Lubiprostone Drug Information

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 CIC and OIC IBS-C Recommended Adult Dosage Regimen 24 mcg twice daily 8 mcg twice daily Dosage Adjustment for Hepatic Impairment Moderate Impairment (Child-Pugh Class B): 16 mcg twice daily 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.

Moderate Impairment (Child-Pugh Class B): No adjustment necessary Severe Impairment (Child-Pugh Class C): 8 mcg twice daily Severe Impairment (Child-Pugh Class C): 8 mcg once daily

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.

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. 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 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 % 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.

Table 3. 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 most common adverse reactions (>4%) in IBS-C were nausea, diarrhea, and abdominal pain. Table 4. 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.

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, tachycardia Gastrointestinal: ischemic colitis General: asthenia Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise Muscoskeletal: muscle cramps or muscle spasms.

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 in the treatment of OIC in patients taking diphenylhepatane opioids (e.g., methadone) has not been established.

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. 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 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. The potential of lubiprostone to cause fetal loss was also examined in pregnant rhesus monkeys. 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.

Pediatric Use Safety and effectiveness have not been established in pediatric patients with IBS-C, pediatric functional constipation (PFC), and OIC. 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 ), AST (13-times ULN), and GGT (9-times ) 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.

Lubiprostone is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

There have been six reports of overdosage with lubiprostone 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, and another reported diarrhea and a joint injury on the day of overdose after taking 36 mcg of lubiprostone.