WINREVAIR

WINREVAIR
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D. [2]

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Black Box Warning

Warning: Thromboembolic events See full prescribing information for complete Boxed Warning. *Erythrocytosis: If severe, may increase the risk of thromboembolic events and hyperviscosity syndrome. 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 Serious Bleeding: Serious bleeding events were reported and were more likely with concomitant prostacyclin and/or antithrombotic agents, or with low platelet counts. Do not administer WINREVAIR if the patient is experiencing serious bleeding. Embryo-Fetal Toxicity Impaired Fertility

Overview

WINREVAIR is an activin signaling inhibitor that is FDA approved 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, epistaxis, rash, telangiectasia, diarrhea, dizziness, and erythema.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

WINREVAIR™ is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events. 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

• 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 due to increased hemoglobin (Hgb) and decreased platelets may be necessary. Check Hgb and platelets before each dose for the first 5 doses, or longer if values are unstable, and monitor periodically thereafter. See full prescribing information for preparation and administration instructions.

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding WINREVAIR FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

There is limited information regarding WINREVAIR Contraindications in the drug label.

Warnings

Warning: Thromboembolic events See full prescribing information for complete Boxed Warning. *Erythrocytosis: If severe, may increase the risk of thromboembolic events and hyperviscosity syndrome. 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 Serious Bleeding: Serious bleeding events were reported and were more likely with concomitant prostacyclin and/or antithrombotic agents, or with low platelet counts. Do not administer WINREVAIR if the patient is experiencing serious bleeding. Embryo-Fetal Toxicity Impaired Fertility

• Erythrocytosis

Risk: May increase hemoglobin (Hgb), leading to severe erythrocytosis and risks of *thromboembolic events or hyperviscosity syndrome. Incidence: Moderate Hgb elevations (>2 g/dL above ULN) occurred in 15% of patients. Monitoring: Check Hgb before each dose for the first five doses, or longer if unstable, and periodically thereafter.

• Severe Thrombocytopenia

Risk: May decrease platelet count, increasing bleeding risk. Incidence: Severe thrombocytopenia (<50,000/mm³) occurred in 3% of patients, especially those on prostacyclin infusion. Monitoring: Do not start if platelet count is <50,000/mm³. Monitor platelets before each dose for the first five doses, or longer if unstable, and periodically thereafter.

• Serious Bleeding

Risk: Reported in 4% of patients on WINREVAIR, compared to 1% on placebo. Factors: More likely in patients on prostacyclin therapy, antithrombotic agents, or with low platelet counts. Management: Advise patients on blood loss signs, evaluate and treat accordingly, and avoid use during serious bleeding.

• Embryo-Fetal Toxicity

Risk: May cause fetal harm based on animal studies, leading to embryo-fetal mortality and developmental issues. Guidance: Advise pregnant women of risks and females of reproductive potential to use effective contraception during and for 4 months after treatment.

• Impaired Fertility

Risk: May impair female and male fertility based on animal studies. Guidance: Inform patients about potential fertility effects.

Adverse Reactions

Clinical Trials Experience

• Erythrocytosis
• Severe Thrombocytopenia
• Serious Bleeding
• Embryo-Fetal Toxicity
• Impaired Fertility

STELLAR Trial: 323 patients were randomized 1:1 to receive WINREVAIR or placebo with standard care. Dosage: Initial 0.3 mg/kg, increased to 0.7 mg/kg every 3 weeks for 24 weeks. Duration: Median treatment duration was 273 days (placebo) and 313 days (WINREVAIR). Common Adverse Reactions: Headache: 24.5% (WINREVAIR) vs. 17.5% (placebo) Epistaxis (nosebleeds): 22.1% (WINREVAIR) vs. 1.9% (placebo) Rash: 20.2% (WINREVAIR) vs. 8.1% (placebo) Telangiectasia: 16.6% (WINREVAIR) vs. 4.4% (placebo) Diarrhea: 15.3% (WINREVAIR) vs. 10.0% (placebo) Dizziness: 14.7% (WINREVAIR) vs. 6.2% (placebo) Erythema: 13.5% (WINREVAIR) vs. 3.1% (placebo) Specific Findings: Increased Hemoglobin: Managed by dose delays (10%), reductions (6%), or both (5%). Hgb shifts from normal to above normal in 53% (WINREVAIR) vs. 14% (placebo). Thrombocytopenia: Managed by dose delays (2%), reductions (2%), or both (2%). Platelet count shifts from normal to below normal in 25% (WINREVAIR) vs. 16% (placebo). Telangiectasia: Median onset at 47.1 weeks. Increased Blood Pressure: Mean increase of 2.2/4.9 mmHg (WINREVAIR) vs. decrease of -1.6/-0.6 mmHg (placebo). Treatment Discontinuation: 4% (WINREVAIR) vs. 7% (placebo). No specific adverse reaction >1% causing more frequent discontinuation in WINREVAIR. Long-term Safety Data: PULSAR Study: Long-term safety profile similar to STELLAR. Mean exposure duration of 151 weeks (maximum 218 weeks) for 104 patients on WINREVAIR 0.3 mg/kg or 0.7 mg/kg.

Postmarketing Experience

There is limited information regarding WINREVAIR Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding WINREVAIR Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Based on findings in animal reproduction studies, WINREVAIR 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
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of WINREVAIR in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of WINREVAIR during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of WINREVAIR in women who are nursing.

Pediatric Use

The safety and effectiveness of WINREVAIR have not been established in patients less than 18 years of age.

Geriatic Use

A total of 81 patients ≥65 years of age participated in clinical studies for PAH, of which 52 (16%) were treated with WINREVAIR. No differences in efficacy of WINREVAIR 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 WINREVAIR subgroup, but with no imbalance between age subgroups for any specific bleeding event. Clinical studies of WINREVAIR did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger patients.

Gender

There is no FDA guidance on the use of WINREVAIR with respect to specific gender populations.

Race

There is no FDA guidance on the use of WINREVAIR with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of WINREVAIR in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of WINREVAIR in patients with hepatic impairment.

Females of Reproductive Potential and Males

Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.

Immunocompromised Patients

There is no FDA guidance one the use of WINREVAIR in patients who are immunocompromised.

Administration and Monitoring

Administration

WINREVAIR is administered via subcutaneous injection every three weeks based on patient body weight, with a starting dose of 0.3 mg/kg.

• Before the first dose, obtain the patient's hemoglobin and platelet count. Do not initiate treatment if the platelet count is below 50,000/mm³.

The injection volume is calculated as:

• Injection Volume (mL) =Weight (kg)× 0.3mg/kg50mg/mL
• Dosage Modifications Due to Hemoglobin Increase or Platelet Count Decrease

Monitoring: Check hemoglobin (Hgb) and platelet count before each dose for the first five doses, or longer if values are unstable. Afterward, monitor Hgb and platelet count periodically. Treatment Delay Criteria: Delay treatment for at least three weeks if any of the following occur: Hgb increases by more than 2.0 g/dL from the previous dose and is above the upper limit of normal (ULN). Hgb increases by more than 4.0 g/dL from baseline. Hgb increases by more than 2.0 g/dL above ULN. Platelet count decreases to less than 50,000/mm³ (<50 x 10^9/L). Reinitiation of Treatment: Recheck Hgb and platelet count before reinitiating treatment. For treatment delays lasting more than nine weeks, restart treatment at 0.3 mg/kg and escalate to 0.7 mg/kg after verifying acceptable Hgb and platelet count.

Monitoring

Preparation and Administration

• Monitoring:

Administration requires monitoring of hemoglobin (Hgb) and platelet count. Guidance: WINREVAIR should be administered under healthcare professional guidance. Patients and caregivers can administer WINREVAIR if trained and monitored by a healthcare provider (HCP). Verification: Confirm at subsequent visits that patients or caregivers can correctly prepare and administer WINREVAIR, especially if the dose changes or a different kit is required. Instructions: Refer to the Instructions for Use (IFU) for detailed preparation and administration steps. Selecting the Appropriate Product Kit Use a 2-vial kit instead of two individual 1-vial kits if a patient’s body weight requires two 45 mg or two 60 mg vials. The 2-vial kit includes instructions to combine the contents, aiding in dosage measurement and reducing the need for multiple injections. Reconstitution Instructions: Preparation: Remove the injection kit from the refrigerator and let it reach room temperature (about 15 minutes). Attach the vial adapter to the vial. Inspect the pre-filled syringe and Sterile Water for Injection for damage, leaks, or particles. Mixing: Snap off the syringe cap and attach it to the vial adapter. Inject all Sterile Water for Injection into the lyophilized powder vial (final concentration: 50 mg/mL). Gently swirl the vial to reconstitute. Do not shake. Let the vial stand for up to 3 minutes for bubbles to disappear. Inspect the solution for particulates and discoloration before use. The solution should be clear to opalescent and colorless to slightly brownish-yellow, without clumps or powder. If using a 2-vial presentation, repeat these steps for the second vial. Usage: Use the reconstituted solution within 4 hours. Discard any unused solution. Syringe Preparation: Drawing the Solution: Turn the syringe and vial upside-down and withdraw the appropriate volume based on patient weight. If using two vials, transfer the full contents of the first vial to the second vial and withdraw the required amount. Remove excess drug product and air from the syringe if necessary. Administration Instructions: Injection: Administer WINREVAIR subcutaneously.

• Select an injection site on the abdomen (at least 2 inches from the navel), upper thigh, or upper arm, and clean it with an alcohol wipe.

Rotate the injection site for each administration to avoid areas that are scarred, tender, or bruised.

• Patients or caregivers should use only the abdomen and upper thigh for injection.

IV Compatibility

There is limited information regarding the compatibility of WINREVAIR and IV administrations.

Overdosage

In healthy volunteers, WINREVAIR dosed at 1 mg/kg resulted in increases in Hgb associated with hypertension; both improved with phlebotomy. In the event of overdose, monitor closely for increases in Hgb and blood pressure, and provide supportive care as appropriate. WINREVAIR is not dialyzable.

Pharmacology

There is limited information regarding WINREVAIR Pharmacology in the drug label.

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.

Structure

Sotatercept-csrk is a homodimeric recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA (ActRIIA) linked to the human IgG1 Fc domain. The molecular weight based on the amino acid sequence of sotatercept-csrk is approximately 78 kDa as a homodimer.

Sotatercept-csrk for injection is a sterile, preservative-free, white to off-white lyophilized cake or powder appearance in single-dose vials for subcutaneous administration after reconstitution.

Each 45 mg single-dose vial provides 45 mg of sotatercept-csrk and citric acid monohydrate (0.40 mg), polysorbate 80 (0.18 mg), sodium citrate (1.84 mg), and sucrose (72 mg) at pH 5.8. After reconstitution with 1 mL Sterile Water for Injection, the resulting concentration is 50 mg/mL of sotatercept-csrk and the nominal deliverable volume is 0.9 mL.

Each 60 mg single-dose vial provides 60 mg of sotatercept-csrk and citric acid monohydrate (0.53 mg), polysorbate 80 (0.24 mg), sodium citrate (2.45 mg), and sucrose (96 mg) at pH 5.8. After reconstitution with 1.3 mL Sterile Water for Injection, the resulting concentration is 50 mg/mL of sotatercept-csrk and the nominal deliverable volume is 1.2 mL.

Pharmacodynamics

• PVR:

A statistically significantly greater decrease from baseline in PVR was observed in the WINREVAIR group compared to the placebo group in the Phase 3 STELLAR study. The median treatment difference in PVR between sotatercept-csrk and placebo was -235 dynes*sec/cm5 (95% CI: -288, -181; p<0.001). Sotatercept-csrk steady state exposure at 0.7 mg/kg dose was associated with near maximal reduction in PVR based on exposure-response analysis.

• NT-proBNP:

A statistically significantly greater decrease from baseline in NT-proBNP was observed in the WINREVAIR group compared to the placebo group in the Phase 3 STELLAR study. The median treatment difference in NT-proBNP between the sotatercept-csrk and placebo was -442 pg/mL (95% CI: -574, -310; p<0.001).

Pharmacokinetics

• Steady State and Accumulation

Dosage: 0.7 mg/kg every three weeks. Steady State: Achieved after ~15 weeks. AUC: 172 mcg×d/mL (34.2% CV). Cmax: 9.7 mcg/mL (30% CV). Accumulation Ratio: AUC approximately 2.2 times. Absorption Bioavailability: Approximately 66% following subcutaneous administration. Tmax: Median time to peak concentration is ~7 days (range 2-8 days). Distribution Volume of Distribution: Estimated at 5.3 L (27.3% CV) at steady state. Elimination Half-life: Approximately 24 days. Clearance: Approximately 0.18 L/day. Metabolism Pathways: Expected to be metabolized into small peptides by catabolic pathways. Specific Populations No Significant Differences: Observed in PK based on age (18-81 years), sex, race, renal impairment (mild to moderate), or end-stage kidney disease with dialysis. Severe Renal Impairment: Not expected to impact PK. Hepatic Impairment: PK effects not studied. Dialysis: Sotatercept-csrk is not dialyzable. Body Weight Effect: Clearance (CL) and central volume of distribution (Vc) increase with body weight, but this is not clinically significant with weight-based dosing

Nonclinical Toxicology

There is limited information regarding WINREVAIR Nonclinical Toxicology in the drug label.

Clinical Studies

Trial Overview STELLAR Trial (NCT04576988): Double-blind, placebo-controlled, multicenter trial. Participants: 323 adult PAH patients (WHO Group 1 FC II or III). Randomization: 1:1 to WINREVAIR (target dose 0.7 mg/kg) or placebo. Administration: Subcutaneously once every 3 weeks. Participant Characteristics Demographics: 79% female; median age 48 years; median body weight 68 kg. Ethnicity: 89% White/Caucasian, with varied representation of other ethnicities. Etiologies: Predominantly idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (15%). Exclusions: Patients with certain PAH etiologies were excluded. Background Therapy: Most participants were on three (61%) or two (35%) background drugs for PAH, with 40% receiving prostacyclin infusions. Baseline Functional Class: WHO FC II (49%) or III (51%). Primary Efficacy Endpoint Endpoint: Change from baseline at Week 24 in 6-Minute Walk Distance (6 MWD). Results: WINREVAIR group showed a placebo-adjusted median increase of 41 meters (95% CI: 28, 54 p<0.001). Imputation for Missing Data Subjects Who Died: Change from baseline in 6 MWD at Week 24 imputed to -2000 meters. Subjects with Missing Data (Non-fatal Clinical Worsening): Change imputed to -1000 meters. Improvement in WHO Functional Class Outcome: Improvement from baseline by at least 1 WHO FC at Week 24. Results: Treatment with WINREVAIR resulted in improvement in 29% of patients compared to 14% with placebo (p<0.001). Death from Any Cause or PAH Clinical Worsening Events

How Supplied

WINREVAIR (sotatercept-csrk) for injection is a white to off-white lyophilized cake or powder appearance supplied in single-dose vials (45 mg or 60 mg) packaged in kits that contain one measuring syringe and one safety needle. Each kit also contains Sterile Water for Injection in prefilled syringes necessary to reconstitute the product

Storage

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. The kit should remain in the refrigerator until ready for use. The unused kit can be out of the refrigerator for (up to 25°C/77°F) up to 24 hours. For additional information on temperature excursions, call Merck Sharp & Dohme LLC at 1-800-672-6372.

WINREVAIR™ (sotatercept-csrk) for injection

60 mg/vial

Package contains 2 Vials

Dose based on patient weight

For Subcutaneous Use Only Must be reconstituted with diluent provided prior to administration

2 Single-Dose Vials Discard unused portion

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding WINREVAIR Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-WINREVAIR interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding WINREVAIR Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding WINREVAIR Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.