Chronic idiopathic constipation is defined by infrequent or difficult passage

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1 NEW DRUG REVIEW Lubiprostone: A New Drug for the Treatment of Chronic Idiopathic Constipation Danial E. Baker, PharmD, FASCP, FASHP College of Pharmacy, Washington State University Spokane, Spokane, WA Lubiprostone offers an additional alternative for patients with chronic idiopathic constipation. Lubiprostone is more efficacious than placebo in the treatment of chronic idiopathic constipation. In placebo-controlled clinical trials, lubiprostone therapy was generally well tolerated and was not associated with severe adverse effects; however, the high incidence of nausea may be problematic for some patients. The nausea may be alleviated or minimized by administering the dose with food, and some patients may require a dosage reduction to 24 g once daily. The key limitations of the placebo-controlled clinical trials include the absence of information regarding the duration of the constipation and previous types of therapies that had been used to treat the constipation and the absence of an active control group. Comparative studies with other therapies (eg, saline laxatives, polyethylene glycol) used for constipation are necessary to determine the clinical and economic value of this agent relative to other forms of therapy. [Rev Gastroenterol Disord. 2007;7(4): ] 2007 MedReviews, LLC Key words: Constipation Irritable bowel syndrome Lubiprostone Chronic idiopathic constipation is defined by infrequent or difficult passage of stool. The signs and symptoms include abdominal pain or discomfort, bloating, straining, and hard or lumpy stools. These signs and symptoms may be the result of abnormal colonic motility that can delay the transit of intestinal contents and impede the evacuation of rectal contents. Causes of 214 VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS

2 Lubiprostone Table 1 Medical Conditions Associated With Constipation Mechanical obstruction Colon cancer External compression from malignant lesion Strictures: diverticular or postischemic Rectocele (if large) Postsurgical abnormalities Megacolon Anal fissure Metabolic conditions Diabetes mellitus Hypothyroidism Hypercalcemia Hypokalemia Hypomagnesemia Uremia Heavy metal poisoning Myopathies Amyloidosis Scleroderma Adapted with permission from the American Gastroenterological Association. 1 Neuropathies Parkinson s disease Spinal cord injury or tumor Cerebrovascular disease Multiple sclerosis ther conditions Depression Degenerative joint disease Autonomic neuropathy Cognitive impairment Immobility Cardiac disease Table 2 Classes of Medications Associated With Constipation Antacids Calcium supplements Anticholinergic agents Diuretics Antidiarrheal agents Iron supplements Antihistamines Nonsteroidal anti-inflammatory agents Antiparkinsonian drugs piates Antipsychotics Sympathomimetics Calcium channel blockers Tricyclic antidepressants Adapted with permission from the American Gastroenterological Association. 1 secondary constipation from medical conditions (Table 1) and drug therapy (Table 2) should be ruled out. The most common treatment regimens include an increase in dietary fiber intake and the use of a saline laxative. If additional therapy is needed, agents such as polyethylene glycol, lactulose, or stimulant laxatives are used. 1-4 Newer approaches include the use of agents that promote the secretion of fluids into the abdominal lumen (eg, misoprostol, tegaserod). 3,4 Tegaserod was initially available by prescription for the treatment of irritable bowel syndrome with constipation in women or chronic idiopathic constipation in patients under 65 years of age. Marketing of the product was then suspended in March 2007 because of concerns related to the small but statistical increase in heart attack, stroke, and unstable angina in tegaserod-treated patients. Although these events occurred in patients with pre-existing cardiovascular disease and/or cardiovascular risk factors, and no cause-and-effect relationship could be established, the marketing of the drug was suspended to evaluate the data and the need for the product. Subsequently the drug was made available to patients under a treatment investigational new drug (IND) designation in July This allows patients access to the drug if they are female, younger than 55 years, have irritable bowel syndrome with constipation or chronic idiopathic constipation, and with no satisfactory response to other available treatments, and/or patients who had satisfactory improvement of their symptoms with prior tegaserod treatment. Patients with a history or current diagnosis of cardiovascular ischemic disease, symptoms suggestive of cardiovascular ischemic disease, presence of any cardiovascular risk factors, or with uncompensated depression or anxiety or suicidal ideation or behavior will not be allowed to enroll in the treatment IND. 5 Lubiprostone is the newest agent available for the treatment of chronic idiopathic constipation. It acts by promoting the secretion of fluid into the abdominal lumen through the activation of chloride channels in the apical membrane of the gastrointestinal epithelium and is indicated for the VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS 215

3 Lubiprostone continued H H F H F H CH 3 Lubiprostone treatment of chronic idiopathic constipation in the adult population. 6,7 H H Figure 1. Structural comparison of lubiprostone and prostaglandin E 1. H Prostaglandin E 1 H tion of a specific chloride channel; it stimulates the activity of the ClC-2 chloride channel (Figures 2 and 3). 8,14 This chloride channel is an -helical transmembrane protein that has 10 to 12 intramembrane portions with 2 pore channels. It can be found throughout the body and is involved with the regulation of the membrane potential of the cell, regulation of ph and cell volume, and chloride ion transport and fluid secretion. 8,14,15 Activation of the ClC-2 causes an efflux of chloride Apical ClC-2 CI channel Clinical Pharmacology Lubiprostone is a member of a new class of bicyclic fatty acid compounds called prostones. This compound was derived from a metabolite of prostaglandin E 1 (Figure 1 shows a structural comparison of prostaglandin E 1 and lubiprostone) but has minimal binding affinity for prostaglandin E or F receptors. 8,9 Instead, lubiprostone is a potent, selective, locally acting activator of the ClC-2 chloride channels, a voltage-dependent chloride channel found in the apical membrane of the human intestine. 7,8,10-13 Lubiprostone did not exert clinically important activity on prostaglandin receptors. In an assessment of the effects of lubiprostone on isolated smooth muscle, lubiprostone elicited 54% and 23.4% of the maximal activity of prostaglandin E 2 or prostaglandin F 2 on prostaglandin EP 1 (ileum longitudinal smooth muscle contraction) and FP (iris sphincter contraction) receptors, respectively, and was less active than prostaglandin E 2 and misoprostol in inhibiting prostaglandin EP 2 receptor mediated ileum circular smooth muscle twitch. 9 Lubiprostone s primary mechanism of action seems to involve the activathrough the channel into the lumen of the small and large intestine. This is followed by secretion of sodium ions through a paracellular pathway to maintain electrical neutrality and water to keep the isotonic equilibrium without altering sodium and potassium concentrations in the serum. The net result is an increased secretion of fluid into the lumen of the intestinal tract and increased fluid in the stool, which increases the bulk of the contents of the intestine and distention of the intestinal tract which causes the local receptors to be stimulated because of the stretching of this tissue. The stimulation of these receptors produces an increase in the intestinal transit and passage of stool through the intestinal tract. 6,8,12-14 Lubiprostone may also accelerate the recovery of mucosal barrier function after ischemic injury. The animal model showed that lubiprostone increased the level of transepithelial electrical resistance and reduced mannitol flux in ischemia-injured porcine ileum. 16 The clinical usefulness of this finding remains to be proven. Figure 2. Intestinal expression of chloride channels. The ClC-2 channel is located on the apical (luminal) side of the gastrointestinal epithelial cell. Although not a chloride channel, the Na -K -2Cl cotransporter is one of the major pathways for the movement of chloride from the bloodstream into the cell. This cotransporter is present on the basolateral (abluminal) cell membrane of intestinal epithelial cells. Reproduced with permission from Lacy BE and Levy LC. 14 CI Na K K Cl Na /K /2Cl Na Cotransporter K Basolateral Na pump K channel Na paracellular path 216 VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS

4 Lubiprostone K 1 Na 1 Cl 2 Chloride channel Cl 2 Na 1 K 1 Pharmacokinetics The oral systemic bioavailability of lubiprostone is low. Concentrations of lubiprostone in the plasma are below the level of quantitation (10 pg/ml); therefore, standard pharmacokinetic parameters cannot be reliably calculated for lubiprostone. 6 Peak plasma concentrations of the M3 metabolite, the only measurable active metabolite, are reached within 1.1 hours after oral lubiprostone administration. The area under the plasma concentration time curve of M3 increases dose proportionally after single 24- g and 144- g lubiprostone doses. 6 Administration with a high-fat meal resulted in a reduced peak concentration but unchanged area under the curve. Lubiprostone was administered with food in the majority of clinical trials. 6 In vitro, lubiprostone is approximately 94% plasma protein bound. 6 Animal studies indicate limited distribution beyond the gastrointestinal tissues. 6,17 Lubiprostone is rapidly and extensively metabolized by 15-position reduction, -chain -oxidation, and -chain -oxidation mediated by K 1 1 Chloride Na 1 H 2 2 Sodium 3 Water Na 1 pump Na 1 K 1 2Cl cotransporter K 1 channel Intestinal lumen Tight junction Epithelial cell Figure 3. Mechanism of action. Lubiprostone activates ClC-2 channels on the apical membrane of intestinal epithelial cells. This causes an efflux of Cl ions into the lumen of the GI tract, which is followed by Na ions and then water. Figure courtesy of Sucampo Pharmaceuticals. carbonyl reductase. The hepatic cytochrome P450 enzymes are not involved in lubiprostone metabolism. Animal studies show that lubiprostone metabolism occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. 6 M3 has a half-life ranging from 0.9 to 1.4 hours. After a single dose of radiolabeled lubiprostone, 60% of the total administered radioactivity was recovered in the urine within 24 hours, and 30% was recovered in the feces by 168 hours. Lubiprostone and M3 are detected in trace amounts in the feces. 6 Lubiprostone has not been studied in patients with renal or hepatic impairment. 6 Clinical Efficacy Constipation Three doses of lubiprostone were assessed in a dose-ranging study. This study enrolled 129 patients with constipation. The majority of patients were female and Caucasian. Constipation was defined as fewer than 3 spontaneous bowel movements per week plus a 6-month history of one or more of the following symptoms at least 25% of the time: straining, hard stools, or sensation of incomplete evacuation. After a 2-week drug-free period, patients were randomized to placebo (33 patients) or lubiprostone 24 g (29 patients), 48 g (32 patients), or 72 g (33 patients) daily for 3 weeks. A total of 127 patients received at least 1 study dose and made up the intent-to-treat population. An increase in average spontaneous bowel movements per week was greater in the lubiprostone group than in the placebo group during Weeks 1 and 2 for the 48- g and 72- g groups. Between Weeks 2 and 3 there was no improvement in clinical response at the higher doses compared with the 24- g dose. More patients in An increase in average spontaneous bowel movements per week was greater in the lubiprostone group than in the placebo group during Weeks 1 and 2 for the 48- g and 72- g groups. the 48- g and 72- g groups also experienced a bowel movement on the first day of treatment. Improvements were also observed in stool consistency, bloating, and global assessment of constipation severity in patients treated with lubiprostone. 6,18,19 Lubiprostone has been assessed in 2 Phase III studies including 479 patients with chronic idiopathic constipation. Constipation was defined as fewer than 3 spontaneous bowel movements per week plus a 6-month history of at least 1 of the other Rome II criteria for functional constipation (very hard stools for at least a quarter of all bowel movements, sensation of incomplete evacuation after at least a VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS 217

5 Lubiprostone continued quarter of all bowel movements, and straining with defecation at least a quarter of the time). After a 2-week drug-free period, patients were randomized to lubiprostone 24 g or placebo twice daily for 4 weeks, followed by another 2-week drug-free period. A total of 479 patients (88.9% female; mean age 47.2 years; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% aged 65 years or older) were randomized. Study 1 included 242 patients; mean patient age was 48.6 years; 90% were female, and 86% were Caucasian. Study 2 included 237 patients, also predominately female and Caucasian. The primary endpoint of both studies was spontaneous bowel movement frequency after initiation of doubleblind treatment. 6,20-23 The populations from these studies and 1 other study were combined to determine the efficacy and safety of lubiprostone in several smaller subpopulations. Pooling the data still produced small numbers of patients, but it seems that lubiprostone was equally efficacious and safe in elderly patients, male patients, and those with irritable bowel syndrome with constipation Spontaneous bowel movement frequency was increased during all 4 weeks with lubiprostone in both studies. In Study 1, weekly frequencies ranged from 5.1 to 5.7 in the lubiprostone group and 2.8 to 3.5 in the placebo group (P.002 at all weeks). Similar results were observed in Study 2. Complete results from both studies are summarized in Figure 4. Time to first spontaneous bowel movement was shorter with lubiprostone therapy compared with placebo. A spontaneous bowel movement within 24 hours of the first dose occurred in 56.7% of patients in the lubiprostone group compared with 36.9% of placebo-treated patients in Study 1 (P.0024) and in 62.9% in the lubiprostone group compared Mean spontaneous bowel movement frequency rates Baseline Week 1 Week 2 Week 3 Week 4 Week 4 - change from baseline Study 1 Placebo Lubiprostone with 31.9% in the placebo group in Study 2 (P ). Within 48 hours of dosing in Study 2 a spontaneous bowel movement occurred in 79.3% of lubiprostone-treated patients compared with 65.5% of placebo recipients (P.05). Response (defined as 4 or more spontaneous bowel movements per week without rescue drugs) occurred within Week 1 in 72.1% of lubiprostone-treated patients compared with 48.7% of placebo-treated patients (P.0001). Improvements in bloating, abdominal discomfort, stool consistency, and straining were also reported in the lubiprostone group compared with the placebo group. In Study 1, patient global assessment of treatment effectiveness also favored lubiprostone during all 4 weeks of therapy (P.0001 at all weeks). Lubiprostone has also been assessed in a Phase III study including 128 patients with chronic constipation. After a 2-week drug-free period, patients Study 2 Placebo Lubiprostone Figure 4. Mean spontaneous bowel movement frequency rates from Pivotal Study 1 and 2. Data from Sucampo Pharmaceuticals. 6 were treated with lubiprostone 24 g twice daily for 4 weeks, followed by randomization to continued lubiprostone or placebo twice daily for 3 weeks. A responder (defined as having 3 or more spontaneous bowel movements per week during lubiprostone therapy) who converted to nonresponder status (ie, with fewer than 3 spontaneous bowel movements per week) during the randomized phase was defined as a relapse. A total of 128 patients received at least 1 dose of study medication and were included in the assessment. Spontaneous bowel movements increased from 1.36 per week at baseline to 6.25, 5.94, 5.52, and 6.2 per week at Weeks 1, 2, 3, and 4, respectively (P.0001 at all weeks). During the randomized phase, spontaneous bowel movement frequency progressively declined in the placebo group but not in the lubiprostone group. At Week 7, spontaneous bowel movement frequency for patients responding to initial treatment 218 VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS

6 Lubiprostone was still 5.59 in the lubiprostone group but declined to 3.04 in the placebo group (P.0464 for lubiprostone vs placebo; P.0223 for placebo vs baseline). The relapse rate was 44.4% for placebo compared with 18.2% for lubiprostone (P.0223). 27 Three open-label, long-term clinical safety studies also assessed lubiprostone 24 g twice daily for 6 to 12 months in 871 patients with chronic idiopathic constipation. 6,28 The patient population in these 3 studies was 86.1% female, mean age 51 years, 87% Caucasian, 7.3% African American, 18.4% aged 65 years or older. Lubiprostone reduced abdominal bloating, abdominal discomfort, and constipation severity over the 6- to 12-month treatment periods, and significant improvements were reported for constipation severity, bloating, and abdominal discomfort scores (P.001). Similar results were observed in the patients treated for up to 48 weeks. 29,30 The constipation severity improved in all 3 studies. The average improvement in the constipation severity score was 1.28 points at Weeks 4 to 6, 1.47 points at Week 24, 1.38 points at Week 48, and 1.15 points for the last on-drug measurement. Abdominal bloating improved by 0.89 points at Weeks 4 to 6, 0.98 points at Week 24, 1 point at Week 48, and 0.79 points for the last on-drug measurement. The improvements in abdominal discomfort were 0.74 points at Week 1, 0.91 points at Week 24, 0.87 points at Week 48, and 0.72 points for the last on-drug measurement. 29 Data related to the elderly subjects enrolled in these 3 open-label studies were pooled and evaluated for safety and efficacy. There were 163 elderly patients (aged 65 years or older) and 715 non-elderly patients in this combined population. The drug was efficacious in both groups, resulting in an improvement in constipation severity, abdominal bloating, and abdominal discomfort at all assessment points from Week 1 to Week 48. The incidence of adverse events was lower in the elderly group (74.2% vs 80.1%), especially the incidence of nausea (17.8% vs 29.4%). 31 The relapse rate was 44.4% for placebo compared with 18.2% for lubiprostone. Irritable Bowel Syndrome Constipation Predominant A 12-week double-blind, dose-ranging study was conducted, enrolling patients with irritable bowel syndrome with constipation (defined according to the Rome II criteria). Patients were randomized to 1 of 4 treatment groups: placebo, lubiprostone 8 g twice daily, lubiprostone 16 g twice daily, or lubiprostone 24 g twice daily. Dose-dependent improvements were observed in abdominal discomfort/pain, abdominal bloating, spontaneous bowel movement, stool consistency, bowel straining, and assessments of constipation severity during at least 2 of the 3 months of therapy. All doses were better than placebo, and the best overall improvements in the signs and symptoms of the disease occurred in the group treated with lubiprostone 24 g twice daily; however, there was a dose-dependent increased incidence of adverse reactions and drop-outs. 32 Two 12-week Phase III multicenter, double-blind, randomized, placebocontrolled trials were conducted to evaluate the safety and efficacy of lubiprostone in the treatment of adults with irritable bowel syndrome with constipation (defined according to the Rome II criteria). 33 The studies enrolled a total of 1167 adults (91.6% female and 91.7% aged years). The patients were randomized using a 2:1 distribution to 12 weeks of therapy with lubiprostone 8 g twice daily (n 780) or placebo (n 387). The primary endpoint was the change in a symptom relief score (a 7-point scale with the 2 highest points qualifying as response ). The patients were classified as monthly responders if they reported at least moderate relief 4 out of 4 weeks or had significant relief for 2 out of 4 weeks. An overall responder was an individual who achieved monthly responder status for at least 2 out of 3 months. Patients were classified as non-responders if they discontinued therapy for any reason, increased the use of their rescue medication, reported lack of efficacy, or had a worsening of symptoms that was classified as moderate or significant. At the end of the 12-week treatment period, the overall response rate for the pooled population was 17.9% with lubiprostone and 10.1% with placebo (P.001). Individual data from the studies were not reported, but the overall response was reported to be superior to placebo in both studies (P.009 and P.031). Improvements were also reported for the secondary endpoints (eg, abdominal discomfort/pain, stool consistency, straining, constipation severity, and quality of life). The therapy was well tolerated, and the incidence of adverse events was similar in both groups (22% vs 21%). Contraindications Lubiprostone is contraindicated in patients with a history of mechanical gastrointestinal obstruction. 6 It should also be considered contraindicated in patients with a known hypersensitivity to any of the product ingredients (lubiprostone, medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10). VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS 219

7 Lubiprostone continued Warnings and Precautions Nausea may occur with lubiprostone therapy. Administration with food may reduce the nausea symptoms. 6 Lubiprostone should not be prescribed to patients with severe diarrhea. If severe diarrhea occurs during therapy, the need for the lubiprostone should be re-evaluated. 6 Patients with symptoms suggestive of mechanical gastrointestinal obstruction should be evaluated before initiating lubiprostone therapy. 6 Lubiprostone has not been studied in pediatric patients or in patients with renal or hepatic dysfunction. 6 Lubiprostone is classified in Pregnancy Category C. In guinea pigs, lubiprostone exhibited the potential to cause fetal loss; no teratogenic effects were observed in rats or rabbits. 6 Lubiprostone at doses 4.2 to 12.5 times higher than recommended had no effect on pregnant rhesus monkeys. 34 Lubiprostone has not been studied in pregnant women; however, 4 women did become pregnant during lubiprostone clinical trials. Lubiprostone was discontinued in all 4 women. Three of the 4 delivered healthy babies; in the fourth the pregnancy was progressing as expected when the woman was lost to follow-up. Women who could become pregnant should have a negative pregnancy test result before beginning therapy and should be capable of complying with effective contraceptive measures. 6 It is not known whether lubiprostone is excreted in human milk. The manufacturer recommends that either nursing or drug therapy should be discontinued, taking into the account the importance of the drug to the mother. 6 Adverse Reactions Adverse effects reported in lubiprostone clinical studies included nausea, diarrhea, headache, abdominal pain, flatulence, and abdominal distension. 6,18-20,22,35 Nausea was reported in 29% of constipated patients treated with lubiprostone, with 3% reporting severe nausea and 8% discontinuing therapy due to nausea. The incidence was lower in men (7%), the elderly (18%), and patients treated with lubiprostone 24 g once daily (17%). However, the majority of patients enrolled in the clinical trials were female, non-elderly, and received the drug twice daily. In open-label studies the dose could be titrated down to 24 g once daily from 24 g twice daily if the patient was experiencing nausea. As mentioned above, administration with food also reduces the symptoms of nausea. 6 The incidence of diarrhea was 12%. The diarrhea was classified as severe in 3% of the patients, and drug therapy had to be discontinued because of the diarrhea in 2% of the patients. 6 Lubiprostone does not affect serum electrolyte balance in elderly and non-elderly patients with chronic constipation. The pooled data from the various clinical trials showed no change in the serum electrolyte levels or balance in either population. 6,36 Nor did lubiprostone prolong the QTc interval in healthy volunteers after a single dose. This was evaluated with a single-dose study using clinical (24 g) and supratherapeutic (144 g) doses of lubiprostone versus placebo and moxifloxacin administration. Neither of the lubiprostone doses induced a change in the QTc interval. 37 This supports the lack of reports of serious cardiac adverse events and QTc prolongation from the clinical trials along with the electrocardiogram data from the Phase II clinical trials enrolling patients with irritable bowel syndrome or chronic constipation. 37 Table 3 lists the most common adverse effects reported with lubiprostone therapy in patients treated for chronic constipation in the clinical trials. Practitioners are encouraged to report suspected adverse reactions associated with lubiprostone therapy to Takeda Pharmaceuticals North America ( ) or to the US Food and Drug Administration (FDA) (1-800-FDA-1088 or medwatch). 6 Drug Interactions Cytochrome P450 enzymes are not involved in the metabolism of lubiprostone. In vitro, lubiprostone did not inhibit the cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1 or induce isoforms 1A2, 2B6, 2C9, and 3A4. 6 Patients with morphine-induced constipation may benefit from lubiprostone therapy without affecting the central analgesic activity of the morphine, according to the results of studies conducted in mice. The analgesic effects of the morphine were not altered but the bowel function of these mice did improve with the lubiprostone treatment. 38 No additional drug drug interaction studies have been conducted. No protein binding mediated drug interactions are anticipated. 6 Dosing The recommended dose of lubiprostone is 24 g twice daily orally with food, to decrease the risk of nausea. The need for continued therapy should be periodically reassessed. 6 Product Availability Lubiprostone is available as 24- g soft gelatin capsules for the treatment of chronic idiopathic constipation in the adult population. Each capsule contains 24 g of lubiprostone with the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water. It is supplied in bottles of ther dosage strengths will be 220 VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS

8 Lubiprostone Table 3 Most Common Adverse Events Reported With Lubiprostone Therapy in Patients Treated for Chronic Constipation for Up to 12 Months in Clinical Trials Lubiprostone Lubiprostone Lubiprostone Placebo 24 g once 24 g twice Any Dosage Adverse Event (n 316) daily (n 29) daily (n 1113) (n 1175) Nausea Diarrhea Headache Abdominal pain Flatulence Abdominal distension Dizziness Vomiting 3 3 Loose stools 3 3 Edema Abdominal discomfort Chest discomfort/ pain Dyspnea Dyspepsia Fatigue Dry mouth Stomach discomfort Values are percentages. Data from Sucampo Pharmaceuticals 6 and Ueno R et al. 35 available in the future. The new drug application for the use of lubiprostone 8 g twice daily as a treatment for irritable bowel syndrome with constipation was accepted for review by the FDA in September The capsules and bottle should be stored at room temperature (25 C; 77 F) with excursions permitted to 15 C to 30 C (59 F to 86 F). 6 Conclusions Lubiprostone offers an additional alternative for patients with chronic idiopathic constipation. Lubiprostone is more efficacious than placebo in the treatment of chronic idiopathic constipation. Lubiprostone therapy is generally well tolerated and has not been associated with severe adverse effects; however, the high incidence of nausea may be problematic for some patients. The nausea may be alleviated or minimized by administering the dose with food, and some patients may require a dosage reduction to 24 g once daily. The key limitations of these placebo-controlled clinical trials include the absence of information regarding the duration of the constipation and previous types of therapies that had been used to treat the constipation and the absence of an active control group. Comparative Main Points Lubiprostone is the newest agent available for the treatment of chronic idiopathic constipation. It acts by promoting the secretion of fluid into the abdominal lumen through the activation of chloride channels in the apical membrane of the gastrointestinal epithelium and is indicated for the treatment of chronic idiopathic constipation in the adult population. Lubiprostone is more efficacious than placebo in the treatment of chronic idiopathic constipation. Lubiprostone is contraindicated in patients with a history of mechanical gastrointestinal obstruction and in patients with a known hypersensitivity to any of the product ingredients. Adverse effects reported in lubiprostone clinical studies included nausea, diarrhea, headache, abdominal pain, flatulence, and abdominal distension. Administration with food may reduce the nausea symptoms. Lubiprostone should not be prescribed to patients with severe diarrhea. Lubiprostone is classified in Pregnancy Category C. Lubiprostone has not been studied in pediatric patients or in patients with renal or hepatic dysfunction. It is not known whether lubiprostone is excreted in human milk. The recommended dose of lubiprostone is 24 g twice daily orally with food, to decrease the risk of nausea. The need for continued therapy should be periodically reassessed. VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS 221

9 Lubiprostone continued studies with other therapies (eg, saline laxatives, polyethylene glycol) used for constipation are necessary to determine the clinical and economic value of this agent relative to other forms of therapy. References 1. American Gastroenterological Association. AGA technical review on constipation. Gastroenterology. 2000;119: American Gastroenterological Association. American Gastroenterological Association medical position statement: guidelines on constipation. Gastroenterology. 2000;119: Hsieh C. Treatment of constipation in older adults. Am Fam Physician. 2005;72: Johnson DA. Treating chronic constipation: how should we interpret the recommendations? Clin Drug Invest. 2006;26: Novartis Pharmaceuticals. Zelnorm (tegaserod maleate). East Hanover, NJ: Novartis Pharmaceuticals; July Available at: www. zelnorm.com. Accessed September 11, Sucampo Pharmaceuticals. Amitiza (lubiprostone) soft gelatin capsules [package insert]. Bethesda, MD: Sucampo Pharmaceuticals; February Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. Am J Physiol Cell Physiol. 2004;287:C1173- C Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol. 2006;290:G942-G Perentesis GP, Crawford DF, Engelke KJ, et al. Effects of lubiprostone, a novel GI chloride channel activator, on isolated smooth muscle [abstract 900]. Am J Gastroenterol. 2005;100(9 suppl):s Moeser A, Engelke K, Perentesis GP, et al. Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the Clc-2 chloride channel, Spi-0211 [abstract]. Gastroenterology. 2005;128(4 suppl 2):A Cuppoletti J, Malinowska DH, Ramisetti S, Ueno R. Lubiprostone activates Cl currents in caco-2 cells from the apical side [abstract T1887]. Presented at Digestive Disease Week 2007; May 19-24, 2007; Washington, DC. 12. Eaton DC, Bao H, Liu L, Ueno R. Lubiprostone activates single chloride channels in the apical membrane of A6 epithelial cells [abstract T1875]. Presented at Digestive Disease Week 2007; May 19-24, 2007; Washington, DC. 13. Fei G, Liu S, Wang G, et al. Stimulation of mucosal secretion by lubiprostone in guinea-pig small intestine and colon [abstract W1206]. Presented at Digestive Disease Week 2007; May 19-24, 2007; Washington, DC. 14. Lacy BE, Levy LC. Lubiprostone: a chloride channel activator. J Clin Gastroenterol. 2007;41: Chen TY. Structure and function of CLC channels. Annu Rev Physiol. 2005;67: Moeser AJ, Nighot PK, Engelke KJ, et al. Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the CIC-2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol. 2007;292:G647-G Crawford DF, Perentesis GP, Engelke KJ, et al. Pharmacokinetic profile on lubiprostone, a selective GI chloride channel activator, after a single oral dose in multiple animal species [abstract 901]. Am J Gastroenterol. 2005;100(9 suppl): S Johanson JF, Gargano MA, Patchen ML, Ueno R. Efficacy and safety of a novel compound, RU- 0211, for the treatment of constipation [abstract 1511]. Gastroenterology. 2002;122:A Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther. 2007;25: Johanson JF, Gargano MA, Holland PC, et al. Phase III efficacy and safety of RU-0211, a novel chloride channel activator, for the treatment of constipation [abstract]. Gastroenterology. 2003; 124:A Johanson JR, Gargano MA, Holland PC, et al. Initial and sustained effects of lubiprostone, a chloride channel-2 (ClC-2) activator for the treatment of constipation: data from a 4-week phase III study [abstract 884]. Am J Gastroenterol. 2005;100(9 suppl):s324-s Johanson JF, Gargano MA, Holland PC, et al. Phase III study of lubiprostone, a chloride channel-2 (ClC-2) activator for the treatment of constipation: safety and primary efficacy [abstract 896]. Am J Gastroenterol. 2005;100(9 suppl): S328-S Johanson JF, Gargano MA, Holland PC, et al. Phase III patient assessments of the effects of lubiprostone, a chloride channel-2 (ClC-2) activator, for the treatment of constipation [abstract 899]. Am J Gastroenterol. 2005;100(9 suppl): S329-S Ueno R, Joswick TR, Wahle A, et al. Efficacy and safety of lubiprostone for the treatment of chronic constipation in elderly vs non-elderly subjects [abstract] Gastroenterology. 2006;130: A Ueno R, Joswick TR, Wahle A, et al. Efficacy and safety of lubiprostone for the treatment of chronic constipation in male vs female subjects [abstract]. Gastroenterology. 2006;130:A Johanson J, Wahle A, Ueno R. Efficacy and safety of lubiprostone in a subgroup of constipation patients diagnosed with irritable bowel syndrome with constipation (IBS-C) [abstract]. Am J Gastroenterol. 2006;101(9 suppl):s Johanson JF, Gargano MA, Holland PC, et al. Phase III, randomized withdrawal study of RU- 0211, a novel chloride channel activator for the treatment of constipation [abstract]. Gastroenterology. 2004;128:A Johanson JF, Gargano MA, Holland PC, et al. Multicenter open-label study of oral lubiprostone for the treatment of chronic constipation [abstract 903]. Am J Gastroenterol. 2005;100(9 suppl):s Johanson J, Panas R, Holland PC, Ueno R. Longterm efficacy of lubiprostone for the treatment of chronic constipation [abstract]. Gastroenterology. 2006;130:A Ueno R, Wahle A, Panas R, et al. Evaluation of safety and efficacy in a twelve-month study of lubiprostone for the treatment of chronic idiopathic constipation [abstract]. Am J Gastroenterol. 2006;101(9 suppl):s Ueno R, Panas R, Wahle A, et al. Long-term safety and efficacy of lubiprostone for the treatment of chronic constipation in elderly subjects [abstract]. Gastroenterology. 2006;130:A Johanson J, Panas R, Holland PC, Ueno R. A dose-ranging, double-blind, placebo-controlled study of lubiprostone in subjects with irritable bowel syndrome and constipation (c-ibs) [abstract]. Gastroenterology. 2006;130:A Drossman DA, Chey W, Panas R, et al. Lubiprostone significantly improves symptom relief rates in adults with irritable bowel syndrome and constipation (IBS-C): data from two twelve-week, randomized, placebo-controlled, double-blind trials [abstract]. Gastroenterology. 2007;132: Engelke K, Harris S, Roerig B, Ueno R. Effect of lubiprostone, a novel type-2 chloride channel (CIC-2) activator, in pregnant Rhesus monkeys [abstract T1683]. Presented at Digestive Disease Week 2007; May 19-24, 2007; Washington, DC. 35. Ueno R, Wahle A, Rivera E. Pooled analysis of the most frequent adverse events associated with the use of lubiprostone [abstract]. Am J Gastroenterol. 2006;101(9 suppl):s Rivera E, Wahle A, Joswick TR, Ueno R. Lubiprostone, a novel type-2 chloride channel (Clc- 2) activator, does not affect serum electrolyte balance in elderly and non-elderly patients with chronic idiopathic constipation [abstract]. Gastroenterology. 2007;132:A191-A Sprenger C, Copa A, Morganroth J, et al. Effect of lubiprostone, a unique agent for the treatment of chronic idiopathic constipation, on clinical electrocardiographic results [abstract]. Gastroenterology. 2007;132:A Ueno R, sama H, Engelke KJ. Effects of lubiprostone on morphine-induced constipation and analgesia [abstract]. Gastroenterology. 2006; 130:A PR Newswire. FDA accepts Sucampo s snda for lubiprostone (8 g) for the treatment of irritable bowel syndrome with constipation (IBS-C). Available at: (key word: lubiprostone). Accessed September 17, VL. 7 N REVIEWS IN GASTRENTERLGICAL DISRDERS