Drug Safety-related Labeling Changes (SrLC)

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LINZESS (NDA-202811)

(LINACLOTIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/12/2023 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Diarrhea

Additions and/or revisions underlined:

In adults, 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 (6.1)].

Diarrhea has also been reported in pediatric patients 6 to 17 years of age with FC treated with LINZESS. In a double-blind placebo-controlled trial, diarrhea was the most common adverse reaction and was reported in 4% of pediatric patients 6 to 17 years of age treated with LINZESS 72 mcg once daily. Severe diarrhea was reported in one LINZESS-treated patient [see Adverse Reactions (6.1))].

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Exposure in clinical development included approximately 2570, 2040, and 1220 adult patients with either IBS-C or CIC, treated with LINZESS for 6 months or longer, 1 year or longer, and 18 months or longer, respectively (not mutually exclusive).

…

Irritable Bowel Syndrome with Constipation (IBS-C) in Adults

…

Table 1: Most Common Adverse Reactionsa in Two Placebo-Controlled Trials (1 and 2) in Adult Patients with IBS-C

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Chronic Idiopathic Constipation (CIC) in Adults

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Table 2: Most Common Adverse Reactionsa in the Two Placebo-controlled Trials (3 and 4) in Adult Patients with CIC

…

Functional Constipation (FC) in Pediatric Patients 6 to 17 Years of Age

The safety of LINZESS 72 mcg once daily was evaluated in pediatric patients 6 to 17 years of age with FC in a 12-week double-blind, placebo-controlled clinical trial (Trial 7) [see Clinical Studies (14.3)]. There were 164 patients per treatment group.

Diarrhea was the most common adverse reaction and was reported in 4% of LINZESS-treated patients compared to 2% of placebo-treated patients. One patient in the LINZESS-treated group reported severe diarrhea and discontinued treatment. No patient in the placebo-treated group discontinued treatment due to severe diarrhea. Most reported cases of diarrhea started within the first 2 weeks of LINZESS treatment [see Warnings and Precautions (5.2)].

Other adverse reactions reported at a higher incidence in the LINZESS group than the placebo group included nausea (2 patients) and abdominal discomfort and dehydration (1 patient each).

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

A clinical GC-C ontogeny study in children 6 months to less than 18 years of age (N=99) was conducted to measure GC-C mRNA expression levels in duodenal and colonic samples to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism. The results showed no age dependent trend in GC-C intestinal expression in children 2 to less than 18 years of age. There was insufficient data on GC-C intestinal expression to assess the risk of developing diarrhea and its potentially serious consequences in children less than 2 years of age [see Warnings and Precautions (5.1)].

The safety and effectiveness of LINZESS for the treatment of FC in pediatric patients 6 to 17 years of age have been established. Use of LINZESS for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients 6 years of age and older. The safety of LINZESS in adult and pediatric patients 6 to 17 years of age in clinical studies was similar [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

The safety and effectiveness of LINZESS in patients with FC less than 6 years of age or in patients with IBS-C less than 18 years of age have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and/or revisions underlined:

What is LINZESS?

LINZESS is a prescription medicine used to treat:

• irritable bowel syndrome with constipation (IBS-C) in adults.

• a type of constipation called chronic idiopathic constipation (CIC) in adults. “Idiopathic” means the cause of the constipation is unknown.

• functional constipation in children and adolescents 6 to 17 years of age.

It is not known if LINZESS is safe and effective in children with functional constipation less than 6 years of age or in children with IBS-C less than 18 years of age.

…

How should I take LINZESS?

• Take LINZESS exactly as your doctor tells you to take it.

• Take LINZESS 1 time each day on an empty stomach, at least 30 minutes before a meal , at approximately the same time each day. You should also wait 30 minutes before eating a meal if you take LINZESS with applesauce or mixed with water.

• 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.

• LINZESS capsules should be swallowed whole. Do not crush or chew LINZESS.

  • Patients who cannot swallow LINZESS capsules whole may open the LINZESS capsule and sprinkle the LINZESS beads over applesauce or mix LINZESS with bottled water before swallowing

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What are the possible side effects of LINZESS?

…

Other common side effects of LINZESS in people with IBS-C and CIC include:

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Patient Counseling Information

Additions and/or revisions underlined:

…

Administration and Handling Instructions

• To take LINZESS once daily on an empty stomach at least 30 minutes prior to a meal at approximately the same time each day [see Dosage and Administration (2.2)].

  …

• For patients who are unable to swallow the capsule whole, 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.

  …

08/24/2021 (SUPPL-18)

Approved Drug Label (PDF)

Boxed Warning

Additions and or revisions underlined:

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE

LINZESS is contraindicated in patients less than 2 years of age; in nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

This is the Box Warning in its entirety; all other bullet points have been deleted.

4 Contraindications

Age has changed from 6 years to 2 years in first bullet point

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Risk of Serious Dehydration in Pediatric Patients Less Than 2 Years of Age

LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as a consequence of age-dependent elevated GC-C agonism which was associated with increased mortality within the first 24 hours due to dehydration. There was no age-dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients [see Warnings and Precautions (5.2) and Use in Specific Populations (8.4).

The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

LINZESS is contraindicated in patients less than 2 years of age. 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 which increased fluid secretion as a consequence of age-dependent elevated GC-C agonism resulting in rapid and severe dehydration, as described below in Juvenile Animal Toxicity Data.

A GC-C ontogeny study measured GC-C mRNA expression levels in duodenal and colonic mucosal tissue samples from children aged 6 months to less than 18 years (N=99) to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism in children. The results showed no age-dependent trend in GC-C intestinal expression in children 2 to less than 18 years of age. However, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences [see Warnings and Precautions (5.1)].

The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about LINZESS?

• Do not give LINZESS to children who are less than 2 years of age. It may harm them.

See the section “What are the possible side effects of LINZESS?” for more information about side effects.

Who should not take LINZESS?

• Do not give LINZESS to children who are less than 2 years of age. LINZESS can cause severe diarrhea …

04/12/2021 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions underlined

Risk Summary

Linaclotide and its active metabolite were not detected in the milk of lactating women (see Data). In adults, concentrations of linaclotide and its active metabolite were below the limit of quantitation in plasma following multiple doses of LINZESS [see Clinical Pharmacology (12.3)]. Maternal use of LINZESS is not expected to result in exposure to linaclotide or its active metabolite in breastfed infants. There is no information on the effects of linaclotide or its active metabolite on milk production. 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.

Data

Following oral administration of 72 mcg, 145 mcg, or 290 mcg of LINZESS once daily for 3 days to breastfeeding mothers taking linaclotide therapeutically, the concentrations of linaclotide and its metabolite were below the limits of quantitation (<0.25 ng/mL and <1 ng/mL, respectively) in all breast milk samples collected over 24 hours.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

Before you take LINZESS, tell your doctor about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. It is not known if LINZESS will harm your unborn baby.

• are breastfeeding or plan to breastfeed. You and your doctor should decide if you will take LINZESS and breastfeed.

  …

  General information about the safe and effective use of LINZESS.

  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LINZESS for a condition for which it was not prescribed. Do not give LINZESS to other people, even if they have the same symptoms that you have. It may harm them.

  You can ask your doctor or pharmacist for information about LINZESS that is written for health professionals.

…

09/22/2020 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Irritable Bowel Syndrome with Constipation (IBS-C)

Most Common Adverse Reactions

The data described below reflect exposure to LINZESS in the two placebo-controlled clinical trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the LINZESS treatment group and at an incidence that was greater than in the placebo group.

Adverse reactions in an additional placebo-controlled trial in 614 IBS-C patients randomized to placebo or LINZESS 290 mcg once daily on an empty stomach for 12 weeks (Trial 6) were similar to those in Table 1.

6.2   Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of LINZESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions: Anaphylaxis, angioedema, rash (including hives or urticaria)

Gastrointestinal reactions: Hematochezia, nausea, rectal hemorrhage

8 Use in Specific Populations

8.4 Geriatric Use

(Additions and/or revisions underlined)

Irritable Bowel Syndrome with Constipation (IBS-C)

Of 2219 IBS-C patients in the placebo-controlled clinical studies of LINZESS (Trials 1, 2, and 6), 154 (7%) were 65 years of age and over, while 34 (2%) were 75 years and over. Clinical studies of LINZESS did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

03/08/2017 (SUPPL-13)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Mrdication Guide

(addition underlined)

What is the most important information I should know about LINZESS?

•         Do not give LINZESS to children who are less than 6 years of age. It may harm them.

•         You should not give LINZESS to children 6 years to less than 18 years of age. It may harm them.

…

01/25/2017 (SUPPL-10)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS

• LINZESS is contraindicated in patients less than 6 years of age; in nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration.

• Avoid use of LINZESS in patients 6 years to less than 18 years of age.

4 Contraindications

(Additions and/or revisions are underlined)

• Patients less than 6 years of age due to the risk of serious dehydration

5 Warnings and Precautions

5.1 Risk of Serious Dehydration in Pediatric Patients

(Additions and/or revisions are underlined)

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.

5.2 Diarrhea

(Additions and/or revisions are underlined)

…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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Demographic characteristics were comparable between treatment groups in all studies.

Table 1: Most Common Adverse Reactions (superscript a) in Two Placebo-Controlled Trials (1 and 2) in Patients with IBS-C

Less Common Adverse Reactions

Defecation urgency, fecal incontinence, vomiting, and gastroesophagal reflux disease were reported in <2% of patients in the LINZESS treatment group and at an incidence greater than in the placebo treatment group.

 

Table 2: Most Common Adverse Reactions (superscript a) in the Two Placebo-controlled Trials (3 and 4) in Patients with CIC

 

The safety of a 72 mcg dose was evaluated in an additional placebo-controlled trial in which 1223 patients were randomized to LINZESS 72 mcg, 145 mcg, or placebo once daily for 12 weeks (Trial 5).

In Trial 5, adverse reactions that occurred at a frequency of ? 2% in LINZESS-treated patients (n=411 in each LINZESS 72 mcg and 145 mcg group) and at a higher rate than placebo (n=401) were:

• Diarrhea (LINZESS 72 mcg 19%; LINZESS 145 mcg 22%; placebo 7%)

• Abdominal distension (LINZESS 72 mcg 2%; LINZESS 145 mcg 1%; placebo < 1%)

 

Diarrhea

This section summarizes information from Trials 3 and 4 (pooled) and Trial 5 regarding diarrhea, the most commonly reported adverse reaction reported in LINZESS-treated patients in CIC placebo-controlled studies.

In all trials, the majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment.

Severe diarrhea was reported in less than 1% of the 72 mcg LINZESS-treated patients (Trial 5), in 2% of the 145 mcg LINZESS-treated patients (Trials 3 and 4; Trial 5), and less than 1% of the placebo-treated patients (Trials 3, 4, and 5).

 

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with CIC, 3% of patients treated with 72 mcg (Trial 5) and between 5% (Trial 5) and 8% (Trials 3 and 4) of patients treated with 145 mcg of LINZESS discontinued prematurely due to adverse reactions compared to between less than 1% (Trial 5) and 4% (Trials 3 and 4) of patients treated with placebo.

In patients treated with 72 mcg LINZESS the most common reason for discontinuation due to adverse reactions was diarrhea (2% in Trial 5) and in patients treated with 145 mcg LINZESS, the most common reasons for discontinuation due to adverse reactions were diarrhea (3% in Trial 5 and 5% in Trials 3 and 4) and abdominal pain (1% in Trials 3 and 4). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain (Trials 3 and 4; Trial 5).

 

Less Common Adverse Reactions

Defecation urgency, fecal incontinence, dyspepsia, and viral gastroenteritis, were reported in less than 2% of patients in the LINZESS treatment group and at an incidence greater than placebo treatment group.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post approval use of LINZESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

 

Hematochezia, rectal hemorrhage, nausea, and allergic reactions, urticaria or hives.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration, 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.

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…

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.

…Limited systemic exposure to linaclotide was achieved in animals during organogenesis … Linaclotide and its active metabolite are not measurable in human plasma following administration of the recommended clinical dosages.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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.

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. 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.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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. 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).

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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 … 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

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

Administration and Handling Instructions

• 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.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

How should I take LINZESS?

• LINZESS capsules should be swallowed whole. Do not crush or chew LINZESS.

  • Adults who cannot swallow LINZESS capsules whole may open the LINZESS capsule and sprinkle the LINZESS beads over applesauce or mix LINZESS with bottled water before swallowing.

Taking LINZESS in applesauce:

• Place 1 teaspoon of room temperature applesauce into a clean container.

Taking LINZESS in water:

• Pour 1 ounce (30 mL) of room temperature bottled water into a clean cup. Open the LINZESS capsule and sprinkle all of the LINZESS beads into the cup of water.

• Gently swirl the beads and water for at least 20 seconds.

• If you see any LINZESS beads left in the cup, add another 1 ounce (30mL) of water to the beads in the cup, swirl for at least 20 seconds, and swallow right away.

Taking LINZESS in a nasogastric or gastrostomy feeding tube:

• Open the LINZESS capsule and pour all of the LINZESS beads into a clean container with 1 ounce (30 mL) of room temperature bottled water.

• Gently swirl the beads and water for at least 20 seconds.

• If you see any LINZESS beads left in the container, add another 1 ounce (30 mL) of water to the beads in the container and repeat the process.

• After giving the LINZESS dose, flush the nasogastric or gastrostomy tube with at least 10 mL of water.

What are the ingredients in LINZESS?

Inactive ingredients for the 145 mcg and 290 mcg capsules: calcium chloride dihydrate, hypromellose, L-leucine, and microcrystalline cellulose. Capsule shell: gelatin and titanium dioxide.

Inactive ingredients for the 72 mcg capsules: calcium chloride dihydrate, L-histidine, microcrystalline cellulose, polyvinyl alcohol, and talc. Capsule shell: gelatin and titanium dioxide.

08/31/2016 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

Diarrhea

• 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. (addition)

• If severe diarrhea occurs consider dose suspension and rehydration. (addition)