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Warning

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 [see Contraindications ( 4 ), Use in Specific Populations ( 8.4 )]. Avoid use of LINZESS in patients 6 years to less than 18 years of age [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )]. The safety and effectiveness of LINZESS have not been established in patients less than 18 years of age [see Use in Specific Populations ( 8.4 )]. WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS See full prescribing information for complete boxed warning. LINZESS is contraindicated in patients less than 6 years of age; in neonatal mice, linaclotide caused deaths due to dehydration. ( 4 , 8.4 ) Avoid use of LINZESS in patients 6 years to less than 18 years of age. ( 5.1 , 8.4 ) The safety and effectiveness of LINZESS have not been established in patients less than 18 years of age ( 8.4 ).

Indications And Usage

LINZESS® is indicated in adults for the treatment of: irritable bowel syndrome with constipation (IBS-C) chronic idiopathic constipation (CIC). LINZESS is a guanylate cyclase-C agonist indicated in adults for treatment of: Irritable bowel syndrome with constipation. (IBS-C) (1) Chronic idiopathic constipation. (CIC) (1)

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Dosage Forms And Strengths

LINZESS capsules are white to off-white opaque: 72 mcg; gray imprint “FL 72” 145 mcg; gray imprint “FL 145” 290 mcg; gray imprint “FL 290” Capsules: 72 mcg, 145 mcg and 290 mcg (3)

Contraindications

LINZESS is contraindicated in: Patients less than 6 years of age due to the risk of serious dehydration [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )] Patients with known or suspected mechanical gastrointestinal obstruction Patients less than 6 years of age due to the risk of serious dehydration. (4, 5.1, 8.4) Patients with known or suspected mechanical gastrointestinal obstruction. (4)

Warning and Cautions

Diarrhea: Patients may experience severe diarrhea. If severe diarrhea occurs,suspend dosing and rehydrate the patient. (5.2) 5.1 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 ( 4 ), Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.4 )]. 5. 2 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 ( 6.1 )]. 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.

Adverse Reactions

Most common adverse reactions (≥2%) reported in IBS-C or CIC patients are: diarrhea, abdominal pain, flatulence and abdominal distension. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Exposure in clinical development included approximately 2570, 2040, and 1220 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). Demographic characteristics were comparable between treatment groups in all studies [see Clinical Studies ( 14 )]. 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. Table 1: Most Common Adverse Reactionsa in Two Placebo-Controlled Trials (1 and 2) in Patients with IBS-C Adverse Reactions LINZESS 290 mcg [N=807] % Placebo [N=798] % Gastrointestinal Diarrhea Abdominal painb Flatulence Abdominal distension 20 7 4 2 3 5 2 1 Infections and Infestations Viral Gastroenteritis 3 1 Nervous System Disorders Headache 4 3 a: Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo b: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain. Diarrhea Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment [see Warnings and Precautions ( 5.2 )]. Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. Adverse Reactions Leading to Dose Reductions In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. 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. Chronic Idiopathic Constipation (CIC) Most Common Adverse Reactions The data described below reflect exposure to LINZESS in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12 weeks. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group. Table 2: Most Common Adverse Reactionsa in the Two Placebo-controlled Trials (3 and 4) in Patients with CIC Adverse Reactions LINZESS 145 mcg [N=430] % Placebo [N=423] % Gastrointestinal Diarrhea Abdominal painb Flatulence Abdominal distension 16 7 6 3 5 6 5 2 Infections and Infestations Upper respiratory tract infection Sinusitis 5 3 4 2 a: Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo b: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain. 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) [see Warnings and Precautions ( 5.2 )]. 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). Adverse Reactions Leading to Dose Reductions In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. 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 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.

Use In Specific Populations

8.1 Pregnancy Risk Summary Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration [see Clinical Pharmacology ( 12.3 )], 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. 8.2 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 ( 12.3 ) ]. 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 Use in Specific Populations ( 8.4 ) ]. 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 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 ( 4 ), Warnings and Precautions ( 5.1 )]. 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 ( 4 ) and Warnings and Precautions ( 5.1 )]. 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. 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 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.