Diclofenac Sodium and Misoprostol

RECENT MAJOR CHANGES Boxed Warning 05/2016 Indications and Usage ( 1 ) 05/2016 Dosage and Administration (2) 05/2016 Contraindications ( 4 ) 05/2016 Warnings and Precautions ( 5 ) 05/2016

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 (PG E1) 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 0.2 mg 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 0.2 mg 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, are administered as diclofenac sodium and misoprostol delayed-release tablets (50 mg diclofenac sodium/0.2 mg misoprostol) or as diclofenac sodium and misoprostol delayed-release tablets (75 mg diclofenac sodium/0.2 mg 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 and misoprostol delayed-release tablets 50 mg/0.2 mg three times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75 mg/0.2 mg two times a day or diclofenac sodium and misoprostol delayed-release tablets 50 mg/0.2 mg 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 and Misoprostol Delayed-Release Tablets 50 mg/0.2 mg three times a day 150 600 two times a day* 100 400 Diclofenac Sodium and Misoprostol Delayed-Release Tablets 75 mg/0.2 mg two times a day* 150 400 *For patients who experience intolerance; these dosages are less effective in preventing ulcers 2.3 Recommended Dosage in Patients with Rheumatoid Arthritis The recommended dosage for the treatment of rheumatoid arthritis is diclofenac sodium and misoprostol delayed-release tablets 50 mg/0.2 mg three or four times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75 mg/0.2 mg two times a day or diclofenac sodium and misoprostol delayed-release tablets 50 mg/0.2 mg 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 and Misoprostol Delayed-Release Tablets 50 mg/0.2 mg four times a day 200 800 three times a day 150 600 two times a day* 100 400 Diclofenac Sodium and Misoprostol Delayed-Release Tablets 75 mg/0.2 mg two times a day* 150 400 * For patients who experience intolerance; these dosages are less effective in preventing ulcers 2.4 Additional Dosage Recommendations Diclofenac s …

3 DOSAGE FORMS AND STRENGTHS Delayed-release tablets: 50 mg diclofenac sodium and 0.2 mg misoprostol is a white to off white, round, biconvex tablets, plain on one side and debossed with “ 0397 ” on the other side. 75 mg diclofenac sodium 0.2 mg misoprostol is a white to off white, round, biconvex tablets, plain on one side and debossed with “ 0398 ” on the other side. Delayed-release tablets: 50 mg diclofenac sodium and 0.2 mg misoprostol ( 3 ) 75 mg diclofenac sodium and 0.2 mg misoprostol ( 3 )

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 )

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 Teva at 1-888-838-2872 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/0.2 mg or diclofenac sodium and misoprostol delayed-release tablets, 75 mg/0.2 mg, 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 to discontinuation of therapy in 9% of patients on diclofenac sodium and misoprostol delayed-release tablets and 5% of patients on diclofenac sodium. For GI ulcer rates, [see Clinical Studies (14) ] . GI disorder Diclofenac Sodium and Misoprostol Delayed-Release Tablets Diclofenac Sodium Abdominal pain 21% 15% Diarrhea 19% 11% Dyspepsia 14% 11% Nausea 11% 6% Flatulence 9% 4% Diclofenac sodium and misoprostol delayed-release 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 and misoprostol delayed-release tablets is prescribed. The incidence of diarrhea can be minimized by administering diclofenac sodium and misoprostol delayed-release 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 and misoprostol delayed-release tablets (see below). Postmenopausal vaginal bleeding may be related to administration of diclofenac sodium and misoprostol delayed-release tablets. 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 and misoprostol delayed-release tablets, 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. Digest …

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 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 and misoprostol delayed-release tablets 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 and misoprostol delayed-release tablets 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 and misoprostol delayed-release tablets 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 and misoprostol delayed-release tablets and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in pl …

8 USE IN SPECIFIC POPULATIONS Reversible Infertility: Consider withdrawal in women who have difficulties conceiving. ( 8.3 ) Geriatric Patients: Avoid use in patients with cardiovascular and/or renal risk factors. ( 8.5 ) Renal Impairment : Avoid use in patients with advanced renal disease. ( 8.6 ) 8.1 Pregnancy Risk Summary Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications (4) ] . If a woman becomes pregnant while taking diclofenac sodium and misoprostol delayed-release tablets, discontinue the drug and advise the woman of the potential risks to her and to a fetus. There are no adequate and well-controlled studies of diclofenac sodium and misoprostol in pregnant women; however, there is information available about the active drug components of diclofenac sodium and misoprostol delayed-release tablets, 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) ] . Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac a component of diclofenac sodium and misoprostol delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment (see Data) . There are clinical considerations when misoprostol and diclofenac are used in pregnant women (see Clinical Considerations) . In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure (see Data) . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. 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 and misoprostol delayed-release tablets, 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 and misopr …

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 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.

11 DESCRIPTION Diclofenac sodium and misoprostol delayed-release tablets, USP are a combination product containing diclofenac sodium, USP an NSAID with analgesic properties, and misoprostol, USP a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release tablets, USP are white to off-white, round, biconvex tablets, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg or 75 mg diclofenac sodium, USP (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 0.2 mg misoprostol, USP. Diclofenac sodium, USP is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium, USP is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium, USP is sparingly soluble in water. Its chemical formula and name are: C 14 H 10 Cl 2 NO 2 Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Misoprostol, USP is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are: C 22 H 38 O 5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate. Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide, crospovidone, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid and ethyl acrylate copolymer dispersion, microcrystalline cellulose, povidone K-30, sodium hydroxide, corn starch, talc, and triethyl citrate.

10 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 and misoprostol delayed-release tablets 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 ( 5.2 , 5.3 , 5.5 , 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.g., 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 and Misoprostol Delayed-Release Tablets Symptoms of acute overdosage with diclofenac sodium and misoprostol delayed-release tablets should be treated with supportive and symptomatic therapy. There are no specific antidotes. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a tablet in dosage strengths of either 50 mg diclofenac sodium, USP/200 mcg misoprostol, USP or 75 mg diclofenac sodium, USP/200 mcg misoprostol, USP. The 50 mg/200 mcg dosage strength is supplied as white to off-white, round shaped, biconvex tablets debossed with “AN” on one side and “436” on the other side. They are available as follows: Bottles of 30: NDC 65162-436-03 Bottles of 60 NDC 65162-436-06 Bottles of 90 NDC 65162-436-09 Bottles of 100: NDC 65162-436-10 The 75 mg/200 mcg dosage strength is supplied as white to off-white, round shaped, biconvex tablets debossed with “AN” on one side and “438” on the other side. They are available as follows: Bottles of 30: NDC 65162-438-03 Bottles of 60: NDC 65162-438-06 Bottles of 100: NDC 65162-438-10 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].