Macitentan and Tadalafil (Monograph)

Brand name: Opsynvi
Drug class: Endothelin receptor antagonists
VA class: 48:48.24

Introduction

Macitentan/tadalafil is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor.¹

Uses for Macitentan and Tadalafil

Macitentan and tadalafil has the following uses:

Macitentan/tadalafil is indicated for chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients with WHO functional class (FC) II–III.¹

Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. ¹

Macitentan and Tadalafil Dosage and Administration

General

Macitentan/tadalafil is available in the following dosage form(s) and strength(s):

Film-coated tablets containing the following fixed-combination doses:¹

• Macitentan 10 mg and tadalafil 20 mg¹

• Macitentan 10 mg and tadalafil 40 mg¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Macitentan/tadalafil is taken orally once daily with or without food.¹

• Recommended dosage in patients who are treatment-naïve to any PAH specific therapy or transitioning from ERA monotherapy: Initially, one 10 mg/20 mg tablet once daily for 1 week; if tolerated, up-titrate to one 10 mg/40 mg tablet once daily as the maintenance dosage.¹

• Recommended dosage in patients transitioning from PDE5 inhibitor monotherapy or PDE5 inhibitor and ERA combination therapy: One 10 mg/40 mg tablet once daily.¹

Related/similar drugs

tadalafil, sildenafil, Adcirca, Revatio, ambrisentan, Opsumit

Cautions for Macitentan and Tadalafil

Contraindications

• Pregnancy.¹

• Hypersensitivity.¹

• Concomitant use of organic nitrates.¹

• Concomitant use of guanylate cyclase (GC) stimulators.¹

Warnings/Precautions

Embryo-fetal Toxicity

Macitentan/tadalafil may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant.¹ In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests. ¹

Macitentan/tadalafil is available for females through the Macitentan-Containing Products REMS, a restricted distribution program. ¹

Macitentan-containing Products REMS

For all females, macitentan/tadalafil is available only through a restricted program called the Macitentan-Containing Products REMS because of the risk of embryo-fetal toxicity. ¹

Notable requirements of the Macitentan-Containing Products REMS include the following:¹

• Prescribers must be certified with the REMS program by enrolling and completing training.¹

• All females, regardless of reproductive potential, must enroll in the REMS program prior to initiating macitentan/tadalafil.¹ Male patients are not enrolled in the REMS.¹

• Females of reproductive potential must comply with the pregnancy testing and contraception requirements. ¹

• Pharmacies must be certified with the REMS program and must only dispense to patients who are authorized to receive macitentan/tadalafil.¹

Further information is available at [Web] or 1-888-572-2934.¹ Information on Macitentan-Containing Products REMS certified pharmacies or wholesale distributors is available at 1-888-572-2934.¹

Hepatotoxicity

ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.¹

The incidence of elevated aminotransferases in the double-blind and combined double-blind (DB)/open-label (OL) arms of the study of macitentan/tadalafil in PAH are shown in Table 1.¹

The incidence of elevated aminotransferases in the study of macitentan in PAH is shown in Table 2.¹

Obtain liver enzyme tests prior to initiation of macitentan/tadalafil and repeat during treatment as clinically indicated.¹

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).¹ If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × upper limit of normal (ULN), or by clinical symptoms of hepatotoxicity, discontinue macitentan/tadalafil.¹ Consider re-initiation of therapy when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.¹

Do not initiate macitentan/tadalafil in patients with elevated aminotransferases (>3 × ULN) at baseline.¹ Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied; therefore, avoid use of macitentan/tadalafil in these patients.¹

Hypotension

Macitentan/tadalafil tablets have vasodilatory properties that may result in transient decreases in blood pressure.¹ Prior to prescribing the fixed-combination preparation, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.¹ Patients with pre-existing hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators. ¹

Hemoglobin Decrease

Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with macitentan/tadalafil and the single-entity macitentan product.¹ These decreases occurred early and stabilized thereafter.¹

In the placebo-controlled study of macitentan in PAH, administration of a 10 mg dose caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group.¹ A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the macitentan 10 mg group and in 3.4% of the placebo group.¹ Similar results were observed in the trial with macitentan/tadalafil.¹

Decreases in hemoglobin seldom require transfusion.¹ Initiation of macitentan/tadalafil is not recommended in patients with severe anemia.¹ Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated. ¹

Worsening Pulmonary Veno-occlusive Disease (PVOD)

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD).¹ Since there are no clinical data on administration of macitentan/tadalafil tablets to patients with veno-occlusive disease, administration is not recommended.¹ Should signs of pulmonary edema occur when the fixed-combination preparation is administered, the possibility of associated PVOD should be considered.¹ If confirmed, discontinue macitentan/tadalafil.¹

Visual Loss

Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil.¹ Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio ("crowded disc"), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking.¹ Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males greater than or equal to 50 years of age in the general population.¹ Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION.¹

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use of macitentan/tadalafil in these patients is not recommended.¹

Hearing Impairment

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil.¹ It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.¹

Fluid Retention

Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs and heart failure has been reported in patients taking macitentan/tadalafil.¹ In the active-controlled and combined double-blind/open-label arms of the study of macitentan/tadalafil in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active-controlled and 17.3% in the double-blind/open-label arm.¹ In the placebo-controlled study of macitentan in PAH, the incidence of edema was 21.9% in the macitentan 10 mg group and 20.5% in the placebo group. ¹

Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment.¹ In a small study of macitentan in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the macitentan group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo.¹ Postmarketing cases of edema and fluid retention occurring within weeks of starting macitentan, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported. ¹

Monitor for signs of fluid retention after macitentan/tadalafil initiation.¹ If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as the drug or underlying heart failure, and the possible need to discontinue the fixed combination therapy.¹

Combination with Other PDE5 Inhibitors

Tadalafil is also indicated for erectile dysfunction.¹ The safety and efficacy of taking tadalafil tablets together with another PDE5 inhibitors or other treatments for erectile dysfunction have not been studied.¹ Instruct patients taking macitentan/tadalafil tablets not to take other PDE5 inhibitors.¹

Decreased Sperm Count

Macitentan, like other ERAs, may have an adverse effect on spermatogenesis.¹ Counsel men about potential effects on fertility. ¹

Prolonged Erection

There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) in patients taking PDE5 inhibitors such as tadalafil.¹ Patients with conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia) or patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) are at an increased risk.¹ Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.¹ Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.¹

Specific Populations

Pregnancy

Based on data from animal reproduction studies, macitentan/tadalafil is contraindicated during pregnancy.¹ Macitentan may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female.¹ 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.¹ Macitentan was teratogenic in rabbits and rats at all doses tested.¹

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.¹ 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. ¹

There are risks to the mother and the fetus associated with PAH in pregnancy.¹ 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. ¹

The background risk of major birth defects and miscarriage for the indicated population is unknown.¹ All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.¹ 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.¹

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.¹

Lactation

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.¹ Tadalafil and/or its metabolites are present in the milk of lactating rats.¹ When a drug is present in animal milk, it is likely that the drug will be present in human milk.¹ Because of the potential for serious adverse reactions in breastfed infants from macitentan/tadalafil, advise women not to breastfeed during treatment with the fixed-combination preparation.¹

Females and Males of Reproductive Potential

Verify the pregnancy status of females of reproductive potential prior to initiating macitentan/tadalafil, monthly during treatment, and 1 month after stopping treatment.¹ The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected.¹ If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. ¹

Female patients of reproductive potential must use acceptable methods of contraception during treatment with macitentan/tadalafil and for 1 month after treatment.¹ Patients may choose one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods).¹ If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method.¹ Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling. ¹

Based on findings in animals, macitentan may impair fertility in males of reproductive potential.¹ It is not known whether effects on fertility would be reversible. ¹

Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months.¹ This effect was not seen in the study of 20 mg tadalafil taken for 6 months.¹ There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone, or follicle stimulating hormone.¹ The clinical significance of the decreased sperm concentrations in the two studies is unknown.¹ There have been no studies evaluating the effect of tadalafil on fertility in men or women. ¹

Pediatric Use

The safety and efficacy of macitentan/tadalafil in children have not been established.¹

Geriatric Use

Of the total number of subjects in the clinical study of macitentan/tadalafil for PAH, 20% were 65 years of age and over.¹ No overall differences in safety or effectiveness were observed between these subjects and younger subjects.¹

Renal Impairment

The use of macitentan/tadalafil is not recommended in patients undergoing dialysis.¹ 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.¹ For patients with mild (creatinine clearance 51–80 mL/min) to moderate (creatinine clearance 30–50 mL/min) renal impairment, the recommended dose should be consistent with the adult dosing. ¹

Hepatic Impairment

Macitentan/tadalafil was not studied in patients with severe hepatic impairment (defined as a Model for End-Stage Liver Disease score ≥19).¹ Macitentan/tadalafil must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (> 3 × ULN).¹ For patients with mild to moderate hepatic impairment (Child Pugh Class A or B) the recommended dose should be consistent with the adult dosing. ¹

Common Adverse Effects

Most common adverse reactions (≥10%) are edema/fluid retention, anemia, and headache/migraine.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A4 Inducers/Inhibitors: Avoid concomitant use. ¹

• Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors: Avoid concomitant use.¹

Actions

Mechanism of Action

Macitentan¹

Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.¹ In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.¹

Macitentan is an endothelin receptor antagonist (ERA) that inhibits the binding of ET-1 to both ETA and ETB receptors.¹ Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells.¹ One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.¹ The clinical impact of dual endothelin blockage is unknown. ¹

Tadalafil¹

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP).¹ PAH is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle.¹ PDE5 is the predominant phosphodiesterase in the pulmonary vasculature.¹ Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.¹

Studies in vitrohave shown that tadalafil is a selective inhibitor of PDE5.¹ PDE5 is an enzyme found in corpus cavernosum, vascular smooth muscle, visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum.¹ The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases.¹ Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4 and PDE7, enzymes which are found in the heart, brain, blood vessels, liver, and other organs.¹ Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels.¹ This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility.¹ Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction.¹ Tadalafil is also >9,000-fold more potent for PDE5 than for PDE8, PDE9 and PDE10. ¹

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).¹

• Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with macitentan/tadalafil and for 1 month after treatment discontinuation.¹ Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking macitentan/tadalafil and for 1 month after discontinuing therapy. ¹

• For female patients, macitentan/tadalafil is available only through a restricted program called the Macitentan-Containing Products REMS.¹ Male patients are not enrolled in the REMS program. ¹

• Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods).¹ Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control to ensure that another acceptable form of birth control is selected.¹

• Patients should be instructed to contact their physician if they suspect they may be pregnant.¹ Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.¹

• Inform female patients (and their guardians, if applicable) that they must sign an enrollment form.¹ Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.¹

• Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.¹

• Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.¹

• Review the Medication Guide and REMS educational materials with female patients.¹

• Advise women not to breastfeed during treatment with macitentan/tadalafil. ¹

• Advise males of reproductive potential that macitentan/tadalafil may impair fertility. ¹

• Some members of this pharmacological class are hepatotoxic.¹ Educate patients on signs of hepatotoxicity.¹ Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.¹

• Advise patients that they may develop anemia.¹ Advise patients that they will have blood tests to check their red blood cells before starting macitentan/tadalafil.¹

• Inform patients of contraindication of macitentan/tadalafil with any use of organic nitrates or guanylate cyclase (GC) stimulators.¹

• Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking macitentan/tadalafil.¹ Such an event may be a sign of NAION.¹ Also inform patients that there is an increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors.¹

• Educate patients on signs of fluid retention.¹ Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.¹

• Patients should be advised not to cut, crush, or chew tablets.¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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