Drug products: Constella, LINZESS
ATC code: A06AX04
No consistent differences between men and women in effect or safety has been reported in the clinical studies. However, few men have been included in the studies and thus relevant analysis of differences due to patient’s sex was often not possible.
Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are more common in women. In a meta-analysis of 22 studies, the pooled prevalence of IBS-C in women with IBS was found to be 40%, compared to 21% in men with IBS (OR, 2.38; 95% CI,1.45-3.92) .
Human absorption of linaclotide at recommended doses is negligible. Due to minimal systemic exposure linaclotide is rarely detectable in plasma . No clinical studies were conducted to determine sex differences of the pharmacokinetics of linaclotide .
In the pivotal phase 3 randomized, double-blind, placebo-controlled study of 290 µg linaclotide most IBS-C patients were women (n=720, 89.6%) . Subgroup analyses showed that in men (n=84) the primary efficacy endpoints (abdominal pain/ discomfort and IBS relief) were missing statistical significance due to the low numbers of patients .
Subgroup analyses by patient’s sex of primary efficacy of 290 µg linaclotide was performed using pooled data from phase 3 studies of IBS-C (159 men, 1443 women). Compared to placebo both men and women yielded significant IBS relief on linaclotide, however men did not show significant improvement regarding abdominal pain/discomfort .
The phase 3 randomized, double-blind, placebo-controlled trial of low-dose linaclotide (72 µg) in CIC included 281 men and 942 women . The response rate in the linaclotide group versus placebo was 14.4% vs. 4.4% in women (n=316 placebo/n=312 linaclotide) and 10.1% vs. 5.9% in men (n=85 placebo/n=99 linaclotide). Women showed a highly significant result on the primary efficacy endpoint (abdominal pain/discomfort) compared to placebo. No significant result was found in men. No changes to the labeling were proposed in the NDA review as the study was not powered to detect treatment differences in the subgroups .
There were no relevant sex differences in the adverse event profile in the clinical trials involving patients with IBS-C . The proportion of patients with diarrhea, the most commonly reported adverse reaction for linaclotide, was similar between men and women in the trials conducted in patients with CIC . In the IBS-C trials more men developed diarrhea than women (15.6% vs. 6.5%) . In CIC study of lower doses linaclotide diarrhea was reported less frequently by men than women (16.2% vs 20.2% in the linaclotide 72 µg group; 17.5% vs 23.6% in the linaclotide 145 µg group) .
Pooled data from six RCTs involving patients who received over one dose linaclotide 72, 145 or 290 µg (n=2792 linaclotide and n=1792 placebo), were analyzed to identify potential age, race or sex differences regarding treatment-emergent adverse effects (TEAEs) . The patient population was predominantly female (87.3%). No differences between men and women in incidence of TEAEs are reported in results of analysis.
There is no human data available on the effects of linaclotide on fertility in women and men. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-06-04
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson