Modulex

Chronic Idiopathic Constipation

Modulex® is indicated for the treatment of chronic idiopathic constipation in adults.

Opioid-induced Constipation

Modulex is indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.

Limitations of Use

• Effectiveness of Modulex in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established.

Irritable Bowel Syndrome with Constipation

Modulex is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women ≥ 18 years old.

Take Modulex 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.

Chronic Idiopathic Constipation and Opioid-induced Constipation

The recommended dose is 24 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment

For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this 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.

Irritable Bowel Syndrome with Constipation

The recommended dose is 8 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment

For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily. If this 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. Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B).

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Nausea

Patients taking Modulex may experience nausea. Concomitant administration of food with Modulex may reduce symptoms of nausea.

Diarrhea

Modulex should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to discontinue Modulex and inform their physician if severe diarrhea occurs.

Dyspnea

In clinical trials, dyspnea was reported by 3%, 1%, and < 1% of the treated CIC, OIC, and IBS-C populations receiving Modulex, respectively, compared to 0%, 1%, and < 1% of placebo-treated patients. There have been postmarketing reports of dyspnea when using Modulex 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 30–60 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.

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 Modulex.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.

Mutagenesis

Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK^+/-) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 169 times the highest recommended human dose of 48 mcg/day, based on body surface area.

Use In Specific Populations

Pregnancy

Pregnancy Category C - Risk Summary

There are no adequate and well-controlled studies with Modulex in pregnant women. 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). Animal studies did not show an increase in structural malformations. Modulex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Current available data suggest that miscarriage occurs in 15-18% of clinically recognized pregnancies, regardless of any drug exposure. Consider the risks and benefits of available therapies when treating a pregnant woman for chronic idiopathic constipation, opioid-induced constipation or irritable bowel syndrome with constipation.

Animal Data

In developmental toxicity studies, pregnant rats and rabbits received oral lubiprostone during organogenesis at doses up to approximately 338 times (rats) and approximately 34 times (rabbits) the maximum recommended human dose (MHRD) based on body surface area (mg/m²). Maximal animal doses were 2000 mcg/kg/day (rats) and 100 mcg/kg/day (rabbits). In rats, there were increased incidences of early resorptions and soft tissue malformations (situs inversus, cleft palate) at the 2000 mcg/kg/day dose; however, these effects were probably secondary to maternal toxicity. A dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m²)). The potential of lubiprostone to cause fetal loss was also examined in pregnant Rhesus monkeys. Monkeys received lubiprostone post-organogenesis on gestation days 110 through 130 at daily oral doses of 10 and 30 mcg/kg/day (approximately 3 and 10 times the MHRD based on body surface area (mg/m²)). Fetal loss was noted in one monkey from the 10mcg/kg dose group, which is within normal historical rates for this species. There was no drug-related adverse effect seen in monkeys.

Nursing Mothers

It is not known whether lubiprostone is excreted in human milk. In rats, neither lubiprostone nor its active metabolites were detectable in breast milk following oral administration of lubiprostone. Because lubiprostone increases fluid secretion in the intestine and intestinal motility, human milk-fed infants should be monitored for diarrhea. Caution should be exercised when Modulex is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Chronic Idiopathic Constipation

The efficacy of Modulex in the elderly ( ≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Modulex, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking Modulex 24 mcg twice daily experienced a lower rate of associated nausea compared to the overall study population taking Modulex (19% vs. 29%, respectively).

Opioid-induced Constipation

The safety profile of Modulex in the elderly ( ≥ 65 years of age) subpopulation (8.8% were ≥ 65 years of age and 1.6% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Modulex did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Irritable Bowel Syndrome with Constipation

The safety profile of Modulex in the elderly ( ≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Modulex did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Renal Impairment

No dosage adjustment is required in patients with renal impairment.

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to normal subjects. Clinical safety results demonstrated an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment.

In case of chronic idiopathic constipation or opioid-induced constipation indications, the starting dosage of Modulex should be reduced in patients with moderate hepatic impairment. The starting dose of Modulex should be reduced in all patients with severe hepatic impairment, regardless of the indication. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

The following adverse reactions are described below and elsewhere in labeling:

• Nausea
• Diarrhea
• Dyspnea

Clinical Studies 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 Modulex for CIC, OIC, and IBS-C, 1234 patients were treated with Modulex for 6 months and 524 patients were treated for 1 year (not mutually exclusive).

Chronic Idiopathic Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Modulex 24 mcg twice daily in 1113 patients with chronic idiopathic constipation 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 47.8 (range 21–81) years; was 87.3% female; 80.7% Caucasian, 10.1% African American, 7.3% Hispanic, 0.9% Asian; and 11.7% elderly ( ≥ 65 years of age). Of those patients treated with Modulex 24 mcg twice daily (N=1113), the mean age was 50.3 (range 19-86) years; 86.9% were female; 86.1% Caucasian, 7.6% African American, 4.7% Hispanic, 1.0% Asian; and 16.7% elderly ( ≥ 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Modulex 24 mcg twice daily and that occurred more frequently with study drug than placebo.

Table 1: Percent of Patients with Adverse Reactions (Chronic Idiopathic Constipation)

The most common adverse reactions (incidence > 4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence.

Nausea: Approximately 29% of patients who received Modulex 24 mcg twice daily experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Modulex 24 mcg twice daily 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 Modulex 24 mcg twice daily 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 Modulex.

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Modulex 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: 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 efficacy and long-term clinical studies: The data described below reflect exposure to Modulex 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 50.4 (range 20–89) years; was 62.7% female; 82.7% Caucasian, 14.2% African American, 0.8% American Indian/Alaska Native, 0.8% Asian; 5.2% were of Hispanic ethnicity; and 8.8% were elderly ( ≥ 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Modulex 24 mcg twice daily and that occurred more frequently with study drug than placebo.

Table 2: Percent of Patients with Adverse Reactions (OIC Studies)

The most common adverse reactions (incidence > 4%) in OIC were nausea and diarrhea.

Nausea: Approximately 11% of patients who received Modulex 24 mcg twice daily experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea.

Diarrhea: Approximately 8% of patients who received Modulex 24 mcg twice daily experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea.

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Modulex 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, blood potassium decreased.

Irritable Bowel Syndrome with Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Modulex 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18–85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly ( ≥ 65 years of age). Table 3 presents data for the adverse reactions that occurred in at least 1% of patients who received Modulex 8 mcg twice daily and that occurred more frequently with study drug than placebo.

Table 3: Percent of Patients with Adverse Reactions (IBS-C Studies)

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

Nausea: Approximately 8% of patients who received Modulex 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 Modulex 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: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Modulex 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of Modulex. 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.

Voluntary reports of adverse reactions occurring with the use of Modulex include the following: syncope, ischemic colitis, hypersensitivity/allergic-type reactions (including rash, swelling, and throat tightness), malaise, tachycardia, muscle cramps or muscle spasms, and asthenia.

There have been two confirmed reports of overdosage with Modulex. The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Modulex and fully recovered. The second report was a study patient who self-administered a total of 96 mcg of Modulex per day for 8 days. The patient experienced no adverse reactions during this time. Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 healthy volunteers given a single oral dose of 144 mcg of Modulex (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug. Adverse reactions that occurred in at least 1% of these volunteers included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).