Version May 2024
Do not administer macitentan to a pregnant female patient because it may cause fetal harm. In female patients of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception.
For all female patients, macitentan is available only through a restricted program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS).
Pulmonary arterial hypertension:
Note: Consult a pulmonary arterial hypertension specialist for all management decisions; choice of therapy is dependent on etiology, risk stratification, and cardiopulmonary comorbidities (Ref).
Oral: 10 mg once daily; maximum 10 mg/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic changes were not considered clinically relevant. Canadian labeling does not recommend use in dialysis patients (has not been studied).
US labeling: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetic changes were not considered clinically relevant.
Canadian labeling:
Baseline ALT or AST >3x ULN: Initiation of therapy is not recommended.
Mild impairment: Dosage adjustment not necessary.
Moderate to severe impairment: Use is not recommended.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Hematologic & oncologic: Anemia (13%)
Nervous system: Headache (14%)
Respiratory: Bronchitis (12%), nasopharyngitis (≤20%), pharyngitis (≤20%)
1% to 10%:
Genitourinary: Urinary tract infection (9%)
Hepatic: Increased serum transaminases (>8 × ULN: 2%; including increased serum alanine aminotransferase, increased serum aspartate aminotransferase)
Infection: Influenza (6%)
Postmarketing:
Cardiovascular: Edema, flushing, symptomatic hypotension
Endocrine & metabolic: Fluid retention
Hepatic: Hepatic injury (including fulminant hepatitis, hepatic failure) (Tran 2018)
Hypersensitivity: Angioedema, hypersensitivity reaction
Respiratory: Nasal congestion
Hypersensitivity to macitentan or any component of the formulation; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling): breastfeeding.
Concerns related to adverse effects:
• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization) associated with other endothelin antagonists. Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with severe chronic heart failure.
• Hematologic effects: A reduction in hematocrit/hemoglobin has been observed and may occur early in therapy with subsequent stabilization. Decreases in hemoglobin rarely required transfusion. Measure hemoglobin prior to initiating therapy and repeat as clinically appropriate. Use is not recommended in patients with severe anemia.
• Hepatic effects: Increases in serum liver aminotransferases, hepatotoxicity, and liver failure have been reported. Monitor transaminases prior to initiation of therapy and repeat as clinically appropriate. Discontinue treatment in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (eg, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, right upper quadrant pain, vomiting) or elevated bilirubin (>2 x the upper limit of normal [ULN]). Upon normalization of hepatic enzymes, may consider reinitiation of therapy in patients not experiencing clinical signs of hepatotoxicity.
Disease-related concerns:
• Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the possibility of PVOD; discontinue if PVOD is confirmed.
Special populations:
• Pregnancy: [US Boxed Warning]: Macitentan may cause fetal harm if given to pregnant women; do not administer to women who are pregnant. All females of reproductive potential should have a negative pregnancy test prior to beginning therapy and testing should continue monthly during treatment and one month after discontinuing therapy.
• REMS program: [US Boxed Warning]: Macitentan is available to females only through the restricted OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) Program. All females regardless of their reproductive potential must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program. Call 1-866-228-3546 or visit http://www.opsumitrems.com for more information.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Opsumit: 10 mg [contains soybean lecithin]
No
Tablets (Opsumit Oral)
10 mg (per each): $483.19
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Opsumit: 10 mg [contains soybean lecithin]
Oral: Swallow tablet whole. Do not split, crush, or chew tablets. May be administered with or without food.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204410s024lbl.pdf#page=20, must be dispensed with this medication.
Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to reduce risks of disease progression and hospitalization
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Amiodarone: May increase the serum concentration of Macitentan. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Macitentan. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Macitentan. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Macitentan. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Macitentan. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Macitentan. Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Sparsentan: May enhance the adverse/toxic effect of Endothelin Receptor Antagonists. Risk X: Avoid combination
[US Boxed Warnings]: For all female patients, macitentan is available only through a restricted program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS). All females regardless of their reproductive potential must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program.
[US Boxed Warnings]: In female patients of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception. Women may use one highly effective form of contraception (intrauterine device, contraceptive implant, or tubal sterilization) or a combination of methods (hormonal contraceptive with a barrier method or two barrier methods). A hormonal contraceptive or barrier method must be used in addition to a partner’s vasectomy, if that method is chosen. Females should be counseled on pregnancy prevention and planning and instructed to notify their prescriber immediately if a pregnancy should occur.
Sperm count may be reduced in men during treatment. Advise male patients of potential effects on fertility.
[US Boxed Warnings]: Do not administer macitentan to a pregnant female because it may cause fetal harm. Based on data from animal reproduction studies, macitentan may cause harm if administered during pregnancy; therefore, use is contraindicated in pregnant women. Untreated maternal pulmonary arterial hypertension is also associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (ESC [Regitz-Zagrosek 2018]; McLaughlin 2009; Taichman 2014).
[US Boxed Warnings]: For all female patients, macitentan is available only through a restricted program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS).
It is not known if macitentan is present in breast milk.
Due to the potential for adverse reactions in breastfeeding infants, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug.
Monitor for significant peripheral edema and evaluate etiology if it occurs; measure liver enzymes prior to initiation and repeat as clinically appropriate (Canadian labeling recommends monthly monitoring of liver enzymes during the first year of therapy and then as clinically appropriate); monitor for clinical signs and symptoms of liver injury (eg, abdominal pain, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, vomiting); hemoglobin and hematocrit prior to initiation and repeat as clinically appropriate (Canadian labeling recommends to repeat hemoglobin after first month of therapy and then as clinically appropriate).
A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy, monthly during treatment, and 1 month after stopping treatment.
Blocks endothelin (ET)-1 from binding to endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.
Distribution: Vss: 50 L (active metabolite: 40 L)
Protein binding, plasma: >99% primarily to albumin
Metabolism: Hepatic via CYP3A4 (major) and CYP2C19 to its active metabolite
Half-life elimination: ~16 hours (active metabolite: ~48 hours)
Time to peak, plasma: 8 hours
Excretion: Urine (~50%); feces (~24%)
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