Sotatercept-csrk
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Sotatercept-csrk is an activin signalling inhibitor that is FDA approved for the treatment of 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.. Common adverse reactions include *Erythrocytosis
- Severe Thrombocytopenia
- Serious Bleeding
- Embryo-Fetal Toxicity
- Impaired Fertility.
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.
- Recommended Starting Dosage
WINREVAIR is administered once every 3 weeks by subcutaneous injection according to patient body weight. The starting dose of WINREVAIR is 0.3 mg/kg.
Obtain hemoglobin (Hgb) and platelet count prior to the first dose of WINREVAIR. Do not initiate treatment if platelet count is <50,000/mm3 (<50 x 109/L)
Injection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.3 mg/kg) ÷ 50 mg/mL = 0.42 mL, rounds to 0.4 mL.
- Recommended Target Dosage
After verifying acceptable Hgb and platelet count, increase to the target dose of 0.7 mg/kg. Continue treatment at 0.7 mg/kg every 3 weeks unless dosage adjustments are required Injection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.7 mg/kg) ÷ 50 mg/mL = 0.98 mL, rounds to 1 mL
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sotatercept-csrk in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sotatercept-csrk in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sotatercept-csrk FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sotatercept-csrk in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sotatercept-csrk in pediatric patients.
Contraindications
None
Warnings
- Erythrocytosis
WINREVAIR 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 WINREVAIR 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
WINREVAIR 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 WINREVAIR. 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., gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR 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 WINREVAIR if the patient is experiencing serious bleeding
- Embryo-Fetal Toxicity
Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of WINREVAIR 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 area under the curve [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 WINREVAIR and for at least 4 months after the final dose
- Impaired Fertility
Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertilit
Adverse Reactions
Clinical Trials Experience
- Erythrocytosis
- Serious Bleeding
- Severe Thrombocytopenia
- Serious Bleeding
- Embryo-Fetal Toxicity
- Impaired Fertility
Postmarketing Experience
There is limited information regarding Sotatercept-csrk Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Sotatercept-csrk 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. There are no available data on WINREVAIR 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 WINREVAIR 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 area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD), respectively (see Data). 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sotatercept-csrk in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sotatercept-csrk during labor and delivery.
Nursing Mothers
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 WINREVAIR, and for 4 months after the final dose.
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 Sotatercept-csrk with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sotatercept-csrk with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Sotatercept-csrk in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Sotatercept-csrk in patients with hepatic impairment.
Females of Reproductive Potential and Males
- WINREVAIR may cause fetal harm when administered to pregnant women
- Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.
- Contraception:
Advise female patients of reproductive potential to use effective contraception during treatment with WINREVAIR and for at least 4 months after the final dose if treatment is discontinued
- Infertility:
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.
Immunocompromised Patients
There is no FDA guidance one the use of Sotatercept-csrk in patients who are immunocompromised.
Administration and Monitoring
Administration
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.
- Recommended Starting Dosage
WINREVAIR is administered once every 3 weeks by subcutaneous injection according to patient body weight. The starting dose of WINREVAIR is 0.3 mg/kg.
Obtain hemoglobin (Hgb) and platelet count prior to the first dose of WINREVAIR. Do not initiate treatment if platelet count is <50,000/mm3 (<50 x 109/L)
Injection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.3 mg/kg) ÷ 50 mg/mL = 0.42 mL, rounds to 0.4 mL.
- Recommended Target Dosage
After verifying acceptable Hgb and platelet count, increase to the target dose of 0.7 mg/kg. Continue treatment at 0.7 mg/kg every 3 weeks unless dosage adjustments are required Injection volume should be rounded to the nearest 0.1 mL.
For example: (70 kg x 0.7 mg/kg) ÷ 50 mg/mL = 0.98 mL, rounds to 1 mL
Monitoring
There is limited information regarding Sotatercept-csrk Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Sotatercept-csrk 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 Sotatercept-csrk 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
There is limited information regarding Sotatercept-csrk Structure in the drug label.
Pharmacodynamics
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
Following subcutaneous administration of 0.7 mg/kg WINREVAIR every three weeks to PAH patients, the steady state geometric mean (%CV) area under the time concentration curve (AUC) is 172 mcg×d/mL (34.2%), and peak concentration (Cmax) is 9.7 mcg/mL (30%). Sotatercept-csrk AUC and Cmax increased proportionally with dose. Steady state is achieved after approximately 15 weeks following initiation of multiple dosing. The accumulation ratio of sotatercept-csrk AUC is approximately 2.2.
Nonclinical Toxicology
No carcinogenicity or mutagenicity studies have been conducted with sotatercept-csrk.
In a fertility and early embryonic development study in female rats, sotatercept-csrk was administered SC once weekly at doses of 5, 15, and 50 mg/kg beginning 2 weeks prior to mating and through gestation day 7. At doses ≥15 mg/kg (≥9 fold the MRHD, based on estimated AUC), pregnancy rates were decreased and there were increases in preimplantation and postimplantation loss and reductions in live litter size. Increased estrous cycle duration occurred at 50 mg/kg only (21-fold the MRHD, based on estimated AUC).
In a fertility study in male rats, sotatercept-csrk was administered SC once weekly at doses of 0.3, 3, and 30 mg/kg for 13 weeks (beginning 10 weeks prior to mating). A subset of animals was examined after a 13-week recovery period. At ≥0.3 mg/kg (0.5-fold the MRHD, based on estimated AUC) there were non-reversible histologic changes in the efferent ducts, testes, and epididymides. Reversible decreases in functional fertility endpoints occurred at 30 mg/kg (20-fold the MRHD, based on estimated AUC).
Clinical Studies
Pulmonary Arterial Hypertension: The efficacy of WINREVAIR was evaluated in adult patients with PAH in the STELLAR trial (NCT04576988). STELLAR was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks.
Participants were: 79% female; had a median age of 48 years (range: 18 to 82 years), and median body weight of 68 kg (range 38 to 141 kg); and 89% White/Caucasian, 2% Black/African American, 2% Asian, 0.3% American Indian or Alaska Native, 0.3% Native Hawaiian or Other Pacific Islander, 6% Missing/Other races. The most common PAH etiologies were idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (CTD) (15%). STELLAR excluded patients with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and pulmonary veno occlusive disease. The mean time from PAH diagnosis to screening was 8.8 years. Most participants were receiving either three (61%) or two (35%) background drugs for PAH, and 40% were receiving prostacyclin infusions. Patients had a WHO FC II (49%) or III (51%) at baseline.
The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6 MWD). In the WINREVAIR group, the placebo-adjusted median increase in 6 MWD was 41 meters (95% CI: 28, 54; p<0.001). Figure 1 displays placebo-adjusted changes in 6 MWD at Week 24 in relevant subgroups.
hange from baseline in 6 MWD at Week 24 for subjects who died was imputed to -2000 meters to receive the worst rank. Change from baseline in 6 MWD at Week 24 for subjects who had missing data due to a non-fatal clinical worsening event was imputed to -1000 meters to receive the next-worst rank.
Treatment with WINREVAIR led to an improvement from baseline by at least 1 WHO FC at Week 24 in 29% of patients compared to 14% of patients treated with placebo (p<0.001).
Treatment with WINREVAIR resulted in an 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo.
,These outcomes were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks)
These outcomes were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks).
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.
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.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
- Erythrocytosis:
Caution patients that WINREVAIR 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
- Severe Thrombocytopenia:
Caution patients that WINREVAIR 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
- Serious Bleeding:
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
- Embryo-Fetal Toxicity:
Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving WINREVAIR 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 WINREVAIR
- Lactation:
Advise females not to breastfeed during treatment with WINREVAIR and for 4 months after the final dose
- Females and Males of Reproductive Potential:
Advise females and males of reproductive potential that WINREVAIR may impair fertility.
- Administration by Patient or Caregiver:
Review the IFU with the patient or caregiver step-by-step. Provide training to the patient or caregiver regarding proper preparation and administration of WINREVAIR and decide whether a patient or caregiver is capable of preparing and administering WINREVAIR independently
- 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.
- Incorrect Dose or Missed Dose:
Instruct the patient that if they miss the prescribed dose of WINREVAIR, 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.
Precautions with Alcohol
Alcohol-Sotatercept-csrk interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Winrevair
Look-Alike Drug Names
There is limited information regarding Sotatercept-csrk 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.