Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with CIC, 8% of patients treated with LINZESS and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the 145 mcg LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain.

Adverse Reactions Leading to Dose Reductions

In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions.

Other Adverse Reactions

Adverse reactions that were reported in at least 1% and less than 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system:

Gastrointestinal Disorders: dyspepsia, fecal incontinence

Infections and Infestations: viral gastroenteritis

Other Adverse Events

In placebo-controlled trials in patients with CIC, less than 1% of both LINZESS-treated and placebo-treated patients reported rectal hemorrhage, hematochezia or melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events.

77 DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with LINZESS. Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses; hence, no systemic drug-drug interactions or drug interactions mediated by plasma protein binding of linaclotide or its metabolite are anticipated [see Clinical Pharmacology (12.3)].

Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, linaclotide is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp).

88 USE IN SPECIFIC POPULATIONS

8.18.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with LINZESS in pregnant women. In animal developmental studies, adverse fetal effects were observed only with maternal toxicity and at doses of linaclotide much higher than the maximum recommended human dose. LINZESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40,000 mcg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal mor