HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LINZESS safely and effectively. See full prescribing information
`for LINZESS.
`
`LINZESS® (linaclotide) capsules, for oral use
`Initial U.S. Approval: 2012
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
`PATIENTS LESS THAN 2 YEARS OF AGE
`See full prescribing information for complete boxed warning.
`
`• LINZESS is contraindicated in patients less than 2 years of
`age; in neonatal mice, linaclotide caused deaths due to
`dehydration. (4, 5.1, 8.4)
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Boxed Warning
`8/2021
`Contraindications (4)
`8/2021
`Warnings and Precautions (5.1)
`8/2021
`
`-----------------------------INDICATIONS AND USAGE--------------------------
`LINZESS is a guanylate cyclase-C agonist indicated in adults for
`treatment of:
`• Irritable bowel syndrome with constipation . (IBS-C) (1)
`• Chronic idiopathic constipation. (CIC) (1)
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`The recommended dosage in adults is:
`• IBS-C: 290 mcg orally once daily. (2.1)
`• CIC: 145 mcg orally once daily or 72 mcg orally once daily based on
`individual presentation or tolerability. (2.1)
`Administration Instructions (2.2):
`• Take on empty stomach at least 30 minutes prior to first meal of the
`day.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
`PATIENTS LESS THAN 2 YEARS OF AGE
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Preparation and Administration Instructions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Serious Dehydration in Pediatric Patients Less
`Than 2 Years of Age
`5.2 Diarrhea
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`
`• Do not crush or chew LINZESS capsule or capsule contents.
`• For patients who have difficulty swallowing capsules whole or those
`with a nasogastric or gastrostomy tube, see full prescr bing
`information for instructions for opening the capsule and
`administering with applesauce or water.
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Capsules: 72 mcg, 145 mcg and 290 mcg (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Patients with known or suspected mechanical gastrointestinal
`obstruction. (4)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`Diarrhea: Patients may experience severe diarrhea. If severe diarrhea
`occurs, suspend dosing and rehydrate the patient. (5.2)
`
`-------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions (≥2%) reported in IBS -C or CIC
`patients are: diarrhea, abdominal pain, flatulence and abdominal
`distension. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Allergan
`at 1-800-678-1605 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
` Revised: 8/2021
`
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Irritable Bowel Syndrome with Constipation (IBS -C)
`14.2 Chronic Idiopathic Constipation (CIC)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
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`FULL PRESCRIBING INFORMATION
`
`
`WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2
`YEARS OF AGE
`
`• LINZESS is contraindicated in patients less than 2 years of age; in nonclinical
`studies in neonatal mice, administration of a single, clinically relevant adult oral
`dose of linaclotide caused deaths due to dehydration [see Contraindications (4),
`Warnings and Precautions (5.1), Use in Specific Populations (8.4)].
`
`1 INDICATIONS AND USAGE
`
`LINZESS is indicated in adults for the treatment of:
`irritable bowel syndrome with constipation (IBS-C)
`•
`• chronic idiopathic constipation (CIC)
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`Irritable Bowel Syndrome with Constipation (IBS-C)
`
`The recommended dosage of LINZESS is 290 mcg orally once daily.
`
`Chronic Idiopathic Constipation (CIC)
`
`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.
`
`•
`
`2.2 Preparation and Administration Instructions
`• 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.
`
`
`Oral Administration in Applesauce:
`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.
`
`
`
`
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`Oral Administration in Water:
`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.
`
`Administration with Water via a Nasogastric or Gastrostomy Tube:
`1. Open the capsule and empty the beads into a clean container with 30 mL of 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`LINZESS capsules are white to off-white opaque:
`• 72 mcg; gray imprint “FL 72”
`• 145 mcg; gray imprint “FL 145”
`• 290 mcg; gray imprint “FL 290”
`
`4 CONTRAINDICATIONS
`
`LINZESS is contraindicated in:
`• Patients less than 2 years of age due to the risk of serious dehydration [see Warnings
`and Precautions (5.1), Use in Specific Populations (8.4)].
`• Patients with known or suspected mechanical gastrointestinal obstruction.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Serious Dehydration in Pediatric Patients Less Than 2 Years of Age
`LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice (human age
`equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as a
`
`
`
`
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`consequence of age-dependent elevated GC-C agonism which was associated with increased
`mortality within the first 24 hours due to dehydration. There was no age-dependent trend in
`GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age;
`however, there are insufficient data available on GC-C intestinal expression in children less
`than 2 years of age to assess the risk of developing diarrhea and its potentially serious
`consequences in these patients [see Warnings and Precautions (5.2) and Use in Specific
`Populations (8.4).
`
`The safety and effectiveness of LINZESS in patients less than 18 years of age have not been
`established.
`
`5.2 Diarrhea
`Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled
`IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar
`between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and
`290 mcg LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC patients [see
`Adverse Reactions (6.1)].
`
`In post-marketing experience, severe diarrhea associated with dizziness, syncope,
`hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring
`hospitalization or intravenous fluid administration have been reported in patients treated with
`LINZESS.
`
`If severe diarrhea occurs, suspend dosing and rehydrate the patient.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
`trials of another drug and may not reflect the rates observed in practice.
`
`Exposure in clinical development included approximately 2570, 2040, and 1220 patients with
`either IBS-C or CIC treated with LINZESS for 6 months or longer, 1 year or longer, and 18
`months or longer, respectively (not mutually exclusive).
`
`Demographic characteristics were comparable between treatment groups in all studies [see
`Clinical Studies (14)].
`
`
`
`
`
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`Irritable Bowel Syndrome with Constipation (IBS-C)
`
`Most Common Adverse Reactions
`The data described below reflect exposure to LINZESS in the two placebo-controlled clinical
`trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to
`receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks.
`Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients
`in the LINZESS treatment group and at an incidence that was greater than in the placebo
`group.
`
`Table 1: Most Common Adverse Reactionsa in Two Placebo-Controlled Trials (1 and
`2) in Patients with IBS-C
`
`Adverse Reactions
`
`
`
`Placebo
`[N=798]
`%
`
`LINZESS
`290 mcg
`[N=807]
`%
`
`20
`7
`4
`2
`
` 3
`
`
`
` 4
`
` 3
`
`
`5
`2
`1
`
` 1
`
`
`
` 3
`
`Gastrointestinal
`Diarrhea
`Abdominal painb
`Flatulence
`Abdominal distension
`Infections and Infestations
` Viral Gastroenteritis
`Nervous System Disorders
`
`
`Headache
`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.
`
`
`Adverse reactions in an additional placebo-controlled trial in 614 IBS-C patients randomized to
`placebo or LINZESS 290 mcg once daily on an empty stomach for 12 weeks (Trial 6) were
`similar to those in Table 1.
`
`Diarrhea
`
`Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients
`in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated
`patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was
`reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated
`patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of
`placebo-treated patients. The majority of reported cases of diarrhea started within the first 2
`weeks of LINZESS treatment [see Warnings and Precautions (5.2)].
`
`Adverse Reactions Leading to Discontinuation
`
`In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3%
`of patients treated with placebo discontinued prematurely due to adverse reactions. In the
`LINZESS-treatment group, the most common reasons for discontinuation due to adverse
`
`
`
`
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`reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of
`patients in the placebo group withdrew due to diarrhea or abdominal pain.
`
`Adverse Reactions Leading to Dose Reductions
`In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS
`daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended
`secondary to adverse reactions, the majority of which were diarrhea or other GI adverse
`reactions.
`
`Less Common Adverse Reactions
`Defecation urgency, fecal incontinence, vomiting, and gastroesophageal reflux disease were
`reported in <2% of patients in the LINZESS-treatment group and at an incidence greater than
`in the placebo treatment group.
`
`Chronic Idiopathic Constipation (CIC)
`
`Most Common Adverse Reactions
`The data described below reflect exposure to LINZESS in the two double-blind placebo-
`controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were
`randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an
`empty stomach, for at least 12 weeks. Table 2 provides the incidence of adverse reactions
`reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an
`incidence that was greater than in the placebo treatment group.
`
`Table 2: Most Common Adverse Reactionsa in the Two Placebo-controlled Trials (3
`and 4) in Patients with CIC
`
`Adverse Reactions
`
`
`Placebo
`[N=423]
`%
`
`LINZESS
`145 mcg
`[N=430]
`%
`
`16
`7
`6
`3
`
` 5
`
` 5
`
`
`6
`5
`2
`
` 4
`
`Gastrointestinal
`Diarrhea
`Abdominal painb
`Flatulence
`Abdominal distension
`Infections and Infestations
`
`
` 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.
`
`
`
`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).
`
`
`
`
`
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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
`In Trials 3 and 4 (pooled) and Trial 5, diarrhea was the most commonly reported adverse
`reaction in LINZESS-treated patients in the 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, 4, and 5), and less than 1% of the
`placebo-treated patients (Trials 3, 4, and 5) [see Warnings and Precautions (5.2)].
`
`Adverse Reactions Leading to Discontinuation
`In placebo-controlled trials in patients with CIC, 3% of patients treated with 72 mcg (Trial 5)
`and between 5% and 8% (Trials 3, 4, and 5) of patients treated with 145 mcg of LINZESS
`discontinued prematurely due to adverse reactions compared to between less than 1% and 4%
`(Trials 3, 4, and 5) 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
`(between 3% and 5% in Trials 3, 4, and 5) 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, 4, and 5).
`
`Adverse Reactions Leading to Dose Reductions
`In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily
`for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended
`secondary to adverse reactions, the majority of which were diarrhea or other GI adverse
`reactions.
`
`Less Common Adverse Reactions
`Defecation urgency, fecal incontinence, dyspepsia, and viral gastroenteritis were reported in
`less than 2% of patients in the LINZESS treatment group and at an incidence greater than
`placebo treatment group.
`
`
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during post approval use of LINZESS.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`
`
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`Hypersensitivity reactions: Anaphylaxis, angioedema, rash (including hives or urticaria)
`Gastrointestinal reactions: Hematochezia, nausea, rectal hemorrhage
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
`
`Linaclotide and its active metabolite are negligibly absorbed systemically following oral
`administration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result in
`fetal exposure to the drug. The available data on LINZESS use in pregnant women are not
`sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal
`developmental studies, no effects on embryo-fetal development were observed with oral
`administration of linaclotide in rats and rabbits during organogenesis at doses much higher
`than the maximum recommended human dosage. Severe maternal toxicity associated with
`effects on fetal morphology were observed in mice (see Data).
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`population is unknown. All pregnancies have a background risk of birth defect, loss, or other
`adverse outcomes. In the United States general population, the estimated background risk of
`major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15%
`to 20%, respectively.
`
`Data
`
`Animal Data
`The potential for linaclotide to cause harm to embryo-fetal development was studied in rats,
`rabbits and mice. In pregnant mice, oral dose levels of at least 40,000 mcg/kg/day given during
`organogenesis produced severe maternal toxicity including death, reduction of gravid uterine
`and fetal weights, and effects on fetal morphology. Oral doses of 5,000 mcg/kg/day did not
`produce maternal toxicity or any adverse effects on embryo-fetal development in mice. Oral
`administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits during
`organogenesis produced no maternal toxicity and no effects on embryo-fetal development.
`Additionally, oral administration of up to 100,000 mcg/kg/day in rats during organogenesis
`through lactation produced no developmental abnormalities or effects on growth, learning and
`memory, or fertility in the offspring through maturation.
`
`The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg
`body weight. Limited systemic exposure to linaclotide was achieved in animals during
`organogenesis (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the
`highest dose levels). Linaclotide and its active metabolite are not measurable in human plasma
`following administration of the recommended clinical dosages. Therefore, animal and human
`doses should not be compared directly for evaluating relative exposure.
`
`
`
`
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`8.2 Lactation
`Risk Summary
`Linaclotide and its active metabolite were not detected in the milk of lactating women (see
`Data). In adults, concentrations of linaclotide and its active metabolite were below the limit of
`quantitation in plasma following multiple doses of LINZESS [see Clinical Pharmacology (12.3)].
`Maternal use of LINZESS is not expected to result in exposure to linaclotide or its active
`metabolite in breastfed infants. There is no information on the effects of linaclotide or its active
`metabolite on milk production. The developmental and health benefits of breastfeeding should
`be considered along with the mother’s clinical need for LINZESS and any potential adverse
`effects on the breastfed infant from LINZESS or from the underlying maternal condition.
`
`Data
`
`Following oral administration of 72 mcg, 145 mcg, or 290 mcg of LINZESS once daily for 3
`days to breastfeeding mothers taking linaclotide therapeutically, the concentrations of
`linaclotide and its metabolite were below the limits of quantitation (<0.25 ng/mL and <1 ng/mL,
`respectively) in all breast milk samples collected over 24 hours.
`
`
`8.4 Pediatric Use
`LINZESS is contraindicated in patients less than 2 years of age. In nonclinical studies, deaths
`occurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28
`days) following oral administration of linaclotide which increased fluid secretion as a
`consequence of age-dependent elevated GC-C agonism resulting in rapid and severe
`dehydration, as described below in Juvenile Animal Toxicity Data.
`
` A
`
` GC-C ontogeny study measured GC-C mRNA expression levels in duodenal and colonic
`mucosal tissue samples from children aged 6 months to less than 18 years (N=99) to evaluate
`the risk of diarrhea and severe dehydration due to GC-C agonism in children. The results
`showed no age-dependent trend in GC-C intestinal expression in children 2 to less than 18
`years of age. However, there are insufficient data available on GC-C intestinal expression in
`children less than 2 years of age to assess the risk of developing diarrhea and its potentially
`serious consequences [see Warnings and Precautions (5.1)].
`
`The safety and effectiveness of LINZESS in patients less than 18 years of age have not been
`established.
`
`Juvenile Animal Toxicity Data
`
`In toxicology studies in neonatal mice, oral administration of linaclotide at 10 mcg/kg/day
`caused deaths on post-natal day 7 (human age equivalent of approximately 0 to 28 days).
`These deaths were due to rapid and severe dehydration produced by significant fluid shifts into
`the intestinal lumen resulting from GC-C agonism in neonatal mice [see Contraindications (4)
`and Warnings and Precautions (5.1)].
`
`Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide
`was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of
`
`
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`100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths
`occurred after a single oral dose of 600 mcg/kg.
`
`
`8.5 Geriatric Use
`Irritable Bowel Syndrome with Constipation (IBS-C)
`Of 2219 IBS-C patients in the placebo-controlled clinical studies of LINZESS (Trials 1, 2, and
`6), 154 (7%) were 65 years of age and over, while 34 (2%) were 75 years and over. Clinical
`studies of LINZESS did not include sufficient numbers of patients aged 65 years and over to
`determine whether they respond differently from younger patients.
`
`Chronic Idiopathic Constipation (CIC)
`Of 2498 CIC patients in the placebo-controlled clinical studies of LINZESS (Trials 3, 4, and 5),
`273 (11%) were 65 years of age and over, while 56 (2%) were 75 years and over. Clinical
`studies of LINZESS did not include sufficient numbers of patients aged 65 and over to
`determine whether they respond differently from younger patients. In general, dose selection
`for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic,
`renal or cardiac function and of concomitant disease or other drug therapy.
`
`10 OVERDOSAGE
`
`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.
`
`11 DESCRIPTION
`
`LINZESS (linaclotide) is a guanylate cyclase-C (G-CC) 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 molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The
`amino acid sequence for linaclotide is shown below:
`
`
`Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and
`aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin
`capsules. LINZESS is available as 72 mcg, 145 mcg and 290 mcg capsules for oral
`administration.
`
`The inactive ingredients of LINZESS 72 mcg capsules include: calcium chloride dihydrate, L-
`histidine, microcrystalline cellulose, polyvinyl alcohol, and talc. The components of the capsule
`shell include gelatin and titanium dioxide.
`
`
`
`
`
`1 2 3 4 5 6 7 8 9 10 11 12 13 14
`
`H-Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr-OH
`
`S-S
`
`S-S
`
`S-SS-S
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`The inactive ingredients of LINZESS 145 mcg and 290 mcg capsules include: calcium chloride
`dihydrate, hypromellose, L-leucine, and microcrystalline cellulose. The components of the
`capsule shell include gelatin and titanium dioxide.
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Linaclotide is structurally related to human guanylin and uroguanylin and functions as 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.
`
`In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction and
`decreased the activity of pain-sensing nerves by increasing extracellular cGMP.
`
`
`12.2 Pharmacodynamics
`Food Effect
`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 [see Dosage and Administration
`(2.1, 2.2)]. In clinical trials, LINZESS was administered on an empty stomach, at least 30
`minutes before breakfast.
`
`
`12.3 Pharmacokinetics
`Absorption
`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.
`
`Distribution
`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.
`
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`Bausch Health Ireland Exhibit 2008, Page 11 of 22
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`Elimination
`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.
`
`Specific Populations
`Renal and Hepatic Impairment
`Renal or hepatic impairment is not expected to affect the clearance of linaclotide or the
`active metabolite because linaclotide metabolism occurs within the gastrointestinal tract
`and plasma concentrations are not measurable in plasma following administration of the
`recommended dosage.
`
`Drug Interaction Studies
`No drug-drug interaction studies have been conducted with LINZESS. Systemic exposures of
`drug and active metabolite are negligible following oral administration.
`
`Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of
`in vitro studies. In addition, linaclotide does not interact with common efflux and uptake
`transporters (including the efflux transporter P-glycoprotein (P-gp)). Based on these in vitro
`data no drug-drug interactions through modulation of CYP enzymes or common transporters
`are anticipated.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
`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 body weight. 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.
`
`Mutagenesis
`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.
`
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`Bausch Health Ireland Exhibit 2008, Page 12 of 22
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`Impairment of Fertility
`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.
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Irritable Bowel Syndrome with Constipation (IBS-C)
`The efficacy of LINZESS for the management of symptoms of IBS-C was established in two
`double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1
`(NCT00948818) and 2 (NCT00938717)). A total of 800 patients in Trial 1 and 804 patients in
`Trial 2 [overall mean age of 44 years (range 18 to 87 years), 90% female, 77% white, 19%
`black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily
`and were evaluated for efficacy. All patients met Rome II criteria for IBS and were required,
`during the 2-week baseline period, to meet the following criteria:
`
` •
`
` a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale
`less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is