Renal and urinary disorders: Vision:.

WARNING: RISK OF UTERINE RUPTURE,ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS
Uterine Rupture, Abortion, Premature Birth, and Birth Defects Administration of misoprostol, a component of diclofenac sodium/misoprostol, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered in pregnant women to induce labor or an abortion [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 1) Diclofenac sodium/misoprostol is contraindicated in pregnancy [see Contraindications (4) [see Warnings and Precautions (5. 1) If diclofenac sodium/misoprostol is prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise them to use effective contraception during treatment [see Use in Specific Populations (8. 3) Cardiovascular Thrombotic Events NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5. 2) Diclofenac sodium/misoprostol is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) Warnings and Precautions (5. 2) Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5. 3) WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Administration of misoprostol, a component of diclofenac sodium/misoprostol, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered in pregnant women to induce labor or an abortion. 1 Diclofenac sodium/misoprostol is contraindicated in pregnancy and is not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others. 3 Increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. 2 Diclofenac sodium/misoprostol is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. 2 Increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal and can occur at any time and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk.
CONTRAINDICATIONS
Diclofenac sodium/misoprostol is contraindicated in the following patients: [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) 4 4 4 4 4.

Reversible Infertility 8. 3 Geriatric Patients 8. 5 Renal Impairment 8. 6 Risk Summary Diclofenac sodium/misoprostol is contraindicated in pregnant women [see Contraindications (4) There are no adequate and well-controlled studies of diclofenac sodium/misoprostol in pregnant women; however, there is information available about the active drug components of diclofenac sodium/misoprostol, diclofenac sodium and misoprostol. Administration of misoprostol to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions (5. 1) (see Data (see Clinical Considerations (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal Adverse Reactions Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eighth week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. Diclofenac sodium/misoprostol, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete. Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses. Diclofenac sodium/misoprostol is contraindicated in pregnant women [see Contraindications (4) If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus. Fetal/Neonatal Adverse Reactions Misoprostol Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death (misoprostol is not approved for this use). Diclofenac sodium/misoprostol is contraindicated in pregnant women [see Contraindications (4) Diclofenac Premature Closure of Fetal Ductus Arteriosus: NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy (see Data Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Data Labor or Delivery There are no studies on the effects of diclofenac sodium/misoprostol or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational age and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. Data Human Data Misoprostol Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. Diclofenac Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of diclofenac sodium/misoprostol alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, diclofenac sodium/misoprostol was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m 2 2 In oral teratology studies with misoprostol in pregnant rats at doses up to 1. 6 mg/kg/day (9. 6 mg/m 2 2 In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m 2 2 2 Risk Summary No lactation studies have been conducted with diclofenac sodium/misoprostol; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology (12. 3) Diclofenac sodium/misoprostol is not recommended in women of childbearing potential [see Warnings and Precautions (5. 1) Pregnancy Testing Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating diclofenac sodium/misoprostol. Contraception Females Diclofenac sodium/misoprostol can cause fetal harm when administered to a pregnant woman [see Contraindications (4) Use in Specific Populations (8. 1) Diclofenac sodium/misoprostol may be prescribed if the patient: . Advise females to inform their healthcare provider of a known or suspected pregnancy. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac, a component of diclofenac sodium/misoprostol, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12. 1) Safety and effectiveness of diclofenac sodium/misoprostol in pediatric patients have not been established. Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions [see Warnings and Precautions (5. 7 [see Drug Interactions (7) Use in Specific Populations (8. 6) Avoid use of diclofenac sodium/misoprostol in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions [see Dosage and Administration (2. Of the 2,184 patients in clinical studies with diclofenac sodium/misoprostol, 557 (25. 5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12. 3) Diclofenac and misoprostol are primarily excreted by the kidney. [see Warnings and Precautions (5. 7) Drug Interactions (7) Clinical Pharmacology (12.

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: Intervention: Monitor patients with concomitant use of diclofenac sodium/misoprostol with anticoagulants (e. , warfarin), antiplatelet drugs (e. , 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) ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: Intervention: [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. , 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. 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. , 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. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5. 3) Intervention: The concomitant use of diclofenac sodium/misoprostol with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium/misoprostol and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Avoid diclofenac sodium/misoprostol for a period of two days before, the day of, and two days following administration of pemetrexed. Antacids Clinical Impact: Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. Intervention: Concomitant use of diclofenac sodium/misoprostol and magnesium-containing antacids is not recommended. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding. Intervention Monitor patients with concomitant use of diclofenac sodium/misoprostol with corticosteroids for signs of bleeding [see Warnings and Precautions (5. 3) CYP2C9 Inhibitors or Inducers Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e. , voriconazole) may enhance the exposure and toxicity of diclofenac [see Clinical Pharmacology (12. 3) Intervention: CYP2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of diclofenac sodium/misoprostol 50 twice daily [ Dosage and Administration (2. 4) CYP2C9 inducers: A dosage adjustment may be warranted when diclofenac sodium/misoprostol is administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary. See full prescribing information for a list of clinically important drug interactions.

OVERDOSAGE
Manage patients with symptomatic and supportive care following an acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. The toxic dose of diclofenac sodium/misoprostol has not been determined. However, signs of overdosage from the components of the product have been described. Diclofenac Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5. 7) Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia. If gastric decontamination may be potentially beneficial to the patient, e. , short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Misoprostol The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Diclofenac sodium/misoprostol Symptoms of acute overdosage with diclofenac sodium/misoprostol should be treated with supportive and symptomatic therapy. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven.
NONCLINICAL TOXICOLOGY
Carcinogenesis Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of diclofenac sodium/misoprostol given alone. In a 24 month rat carcinogenicity study, misoprostol administered orally at doses up to 2. 4 mg/kg/day (14. 4 mg/m 2 2 2 In a 24 month rat carcinogenicity study, diclofenac sodium administered orally at up to 2 mg/kg/day (12 mg/m 2 2 2 Mutagenesis Diclofenac sodium and misoprostol combination in 250:1 ratio was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse bone marrow micronucleus test. Impairment of Fertility The effects of diclofenac sodium and misoprostol on male or female fertility have not been studied in animals; however, there are data with diclofenac sodium and misoprostol given alone. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0. 1 to 10 mg/kg/day (0. 6 to 60 mg/m 2 2 2 A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.
CLINICAL STUDIES
Osteoarthritis Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis. Rheumatoid Arthritis Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis. Upper Gastrointestinal Safety Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3). Table 3 Misoprostol 200 mcg Dosage Regimen Placebo two times a day three times a day four times a day Gastric ulcer 11% 6% Misoprostol significantly different from placebo (p<0. 05) 3% 3% Duodenal ulcer 6% 2% 3% 1% N=1623; 12 weeks Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving diclofenac sodium/misoprostol have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4). Table 4 Osteoarthritis patients with history of ulcer or erosive disease (N=572), 6 weeks Incidence of ulcers Gastric Duodenal Diclofenac sodium/misoprostol 50 three times a day 3% Statistically significantly different from diclofenac (p<0. 05) 6% Diclofenac sodium/misoprostol 75 two times a day 4% 3% Diclofenac sodium 75 mg two times a day 11% 7% Placebo 3% 1%.

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DICLOFENAC SODIUM AND MISOPROSTOL- diclofenac sodium and misoprostol_tablet, film coated Product manual source documgent