Lubiprostone

LUBIPROSTONE- lubiprostone capsule
Amneal Pharmaceuticals LLC

1 INDICATIONS AND USAGE

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 [see Clinical Studies (14.2)].

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.

2 DOSAGE AND ADMINISTRATION

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

3 DOSAGE FORMS AND STRENGTHS

Lubiprostone capsules are available as oval, soft gelatin capsules containing 8 mcg or 24 mcg of lubiprostone.

• 8 mcg capsules are pink and are imprinted with “A41”
• 24 mcg capsules are orange and are imprinted with “A42”

4 CONTRAINDICATIONS

Lubiprostone is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction [see Warnings and Precautions (5.5)].

5 WARNINGS AND PRECAUTIONS

5.1 Nausea

Patients taking lubiprostone may experience nausea. Concomitant administration of food with lubiprostone may reduce symptoms of nausea [see Adverse Reactions (6.1)].

5.2 Diarrhea

Avoid use of lubiprostone in patients with severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Instruct patients to discontinue lubiprostone and contact their healthcare provider if severe diarrhea occurs [see Adverse Reactions (6.1)].

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. 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 <1% of the treated CIC, OIC, and IBS-C populations receiving lubiprostone, respectively, compared to 0%, 1%, and <1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using lubiprostone 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 [see Contraindications (4)].

6 ADVERSE 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)]

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=1113), 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 Reactions¹ in Clinical Trials of Adults with CIC

	Placebo	Lubiprostone
System/Adverse Reaction		24 mcg Twice Daily
	N = 316	N = 1113
	%	%
Nausea	3	29
Diarrhea	1	12
Headache	5	11
Abdominal pain	3	8
Abdominal distension	2	6
Flatulence	2	6
Vomiting	0	3
Loose stools	0	3
Edema	<1	3
Abdominal discomfort2	1	3
Dizziness	1	3
Chest discomfort/pain	0	2
Dyspnea	0	2
Dyspepsia	<1	2
Fatigue	1	2
Dry mouth	<1	1

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.”

Nausea: Approximately 29% of patients who received lubiprostone experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea.

Diarrhea: Approximately 12% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea.

Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving lubiprostone.

Less common adverse reactions (<1%): fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.

Opioid-Induced Constipation

Adverse reactions in adult efficacy and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N = 1492) had a mean age of 50 (range 20 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 Reactions¹ in Clinical Trials of Adults with OIC

System/Adverse Reaction1	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 discomfort2	1	1
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.”

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 = 1267) 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 Reactions¹ in Clinical Trials of Adults with IBS-C

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

¹ Reported in at least 1% of patients treated with lubiprostone and greater than placebo

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.