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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` LINZESS safely and effectively. See full prescribing information
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` for LINZESS.
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` LINZESS (linaclotide) capsules, for oral use
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` Initial U.S. Approval: 2012
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` • Take on empty stomach at least 30 minutes prior to first meal of the
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`day.
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` • Do not crush or chew LINZESS capsule or capsule contents.
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` • For patients who have difficulty swallowing capsules whole or those
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` with a nasogastric or gastrostomy tube, see full prescribing
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` information for instructions for opening the capsule and
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` administering with applesauce or water.
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` ---------------------DOSAGE FORMS AND STRENGTHS---------------------­
` Capsules: 72 mcg, 145 mcg and 290 mcg (3)
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`
`-------------------------------CONTRAINDICATIONS-----------------------------­
` • Patients less than 6 years of age due to the risk of serious
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` dehydration. (4, 5.1, 8.4)
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` • Patients with known or suspected mechanical gastrointestinal
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` obstruction. (4)
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` ------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
` • Diarrhea: Patients may experience severe diarrhea. If severe
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` diarrhea occurs,suspend dosing and rehydrate the patient. (5.2)
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` -------------------------------ADVERSE REACTIONS-----------------------------­
`
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` Most common adverse reactions (≥2%) reported in IBS-C or CIC
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` patients are: diarrhea, abdominal pain, flatulence and abdominal
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` distension. (6.1)
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` WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
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`
`PATIENTS
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` See full prescribing information for complete boxed warning.
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` • LINZESS is contraindicated in patients less than 6 years of age;
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` in neonatal mice, linaclotide caused deaths due to dehydration.
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` (4, 8.4)
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` • Avoid use of LINZESS in patients 6 years to less than 18 years
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` of age. (5.1, 8.4)
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` • The safety and effectiveness of LINZESS have not been
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` established in patients less than 18 years of age (8.4).
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`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
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`
`
`Dosage and Administration (2.1)
`01/2017
`
`
`
`Warnings and Precautions (5.2)
`08/2016
`
` -----------------------------INDICATIONS AND USAGE-------------------------­
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`LINZESS is a guanylate cyclase-C agonist indicated in adults for
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`treatment of:
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` • Irritable bowel syndrome with constipation. (IBS-C) (1)
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` • Chronic idiopathic constipation. (CIC) (1)
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`To report SUSPECTED ADVERSE REACTIONS, Allergan at 1-800­
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`433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
` ------------------------DOSAGE AND ADMINISTRATION---------------------­
`
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`The recommended dosage in adults is:
` • IBS-C: 290 mcg orally once daily. (2.1)
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` • CIC: 145 mcg orally once daily or 72 mcg orally once daily based on
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` individual presentation or tolerability. (2.1)
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` Administration Instructions (2.2):
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`Revised: 01/2017
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`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
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`
`
`
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
`PATIENTS
`1 INDICATIONS AND USAGE
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage
`
`
`2.2 Preparation and Administration Instructions
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`
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`5.1 Risk of Serious Dehydration in Pediatric Patients
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`5.2 Diarrhea
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`6.2 Postmarketing Experience
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.2 Lactation
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
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`
`12.1 Mechanism of Action
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`
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`14.1 Irritable Bowel Syndrome with Constipation (IBS-C)
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`14.2 Chronic Idiopathic Constipation (CIC)
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`* Sections or subsections omitted from the full prescribing information
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`are not listed.
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`
`
`Reference ID: 4066835
`
`1
`
`MYLAN EXHIBIT - 1072
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
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` WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS
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` • LINZESS is contraindicated in patients less than 6 years of age; in nonclinical studies
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` in neonatal mice, administration of a single, clinically relevant adult oral dose of
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` linaclotide caused deaths due to dehydration [see Contraindications (4), Use in
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` Specific Populations (8.4)].
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` • Avoid use of LINZESS in patients 6 years to less than 18 years of age [see Warnings
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` and Precautions (5.1), Use in Specific Populations (8.4)].
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` • The safety and effectiveness of LINZESS have not been established in patients less
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` than 18 years of age [see Use in Specific Populations (8.4)].
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` 1 INDICATIONS AND USAGE
` LINZESS is indicated in adults for the treatment of:
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`irritable bowel syndrome with constipation (IBS-C)
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`•
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`• chronic idiopathic constipation (CIC).
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dosage
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`Irritable Bowel Syndrome with Constipation (IBS-C)
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`The recommended dosage of LINZESS is 290 mcg orally once daily.
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`Chronic Idiopathic Constipation (CIC)
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`•
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`The recommended dosage of LINZESS is 145 mcg orally once daily. A dosage of 72 mcg once
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`daily may be used based on individual presentation or tolerability.
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`2.2 Preparation and Administration Instructions
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`• Take LINZESS on an empty stomach, at least 30 minutes prior to the first meal of the
`day
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`If a dose is missed, skip the missed dose and take the next dose at the regular time. Do
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`not take 2 doses at the same time.
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`• Do not crush or chew LINZESS capsule or capsule contents.
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`• Swallow LINZESS capsule whole.
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`• For adult patients with swallowing difficulties, LINZESS capsules can be opened and
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`administered orally in either applesauce or with water or administered with water via a
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`nasogastric or gastrostomy tube. Sprinkling of LINZESS beads on other soft foods or in
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`other liquids has not been tested.
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`Oral Administration in Applesauce:
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`1. Place one teaspoonful of room-temperature applesauce into a clean container.
`
`Reference ID: 4066835
`
`

`

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` 2. Open the capsule.
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` 3. Sprinkle the entire contents (beads) on applesauce.
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` 4. Consume the entire contents immediately. Do not chew the beads. Do not store the
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` bead-applesauce mixture for later use.
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` Oral Administration in Water:
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`1. Pour approximately 30 mL of room-temperature bottled water into a clean cup.
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`2. Open the capsule
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`3. Sprinkle the entire contents (beads) into the water
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`4. Gently swirl beads and water for at least 20 seconds.
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`5. Swallow the entire mixture of beads and water immediately.
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`6. Add another 30 mL of water to any beads remaining in cup, swirl for 20 seconds, and
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`swallow immediately.
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`7. Do not store the bead-water mixture for later use.
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`Note: The drug is coated on the surface of the beads and will dissolve off the beads into the
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`water. The beads will remain visible and will not dissolve. Therefore, it is not necessary to
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`consume all the beads to deliver the complete dose.
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`Administration with Water via a Nasogastric or Gastrostomy Tube:
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`1. Open the capsule and empty the beads into a clean container with 30 mLof room-
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`temperature bottled water.
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`2. Mix by gently swirling beads for at least 20 seconds
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`3. Draw-up the beads and water mixture into an appropriately sized catheter-tipped
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`syringe and apply rapid and steady pressure (10 mL/10 seconds) to dispense the
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`syringe contents into the tube.
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`4. Add another 30 mL of water to any beads remaining in the container and repeat the
`process
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`5. After administering the bead-water mixture, flush nasogastric/ gastrostomy tube with a
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`minimum of 10 mL of water.
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`Note: It is not necessary to flush all the beads through to deliver the complete dose.
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`
`3 DOSAGE FORMS AND STRENGTHS
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`LINZESS capsules are white to off-white opaque:
`• 72 mcg; gray imprint “FL 72”
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`• 145 mcg; gray imprint “FL 145”
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`• 290 mcg; gray imprint “FL 290”
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`
`4 CONTRAINDICATIONS
`
`LINZESS is contraindicated in:
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`
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`• Patients less than 6 years of age due to the risk of serious dehydration [see Warnings
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`and Precautions (5.1), Use in Specific Populations (8.4)]
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`• Patients with known or suspected mechanical gastrointestinal obstruction
`
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`
`
`Reference ID: 4066835
`
`

`

` 5 WARNINGS AND PRECAUTIONS
`
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`
`
`
`
` 5.1 Risk of Serious Dehydration in Pediatric Patients
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` LINZESS is contraindicated in patients less than 6 years of age. The safety and effectiveness
`
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` of LINZESS in patients less than 18 years of age have not been established. In neonatal mice
`
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` (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as
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` a consequence of GC-C agonism resulting in mortality within the first 24 hours due to
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` dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age
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` may be more likely than patients 6 years of age and older to develop severe diarrhea and its
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` potentially serious consequences.
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` Avoid use of LINZESS in pediatric patients 6 years to less than 18 years of age. Although
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` there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the
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` lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in
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` pediatric patients 6 years to less than 18 years of age [see Contraindications (4), Warnings
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` and Precautions (5.2), Use in Specific Populations (8.4)].
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`5.2 Diarrhea
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` Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled
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` IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar
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` between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and
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` 290 mcg LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC patients [see
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` Adverse Reactions (6.1)].
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` In post-marketing experience, severe diarrhea associated with dizziness, syncope,
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` hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring
` hospitalization or intravenous fluid administration have been reported in patients treated with
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`LINZESS.
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`If severe diarrhea occurs, suspend dosing and rehydrate the patient.
`
`
`
`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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`observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
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`trials of another drug and may not reflect the rates observed in practice.
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`Exposure in clinical development included approximately 2570, 2040, and 1220 patients with
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`either IBS-C or CIC treated with LINZESS for 6 months or longer, 1 year or longer, and 18
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`months or longer, respectively (not mutually exclusive).
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`Demographic characteristics were comparable between treatment groups in all studies [see
`Clinical Studies (14)].
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`
`Irritable Bowel Syndrome with Constipation (IBS-C)
`
`
`
`
`Most Common Adverse Reactions
`
`Reference ID: 4066835
`
`

`

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` The data described below reflect exposure to LINZESS in the two placebo-controlled clinical
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` trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to
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` receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks.
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` Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients
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` in the LINZESS treatment group and at an incidence that was greater than in the placebo
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`group.
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` Table 1:
`
` Most Common Adverse Reactionsa in Two Placebo-Controlled Trials (1 and
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` 2) in Patients with IBS-C
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`
`
`
` Adverse Reactions
`
`
`
`Gastrointestinal
`
`Diarrhea
`Abdominal painb
`
`Flatulence
`
`Abdominal distension
` Infections and Infestations
`
`
` Viral Gastroenteritis
`
` Nervous System Disorders
`
`
`3
`4
`Headache
`
`
` a: Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo
`
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`
` b: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain.
`
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`
`
`
`
`
`LINZESS
`
`290 mcg
`[N=807]
`%
`
`20
`7
`4
`2
`
`3
`
`Placebo
`[N=798]
`%
`
`3
`5
`2
`1
`
`1
`
`Diarrhea
`Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients
`
`
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`in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated
`
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`
`
`patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was
`
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`
`
`reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated
`
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`
`
`patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of
`
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`placebo-treated patients. The majority of reported cases of diarrhea started within the first 2
`
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`
`
`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%
`
`
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`
`
`
`
`
`of patients treated with placebo discontinued prematurely due to adverse reactions. In the
`
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`
`
`
`LINZESS treatment group, the most common reasons for discontinuation due to adverse
`
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`
`
`
`
`
`
`reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of
`
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`
`
`patients in the placebo group withdrew due to diarrhea or abdominal pain.
`
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`
`
`
`
`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
`
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`
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`suspended secondary to adverse reactions, the majority of which were diarrhea or other GI
`
`
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`
`
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`
`
`
`
`
`
`
`
`adverse reactions.
`
`
`Reference ID: 4066835
`
`

`

` 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
`
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`
`
`
`
`
`
` in the placebo treatment group.
`
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`
`
` Chronic Idiopathic Constipation (CIC)
`
`
`
`
`
`
`
`
`Most Common Adverse Reactions
`
`
`
`
`
`
`
`
`
`
`
`
`The data described below reflect exposure to LINZESS in the two double-blind placebo-
`
`
`
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`
`
`
`
`
`
`
`
`controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were
`
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`
`
`randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an
`
`
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`
`
`empty stomach, for at least 12 weeks. Table 2 provides the incidence of adverse reactions
`
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`
`reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an
`
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`
`
`
`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
`
`
`
`
`
`
`
`
`LINZESS
`
`145 mcg
`[N=430]
`%
`
`16
`7
`6
`3
`
`Placebo
`[N=423]
`%
`
`5
`6
`5
`2
`
`
`
` Adverse Reactions
`
`
`
`Gastrointestinal
`
`Diarrhea
`Abdominal painb
`
`Flatulence
`
`Abdominal distension
` Infections and Infestations
`
`
`4
`5
` Upper respiratory tract infection
`
`
`
`2
`3
`Sinusitis
`
` 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.
`
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`
`
` 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
`
`
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`
`
` weeks (Trial 5).
`
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`
` 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.
`
`
`
`
`Reference ID: 4066835
`
`

`

` In all trials, the majority of reported cases of diarrhea started within the first 2 weeks of
`
`
`
`
`
` LINZESS treatment.
`
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`
`
` 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)].
`
`
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`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
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`
`
`
`
`
` discontinued prematurely due to adverse reactions compared to between less than 1% (Trial
`
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`
`
` 5) and 4% (Trials 3 and 4) of patients treated with placebo.
`
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`
` 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,
`
`
`
`
`
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`
`
`
`
`
`
` the most common reasons for discontinuation due to adverse reactions were diarrhea (3% in
`
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`
`
` Trial 5 and 5% in Trials 3 and 4) and abdominal pain (1% in Trials 3 and 4). In comparison,
`
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` less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain
`
`
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`
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`
`
`
` (Trials 3 and 4; Trial 5).
`
`
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`
`
`
`
`
`
`
` 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
`
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`
`
`
`
`
`
`
`reactions.
`
`
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`
`
`
`Less Common Adverse Reactions
`
`
`
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`
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`
`
`
`Defecation urgency, fecal incontinence, dyspepsia, and viral gastroenteritis, were reported in
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
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`
`
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`
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`
`
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
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`
`
`Hematochezia, rectal hemorrhage, nausea, and allergic reactions, urticaria or hives.
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Risk Summary
`
`Reference ID: 4066835
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` 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
`
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`
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`
`
`
`
` fetal exposure to the drug.The available data on LINZESS use in pregnant women are not
`
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`
`
` sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal
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` developmental studies, no effects on embryo-fetal development were observed with oral
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`
` administration of linaclotide in rats and rabbits during organogenesis at doses much higher
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`
` than the maximum recommended human dosage. Severe maternal toxicity associated with
`
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`
` effects on fetal morphology were observed in mice [see Data].
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`
` The estimated background risk of major birth defects and miscarriage for the indicated
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`
` population is unknown. All pregnancies have a background risk of birth defect, loss, or other
`
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`
`
` adverse outcomes. In the United States general population, the estimated background risk of
`
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`
` major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15%
`
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`
`
` to 20%, respectively.
`
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`
`Data
`
`
`Animal Data
`
`
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`
`
`The potential for linaclotide to cause harm to embryo-fetal development was studied in rats,
`
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`
`
`rabbits and mice. In pregnant mice, oral dose levels of at least 40,000 mcg/kg/day given
`
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`
`
`during organogenesis produced severe maternal toxicity including death, reduction of gravid
`
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`
`
`uterine and fetal weights, and effects on fetal morphology. Oral doses of 5,000 mcg/kg/day did
`
`
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`
`
`not produce maternal toxicity or any adverse effects on embryo-fetal development in mice.
`
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`
`Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits
`
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`
`
`during organogenesis produced no maternal toxicity and no effects on embryo-fetal
`
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`
`
`development. Additionally, oral administration of up to 100,000 mcg/kg/day in rats during
`
`
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`
`
`organogenesis through lactation produced no developmental abnormalities or effects on
`
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`
`
`growth, learning and memory, or fertility in the offspring through maturation.
`
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`
`The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg
`
`
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`
`
`
`
`body weight. Limited systemic exposure to linaclotide was achieved in animals during
`
`
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`
`
`organogenesis (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the
`
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`
`
`highest dose levels). Linaclotide and its active metabolite are not measurable in human
`
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`
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`
`
`
`plasma following administration of the recommended clinical dosages. Therefore, animal and
`
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`
`
`human doses should not be compared directly for evaluating relative exposure.
`
`
`8.2 Lactation
`
`Risk Summary
`
`
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`
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`
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`
`
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`
`
`
`
`
`There is no information regarding the presence of linaclotide in human milk, or on its effects on
`
`
`
`
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`
`
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`
`
`
`
`
`
`milk production or the breastfed infant. No lactation studies in animals have been conducted.
`
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`
`
`
`
`
`Linaclotide and its active metabolite are negligibly absorbed systemically following oral
`
`
`
`
`
`
`
`administration [see Clinical Pharmacology (12.3)]. It is unknown whether the negligible
`
`
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`
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`
`
`
`
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`
`
`systemic absorption of linaclotide by adults will result in a clinically relevant exposure to
`
`
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`
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`
`
`
`breastfed infants. Exposure to linaclotide in breastfed infants has the potential for serious
`
`
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`
`
`
`adverse effects [see Use in Specific Populations (8.4)]. The developmental and health
`
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`
`
`benefits of breastfeeding should be considered along with the mother’s clinical need for
`
`Reference ID: 4066835
`
`

`

`
`
`
`
` LINZESS and any potential adverse effects on the breastfed infant from LINZESS or from the
` underlying maternal condition.
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`
` 8.4 Pediatric Use
`
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`
`
` 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
`
`
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`
`
`
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`
`
`
` age have not been established.
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`
`
` 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
`
`
`
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`
`
`
`
`
`
` in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients
`
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`
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`
`
` less than 6 years of age may be more likely than patients 6 years of age and older to develop
`
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`
`
` diarrhea and its potentially serious consequences. LINZESS is contraindicated in patients less
`
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`
`
` than 6 years of age.
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`
`
` 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).
`
`
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`
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`
`
`
`
`
`These deaths were due to rapid and severe dehydration produced by significant fluid shifts into
`
`
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`
`
`
`
`
`
`
`the intestinal lumen resulting from GC-C agonism in neonatal mice [see Contraindications (4)
`
`
`
`and Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
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`Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide
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`was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of
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`100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths
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`occurred after a single oral dose of 600 mcg/kg.
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`8.5 Geriatric Use
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`Irritable Bowel Syndrome with Constipation (IBS-C)
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`Of 1605 IBS-C patients in the placebo-controlled clinical studies of LINZESS, 85 (5%) were 65
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`years of age and over, while 20 (1%) were 75 years and over. Clinical studies of LINZESS did
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`not include sufficient numbers of patients aged 65 and over to determine whether they respond
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`Chronic Idiopathic Constipation (CIC)
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`Of 2498 CIC patients in the placebo-controlled clinical studies of LINZESS (Trials 3, 4, and 5),
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`273 (11%) were 65 years of age and over, while 56 (2%) were 75 years and over. Clinical
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`studies of LINZESS did not include sufficient numbers of patients aged 65 and over to
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`determine whether they respond differently from younger patients. In general, dose selection
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`Reference ID: 4066835
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` for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic,
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`10
`OVERDOSAGE
`Single LINZESS doses of 2897 mcg were administered to 22 healthy subjects; the safety
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`profile in these subjects was consistent with that in the overall LINZESS-treated population,
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`with diarrhea being the most commonly reported adverse reaction.
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`11 DESCRIPTION
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`LINZESS (linaclotide) is a guanylate cyclase-C (G-CC) agonist. Linaclotide is a 14-amino acid
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`peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L­
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`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).
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` The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The
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` amino acid sequence for linaclotide is shown below:
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` 9 10 11 12 13 14
` 8
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` 1
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`H-Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr-OH
`S-S
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`S-S
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`S-S
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` Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and
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` aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin
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` capsules. LINZESS is available as 72 mcg, 145 mcg and 290 mcg capsules for oral
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`administration.
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`The inactive ingredients of LINZESS 72 mcg capsules include: calcium chloride dihydrate, L-
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`histidine, microcrystalline cellulose, polyvinyl alcohol, and talc. The components of the capsule
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`shell include gelatin