Linzess is a guanylate cyclase-C agonist indicated in adults for the treatment of:

·         irritable bowel syndrome with constipation (IBS-C)

·         chronic idiopathic constipation (CIC)

Posology

 The recommended dosage in adults is:

• 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.

Special populations

Elderly patients:

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.

Pediatric population:

LINZESS is contraindicated in patients less than 2 years of age.

Avoid use of LINZESS in patients 6 years to less than 18 years of age. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established (see Special Warnings and Precautions for use)(see Pediatric Use).

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 following administration of the recommended dosage.

Method of administration

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.

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.

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 consequence of GC-C agonism resulting in mortality within the first 24 hours due to dehydration. Based on insufficient information regarding GC-C intestinal expression in children less than 2 years of age, these patients may have an increased risk of developing diarrhea and its potentially serious consequences. 

Avoid use of LINZESS in pediatric patients 2 years to less than 18 years of age as the safety and effectiveness of LINZESS in patients less than 18 years of age have not been established.

Diarrhoea

Patients should be aware of the possible occurrence of diarrhoea and lower gastrointestinal bleeding during treatment. Diarrhoea 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 diarrhoea was similar between the IBS-C and CIC populations. Severe diarrhoea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients

In post-marketing experience, severe diarrhoea 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.

Patients should be instructed to inform their physician if severe or prolonged diarrhoea or lower gastrointestinal bleeding occurs (see section 4.8).

Should prolonged (e.g. more than 1 week) or severe diarrhoea occur, medical advice should be sought and temporary discontinuation of linaclotide until diarrhoea episode is resolved may be considered. Additional caution should be exercised in patients who are prone to a disturbance of water or electrolyte balance (e.g. elderly, patients with cardiovascular (CV) diseases, diabetes, hypertension), and electrolyte control should be considered.

Linaclotide has not been studied in patients with chronic inflammatory conditions of the intestinal tract, such as Crohn's disease and ulcerative colitis; therefore it is not recommended to use Linaclotide in these patients.

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.

Concomitant treatment with proton pump inhibitors, laxatives or NSAIDs may increase the risk of diarrhoea. Caution should be used when co-administering LINZESS with such medications.

In cases of severe or prolonged diarrhoea, absorption of other oral medicinal products may be affected. The efficacy of oral contraceptives may be reduced, and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception. Caution should be exercised when prescribing medicinal products absorbed in the intestinal tract with a narrow therapeutic index such as levothyroxine as their efficacy may be reduced.

Pregnancy

Risk Summary

Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. The available data on LINZESS use in pregnant women are not sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of linaclotide in rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. Severe maternal toxicity associated with effects on fetal morphology were observed in mice [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.

Lactation

Risk Summary

LINZESS is minimally absorbed following oral administration and neither linaclotide nor its active metabolite were detected in the milk of lactating women [see Data]. Therefore breastfeeding is not expected to result in exposure of the infant to LINZESS. The effects of linaclotide or its metabolite on milk production in lactating women have not been studied.

Data

A pharmacokinetic study assessed the amount of linaclotide and its active metabolite in breast milk following multiple, once daily doses of oral linaclotide (72 μg, 145 μg, or 290 μg) in seven lactating women receiving the drug therapeutically. The concentrations of linaclotide and its metabolite in breast milk were below the limits of quantitation (LoQ) (<0.25 ng/mL and <1.00 ng/mL, respectively) in all samples during the dosing interval. Therefore breastfeeding is not expected to result in exposure of linaclotide or its metabolite to the breastfed child.

Pediatric Use

LINZESS is contraindicated in patients less than 2 years of age. Avoid use of LINZESS in patients 2 years to less than 18 years of age. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established (see Special Warnings and Precautions for use).

In nonclinical studies, deaths occurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28 days) following oral administration of linaclotide, as described below in Juvenile Animal Toxicity Data. Based on insufficient information regarding GC-C intestinal expression in children less than 2 years of age, these patients may have an increased risk of developing diarrhea and its potentially serious consequences.

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.

Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg.

Geriatric Use

Irritable Bowel Syndrome with Constipation (IBS-C)

Of 2219 IBS-C patients in the placebo-controlled clinical studies of LINZESS (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. Because of the higher risk of diarrhoea seen in the clinical trials (see section 4.8), special attention should be given to these patients and the treatment benefit-risk ratio should be carefully and periodically assessed.

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. Because of the higher risk of diarrhoea seen in the clinical trials (see section 4.8), special attention should be given to these patients and the treatment benefit-risk ratio should be carefully and periodically assessed.

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.

Linaclotide has no influence on the ability to drive and use machines.

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.

Irritable Bowel Syndrome with Constipation (IBS-C)

The data described below reflect exposure to LINZESS 290mcg 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 IBS-C patients in the LINZESS treatment group and at an incidence that was greater than in the placebo group. Frequency categories include the following: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to < 1/1,000) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1:  Tabulated Summary of Adverse Reactions in Two Placebo-Controlled Trials (1 and 2) in Patients with IBS-C

^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.

An additional placebo-controlled trial was conducted in 614  IBS-C patients randomized to placebo or LINZESS 290 mcg once daily on an empty stomach for 12 weeks (Trial 6).

In Trial 6, adverse reactions that occurred at a frequency of ≥ 2% in LINZESS-treated patients (n=306) and at a higher rate than placebo (n=308) were:

• Diarrhoea (LINZESS 290 mcg 5%; placebo 2%)

• Headache (LINZESS 290 mcg 3%; placebo 1%)

Diarrhoea

Diarrhoea 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 diarrhoea compared to 3% of placebo-treated patients. Severe diarrhoea 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 diarrhoea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhoea started within the first 2 weeks of LINZESS treatment. Elderly (>65 years), hypertensive and diabetic patients reported diarrhoea more frequently as compared to the overall IBS-C population included in the clinical trials.

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 reactions were diarrhoea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhoea 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 diarrhoea or other GI adverse reactions.

Chronic Idiopathic Constipation (CIC)

The data described below reflect exposure to LINZESS 145mcg in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC. 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 CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group. Frequency categories include the following: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to < 1/1,000) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 2:  Tabulated Summary of Adverse Reactions in Two Placebo-controlled Trials (3 and 4) in Patients with CIC

Diarrhoea

This section summarizes information from Trials 3 and 4 (pooled) regarding diarrhoea, the most commonly reported adverse reaction reported in LINZESS-treated patients in CIC placebo-controlled studies. In all trials, the majority of reported cases of diarrhoea started within the first 2 weeks of LINZESS treatment. Severe diarrhoea was reported in 2% of the 145 mcg LINZESS-treated patients (Trials 3 and 4, and less than 1% of the placebo-treated patients (Trials 3 and 4). Elderly (>65 years) and diabetic patients reported diarrhoea more frequently as compared to the overall CIC population included in the clinical trials.

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with CIC, 8% (Trials 3 and 4) of patients treated with 145 mcg of LINZESS discontinued prematurely due to adverse reactions compared to less than 4% (Trials 3 and 4) of patients treated with placebo.

In patients treated with 145 mcg LINZESS, the most common reasons for discontinuation due to adverse reactions were diarrhoea (5% in Trials 3 and 4) and abdominal pain (1% in Trials 3 and 4). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhoea or abdominal pain (Trials 3 and 4).

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 diarrhoea or other GI adverse reactions.

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.

Reporting of suspected adverse reactions

-          Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

The national pharmacovigilance center and drug safety center (NPC):

·       Fax:  +966-11-205-7662

·       Call NPC at  +966-11-20382222, Exts: 2353-2356-2317-2354-2334-2340

·       Toll free phone: 8002490000

·       E-mail: npc.drug@sfda.gov.sa

·       Website: www.sfda.gov.sa/npc

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 diarrhoea being the most commonly reported adverse reaction.

ATC code: A06AX04

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 145 mcg and 290 mcg capsules for oral administration.

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 and 2). 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 a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and

•         less than or equal to 5 SBMs per week.

The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation.

Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.

The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.

The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively. In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo.

Table 3:  Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: at Least 9 Out of 12 Weeks

Table 4: Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: at Least 6 Out of 12 Weeks

In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods.  For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week. 

Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study.  The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials.

In each trial, in addition to improvements in abdominal pain and CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the Bristol Stool Form Scale (BSFS)], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool]. 

During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg. In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline.  Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and a decrease in abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period.

Chronic Idiopathic Constipation (CIC)

The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 to 85 years), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:

•      Straining during greater than 25% of bowel movements

•      Lumpy or hard stools during greater than 25% of bowel movements

•      Sensation of incomplete evacuation during greater than 25% of bowel movements

Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation.

The efficacy of LINZESS was assessed using a responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. 

A CSBM responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 5. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose.  Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 5. 

In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo. 

Table 5:  Efficacy Responder Rates in the Two Placebo-controlled CIC Trials: at Least 9 Out of 12 Weeks

CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4.  For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs. 

On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).

In each trial, in addition to improvements in CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in each of the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the BSFS], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool]. 

During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period.

Absorption

In general, linaclotide is minimally detectable in plasma following therapeutic oral doses and

therefore, standard pharmacokinetic parameters cannot be calculated.

Following single doses of up to 966 micrograms and multiple doses up to 290 micrograms of linaclotide, there were no detectable plasma levels of parent compound or the active metabolite (des-tyrosine). When 2,897 micrograms was administered on day 8, following a 7-day course of 290 micrograms/day, linaclotide was detectable in only 2 of 18 subjects at concentrations just above the lower limit of quantification of 0.2 ng/ml (concentrations ranged from 0.212 to 0.735 ng/ml). In the two pivotal phase 3 studies in which patients were dosed with 290 micrograms of linaclotide once daily, linaclotide was only detected in 2 out of 162 patients approximately 2 h following the initial linaclotide dose (concentrations were 0.241 ng/ml to 0.239 ng/ml) and in none of the 162 patients after 4 weeks of treatment. The active metabolite was not detected in any of the 162 patients at any time point.

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 fasted and fed state in healthy subjects.

Distribution

As linaclotide is rarely detectable in plasma following therapeutic doses, standard distribution studies have not been conducted. It is expected that linaclotide is negligibly or not systemically distributed.

Biotransformation

Linaclotide is metabolised locally within the gastrointestinal tract to its active primary metabolite, des-tyrosine. Both linaclotide and des-tyrosine active metabolite are reduced and enzymatically proteolyzed within the gastrointestinal tract to smaller peptides and naturally occurring amino acids.

The potential inhibitory activity of linaclotide and its active primary metabolite MM-419447 on the human efflux transporters BCRP, MRP2, MRP3, and MRP4 and the human uptake transporters OATP1B1, OATP1B3, OATP2B1, PEPT1 and OCTN1 was investigated in vitro. Results of this study showed that neither peptide is an inhibitor of the common efflux and uptake transporters studied at clinically relevant concentrations.

The effect of linaclotide and its metabolites to inhibit the common intestinal enzymes (CYP2C9 and CYP3A4) and liver enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) or to induce liver enzymes (CYP1A2, 2B6, and 3A4/5) was investigated in vitro. Results of these studies showed that linaclotide and des-tyrosine metabolite are not inhibitors or inducers of the cytochrome P450 enzyme system.

Elimination

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.

Following a single oral dose of 2,897 micrograms linaclotide on day 8, after a 7-day course of 290 micrograms/day in 18 healthy volunteers, approximately 3 to 5% of the dose was recovered in the faeces, virtually all of it as the des-tyrosine active metabolite.

Age and gender

Clinical studies to determine the impact of age and gender on the clinical pharmacokinetics of linaclotide have not been conducted because it is rarely detectable in plasma. Gender is not expected to have any impact on dosing. For age related information, please see sections 4.2., 4.4., and 4.8.

Renal impairment

LINZESS has not been studied in patients who have renal impairment. Linaclotide is rarely detectable in plasma, therefore, renal impairment would not be expected to affect clearance of the parent compound or its metabolite.

Hepatic impairment

LINZESS has not been studied in patients who have hepatic impairment. Linaclotide is rarely detectable in plasma and is not metabolised by liver cytochrome P450 enzymes, therefore, hepatic impairment would not be expected to affect the metabolism or clearance of the parent drug or its metabolite.

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 bodyweight. Limited systemic exposure to linaclotide and its active metabolite was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

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.

Impairment of Fertility

Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses up to 100,000 mcg/kg/day.

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.

Not applicable.

Do not store above 30ºC.

Keep Linzess in the original container. Do not subdivide or repackage. Protect from moisture.

Do not remove desiccant from the container. Keep bottles tightly closed in a dry place.

The product is supplied in high-density polyethylene (HDPE) bottle with silica gel desiccant and closed with aluminum heat induction sealed child-resistant polypropylene (PP) cap.

Pack size: 30 capsules

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.