March 29, 2017
Recommended Topic Related To:

Linzess

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Linzess




Warnings
Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Serious Dehydration In Pediatric Patients

LINZESS is contraindicated in patients less than 6 years of age. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established. In neonatal mice (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as a consequence of GC-C agonism resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences.

Avoid use of LINZESS in pediatric patients 6 years to less than 18 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 years to less than 18 years of age [see CONTRAINDICATIONS, Diarrhea, Use In Specific Populations].

Diarrhea

Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC patients [see ADVERSE REACTIONS].

In post-marketing experience, severe diarrhea associated with dizziness, syncope, hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or intravenous fluid administration have been reported in patients treated with LINZESS.

If severe diarrhea occurs, suspend dosing and rehydrate the patient.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients:

Diarrhea

  • To stop LINZESS and contact their healthcare provider if they experience unusual or severe abdominal pain, and/or severe diarrhea, especially if in combination with hematochezia or melena [see WARNINGS AND PRECAUTIONS].

Accidental Ingestion

  • Accidental ingestion of LINZESS in children especially in children less than 6 years of age may result in severe diarrhea and dehydration. Instruct patients to take steps to store LINZESS securely and out of reach of children, and to dispose of unused LINZESS [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].

Administration and Handling Instructions

  • To take LINZESS once daily on an empty stomach at least 30 minutes prior to the first meal of the day [see DOSAGE AND ADMINISTRATION].
  • If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time.
  • To swallow LINZESS capsules whole. Do not crush or chew capsules or capsule contents.
  • If adult patients have swallowing difficulties, LINZESS capsules can be opened and administered orally in either applesauce or with bottled water or administered with water via a nasogastric or gastrostomy tube, as described in the Medication Guide.
  • To 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.

LINZESS® is a registered trademark of Ironwood Pharmaceuticals, Inc.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 and its active metabolite 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

Risk Summary

Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration [see CLINICAL PHARMACOLOGY], and maternal use is not expected to result in fetal exposure to the drug.The available data on LINZESS use in pregnant women are not sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of linaclotide in rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. Severe maternal toxicity associated with effects on fetal morphology were observed in mice [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

The potential for linaclotide to cause harm to embryo-fetal development was studied in rats, rabbits and mice. In pregnant mice, oral dose levels of at least 40,000 mcg/kg/day given during organogenesis produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5,000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits during organogenesis produced no maternal toxicity and no effects on embryo-fetal development. Additionally, oral administration of up to 100,000 mcg/kg/day in rats during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation.

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 in animals during organogenesis (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the highest dose levels). Linaclotide and its active metabolite are not measurable in human plasma following administration of the recommended clinical dosages. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

Lactation

Risk Summary There is no information regarding the presence of linaclotide in human milk, or on its effects on milk production or the breastfed infant. No lactation studies in animals have been conducted. Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration [see CLINICAL PHARMACOLOGY]. It is unknown whether the negligible systemic absorption of linaclotide by adults will result in a clinically relevant exposure to breastfed infants. Exposure to linaclotide in breastfed infants has the potential for serious adverse effects [see Pediatric Use]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LINZESS and any potential adverse effects on the breastfed infant from LINZESS or from the underlying maternal condition.

Pediatric Use

LINZESS is contraindicated in patients less than 6 years of age. Avoid use of LINZESS in patients 6 years to less than 18 years of age [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established.

In nonclinical studies, deaths occurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28 days) following oral administration of linaclotide, as described below in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop diarrhea and its potentially serious consequences. LINZESS is contraindicated in patients less than 6 years of age.

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 patients 6 years to less than 18 years of age.

Juvenile Animal Toxicity Data

In toxicology studies in neonatal mice, oral administration of linaclotide at 10 mcg/kg/day caused deaths on post-natal day 7 (human age equivalent of approximately 0 to 28 days). These deaths were due to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen resulting from GC-C agonism in neonatal mice [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg.

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 65 years of age and over, while 20 (1%) were 75 years and over. Clinical studies of LINZESS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Chronic Idiopathic Constipation (CIC)

Of 2498 CIC patients in the placebo-controlled clinical studies of LINZESS (Trials 3, 4, and 5), 273 (11%) were 65 years of age and over, while 56 (2%) were 75 years and over. Clinical studies of LINZESS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/20/2017

Warnings
Precautions

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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