8.3 Nursing Mothers

It is not known whether linaclotide is excreted in human milk; however, linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses [see Clinical Pharmacology (12.3)].
 
Caution should be exercised when LINZESS is administered to nursing women [see Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

LINZESS is contraindicated in pediatric patients up to 6 years of age. In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (1 to 3 week-old-mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of one or two daily oral doses of linaclotide [see Contraindications (4), Warnings and Precautions (5.1) and Nonclinical Toxicology (13.2)].
Avoid the use of LINZESS in pediatric patients 6 through 17 years of age. Linaclotide did not cause deaths in older juvenile mice (approximately equivalent to humans age 12 to 17 years). Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.2)].

8.5 Geriatric Use

Irritable Bowel Syndrome with Constipation (IBS-C)

Of 1605 IBS-C patients in the placebo-controlled clinical studies of LINZESS, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Chronic Idiopathic Constipation (CIC)

Of 1275 CIC patients in the placebo-controlled clinical studies of LINZESS, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical trials of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic or Renal Impairment

No dose adjustment is necessary based on hepatic or renal function [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is limited experience with overdose of LINZESS. During the clinical development program of LINZESS, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall LINZESS-treated population, with diarrhea being the most commonly reported adverse reaction.

11 DESCRIPTION

LINZESS (linaclotide) is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide).
 
The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below:

Linaclotide is an amorphous, white to off-whi