Amitiza (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 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 Ames reverse mutation assay, the mouse lymphoma (L5178Y TK ) forward mutation assay, the Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the mouse bone marrow micronucleus assay. in vitro in vitro +/– in vitro in vivo

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.

14 CLINICAL STUDIES

14.1 Chronic Idiopathic Constipation

Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation. Chronic idiopathic constipation was defined as, on average, less than 3 spontaneous bowel movements (SBMs) per week (a SBM is a bowel movement occurring in the absence of laxative use) along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.

Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 5).

*
Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).

Table 5: Spontaneous Bowel Movement Frequency Rates * (Efficacy Studies)

Trial

Study Arm

Baseline Mean ± SD Median

Week 1 Mean ± SD Median

Week 2 Mean ± SD Median

Week 3 Mean ± SD Median

Week 4 Mean ± SD Median

Week 1 Change from Baseline Mean ± SD Median

Week 4 Change from Baseline Mean ± SD Median

Placebo

1.6 ± 1.3 1.5

3.5 ± 2.3 3.0

3.2 ± 2.5 3.0

2.8 ± 2.2 2.0

2.9 ± 2.4 2.3

1.9 ± 2.2 1.5

1.3 ± 2.5 1.0

Study 1

Amitiza 24 mcg Twice Daily

1.4 ± 0.8 1.5

5.7 ± 4.4 5.0

5.1 ± 4.1 4.0

5.3 ± 4.9 5.0

5.3 ± 4.7 4.0

4.3 ± 4.3 3.5

3.9 ± 4.6 3.0

Placebo

1.5 ± 0.8 1.5

4.0 ± 2.7 3.5

3.6 ± 2.7 3.0

3.4 ± 2.8 3.0

3.5 ± 2.9 3.0

2.5 ± 2.6 1.5

1.9 ± 2.7 1.5

Study 2

Amitiza 24 mcg Twice Daily

1.3 ± 0.9 1.5

5.9 ± 4.0 5.0

5.0 ± 4.2 4.0

5.6 ± 4.6 5.0

5.4 ± 4.8 4.3

4.6 ± 4.1 3.8

4.1 ± 4.8 3.0

In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.

Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).

During a 7-week randomized withdrawal study, patients who received Amitiza during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with Amitiza. In Amitiza-treated patients randomized to placebo, SBM frequency rates returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on Amitiza maintained their response to therapy over the additional 3 weeks of treatment.

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