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Irritable Bowel Syndrome with Constipation (IBS-C)Most Common Adverse ReactionsThe data described below reflect exposure to LINZESS in the two placebo-controlled clinicaltrials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized toreceive 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 patientsin the LINZESS treatment group and at an incidence that was greater than in the placebogroup.Table 1:Most Common Adverse Reactionsa in Two Placebo-Controlled Trials (1 and2) in Patients with IBS-CLINZESSAdverse Reactions290 mcgPlacebo[N 807][N 798]%%GastrointestinalDiarrhea203bAbdominal pain75Flatulence42Abdominal distension21Infections and InfestationsViral Gastroenteritis31Nervous System DisordersHeadache43a:b:Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo“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 toplacebo or LINZESS 290 mcg once daily on an empty stomach for 12 weeks (Trial 6) weresimilar to those in Table 1.DiarrheaDiarrhea was the most commonly reported adverse reaction of the LINZESS-treated patientsin the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treatedpatients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea wasreported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treatedpatients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% ofplacebo-treated patients. The majority of reported cases of diarrhea started within the first 2weeks of LINZESS treatment [see Warnings and Precautions (5.2)].Adverse Reactions Leading to DiscontinuationIn 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 theLINZESS-treatment group, the most common reasons for discontinuation due to adverse

reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% ofpatients in the placebo group withdrew due to diarrhea or abdominal pain.Adverse Reactions Leading to Dose ReductionsIn the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESSdaily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspendedsecondary to adverse reactions, the majority of which were diarrhea or other GI adversereactions.Less Common Adverse ReactionsDefecation urgency, fecal incontinence, vomiting, and gastroesophageal reflux disease werereported in 2% of patients in the LINZESS-treatment group and at an incidence greater thanin the placebo treatment group.Chronic Idiopathic Constipation (CIC)Most Common Adverse ReactionsThe data described below reflect exposure to LINZESS in the two double-blind placebocontrolled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients wererandomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on anempty stomach, for at least 12 weeks. Table 2 provides the incidence of adverse reactionsreported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at anincidence that was greater than in the placebo treatment group.Most Common Adverse Reactionsa in the Two Placebo-controlled Trials (3and 4) in Patients with CICLINZESS145 mcgPlaceboAdverse Reactions[N 430][N 423]%%GastrointestinalDiarrhea165Abdominal painb76Flatulence65Abdominal distension32Infections and InfestationsUpper respiratory tract infection54Sinusitis32Table 2:a:b:Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo“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 which1223 patients were randomized to LINZESS 72 mcg, 145 mcg, or placebo once daily for 12weeks (Trial 5).

In Trial 5, adverse reactions that occurred at a frequency of 2% in LINZESS-treated patients(n 411 in each LINZESS 72 mcg and 145 mcg group) and at a higher rate than placebo(n 401) were: Diarrhea (LINZESS 72 mcg 19%; LINZESS 145 mcg 22%; placebo 7%) Abdominal distension (LINZESS 72 mcg 2%; LINZESS 145 mcg 1%; placebo 1%)DiarrheaIn Trials 3 and 4 (pooled) and Trial 5, diarrhea was the most commonly reported adversereaction 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 ofLINZESS treatment.Severe diarrhea was reported in less than 1% of the 72 mcg LINZESS-treated patients (Trial5), in 2% of the 145 mcg LINZESS-treated patients (Trials 3, 4, and 5), and less than 1% of theplacebo-treated patients (Trials 3, 4, and 5) [see Warnings and Precautions (5.2)].Adverse Reactions Leading to DiscontinuationIn 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 LINZESSdiscontinued 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 toadverse 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). Incomparison, less than 1% of patients in the placebo group withdrew due to diarrhea orabdominal pain (Trials 3, 4, and 5).Adverse Reactions Leading to Dose ReductionsIn the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS dailyfor up to 18 months. In these trials, 27% of patients had their dose reduced or suspendedsecondary to adverse reactions, the majority of which were diarrhea or other GI adversereactions.Less Common Adverse ReactionsDefecation urgency, fecal incontinence, dyspepsia, and viral gastroenteritis were reported inless than 2% of patients in the LINZESS treatment group and at an incidence greater thanplacebo treatment group.6.2 Postmarketing ExperienceThe 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 notalways possible to reliably estimate their frequency or establish a causal relationship to drugexposure.

Hypersensitivity reactions: Anaphylaxis, angioedema, rash (including hives or urticaria)Gastrointestinal reactions: Hematochezia, nausea, rectal hemorrhage8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk SummaryLinaclotide and its active metabolite are negligibly absorbed systemically following oraladministration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result infetal exposure to the drug. The available data on LINZESS use in pregnant women are notsufficient to inform any drug-associated risk for major birth defects and miscarriage. In animaldevelopmental studies, no effects on embryo-fetal development were observed with oraladministration of linaclotide in rats and rabbits during organogenesis at doses much higherthan the maximum recommended human dosage. Severe maternal toxicity associated witheffects on fetal morphology were observed in mice (see Data).The estimated background risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have a background risk of birth defect, loss, or otheradverse outcomes. In the United States general population, the estimated background risk ofmajor birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15%to 20%, respectively.DataAnimal DataThe 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 duringorganogenesis produced severe maternal toxicity including death, reduction of gravid uterineand fetal weights, and effects on fetal morphology. Oral doses of 5,000 mcg/kg/day did notproduce maternal toxicity or any adverse effects on embryo-fetal development in mice. Oraladministration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits duringorganogenesis 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 organogenesisthrough lactation produced no developmental abnormalities or effects on growth, learning andmemory, or fertility in the offspring through maturation.The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kgbody weight. Limited systemic exposure to linaclotide was achieved in animals duringorganogenesis (AUC 40, 640, and 25 ng hr/mL in rats, rabbits, and mice, respectively, at thehighest dose levels). Linaclotide and its active metabolite are not measurable in human plasmafollowing administration of the recommended clinical dosages. Therefore, animal and humandoses should not be compared directly for evaluating relative exposure.

8.2 LactationRisk SummaryLinaclotide and its active metabolite were not detected in the milk of lactating women (seeData). In adults, concentrations of linaclotide and its active metabolite were below the limit ofquantitation 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 activemetabolite in breastfed infants. There is no information on the effects of linaclotide or its activemetabolite on milk production. The developmental and health benefits of breastfeeding shouldbe considered along with the mother’s clinical need for LINZESS and any potential adverseeffects on the breastfed infant from LINZESS or from the underlying maternal condition.DataFollowing oral administration of 72 mcg, 145 mcg, or 290 mcg of LINZESS once daily for 3days to breastfeeding mothers taking linaclotide therapeutically, the concentrations oflinaclotide 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 UseLINZESS is contraindicated in patients less than 2 years of age. In nonclinical studies, deathsoccurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28days) following oral administration of linaclotide which increased fluid secretion as aconsequence of age-dependent elevated GC-C agonism resulting in rapid and severedehydration, as described below in Juvenile Animal Toxicity Data.A GC-C ontogeny study measured GC-C mRNA expression levels in duodenal and colonicmucosal tissue samples from children aged 6 months to less than 18 years (N 99) to evaluatethe risk of diarrhea and severe dehydration due to GC-C agonism in children. The resultsshowed no age-dependent trend in GC-C intestinal expression in children 2 to less than 18years of age. However, there are insufficient data available on GC-C intestinal expression inchildren less than 2 years of age to assess the risk of developing diarrhea and its potentiallyserious consequences [see Warnings and Precautions (5.1)].The safety and effectiveness of LINZESS in patients less than 18 years of age have not beenestablished.Juvenile Animal Toxicity DataIn toxicology studies in neonatal mice, oral administration of linaclotide at 10 mcg/kg/daycaused 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 intothe 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, linaclotidewas well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of

100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deathsoccurred after a single oral dose of 600 mcg/kg.8.5 Geriatric UseIrritable Bowel Syndrome with Constipation (IBS-C)Of 2219 IBS-C patients in the placebo-controlled clinical studies of LINZESS (Trials 1, 2, and6), 154 (7%) were 65 years of age and over, while 34 (2%) were 75 years and over. Clinicalstudies of LINZESS did not include sufficient numbers of patients aged 65 years and over todetermine 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. Clinicalstudies of LINZESS did not include sufficient numbers of patients aged 65 and over todetermine whether they respond differently from younger patients. In general, dose selectionfor 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 OVERDOSAGESingle LINZESS doses of 2897 mcg were administered to 22 healthy subjects; the safetyprofile in these subjects was consistent with that in the overall LINZESS-treated population,with diarrhea being the most commonly reported adverse reaction.11 DESCRIPTIONLINZESS (linaclotide) is a guanylate cyclase-C (G-CC) agonist. Linaclotide is a 14-amino acidpeptide with the following chemical name: e, cyclic (1-6), (2-10), (5-13)-tris (disulfide).The molecular formula of linaclotide is C 59H79 N15O21S6 and its molecular weight is 1526.8. Theamino acid sequence for linaclotide is shown below:1234567891011 12 13 y-Cys-Tyr-OHS-SS-SS-SLinaclotide is an amorphous, white to off-white powder. It is slightly soluble in water andaqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatincapsules. LINZESS is available as 72 mcg, 145 mcg and 290 mcg capsules for oraladministration.The inactive ingredients of LINZESS 72 mcg capsules include: calcium chloride dihydrate, Lhistidine, microcrystalline cellulose, polyvinyl alcohol, and talc. The components of the capsuleshell include gelatin and titanium dioxide.

The inactive ingredients of LINZESS 145 mcg and 290 mcg capsules include: calcium chloridedihydrate, hypromellose, L-leucine, and microcrystalline cellulose. The components of thecapsule shell include gelatin and titanium dioxide.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionLinaclotide is structurally related to human guanylin and uroguanylin and functions as aguanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-Cand act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results inan increase in both intracellular and extracellular concentrations of cyclic guanosinemonophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride andbicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosistransmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinalfluid and accelerated transit. In animal models, linaclotide has been shown to both accelerateGI transit and reduce intestinal pain.In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction anddecreased the activity of pain-sensing nerves by increasing extracellular cGMP.12.2 PharmacodynamicsFood EffectTaking LINZESS immediately after the high fat breakfast resulted in looser stools and a higherstool 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 30minutes before breakfast.12.3 PharmacokineticsAbsorptionLINZESS is minimally absorbed with negligible systemic availability following oraladministration. Concentrations of linaclotide and its active metabolite in plasma are below thelimit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore,standard pharmacokinetic parameters such as area under the curve (AUC), maximumconcentration (Cmax), and half-life (t½) cannot be calculated.Food EffectNeither linaclotide nor its active metabolite were detected in the plasma followingadministration of LINZESS 290 mcg once daily for 7 days both in the non-fed and fed state inhealthy subjects.DistributionGiven that linaclotide plasma concentrations following recommended oral doses are notmeasurable, linaclotide is not expected to be distributed to tissues to any clinically relevantextent.

EliminationMetabolismLinaclotide is metabolized within the gastrointestinal tract to its principal, active metaboliteby loss of the terminal tyrosine moiety. Both linaclotide and the metabolite areproteolytically degraded within the intestinal lumen to smaller peptides and naturallyoccurring amino acids.ExcretionActive peptide recovery in the stool samples of fed and fasted healthy subjects followingadministration 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 PopulationsRenal and Hepatic ImpairmentRenal or hepatic impairment is not expected to affect the clearance of linaclotide or theactive metabolite because linaclotide metabolism occurs within the gastrointestinal tractand plasma concentrations are not measurable in plasma following administration of therecommended dosage.Drug Interaction StudiesNo drug-drug interaction studies have been conducted with LINZESS. Systemic exposures ofdrug and active metabolite are negligible following oral administration.Linaclotide does not interact with the cytochrome P450 enzyme system based on the results ofin vitro studies. In addition, linaclotide does not interact with common efflux and uptaketransporters (including the efflux transporter P-glycoprotein (P-gp)). Based on these in vitrodata no drug-drug interactions through modulation of CYP enzymes or common transportersare anticipated.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisIn 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended humandose is approximately 5 mcg/kg/day based on a 60-kg body weight. Limited systemic exposureto 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 dosesshould not be compared directly for evaluating relative exposure.MutagenesisLinaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the invitro chromosomal aberration assay in cultured human peripheral blood lymphocytes.

Impairment of FertilityLinaclotide had no effect on fertility or reproductive function in male and female rats at oraldoses of up to 100,000 mcg/kg/day.14 CLINICAL STUDIES14.1 Irritable Bowel Syndrome with Constipation (IBS-C)The efficacy of LINZESS for the management of symptoms of IBS-C was established in twodouble-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 inTrial 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 dailyand 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 scaleless than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is aspontane

Administration Instructions (2.2): Take on empty stomach at least 30 minutes prior to first meal of the day. Do not crush or chew LINZESS capsule or capsule contents. For patients who have diffic