Linzess

Overdose

Single LINZESS doses of 2897 mcg were administered to 22 healthy subjects; 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.

Linzess price

Contraindications

LINZESS is contraindicated in:

• Patients less than 6 years of age due to the risk of serious dehydration
• Patients with known or suspected mechanical gastrointestinal obstruction

Undesirable effects

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.

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

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.

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.

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.

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.

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

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).

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).

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.

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.

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.

Therapeutic indications

LINZESS is indicated in adults for the treatment of:

• irritable bowel syndrome with constipation (IBS-C)
• chronic idiopathic constipation (CIC).

Pharmacodynamic properties

Taking LINZESS immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state. In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before breakfast.

Pharmacokinetic properties

LINZESS is minimally absorbed with negligible systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated.

Food Effect

Neither linaclotide nor its active metabolite were detected in the plasma following administration of LINZESS 290 mcg once daily for 7 days both in the non-fed and fed state in healthy subjects.

Given that linaclotide plasma concentrations following recommended oral doses are not measurable, linaclotide is not expected to be distributed to tissues to any clinically relevant extent.

Metabolism

Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Excretion

Active peptide recovery in the stool samples of fed and fasted healthy subjects following administration of LINZESS 290 mcg once daily for seven days averaged about 5% (fasted) and about 3% (fed) and all of it as the active metabolite.

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Fertility, pregnancy and lactation

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.

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.

Qualitative and quantitative composition

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”

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles tightly closed in a dry place.

Distributed by: Allergan USA, Inc. Irvine, CA 92612. Revised: March 2017.

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

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.

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.

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.

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

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

• To take LINZESS once daily on an empty stomach at least 30 minutes prior to the first meal of the day.
• 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Dosage (Posology) and method of administration

The recommended dosage of LINZESS is 290 mcg orally once daily.

The recommended dosage of LINZESS is 145 mcg orally once daily. A dosage of 72 mcg once daily may be used based on individual presentation or tolerability.

• Take LINZESS on an empty stomach, at least 30 minutes prior to the first meal of the day
• 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.
• Do not crush or chew LINZESS capsule or capsule contents.
• Swallow LINZESS capsule whole.
• For adult patients with swallowing difficulties, LINZESS capsules can be opened and administered orally in either applesauce or with water or administered with water via a nasogastric or gastrostomy tube. Sprinkling of LINZESS beads on other soft foods or in other liquids has not been tested.

1. Place one teaspoonful of room-temperature applesauce into a clean container.
2. Open the capsule.
3. Sprinkle the entire contents (beads) on applesauce.
4. Consume the entire contents immediately. Do not chew the beads. Do not store the bead-applesauce mixture for later use.

1. Pour approximately 30 mL of room-temperature bottled water into a clean cup.
2. Open the capsule
3. Sprinkle the entire contents (beads) into the water
4. Gently swirl beads and water for at least 20 seconds.
5. Swallow the entire mixture of beads and water immediately.
6. Add another 30 mL of water to any beads remaining in cup, swirl for 20 seconds, and swallow immediately.
7. Do not store the bead-water mixture for later use.

Note: The drug is coated on the surface of the beads and will dissolve off the beads into the water. The beads will remain visible and will not dissolve. Therefore, it is not necessary to consume all the beads to deliver the complete dose.

1. Open the capsule and empty the beads into a clean container with 30 mLof room-temperature bottled water.
2. Mix by gently swirling beads for at least 20 seconds
3. Draw-up the beads and water mixture into an appropriately sized catheter-tipped syringe and apply rapid and steady pressure (10 mL/10 seconds) to dispense the syringe contents into the tube.
4. Add another 30 mL of water to any beads remaining in the container and repeat the process
5. After administering the bead-water mixture, flush nasogastric/ gastrostomy tube with a minimum of 10 mL of water.

Note: It is not necessary to flush all the beads through to deliver the complete dose.

Interaction with other medicinal products and other forms of interaction

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.

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

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.

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.

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.

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.

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

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).

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).

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.

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.

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.

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