LUBIPROSTONE: 1,214 Adverse Event Reports & Safety Profile

11.

Description

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

AND USAGE Lubiprostone capsules are a chloride channel activator indicated for the treatment of: chronic idiopathic constipation (CIC) in adults. ( 1.1 ) opioid-induced constipation (OIC) in adult patients with chronic, non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. ( 1.2 ) Limitations of Use: Effectiveness of lubiprostone capsules in the treatment of OIC in patients taking diphenylheptane opioids (e.g., methadone) has not been established. ( 1.2 , 7.1 ) irritable bowel syndrome with constipation (IBS-C) in women ≥18 years old. ( 1.3 )

1.1 Chronic Idiopathic Constipation in Adults Lubiprostone capsules are indicated for the treatment of chronic idiopathic constipation (CIC) in adults.

1.2 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain Lubiprostone capsules are indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Limitations of Use: Effectiveness of lubiprostone capsules in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span>.

1.3 Irritable Bowel Syndrome with Constipation Lubiprostone capsules are indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women at least 18 years old.

AND ADMINISTRATION Recommended Dosage ( 2.1 ) CIC and OIC: 24 mcg twice daily. IBS-C: 8 mcg twice daily. See full prescribing information for dosage adjustment by indication and degree of hepatic impairment.

Administration

Instructions ( 2.2 ) Swallow capsules whole and do not break apart or chew, Take capsules with food and water, Assess periodically the need for continuous therapy.

2.1 Recommended Dosage The recommended oral dosage of lubiprostone capsules 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 [see Use in Specific Populations (8.6)]

Moderate

Impairment (Child-Pugh Class B) : 16 mcg twice daily* 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* *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.

2.2 Administration Instructions Take lubiprostone capsules 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.

4.

Contraindications

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

REACTIONS The following adverse reactions are described below and elsewhere in labeling: Nausea [see Warnings and Precautions ( 5.1 )] Diarrhea [see Warnings and Precautions ( 5.2 )] Syncope and Hypotension [see Warnings and Precautions ( 5.3 )] Dyspnea [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (> 4%) are: CIC: nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. ( 6.1 ) OIC: nausea and diarrhea. ( 6.1 ) IBS-C: nausea, diarrhea, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During clinical development of lubiprostone for CIC, OIC, and IBS-C, 1,648 patients were treated with lubiprostone for 6 months and 710 patients were treated for 1 year (not mutually exclusive).

Chronic Idiopathic Constipation

Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 1,113 patients with CIC over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤ 4 weeks). The placebo population (N = 316) had a mean age of 48 (range 21 to 81) years; was 87% female; 81% Caucasian, 10% African American, 7% Hispanic, 1% Asian, and 12% elderly (≥ 65 years of age). Of those patients treated with lubiprostone 24 mcg twice daily (N=1,113), the mean age was 50 (range 19 to 86) years; 87% were female; 86% Caucasian, 8% African American, 5% Hispanic, 1% Asian, and 17% elderly (≥ 65 years of age). The most common adverse reactions (> 4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.

Table

2 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with lubiprostone than placebo.

Table

2 Adverse Reactions 1 in Clinical Trials of Adults with CIC 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo 2 This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." System/Adverse Reaction Placebo N = 316 % Lubiprostone 24 mcg Twice Daily N = 1,113 % Nausea 3 29 Diarrhea 1 12 Headache 5 11 Abdominal pain 3 8 Abdominal distension 2 6 Flatulence 2 6 Vomiting 0 3 Loose stools 0 3 Edema < 1 3 Abdominal discomfort 2 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 = 1,492) had a mean age of 50 (range 20 to 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 1 in Clinical Trials of Adults with OIC 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo 2 This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." System/Adverse Reaction 1 Placebo N = 632 % Lubiprostone 24 mcg Twice Daily N = 860 % Nausea 5 11 Diarrhea 2 8 Abdominal pain 1 4 Flatulence 3 4 Abdominal distension 2 3 Vomiting 2 3 Headache 1 2 Peripheral edema < 1 1 Abdominal discomfort 2 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 1,011 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 = 1,267) had a mean age of 47 (range 18 to 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 1 in Clinical Trials of Adults with IBS-C 1 Reported in at least 1% of patients treated with lubiprostone and greater than placebo System/Adverse Reaction Placebo N = 435 % Lubiprostone 8 mcg Twice Daily N = 1,011 % Nausea 4 8 Diarrhea 4 7 Abdominal pain 5 5 Abdominal distension 2 3 Nausea: 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> , tachycardia Gastrointestinal: ischemic colitis General: asthenia Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise Musculoskeletal: muscle cramps or muscle spasms.

5.

Warnings And Precautions

Nausea : Patients may experience nausea; concomitant administration of food may reduce this symptom. (2.2, 5.1) Diarrhea : Avoid use in patients with severe diarrhea. Instruct patients to discontinue lubiprostone capsules and contact their healthcare provider if severe diarrhea occurs during treatment. (5.2) Syncope and Hypotension : May occur after taking the first dose or with subsequent doses. Generally resolves prior to the next dose, but may recur with repeat dosing. Instruct patients to discontinue lubiprostone capsules and contact their healthcare provider if symptoms occur. (5.3) Dyspnea : May occur within an hour of first dose. Generally resolves within 3 hours, but may recur with repeat dosing. Instruct patients to contact their healthcare provider if symptoms occur. (5.4)

Bowel

Obstruction : Evaluate patients with symptoms suggestive of mechanical gastrointestinal obstruction prior to initiating treatment with lubiprostone capsules. (4, 5.5)

5.1 Nausea Patients taking lubiprostone capsules may experience nausea. Concomitant administration of food with lubiprostone capsules may reduce symptoms of nausea <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>.

5.2 Diarrhea Avoid use of lubiprostone capsules in patients with severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Instruct patients to discontinue lubiprostone capsules and contact their healthcare provider if severe diarrhea occurs <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>.

5.3 Syncope and Hypotension Syncope and hypotension have been reported with lubiprostone in the postmarketing setting and a few of these adverse reactions resulted in hospitalization. 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 capsules. Some patients had concomitant diarrhea or vomiting prior to developing the adverse reaction. Syncope and hypotension generally resolved following lubiprostone discontinuation or prior to next dose, but 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.

5.4 Dyspnea In clinical trials, dyspnea was reported by 3%, 1%, and &lt;1% of the treated CIC, OIC, and IBS-C populations receiving lubiprostone capsules, respectively, compared to 0%, 1%, and &lt;1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using lubiprostone capsules 24 mcg twice daily. Some patients have discontinued treatment because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30 to 60 minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses. Instruct patients to contact their healthcare provider if dyspnea occurs.

5.5 Bowel Obstruction In patients with symptoms suggestive of mechanical gastrointestinal obstruction, perform a thorough evaluation to confirm the absence of an obstruction prior to initiating therapy with lubiprostone capsules <span class="opacity-50 text-xs">[see Contraindications (4)]</span>.

INTERACTIONS

7.1 Methadone Diphenylheptane opioids (e.g., methadone) have been shown in nonclinical studies to dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of lubiprostone in patients using diphenylheptane opioids. No in vivo interaction studies have been conducted. The effectiveness of lubiprostone capsules in the treatment of OIC in patients taking diphenylhepatane opioids (e.g., methadone) has not been established <span class="opacity-50 text-xs">[see Indications and Usage (1.2)]</span>.