Lubiprostone

1. INDICATIONS AND USAGE Lubiprostone capsules is a chloride channel activator indicated for the treatment of: chronic idiopathic constipation (CIC) in adults. (1.1) opioid-induced constipation (OIC) in adult patients with chronic, non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. (1.2) o Limitations of Use: Effectiveness of lubiprostone capsules in the treatment of OIC in patients taking diphenylheptane opioids (e.g., methadone) has not been established. (1.2, 7.1) irritable bowel syndrome with constipation (IBS-C) in women ≥18 years old. (1.3) 1.1 Chronic Idiopathic Constipation in Adults Lubiprostone capsules are indicated for the treatment of chronic idiopathic constipation (CIC) in adults. 1.2 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain Lubiprostone capsules are indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Limitations of Use: Effectiveness of lubiprostone capsules in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established. [see Clinical Studies (14.2)] 1.3 Irritable Bowel Syndrome with Constipation Lubiprostone capsules are indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women at least 18 years old.

2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.1 ) CIC and OIC: 24 mcg twice daily. IBS-C: 8 mcg twice daily. See full prescribing information for dosage adjustment by indication and degree of hepatic impairment. Administration Instructions ( 2.2 ) Swallow capsules whole and do not break apart or chew, Take capsules with food and water, Assess periodically the need for continuous therapy. 2.1 Recommended Dosage The recommended oral dosage of lubiprostone by indication and adjustments for patients with moderate (Child Pugh Class B) and severe (Child Pugh Class C) hepatic impairment are shown in Table 1. Table 1 Recommended Dosage Regimen * If the dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. CIC and OIC IBS-C Recommended Adult Dosage Regimen 24 mcg twice daily 8 mcg twice daily Dosage Adjustment for Hepatic Impairment [see Use in Specific Populations ( 8.6 )] Moderate Impairment (Child-Pugh Class B): 16 mcg twice daily * Severe Impairment (Child-Pugh Class C): 8 mcg twice daily * Moderate Impairment (Child-Pugh Class B): No adjustment necessary Severe Impairment (Child-Pugh Class C): 8 mcg once daily * 2.2 Administration Instructions Take lubiprostone orally with food and water. Swallow capsules whole and do not break apart or chew. Physicians and patients should periodically assess the need for continued therapy.

3. DOSAGE FORMS AND STRENGTHS Lubiprostone capsules is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone. 8 mcg capsules are light orange oval capsules containing clear liquid printed with '8' with black ink. 24 mcg capsules are clear orange oval capsules containing clear liquid printed with '24' with black ink. Capsules: 8 mcg and 24 mcg (3)

4. CONTRAINDICATIONS Lubiprostone capsules are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction [see Warnings and Precautions (5.5)]. Patients with known or suspected mechanical gastrointestinal obstruction. (4, 5.5)

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in labeling: Nausea [see Warnings and Precautions ( 5.1 )] Diarrhea [see Warnings and Precautions ( 5.2 )] Syncope and Hypotension [see Warnings and Precautions ( 5.3 )] Dyspnea [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (> 4%) are: CIC: nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. ( 6.1 ) OIC: nausea and diarrhea. ( 6.1 ) IBS-C: nausea, diarrhea, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During clinical development of lubiprostone for CIC, OIC, and IBS-C, 1,648 patients were treated with lubiprostone for 6 months and 710 patients were treated for 1 year (not mutually exclusive). Chronic Idiopathic Constipation Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 1,113 patients with CIC over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤ 4 weeks). The placebo population (N = 316) had a mean age of 48 (range 21 to 81) years; was 87% female; 81% Caucasian, 10% African American, 7% Hispanic, 1% Asian, and 12% elderly (≥ 65 years of age). Of those patients treated with lubiprostone 24 mcg twice daily (N=1,113), the mean age was 50 (range 19 to 86) years; 87% were female; 86% Caucasian, 8% African American, 5% Hispanic, 1% Asian, and 17% elderly (≥ 65 years of age). The most common adverse reactions (> 4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. Table 2 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with lubiprostone than placebo. Table 2 Adverse Reactions 1 in Clinical Trials of Adults with CIC 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo 2 This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." System/Adverse Reaction Placebo N = 316 % Lubiprostone 24 mcg Twice Daily N = 1,113 % Nausea 3 29 Diarrhea 1 12 Headache 5 11 Abdominal pain 3 8 Abdominal distension 2 6 Flatulence 2 6 Vomiting 0 3 Loose stools 0 3 Edema 4%) in OIC were nausea and diarrhea. Table 3 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo. Table 3 Adverse Reactions 1 in Clinical Trials of Adults with OIC 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo 2 This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." System/Adverse Reaction 1 Placebo N = 632 % Lubiprostone 24 mcg Twice Daily N = 860 % Nausea 5 11 Diarrhea 2 8 Abdominal pain 1 4 Flatulence 3 4 Abdominal distension 2 3 Vomiting 2 3 Headache 1 2 Peripheral edema 4%) in IBS-C were nausea, diarrhea, and abdominal pain. Table 4 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo. Table 4 Adverse Reactions 1 in Clinical Trials of Adults with IBS-C 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo System/Adverse Reaction Placebo N = 435 % Lubiprostone 8 mcg Twice Daily N = 1,011 % Nausea 4 8 Diarrhea 4 7 Abdominal pain 5 5 Abdominal distension 2 3 Nausea: Approx …

7 DRUG INTERACTIONS 7.1 Methadone Diphenylheptane opioids (e.g., methadone) have been shown in nonclinical studies to dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of lubiprostone in patients using diphenylheptane opioids. No in vivo interaction studies have been conducted. The effectiveness of lubiprostone capsules in the treatment of OIC in patients taking diphenylhepatane opioids (e.g., methadone) has not been established [see Indications and Usage (1.2)].

8. USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. (8.1) Pediatrics : Safety and effectiveness have not been established in pediatric patients with IBS-C, pediatric functional constipation (PFC), and OIC. (8.4) 8.1 Pregnancy Risk Summary Following oral administration, concentrations of lubiprostone in plasma are below the level of quantitation; however, one of the metabolites, M3, has measurable systemic concentrations [see Clinical Pharmacology (12.3)]. Limited available data with lubiprostone use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Animal reproduction studies did not show an increase in structural malformations. Although a dose dependent increase in fetal loss was observed in pregnant guinea pigs that received lubiprostone (doses equivalent to 0.2 to 6 times the maximum recommended human dose (MRHD) based on body surface area (mg/m 2 )), these effects were probably secondary to maternal toxicity and occurred after the period of organogenesis (see Data). The 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In developmental toxicity studies, pregnant rats and rabbits received oral lubiprostone during organogenesis at doses up to approximately 338 times (rats) and approximately 34 times (rabbits) the maximum recommended human dose (MRHD) based on body surface area (mg/m 2 ). Maximal animal doses were 2000 mcg/kg/day (rats) and 100 mcg/kg/day (rabbits). In rats, there were increased incidences of early resorptions and soft tissue malformations ( situs inversus , cleft palate) at the 2000 mcg/kg/day dose; however, these effects were probably secondary to maternal toxicity. A dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m 2 )); however, these effects were probably secondary to maternal toxicity. The potential of lubiprostone to cause fetal loss was also examined in pregnant rhesus monkeys. Monkeys received lubiprostone post-organogenesis on gestation days 110 through 130 at daily oral doses of 10 and 30 mcg/kg/day (approximately 3 and 10 times the MRHD based on body surface area (mg/m 2 )). Fetal loss was noted in one monkey from the 10-mcg/kg dose group, which is within normal historical rates for this species. There was no drug-related adverse effect seen in monkeys. 8.2 Lactation Risk Summary There are no data available on the presence of lubiprostone in human milk or the effect of lubiprostone on milk production. There are limited data available on the effect of lubiprostone on the breastfed infant. Neither lubiprostone nor its active metabolite (M3) were present in the milk of lactating rats. When a drug is not present in animal milk, it is likely that the drug will not be present in human milk. If present, lubiprostone may cause diarrhea in the breastfed infant (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lubiprostone and any potential adverse effects on the breastfed infant from lubiprostone or from the underlying maternal condition. Clinical Considerations Infants of nursing mothers being treated with lubiprostone should be monitored for diarrhea. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients with IBS-C, pediatric functional constipation (PFC), and OIC. Efficacy was not demonstrated for the treatment of PFC in patients 6 years …

12.1 Mechanism of Action Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Lubiprostone, via activation of apical ClC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability. Activation of ClC-2 by lubiprostone has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

11. DESCRIPTION Lubiprostone is a chloride channel activator for oral use. The chemical name for lubiprostone is (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid. The molecular formula of lubiprostone is C20H32F2O5 with a molecular weight of 390.46 g/mol. and a chemical structure as follows: Lubiprostone drug substance occurs as white to off-white powder, is very soluble in diethyl ether and ethanol, and practically insoluble in hexane and water. Lubiprostone capsules is available as an imprinted, oval, soft gelatin capsule in two strengths. Light orange oval capsules contain 8 mcg of lubiprostone and the following inactive ingredients: bloom gelatin, sorbitol sorbitan solution, FD&C yellow no. 6 powder, titanium dioxide, medium chain triglycerides, purified water and lecithin. Clear orange oval capsules contain 24 mcg of lubiprostone and the following inactive ingredients: bloom gelatin, sorbitol sorbitan solution, FD&C yellow no. 6 powder, medium chain triglycerides, purified water and lecithin. The capsules are imprinted with black imprinting ink containing black iron oxide, propylene glycol, and hypromellose. Structure

10. OVERDOSAGE There have been six reports of overdosage with lubiprostone capsules during clinical development. Of these six cases, only two subjects reported adverse events: one reported vomiting, diarrhea and stomach ache after taking 168 to 192 mcg of lubiprostone capsules, and another reported diarrhea and a joint injury on the day of overdose after taking 36 mcg of lubiprostone capsules. Adverse reactions that occurred in at least 1% of healthy subjects given a single oral dose of 144 mcg of lubiprostone capsules (6 times the highest recommended dose) in a cardiac repolarization study included nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).

16 HOW SUPPLIED/STORAGE AND HANDLING Lubiprostone Capsules, 8 mcg are opaque, oval shaped, light pink to pink colored soft gelatin capsules imprinted with "8" in black ink, containing clear colorless to pale yellow oily liquid and are supplied as follows: NDC 76420-777-30 in bottles of 30 capsules (repackaged from NDC 70710-1641-X) NDC 76420-777-60 in bottles of 60 capsules (relabeled from NDC 70710-1641-6) NDC 76420-777-90 in bottles of 90 capsules (repackaged from NDC 70710-1641-X) NDC 76420-777-01 in bottles of 100 capsules (relabeled from NDC 70710-1641-1) Lubiprostone Capsules, 24 mcg are clear, oval shaped, light yellow colored soft gelatin capsules imprinted with "24" in black ink, containing clear colorless to pale yellow oily liquid and are supplied as follows: NDC 76420-778-30 in bottles of 30 capsules (repackaged from NDC 70710-1642-X) NDC 76420-778-60 in bottles of 60 capsules (relabeled from NDC 70710-1642-6) NDC 76420-778-90 in bottles of 90 capsules (repackaged from NDC 70710-1642-X) NDC 76420-778-01 in bottles of 100 capsules (relabeled from NDC 70710-1642-1) Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and extreme temperatures. Keep container tightly closed. Dispense in a tightly closed, light-resistant container.