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Linaclotide Capsules

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: PEDIATRIC RISK

Linaclotide is contraindicated in pediatric patients up to 6 years of age. Avoid use in pediatric patients 6 through 17 years of age. In nonclinical studies, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths in young juvenile mice [see Contraindication, Warnings and Precautions, Use in Specific Populations].


 

1. DESCRIPTION

Linaclotide is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide). The amino acid sequence for linaclotide is shown below:

Empirical formula: C59H79N15O21S6 - Molecular weight: 1526.8

Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). Linaclotide contains linaclotide-coated beads in hard gelatin capsules. Linaclotide is available as 145 mcg and 290 mcg capsules for oral administration.

Inactive ingredients: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide.

2. INDICATIONS AND USAGE

2.1 Irritable Bowel Syndrome with Constipation (IBS-C)

Linaclotide is indicated in adults for the treatment of irritable bowel syndrome with constipation (IBS-C).

2.2 Chronic Idiopathic Constipation (CIC)

Linaclotide is indicated in adults for the treatment of chronic idiopathic constipation (CIC).

3. DOSAGE AND ADMINISTRATION

3.1 Irritable Bowel Syndrome with Constipation (IBS-C)

The recommended dose of linaclotide is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.

3.2 Chronic Idiopathic Constipation (CIC)

The recommended dose of linaclotide is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.

3.3 Important Administration Instructions

Swallow capsules whole; do not break apart or chew.

4. CONTRAINDICATIONS

Linaclotide is contraindicated in:

• Pediatric patients up to 6 years of age [see Warnings and Precautions, Use in Specific Populations]

• Patients with known or suspected mechanical gastrointestinal obstruction

5. MECHANISM OF ACTION

Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with linaclotide 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. Linaclotide 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.

6.2 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.

Caution should be exercised when linaclotide is administered to nursing women [see Contraindications, Warnings and Precautions, and Use in Specific Populations].

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Linaclotide is contraindicated in pediatric patients up to 6 years of age. In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (1 to 3 week-old-mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of one or two daily oral doses of linaclotide [see Contraindications, Warnings and Precautions].

Avoid the use of linaclotide in pediatric patients 6 through 17 years of age. Linaclotide did not cause deaths in older juvenile mice (approximately equivalent to humans age 12 to 17 years). 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 linaclotide in pediatric patients 6 through 17 years of age [see Warnings and Precautions].

6.4 Geriatric Use

Irritable Bowel Syndrome with Constipation (IBS-C)

Of 1605 IBS-C patients in the placebo-controlled clinical studies of linaclotide, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of linaclotide 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 linaclotide, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical trials of linaclotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

6.5 Hepatic or Renal Impairment

No dose adjustment is necessary based on hepatic or renal function.

7. WARNINGS AND PRECAUTIONS

7.1 Pediatric Risk

Linaclotide is contraindicated in pediatric patients up to 6 years of age. In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (1 to 3 week-old mice; approximately equivalent to human pediatric patients less than 2 years of age) following administration of one or two daily oral doses of linaclotide [see Contraindications, Use in Specific Populations].

Avoid the use of linaclotide in pediatric patients 6 through 17 years of age. Linaclotide did not cause deaths in older juvenile mice (approximately equivalent to humans ages 12 to 17 years). 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 linaclotide in pediatric patients 6 through 17 years of age [see Use in Specific Populations].

7.2 Diarrhea

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

Instruct patients to stop linaclotide if severe diarrhea occurs and to contact their healthcare provider, who should consider dose suspension

8. ADVERSE REACTIONS

8.1 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.

During clinical development, approximately 2570, 2040, and 1220 patients with either IBS-C or CIC were treated with linaclotide 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)

Most Common Adverse Reactions

The data described below reflect exposure to linaclotide 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 linaclotide once daily on an empty stomach for up to 26 weeks. Demographic characteristics were comparable between treatment groups. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the linaclotide treatment group and at an incidence that was greater than in the placebo group.

Table 1: Adverse Reactions Reported in at least 2% of Linaclotide-treated Patients and at an Incidence Greater than in Placebo Group Patients in the Two Phase 3 Placebo-controlled Trials (1 and 2) in IBS-C

a: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain.

Diarrhea

Diarrhea was the most commonly reported adverse reaction of the linaclotide-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of linaclotide-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the linaclotide-treated patients versus less than 1% of the placebo-treated patients, and 5% of linaclotide-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 linaclotide treatment. Fecal incontinence and dehydration were each reported in less than or equal to 1% of patients in the linaclotide treatment group [see Warnings and Precautions].

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with IBS-C, 9% of patients treated with linaclotide and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the linaclotide 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 linaclotide 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.

Other Adverse Reactions

Adverse reactions that were reported in at least 1% and less than 2% of IBS-C patients in the linaclotide treatment group and at an incidence greater than in the placebo treatment group are listed below by body system:

Gastrointestinal Disorders: gastroesophageal reflux disease, vomiting

General Disorders and Administration Site Conditions: fatigue

Other Adverse Events

In placebo-controlled trials in patients with IBS-C, less than 1% linaclotide-treated patients and no placebo-treated patients reported hematochezia; no patient in either treatment group reported melena. Less than 1% of linaclotide-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events.

Chronic Idiopathic Constipation (CIC)

Most Common Adverse Reactions

The data described below reflect exposure to linaclotide 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 linaclotide or 290 mcg linaclotide once daily on an empty stomach, for at least 12 weeks. Demographic characteristics were comparable between both linaclotide treatment groups and placebo. Only data for the recommended linaclotide 145 mcg dose and placebo are presented. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg linaclotide treatment group and at an incidence that was greater than in the placebo treatment group.

Table 2: Adverse Reactions Reported in at least 2% of 145 mcg Linaclotide-treated Patients and at an Incidence Greater than in Placebo Group Patients in the Two Phase 3 Placebo-controlled Trials (3 and 4) in CIC

a: “Abdominal pain” term includes the abdominal pain, upper abdominal pain, and lower abdominal pain

Diarrhea

Diarrhea was the most commonly reported adverse reaction of the linaclotide-treated patients in the two pooled placebo-controlled CIC trials. In these trials, 16% of linaclotide-treated patients reported diarrhea compared to 5% of placebo-treated patients. Severe diarrhea was reported in 2% of the 145 mcg linaclotide-treated patients versus less than 1% of the placebo-treated patients, and 5% of linaclotide-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 linaclotide treatment. Fecal incontinence was reported in 1% of patients in the linaclotide treatment group, compared with less than 1% in the placebo group. Dehydration was reported in less than 1% of patients in the linaclotide treatment group [see Warnings and Precautions].

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with CIC, 8% of patients treated with linaclotide and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the 145 mcg linaclotide 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, 1129 patients with CIC received 290 mcg of linaclotide 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.

Other Adverse Reactions

Adverse reactions that were reported in at least 1% and less than 2% of CIC patients in the 145 mcg linaclotide treatment group and at an incidence greater than in the placebo treatment group are listed below by body system:

Gastrointestinal Disorders: dyspepsia, fecal incontinence

Infections and Infestations: viral gastroenteritis

Other Adverse Events

In placebo-controlled trials in patients with CIC, less than 1% of both linaclotide-treated and placebo-treated patients reported rectal hemorrhage, hematochezia or melena. Less than 1% of linaclotide-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events.

9. OVERDOSAGE

There is limited experience with overdose of linaclotide. During the clinical development program of linaclotide, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall linaclotide-treated population, with diarrhea being the most commonly reported adverse reaction.

10. DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with linaclotide. Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses; hence, no systemic drug-drug interactions or drug interactions mediated by plasma protein binding of linaclotide or its metabolite are anticipated.

Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, linaclotide is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp).

11. PHARMACOKINETICS

Absorption

Linaclotide is minimally absorbed with low 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.

Distribution

Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.

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.

Elimination

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

Food Effect

In a cross-over study, 18 healthy subjects were given linaclotide 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its active metabolite was detected in the plasma. Taking linaclotide immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state [see Dosage and Administration]. In clinical trials, linaclotide was administered on an empty stomach, at least 30 minutes before breakfast.

Specific Populations

Age and Gender

Clinical studies to determine the impact of age and gender on the pharmacokinetics of linaclotide have not been conducted. See Use in Specific Populations for information regarding patients aged 65 years and older.

Hepatic Impairment

Linaclotide has not been specifically studied in patients who have hepatic impairment. Hepatic impairment is not expected to affect the metabolism or clearance of the parent drug or its metabolite because linaclotide is metabolized within the gastrointestinal tract [see Use in Specific Populations].

Renal Impairment

Linaclotide has not been specifically studied in patients who have renal impairment. Renal impairment is not expected to affect clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract [see Use in Specific Populations].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: LINZESS, by Forest Labs.

b) Generic drugs: None.

2) How Supplied:

• 145 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 145" .

Bottle of 30: NDC 0456-1201-30

• 290 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 290" .

Bottle of 30: NDC 0456-1202-30

3) Storage and Handling:

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

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.

Rx only

Rev 08/12