Lubiprostone

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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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, 1648 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 1113 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=1113), the mean age was 50 (range 19-86) 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 Reported in at least 1% of patients treated with Lubiprostone and greater than placebo in Clinical Trials of Adults with CIC System/Adverse Reaction Placebo Lubiprostone 24 mcg Twice Daily N = 316 % N = 1113 % 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 <1 3 Abdominal discomfort This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." 1 3 Dizziness 1 3 Chest discomfort/pain 0 2 Dyspnea 0 2 Dyspepsia <1 2 Fatigue 1 2 Dry mouth <1 1 Nausea: Approximately 29% of patients who received lubiprostone experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea. Diarrhea: Approximately 12% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea. Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving lubiprostone. Less common adverse reactions (<1%): fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite. Opioid-Induced Constipation Adverse reactions in adult efficacy and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N = 1492) had a mean age of 50 (range 20–89) years; was 63% female; 83% Caucasian, 14% African American, 1% American Indian/Alaska Native, 1% Asian; 5% were of Hispanic ethnicity, and 9% were elderly (≥65 years of age). The most common adverse reactions (>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 Reported in at least 1% of patients treated with Lubiprostone and greater than placebo in Clinical Trials of Adults with OIC System/Adverse Reaction Placebo Lubiprostone 24 mcg Twice Daily N = 632 % 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 <1 1 Abdominal discomfort This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." 1 1 Nausea: Approximately 11% of patients who received lubiprostone experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea. Diarrhea: Approximately 8% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): fecal incontinence, blood potassium decreased. Irritable Bowel Syndrome with Constipation Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 47 (range 18–85) years; was 92% female; 78% Caucasian, 13% African American, 9% Hispanic, 0.4% Asian, and 8% elderly (≥65 years of age). The most common adverse reactions (>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 Reported in at least 1% of patients treated with lubiprostone and greater than placebo in Clinical Trials of Adults with IBS-C System/Adverse Reaction Placebo Lubiprostone 8 mcg Twice Daily N = 435 % N = 1011 % Nausea 4 8 Diarrhea 4 7 Abdominal pain 5 5 Abdominal distension 2 3 Nausea: Approximately 8% of patients who received lubiprostone 8 mcg twice daily experienced nausea; 1% of patients had severe nausea and 1% of patients discontinued treatment due to nausea. Diarrhea: Approximately 7% of patients who received lubiprostone 8 mcg twice daily experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.

6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of lubiprostone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: syncope and/or hypotension [see Warnings and Precautions (5.3) ] , tachycardia Gastrointestinal: ischemic colitis General: asthenia Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise Muscoskeletal: muscle cramps or muscle spasms.

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 of age and older in a 12 week, randomized, double-blind, placebo-controlled trial conducted in 606 patients 6 to 17 years with PFC comparing lubiprostone to placebo. The primary efficacy endpoint was an overall response based on spontaneous bowel movement frequency over the duration of the trial; the treatment difference from placebo was not statistically significant. In this age group, adverse reactions to lubiprostone were similar to those reported in adults. In a 36-week, long-term safety extension trial after approximately 9 months of treatment with lubiprostone, a single case of reversible elevation of ALT (17-times upper limit of normal [ULN]), AST (13-times ULN), and GGT (9-times [ULN]) was observed in a child with baseline elevated values (less than or equal to 2.5-times ULN). Juvenile Animal Toxicity Data In a 13-week oral toxicity study in juvenile rats, a significant decrease in total bone mineral density was observed in female pups at 0.5 mg/kg/day; in male pups, a significantly lower cortical thickness at the tibial diaphysis was observed at 0.5 mg/kg. The 0.5 mg/kg/day dose is approximately 101 times the maximum recommended adult dose of 48 mcg/day, based on body surface area (mg/m 2 ).

8.5 Geriatric Use Chronic Idiopathic Constipation The efficacy of lubiprostone 24 mcg twice daily in the elderly (at least 65 years of age) subpopulation with CIC was consistent with the efficacy in the overall study population. Of the total number of patients treated in the dose-finding, efficacy, and long-term studies of lubiprostone, 16% were at least 65 years of age, and 4% were at least 75 years of age. Elderly patients taking lubiprostone experienced a lower rate of associated nausea compared to the overall study population taking lubiprostone (19% vs. 29%, respectively). Opioid-Induced Constipation The safety profile of lubiprostone in the elderly (at least 65 years of age) subpopulation with OIC (9% were at least 65 years of age and 2% were at least 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of lubiprostone did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Irritable Bowel Syndrome with Constipation The safety profile of lubiprostone in the elderly (at least 65 years of age) subpopulation with IBS-C (8% were at least 65 years of age and 2% were at least 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of lubiprostone did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to subjects with normal hepatic function [ see Clinical Pharmacology (12.3) ] . Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment. Adjust the dosage of lubiprostone in patients with severe hepatic impairment for all indications. Dosage adjustment is also needed for patients with moderate hepatic impairment treated for CIC, and OIC [ see Dosage and Administration (2.1) ] . No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

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.

12.2 Pharmacodynamics Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.

12.3 Pharmacokinetics Following oral administration, concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t ½ ) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Absorption Peak plasma concentrations of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The C max was 41.5 pg/mL and the mean AUC 0–t was 57.1 pg∙hr/mL. The AUC 0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone (6-times the maximum recommended 24 mcg dose). Food Effect A study was conducted with a single 72-mcg dose of 3 H-labeled lubiprostone (3-times the maximum recommended 24 mcg dose) to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that C max decreased by 55% while AUC 0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials. Distribution In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Elimination Metabolism Lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate that M3, a metabolite of lubiprostone, is formed by the reduction of the 15-carbonyl moiety to a hydroxy moiety by microsomal carbonyl reductase. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. Excretion Lubiprostone could not be detected in plasma; however, M3 has a t ½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3 H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces. Specific Populations Male and Female Patients The pharmacokinetics of M3 were similar between male and female subjects. Patients with Renal Impairment Sixteen subjects, 34 to 47 years old (8 severe renally impaired subjects [creatinine clearance (CrCl) less than 20 mL/min] who required hemodialysis and 8 control subjects with normal renal function [CrCl above 80 mL/min]), received a single oral 24-mcg dose of lubiprostone. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with lubiprostone. Patients with Hepatic Impairment Twenty-five subjects, 38 to 78 years old (9 with severe hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg of lubiprostone under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the C max and AUC 0–t of the active lubiprostone metabolite M3 were increased, as shown in Table 5. Table 5. Pharmacokinetic Parameters of the Metabolite M3 for Subjects with Normal or Impaired Liver Function following Dosing with lubiprostone Liver Function Status Mean (SD) AUC 0–t (pg∙hr/mL) % Change vs. Normal Mean (SD) C max (pg/mL) % Change vs. Normal Normal (n=8) 39.6 (18.7) n.a. 37.5 (15.9) n.a. Child-Pugh Class B (n=8) 119 (104) +119 70.9 (43.5) +66 Child-Pugh Class C (n=8) 234 (61.6) +521 114 (59.4) +183 These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment. [see Use in Specific Populations (8.6) ] Drug Interaction Studies Based upon the results of in vitro human microsome studies, there is low likelihood of pharmacokinetic drug–drug interactions with lubiprostone. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.

Following oral administration, concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t ½ ) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Absorption Peak plasma concentrations of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The C max was 41.5 pg/mL and the mean AUC 0–t was 57.1 pg∙hr/mL. The AUC 0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone (6-times the maximum recommended 24 mcg dose). Food Effect A study was conducted with a single 72-mcg dose of 3 H-labeled lubiprostone (3-times the maximum recommended 24 mcg dose) to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that C max decreased by 55% while AUC 0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials. Distribution In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Elimination Metabolism Lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate that M3, a metabolite of lubiprostone, is formed by the reduction of the 15-carbonyl moiety to a hydroxy moiety by microsomal carbonyl reductase. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. Excretion Lubiprostone could not be detected in plasma; however, M3 has a t ½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3 H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces. Specific Populations Male and Female Patients The pharmacokinetics of M3 were similar between male and female subjects. Patients with Renal Impairment Sixteen subjects, 34 to 47 years old (8 severe renally impaired subjects [creatinine clearance (CrCl) less than 20 mL/min] who required hemodialysis and 8 control subjects with normal renal function [CrCl above 80 mL/min]), received a single oral 24-mcg dose of lubiprostone. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with lubiprostone. Patients with Hepatic Impairment Twenty-five subjects, 38 to 78 years old (9 with severe hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg of lubiprostone under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the C max and AUC 0–t of the active lubiprostone metabolite M3 were increased, as shown in Table 5. Table 5. Pharmacokinetic Parameters of the Metabolite M3 for Subjects with Normal or Impaired Liver Function following Dosing with lubiprostone Liver Function Status Mean (SD) AUC 0–t (pg∙hr/mL) % Change vs. Normal Mean (SD) C max (pg/mL) % Change vs. Normal Normal (n=8) 39.6 (18.7) n.a. 37.5 (15.9) n.a. Child-Pugh Class B (n=8) 119 (104) +119 70.9 (43.5) +66 Child-Pugh Class C (n=8) 234 (61.6) +521 114 (59.4) +183 These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment. [see Use in Specific Populations (8.6) ] Drug Interaction Studies Based upon the results of in vitro human microsome studies, there is low likelihood of pharmacokinetic drug–drug interactions with lubiprostone. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.