Linzess

2.1  Recommended Dosage

Irritable Bowel Syndrome with Constipation (IBS-C) in adults

The recommended dosage of LINZESS is 290 mcg orally once daily.

Chronic Idiopathic Constipation (CIC) in adults

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.   

Functional Constipation (FC) in pediatric patients 6 to 17 years of age

The recommended dosage of LINZESS is 72 mcg orally once daily.

2.2  Preparation and Administration Instructions

• Take LINZESS on an empty stomach, at least 30 minutes prior to a meal, at approximately the same time each 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 patients who are unable to swallow the capsule whole, 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.

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.

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 (see Juvenile Animal Toxicity Data).  

A clinical GC-C ontogeny study in children 6 months to less than 18 years of age (N=99) was conducted to measure GC-C mRNA expression levels in duodenal and colonic samples to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism. The results showed no age dependent trend in GC-C intestinal expression in children 2 to less than 18 years of age. There was insufficient data on GC-C intestinal expression to assess the risk of developing diarrhea and its potentially serious consequences in children less than 2 years of age [see Warnings and Precautions ( 5.1)].

The safety and effectiveness of LINZESS for the treatment of FC in pediatric patients 6 to 17 years of age have been established. Use of LINZESS for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients 6 years of age and older. The safety of LINZESS in adult and pediatric patients 6 to 17 years of age in clinical studies was similar [see Adverse Reactions ( 6.1) and Clinical Studies ( 14.3)].

The safety and effectiveness of LINZESS in patients with FC less than 6 years of age or in patients with IBS-C 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 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.