Included as part of the PRECAUTIONS section.

Pregnancy

The safety of AMITIZA in pregnancy has not been evaluated in humans. In guinea pigs, lubiprostone has been shown to have the potential to cause fetal loss. AMITIZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with AMITIZA and should be capable of complying with effective contraceptive measures. [See Use in Specific Populations].

Nausea

Patients taking AMITIZA may experience nausea. If this occurs, concomitant administration of food with AMITIZA may reduce symptoms of nausea. See ADVERSE REACTIONS.

Diarrhea

AMITIZA 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 inform their physician if severe diarrhea occurs. See ADVERSE REACTIONS.

Bowel Obstruction

In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating physician should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with Amitiza.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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 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.

Lubiprostone was not genotoxic in thein 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.

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. The 1000 mcg/kg/day dose in rats is approximately 166 times the recommended human dose of 48 mcg/day, based on body surface area.

Use In Specific Populations

Pregnancy

Teratogenic effects: Pregnancy Category C. [See WARNINGS and PRECAUTIONS]

Teratology studies with lubiprostone have been conducted in rats at oral doses up to 2000 mcg/kg/day (approximately 332 times the recommended human dose, based on body surface area), and in rabbits at oral doses of up to 100 mcg/kg/day (approximately 33 times the recommended human dose, based on body surface area). Lubiprostone was not teratogenic in rats and rabbits. In guinea pigs, lubiprostone caused fetal loss at repeated doses of 10 and 25 mcg/kg/day (approximately 2 and 6 times the recommended human dose, respectively, based on body surface area) administered on days 40 to 53 of gestation.

There are no adequate and well-controlled studies in pregnant women. However, during clinical testing of AMITIZA at 24 mcg twice daily, four women became pregnant. Per protocol, AMITIZA was discontinued upon pregnancy detection. Three of the four women delivered healthy babies. The fourth woman was monitored for 1 month following discontinuation of study drug, at which time the pregnancy was progressing as expected; the patient was subsequently lost to follow-up.

AMITIZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman is or becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether lubiprostone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lubiprostone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been studied.

Geriatric Use

The efficacy of AMITIZA 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 AMITIZA, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking AMITIZA (any dosage) experienced a lower incidence rate of associated nausea compared to the overall study population taking AMITIZA (18% vs. 29%, respectively).

Renal Impairment

AMITIZA has not been studied in patients who have renal impairment.

Hepatic Impairment

AMITIZA has not been studied in patients who have hepatic impairment.

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