Chemical formula: C₆₅H₁₀₄N₁₈O₂₆S₄ Molecular mass: 1,681.89 g/mol PubChem compound: 70693500
Plecanatide 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 plecanatide use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of plecanatide in mice and rabbits during organogenesis at doses much higher than the recommended human dosage.
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.
Pregnant mice and rabbits were administered plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in rabbits. Oral administration of up to 600 mg/kg/day in mice during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation.
After administration of multiple doses of plecanatide 3 mg once daily for 2 weeks to nursing mothers, plecanatide and its active metabolite were not measurable in breast milk collected at 2 hours, 6 hours, and 12 hours post-dosing. In adults, concentrations of plecanatide and its active metabolite were mostly unmeasurable in plasma following multiple doses of plecanatide 3 mg once daily for up to 12 weeks.
Maternal use of plecanatide is not expected to result in clinically relevant exposure to plecanatide or its active metabolite in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for plecanatide and any potential adverse effects on the breastfed infant from plecanatide or from the underlying maternal condition.
The carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to plecanatide 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.
Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay.
Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day.
Because clinical studies 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.
Demographic characteristics were comparable between the plecanatide and placebo groups in all studies.
The safety data described below reflect data from 1733 adult patients with CIC randomized in two double-blind, placebo-controlled clinical trials (Study 1 and Study 2) to receive placebo or 3 mg of plecanatide once daily for 12 weeks.
Table 1 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the plecanatide-treated group and at an incidence that was greater than in the placebo group.
Table 1. Most Common Adverse Reactionsa in Two Placebo-Controlled Trials of Plecanatide [Study 1 and Study 2] in Patients with CIC:
| Adverse Reaction | Plecanatide, 3 mg (N=863) % | Placebo (N=870) % |
|---|---|---|
| Diarrheab | 5 | 1 |
a Reported in at least 2% of plecanatide-treated patients with CIC and at an incidence greater than placebo.
b Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient.
The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 0.6% of plecanatide-treated patients compared to 0.3% of placebo-treated patients. Severe diarrhea was reported to occur within the first 3 days of treatment.
Discontinuations due to adverse reactions occurred in 4% of plecanatide-treated patients and 2% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 2% of plecanatide-treated patients and 0.5% of placebo-treated patients withdrew due to diarrhea.
Adverse reactions reported in less than 2% of plecanatide-treated patients and at an incidence greater than placebo were: sinusitis, upper respiratory tract infection, abdominal distension, flatulence, abdominal tenderness, and increased liver biochemical tests (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal and 3 patients with aspartate aminotransferase (AST) greater than 5 times the upper limit of normal).
The safety data described below reflect data from 1449 adults patients with IBS-C randomized in two double-blind, placebo-controlled clinical trials (Study 3 and Study 4) to receive placebo or 3 mg plecanatide once daily for 12 weeks.
Table 2 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients treated with plecanatide and at an incidence that was greater than in the placebo group.
Table 2. Most Common Adverse Reactionsa in Two Placebo-Controlled Trials of Plecanatide [Study 3 and Study 4] in Patients with IBS-C:
| Adverse Reaction | Plecanatide, 3 mg (N=723) % | Placebo (N=726) % |
|---|---|---|
| Diarrheab | 4.3 | 1 |
a Reported in at least 2% of plecanatide-treated patients with IBS-C and at an incidence greater than placebo.
b Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient.
The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 1% of plecanatide-treated patients compared to 0.1% of placebo-treated patients. Severe diarrhea was reported to occur within the first day of treatment.
Discontinuations due to adverse reactions occurred in 2.5% of plecanatide-treated patients and 0.4% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 1.2% of plecanatide-treated patients and 0% of placebo-treated patients withdrew due to diarrhea.
Adverse reactions reported in 1% or more but less than 2% of plecanatide-treated patients and at an incidence greater than placebo were: nausea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness. Two patients reported increased liver biochemical tests (alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal).
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