Macitentan and Tadalafil

The use of macitentan/tadalafil is not recommended in patients undergoing dialysis. Avoid use of macitentan/tadalafil in patients with severe renal impairment (creatinine clearance 15–29 mL/min) because of increased tadalafil exposure (AUC), lack of clinical experience and the lack of ability to influence clearance by dialysis.

Risk summary

Based on data from animal reproduction studies, macitentan/tadalafil is contraindicated during pregnancy. Macitentan may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female. The available data from macitentan/tadalafil pharmacovigilance reports and published case reports on macitentan are insufficient to evaluate the potential risk of embryo-fetal toxicity. Macitentan was teratogenic in rabbits and rats at all doses tested.

Available data from a randomized controlled trial, observational studies, and case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In tadalafil animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats and mice during organogenesis at exposures 7 times the maximum recommended human dose (MRHD) of 40 mg/day (see Data).

There are risks to the mother and the fetus associated with PAH in pregnancy (see Clinical Considerations). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise pregnant women of the potential risk to a fetus.

The 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 U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical considerations

Disease-associated maternal and/or embryo/fetal risk

In patients with PAH, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth.

Data

Animal data

Macitentan:

In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.

Tadalafil:

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed-effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance.

Risk Summary

There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants from macitentan/tadalafil, advise women not to breastfeed during treatment with macitentan/tadalafil.

Data

Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma.

Carcinogenesis

Macitentan

Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3-and 42-fold in male and female rats, respectively.

Tadalafil

Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5-fold for mice, and 7-and 14-fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg.

Mutagenesis

Macitentan

Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.

Tadalafil

Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.

Impairment of Fertility

Macitentan

Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.

Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19-to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.

Tadalafil

There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6-fold for males or 17-fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg.

There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety profile of macitentan/tadalafil is based on data from a double-blind, active-controlled, phase 3 clinical study (A DUE) and an open-label extension study, in patients with PAH [see Clinical Studies (14)]. In the double-blind portion of the study, a total of 107 patients were treated with macitentan/tadalafil 10 mg/40 mg, 35 patients were treated with 10 mg macitentan monotherapy, and 44 patients were treated with 40 mg tadalafil monotherapy. The duration of exposure to macitentan/tadalafil during the double-blind portion was 16 weeks.

The most common adverse reactions (occurring in ≥10% of the macitentan/tadalafil-treated patients) from the double-blind study data were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%). The incidence of treatment discontinuations due to adverse events among patients receiving macitentan/tadalafil in the double-blind phase of the study was 8%. The most frequent adverse reactions leading to discontinuation were anemia and hemoglobin decreased (2% grouped) and peripheral edema and peripheral swelling (2% grouped). The table below presents adverse reactions seen in patients treated for 16 weeks during the double-blind portion of A DUE.

Adverse Reactions Occurring in 3% or More of Patients Treated with macitentan/tadalafil During the 16-week Double-blind Study Portion of A DUE:

One-hundred eighty-five patients received macitentan/tadalafil in the double-blind or open-label phase of the study. The median exposure to macitentan/tadalafil during the combined double-blind/open-label extension was 59.9 weeks with a mean exposure of 63.2 weeks. Adverse reactions from the combined double-blind/open-label study data were similar to those observed in the double-blind study.

The following adverse reactions have been reported during clinical trials with the individual components of macitentan/tadalafil but were not observed in 3% or more of subjects treated with macitentan/tadalafil in the A DUE clinical trial:

Macitentan: bronchitis, pharyngitis, transaminases increased, influenza, urinary tract infection.

Tadalafil: lower respiratory tract infection, prolonged erections, gastroesophageal reflux disease, vision blurred, tinnitus, swelling face, chest pain.

Postmarketing experience

Additional adverse reactions have been identified during post-approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Macitentan: liver injury, symptomatic hypotension, hypersensitivity reactions (angioedema, pruritus, and rash).

Tadalafil: Cardiovascular and cerebrovascular events including myocardial infarction, sudden cardiac death, stroke, and tachycardia; Nervous system events including, seizure, transient amnesia; Hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis; visual field defect, NAION, retinal vascular occlusion; sudden hearing loss, priapism.