Linzess

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Pediatric Risk

LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences.

Avoid use of LINZESS in pediatric patients 6 through 17 years of age. 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 CONTRAINDICATIONS, Use In Specific Populations and Nonclinical Toxicology].

Diarrhea

Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of the LINZESS-treated patients. The incidence of diarrhea was similar between the IBS-C and CIC populations [see ADVERSE REACTIONS].

Instruct patients to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider. The healthcare provider should consider dose suspension and rehydration [see PATIENT INFORMATION].

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Patients should be instructed as follows:

  • Do not give LINZESS to children who are under 6 years of age. It may harm them. You should not give LINZESS to children 6 to 17 years of age. It may harm them [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations and Nonclinical Toxicology].
  • Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles closed tightly in a dry place [see HOW SUPPLIED/Storage and Handling].
  • Take LINZESS once daily on an empty stomach as prescribed. Swallow the capsule whole and do not break apart or chew [see DOSAGE AND ADMINISTRATION].
  • If you miss a dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time.
  • Stop LINZESS and contact your physician if you experience severe diarrhea [see WARNINGS AND PRECAUTIONS].
  • Seek immediate medical attention if you develop unusual or severe abdominal pain, and /or severe diarrhea, especially if in combination with hematochezia or melena [see ADVERSE REACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Carcinogenesis

In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg bodyweight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

Mutagenesis

Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes.

Impairment of Fertility

Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day.

Use In Specific Populations

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 morphology. Oral doses of 5000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice.

The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg body weight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the highest dose levels), whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

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].

Caution should be exercised when LINZESS is administered to nursing women [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Pediatric Use

LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop diarrhea and its potentially serious consequences.

Avoid use of LINZESS in pediatric patients 6 through 17 years of age. 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and Nonclinical Toxicology].

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.

Hepatic Or Renal Impairment

No dose adjustment is necessary based on hepatic or renal function [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 7/25/2014
This monograph has been modified to include the generic and brand name in many instances.

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