Sotatercept-csrk (Monograph)

Brand name: Winrevair
Drug class: Respiratory Tract Agents, Miscellaneous

Introduction

Sotatercept-csrk, a recombinant activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, is an activin signaling inhibitor.

Uses for Sotatercept-csrk

Sotatercept-csrk has the following uses:

Sotatercept-csrk is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.

Sotatercept-csrk Dosage and Administration

General

Sotatercept-csrk is available in the following dosage form(s) and strength(s):

For injection: 45 mg lyophilized cake or powder in a single-dose vial
For injection: 60 mg lyophilized cake or powder in a single-dose vial

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

Administer once every 3 weeks by subcutaneous injection according to patient body weight.
The recommended starting dose is 0.3 mg/kg by subcutaneous injection.
The recommended target dose is 0.7 mg/kg every 3 weeks by subcutaneous injection.
Dosage modifications based on hemoglobin (Hgb) and platelet counts may be necessary. Check Hgb and platelet count before each dose for the first 5 doses, or longer if values are unstable, and monitor periodically thereafter.
See full prescribing information for additional instructions on preparation and administration, and dosage modification guidelines for increased Hgb and decreased platelet counts.

Cautions for Sotatercept-csrk

Contraindications

None.

Warnings/Precautions

Erythrocytosis

Sotatercept-csrk may increase hemoglobin. Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. In clinical studies, moderate elevations in Hgb (>2 g/dL above ULN) occurred in 15% of patients taking sotatercept-csrk while no elevations ≥4 g/dL above ULN were observed. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required.

Severe Thrombocytopenia

Sotatercept-csrk may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. In clinical studies, severe thrombocytopenia (platelet count <50,000/mm³ [<50 x 10⁹/L]) occurred in 3% of patients taking sotatercept-csrk. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion.

Do not initiate treatment if platelet count is <50,000/mm³.

Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.

Serious Bleeding

In clinical studies, serious bleeding (e.g., GI, intracranial hemorrhage) was reported in 4% of patients taking sotatercept-csrk and 1% of patients taking placebo. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Evaluate and treat bleeding accordingly. Do not administer sotatercept-csrk if the patient is experiencing serious bleeding.

Embryo-fetal Toxicity

Based on findings in animal reproduction studies, sotatercept-csrk may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of sotatercept-csrk to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on AUC) those occurring at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with sotatercept-csrk and for at least 4 months after the final dose.

Impaired Fertility

Based on findings in animals, sotatercept-csrk may impair female and male fertility. Advise patients on the potential effects on fertility.

Specific Populations

Pregnancy

Based on findings in animal reproduction studies, sotatercept-csrk may cause fetal harm when administered to a pregnant woman. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy. There are no available data on sotatercept-csrk use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, administration of sotatercept-csrk to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on AUC) above those occurring at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known. 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% to 4% and 15% to 20%, respectively.

Report exposure during pregnancy or lactation to the Merck Sharp & Dohme, LLC Adverse Event reporting line at 1-877-888-4231.

In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction, and premature labor.

Lactation

There are no data on the presence of sotatercept-csrk in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with sotatercept-csrk, and for 4 months after the final dose.

Females and Males of Reproductive Potential

Sotatercept-csrk may cause fetal harm when administered to pregnant women.

Pregnancy testing is recommended for females of reproductive potential before starting sotatercept-csrk treatment.

Advise female patients of reproductive potential to use effective contraception during treatment with sotatercept-csrk and for at least 4 months after the final dose if treatment is discontinued.

Based on findings in animals, sotatercept-csrk may impair female and male fertility. In male rats, although adverse histologic changes in reproductive organs were not reversible after a 13-week period, functional fertility demonstrated reversibility.

Pediatric Use

The safety and effectiveness of sotatercept-csrk have not been established in patients younger than 18 years of age.

Geriatric Use

A total of 81 patients ≥65 years of age participated in clinical studies for PAH, of which 52 (16%) were treated with sotatercept-csrk. No differences in efficacy of sotatercept-csrk were observed between the <65-year-old and ≥65-year-old subgroups.

With the exception of bleeding events (a collective group of adverse events of clinical interest), there were no differences in safety between the <65-year-old and ≥65-year-old subgroups. Bleeding events occurred more commonly in the older sotatercept-csrk subgroup, but with no imbalance between age subgroups for any specific bleeding event.

Clinical studies of sotatercept-csrk did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger patients.

Common Adverse Effects

The most common (≥10% in patients receiving sotatercept-csrk and 5% more than placebo) adverse reactions were headache, epistaxis, rash, telangiectasia, diarrhea, dizziness, and erythema.

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:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Sotatercept-csrk, a recombinant activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, is an activin signaling inhibitor that binds to activin A and other TGF- β superfamily ligands. As a result, sotatercept-csrk improves the balance between the pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling to modulate vascular proliferation. In rat models of PAH, a sotatercept-csrk analog reduced inflammation and inhibited proliferation of endothelial and smooth muscle cells in diseased vasculature. These cellular changes were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Caution patients that sotatercept-csrk may raise Hgb to levels that increase their risk of thrombotic events. Inform patients that Hgb levels will be assessed before at least the first 5 doses and then periodically, as dosage may need to be adjusted.
Caution patients that sotatercept-csrk may cause platelet count to decrease, which if severe could cause bleeding. Inform patients that platelet count will be assessed before at least the first 5 doses and then periodically, as dosage may need to be adjusted.
Inform patients of the possibility of serious bleeding, which is more likely to occur if they have low platelet counts or while on prostacyclin background therapy and/or antithrombotic agents. Advise patients to notify their healthcare provider about signs and symptoms of bleeding.
Advise females of reproductive potential of the potential risk to a fetus. Advise such females to use effective contraception while receiving sotatercept-csrk and for at least 4 months after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with sotatercept-csrk. Report exposure during pregnancy or lactation to the Merck Sharp & Dohme, LLC Adverse Event reporting line at 1-877-888-4231.
Advise females not to breastfeed during treatment with sotatercept-csrk and for 4 months after the final dose.
Advise females and males of reproductive potential that sotatercept-csrk may impair fertility.
Review the instructions for use with the patient or caregiver step-by-step. Provide training to the patient or caregiver regarding proper preparation and administration of sotatercept-csrk and decide whether a patient or caregiver is capable of preparing and administering sotatercept-csrk independently.
Make sure the patient or caregiver can do the following correctly: reconstitute the medicine, measure the correct amount of medicine according to the patient’s prescription, select and prepare a proper injection site, and inject the medicine subcutaneously.
Inform patients to call their healthcare provider for further instruction if they take more than or less than the correct dose. Advise them about signs/symptoms to monitor for and what to do if any of these signs/symptoms should occur. Advise them that additional laboratory tests may be required prior to the next scheduled dose to ensure that the next dose can be safely administered.
Instruct the patient that if they miss the prescribed dose of sotatercept-csrk, they should take it within 3 days and maintain the original schedule for the next dose. If not taken within 3 days, instruct them to call their healthcare provider for guidance.

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.