Lubiprostone is a unique gastrointestinal agent for the treatment of constipation. Chemically, the drug is a bicyclic fatty acid, prostaglandin E1 (PGE 1) derivative that increases intestinal fluid secretion by activating specific ClC-2 chloride channels in the luminal cells of the intestinal epithelium. Lubiprostone is used to treat adults with chronic idiopathic constipation or opiate agonist-induced constipation (OIC), and is also used in adult women with constipation-predominant irritable bowel syndrome (IBS-C). Guidelines strongly recommend lubiprostone to treat global IBS-C symptoms. Clinically, lubiprostone alters stool consistency and promotes regular bowel movements, without altering serum electrolyte concentrations or producing tolerance, using this unique mechanism. In comparison, fluid and electrolyte problems, as well as product dependency, have been associated with other products for constipation, such as selected laxatives. Furthermore, other agents which effect gastrointestinal motility or inhibit visceral sensitivity (e.g., tegaserod), have not been adequately studied in the elderly suffering from chronic constipation. Overall, lubiprostone is well tolerated in all adult populations, including in elderly patients. In clinical evaluation, statistically significant differences in the timing of the first spontaneous bowel movement (SMB) following initiation of treatment were observed in lubiprostone-treated patients compared to placebo-treated patients; approximately 60% of patients experienced an SMB within 24 hours of the first lubiprostone dose compared to roughly 35% in placebo groups. Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved in the lubiprostone group. Additionally, long-term, open-label data suggest a sustained response over a 6 to 12 month treatment period.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Patients should swallow capsules whole. Do not break apart or chew.
-Administer with food. Administration with food minimizes the symptoms of drug-induced nausea.
One of the most common adverse reactions associated with lubiprostone is nausea, with a reported incidence of 8% in patients taking 8 mcg twice daily for IBS-C, 17% of patients taking 24 mcg/day for chronic idiopathic constipation, and 11% and 29% of patients taking 24 mcg twice daily for chronic idiopathic constipation and opioid-induced constipation (OIC), respectively. Among patients receiving 24 mcg twice daily, 1 to 4% reported severe nausea and 2 to 9% discontinued treatment due to nausea. Administering lubiprostone with food decreases the incidence of reported nausea. Of note, the incidence of nausea was substantially lower among men (7%) and elderly patients (18%) when compared to the overall rate. In the open-label, long-term studies (6 to 12 months), patients were allowed to reduce the dose of lubiprostone to 24 mcg once daily if experiencing nausea.
Headache is infrequently reported with lubiprostone, occurring in 2% to 11% of patients at the 24 mcg twice daily dose. Only 3.4% of patients receiving lubiprostone 24 mcg once daily reported headache; however, the sample size of the once daily group was extremely small (n = 29).
Diarrhea is reported in 8% to 12% of patients taking lubiprostone 24 mcg PO twice and in 7% of patients taking 8 mcg PO twice daily. Of those patients at the 24 mcg twice daily dose, 2% reported severe diarrhea and 1 to 2% discontinued treatment due to diarrhea. The incidence of diarrhea did not appear to be dose-dependent. Patients should be aware of the possible occurrence of diarrhea during treatment, and to report severe diarrhea to their provider. If diarrhea occurs, treatment with lubiprostone may need to be interrupted until diarrhea resolves. Vomiting was reported in 3% of patients receiving lubiprostone 24 mcg twice daily in opioid-induced constipation (OIC) trials. Patients who experience diarrhea and vomiting with lubiprostone have an increased risk of syncope and hypotension. Cases of syncope and hypotension, some requiring hospitalization, have been reported during postmarketing experience with lubiprostone. Most cases occurred in patients taking 24 mcg twice daily and some occurred within an hour after taking the first dose or subsequent doses of lubiprostone. Concomitant diarrhea or vomiting was noted in some patients prior to developing the adverse reaction. Although syncope and hypotension generally resolved following lubiprostone discontinuation or prior to next dose, recurrence has been reported with subsequent doses. Several cases reported concomitant use of medications known to lower blood pressure, which may increase the risk for the development of syncope or hypotension. Patients should be aware of the risk of syncope and hypotension during treatment and that other adverse reactions may increase this risk, such as diarrhea or vomiting.
Additional gastrointestinal adverse reactions reported by at least 1% of patients who received lubiprostone (independent of indication) and at a greater incidence than placebo included abdominal distension (3% to 6%), abdominal pain (4% to 8%), flatulence (4% to 6%), loose stools (3%), and dyspepsia (2%).
The following additional gastrointestinal (GI) adverse events were considered by the investigators to be possibly related to lubiprostone and were reported at incidences less than 1% but more frequently (0.2% or more) on the drug compared to placebo, and those events that lead to discontinuation more frequently in patients on lubiprostone. Although these events occurred during treatment with lubiprostone, the events were not necessarily attributed to lubiprostone. The GI events were watery stools, fecal incontinence, abnormal bowel sounds, frequent bowel movements (fecal urgency), retching, and decreased appetite.
Potential allergic, cardiovascular, dermatologic neurologic, psychiatric, and respiratory adverse reactions have been reported with lubiprostone. In clinical trials, dyspnea was reported by 3%, 1%, and less than 1% of the treated chronic idiopathic constipation, opioid-induced constipation (OIC), and IBS-C populations receiving lubiprostone, respectively, compared to 0%, 1%, and less than 1% of placebo-treated patients, respectively. Patients have discontinued therapy secondary to the dyspnea. Patients have described the event as a sensation of chest tightness and difficulty taking a breath; the symptoms have generally occurred within 30 to 60 minutes after taking the first dose. The symptoms generally resolve within a few hours of a dose; recurrence is frequently reported after subsequent doses. Adverse reactions reported by at least 1% of patients who received lubiprostone (independent of indication) and at a greater incidence than placebo included dizziness (1% to 3%), peripheral edema (3%), chest pain (unspecified) (2%), and fatigue (2%). The following additional adverse events are those that were considered by the investigators to be possibly related to lubiprostone and reported at incidences less than 1% but more frequently (greater than 0.2%) on the drug compared to placebo, and those events that lead to discontinuation more frequently in those receiving lubiprostone than placebo. Although these events occurred during treatment with lubiprostone, the events were not necessarily attributed to lubiprostone. The events were classified as Neurologic: tremor, dysgeusia, paresthesias; General: rigors (chills), asthenia, malaise; Respiratory: asthma or wheezing, painful respiration, throat tightness, Allergic/Dermatologic: hyperhidrosis, urticaria, rash (unspecified); Psychiatric: nervousness or anxiety; Vascular: flushing or hot flushes, palpitations; Special senses: vertigo.
Lubiprostone is contraindicated in any patient with a known hypersensitivity to the drug or any of its excipients.
Lubiprostone is contraindicated in patients with a history of mechanical GI obstruction. Patients with current symptoms (e.g., abdominal pain) that may be suggestive of mechanical GI obstruction should be medically evaluated before using lubiprostone. Use lubiprostone cautiously in patients with GI disease who are at risk of mechanical GI obstruction. Common causes of mechanical obstruction include abdominal adhesions, hernias, tumors (gastric cancer, disseminated intraperitoneal cancer), foreign bodies (including gallstones, cholelithiasis), diverticulitis, inflammatory bowel disease (Crohn's disease), Hirschsprung's disease, fecal impaction, and volvulus.
Lubiprostone should not be administered to patients with severe diarrhea. Diarrhea is a common adverse effect of lubiprostone. Patients should be informed of this side effect and should notify their health care provider if the diarrhea becomes severe. Patients who experience diarrhea and vomiting with lubiprostone have an increased risk of syncope and hypotension. Cases of syncope and hypotension, some requiring hospitalization, have been reported during postmarketing experience with lubiprostone. Most cases occurred in patients taking 24 mcg twice daily and some occurred within an hour after taking the first dose or subsequent doses of lubiprostone. Concomitant diarrhea or vomiting was noted in some patients prior to developing the adverse reaction. Although syncope and hypotension generally resolved following lubiprostone discontinuation or prior to next dose, recurrence has been reported with subsequent doses. Several cases reported concomitant use of medications known to lower blood pressure, which may increase the risk for the development of syncope or hypotension. Patients should be aware of the risk of syncope and hypotension during treatment.
Limited available data with lubiprostone use in pregnancy 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/m2), these effects were probably secondary to maternal toxicity and occurred after the period of organogenesis.
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; therefore, infants of nursing mothers being treated with lubiprostone should be monitored for diarrhea. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The safety and effectiveness of lubiprostone have not been established in pediatric patients (adolescents, children or infants) with irritable bowel syndrome with constipation (IBS-C), pediatric functional constipation (PFC), or opioid-induced constipation (OIC). Efficacy was not demonstrated for the treatment of PFC in pediatric patients 6 years of age and older in a 12-week 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, safety extension trial after approximately 9 months of treatment, a single case of reversible elevation of liver enzymes was observed in a child with baseline elevated values.
Lubiprostone should be used with caution in patients with moderate to severe hepatic disease, and initial dosages reduced to account for increased drug exposure in these patients. Study results demonstrate an increase in M3, an active metabolite of lubiprostone, in subjects with severe (Child-Pugh Class C) and moderate (Child-Pugh Class B) hepatic impairment. These results, coupled with safety data demonstrating increased incidence and severity of adverse events in these patients, warrant a reduced starting dose of lubiprostone (see Indications/Dosage). No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
In clinical trials, the efficacy of lubiprostone for treatment of constipation in the 65 years of age and older subpopulation was consistent with the efficacy in the overall study population. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents (e.g., geriatric adults) of long-term care facilities. The OBRA guidelines caution that laxatives may cause flatulence, bloating, and abdominal pain.
For the treatment of chronic idiopathic constipation (e.g., 6 month or longer history of less than 3 spontaneous bowel movements per week, with at least 25% of bowel movements with hard stools, sensation of incomplete evacuation, or straining):
Oral dosage:
Adults: 24 mcg PO twice daily with food and water. Periodically assess the need for continued therapy. In clinical trials, some patients received a reduction in dosage to 24 mcg PO once daily if significant side effects (e.g., nausea) occurred.
For the treatment of irritable bowel syndrome with constipation (IBS-C) in females:
NOTE: Safe and effective use in men has not been established.
Oral dosage:
Adult Females: 8 mcg PO twice daily.
For the treatment of opiate agonist-induced constipation in 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 dose escalation:
Oral dosage:
Adults: 24 mcg PO twice daily with food and water. Lubiprostone improves spontaneous bowel movements in patients taking non-diphenylheptane opioids like morphine. Effectiveness in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established; patients in clinical trials who were taking methadone had responder rates to lubiprostone that were worse than placebo, and other studies have indicated methadone may actually negate lubiprostone's effects.
Maximum Dosage Limits:
-Adults
Females: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; 16 mcg/day PO for irritable bowel syndrome.
Males: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; safety and efficacy have not been established for irritable bowel syndrome.
-Geriatric
Females: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; 16 mcg/day PO for irritable bowel syndrome.
Males: 48 mcg/day PO for chronic idiopathic constipation and opiate agonist-induced constipation; safety and efficacy have not been established for irritable bowel syndrome.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Not indicated.
-Neonates
Not indicated.
Patients with Hepatic Impairment Dosing
For chronic idiopathic constipation and opiate agonist-induced constipation: The recommended dose is 16 mcg PO twice daily in patients with moderate hepatic impairment (Child-Pugh Class B) and 8 mcg PO twice daily in patients with severe hepatic impairment (Child-Pugh Class C). If tolerated, the dose may be increased to reach desired clinical effect; however, close monitoring is warranted. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
For irritable bowel syndrome with constipation: The recommended dose is 8 mcg PO once daily in patients with severe hepatic impairment (Child-Pugh Class C). If tolerated, the dose may be increased to reach desired clinical effect; however, close monitoring is warranted. No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustment is needed in patients with renal impairment.
*non-FDA-approved indication
Alosetron: (Moderate) Alosetron can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone. However, lubiprostone may cause diarrhea as a side effect, but drug discontinuation alone may resolve the diarrhea.
Anticholinergics: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Atropine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Atropine; Difenoxin: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Belladonna; Opium: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain. (Moderate) Opium can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Benztropine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Bumetanide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Calcium Phosphate, Supersaturated: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Chlordiazepoxide; Clidinium: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Crofelemer: (Moderate) Crofelemer, through its local effects as an antidiarrheal on chloride channels in the intestine, may theoretically antagonize the pharmacologic effects of lubiprostone. In general, it would be illogical to concurrently administer crofelemer in combination with lubiprostone. While lubiprostone may cause diarrhea as a side effect, drug discontinuation alone may resolve the diarrhea.
Dichlorphenamide: (Moderate) Use dichlorphenamide and lubiprostone together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including laxatives. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Dicyclomine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Diphenoxylate; Atropine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Ethacrynic Acid: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Flavoxate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Furosemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Glycopyrrolate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Glycopyrrolate; Formoterol: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Homatropine; Hydrocodone: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Hyoscyamine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Indacaterol; Glycopyrrolate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Lactulose: (Major) In general, other laxatives, such as lubiprostone, should not be used concurrently with lactulose, especially during the initial phase of therapy for portal-systemic encephalopathy, because the loose stools resulting from their use may falsely suggest that adequate lactulose dosage has been achieved.
Loop diuretics: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Methadone: (Major) Non-clinical studies have shown that opioids of the diphenylheptane chemical class (e.g., methadone) 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. Effectiveness in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established; patients taking methadone during clinical trials for opioid induced constipation had lower response rates than placebo-treated patients.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Methscopolamine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Neostigmine; Glycopyrrolate: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Oxybutynin: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Propantheline: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Scopolamine: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Solifenacin: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Torsemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Trihexyphenidyl: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Lubiprostone increases intestinal fluid secretion. Lubiprostone acts by specifically activating ClC-2 chloride channels; the action of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Activation of the CIC-2 channels produces a chloride-rich intestinal fluid secretion without altering serum electrolyte concentrations. This action softens the stool, increases motility in the intestine, promotes spontaneous bowel movements, and thereby alleviates signs and symptoms (e.g., bloating, discomfort, straining, hard stools) associated with constipation.
Clinically, the administration of lubiprostone typically produces clinical results within 1 week, and an increase in spontaneous bowel movements may be noted in some patients within 24 hours of administration. Unlike many laxatives, tolerance to use has not been observed. Following 4 weeks of treatment during clinical trials, withdrawal of the drug did not result in rebound effect. After cessation of treatment there is a gradual decrease in the frequency of bowel movements to pre-treatment levels.
Lubiprostone is administered orally. Human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by reduction and oxidation, and this extensive metabolism appears to be mediated by carbonyl reductase. Biotransformation is not mediated by the hepatic CYP450 system. M3 is the only measurable metabolite and makes up < 10% of a total administered dose; the half-life of M3 is roughly 0.9-1.4 hours. Animal data indicate that metabolism occurs locally within the stomach and jejunum; similar metabolism is assumed in humans. After a single oral dose of 72 mcg of radiolabeled lubiprostone, 60% of the total dose was recovered in the urine within 24 hours; 30% of the radioactivity is recovered in the feces by 168 hours. Lubiprostone and the M3 active metabolite are only detected in trace amounts in feces in humans.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, lubiprostone has a low systemic availability and plasma concentrations are below the level of quantitation (< 10 pg/ml), and standard pharmacokinetic parameters for the parent drug cannot be calculated. Plasma levels of M3, the only measurable active metabolite, are also very low. Minimal distribution occurs beyond the gastrointestinal tissues.
-Special Populations
Hepatic Impairment
During clinical evaluation, 9 subjects 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. In moderately and severely impaired subjects, the AUC and Cmax of M3 were increased. In moderately impaired subjects, a +119% and +66% change from normal was observed in AUC and Cmax, respectively. In severely impaired subjects, a +521% and +183% change from normal was observed in AUC and Cmax, respectively. These results, coupled with safety data demonstrating increased incidence and severity of adverse events associated with greater severity of hepatic impairment, warrant a reduced starting dose of lubiprostone in this population (see Indications/Dosage). No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
Renal Impairment
During clinical evaluation, administration of a single 24 mcg lubiprostone dose to 8 subjects with severe renal impairment (CrCl < 20 mL/min) requiring hemodialysis resulted in lubiprostone plasma concentrations below the limit of quantitation (10 pg/mL) and M3 plasma concentrations within range of exposure from previous clinical experience. Similar results are observed in control subjects. Therefore, no dosage adjustment is needed in patients with renal impairment.
Pediatrics
Lubiprostone has not been studied in pediatric patients.