Winrevair

Powder: white to off-white powder.
Solvent: clear colourless water for injections.
Winrevair powder and solvent for solution for injection 45 mg: Each vial contains 45 mg of sotatercept. After reconstitution, each mL of solution contains 50 mg sotatercept.
Winrevair powder and solvent for solution for injection 60 mg: Each vial contains 60 mg of sotatercept. After reconstitution, each mL of solution contains 50 mg sotatercept.
Sotatercept is a recombinant homodimeric fusion protein consisting of the extracellular domain of human activin receptor type IIA (ActRIIA) linked to the Fc domain of human IgG1, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Powder: Citric acid monohydrate (E330), Sodium citrate (E331), Polysorbate 80 (E433), Sucrose.
Solvent: Water for injections.

Pharmacotherapeutic group: antihypertensives, antihypertensives for pulmonary arterial hypertension. ATC code: C02KX06.
Pharmacology: Pharmacodynamics: Mechanism of action: Sotatercept is an activin signalling inhibitor with high selectivity for Activin-A, a dimeric glycoprotein which belongs to the transforming growth factor-β (TGF-β) superfamily of ligands. Activin-A binds to the activin receptor type IIA (ActRIIA) regulating key signalling for inflammation, cell proliferation, apoptosis, and tissue homeostasis.
Activin-A levels are increased in PAH patients. Activin binding to ActRIIA promotes proliferative signalling while there is a decrease in anti-proliferative bone morphogenetic protein receptor type II (BMPRII) signalling. The imbalance of ActRIIA-BMPRII signalling underlying PAH results in vascular cell hyperproliferation, causing pathological remodelling of the pulmonary arterial wall, narrowing the arterial lumen, increasing pulmonary vascular resistance, and leads to increased pulmonary artery pressure and right ventricular dysfunction.
Sotatercept consists of a recombinant homodimeric activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, which acts as a ligand trap that scavenges excess Activin-A and other ligands for ActRIIA to inhibit activin signalling. As a result, sotatercept rebalances the pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signalling to modulate vascular proliferation.
Pharmacodynamic effects: A phase 2 clinical study (PULSAR) assessed pulmonary vascular resistance (PVR) in patients with PAH after 24 weeks of treatment with sotatercept. The decrease from baseline in PVR was significantly greater in the sotatercept 0.7 mg/kg and 0.3 mg/kg groups compared with the placebo group. The placebo-adjusted least squares (LS) mean difference from baseline was -269.4 dyn*sec/cm⁵ (95% CI: -365.8, -173.0) for the sotatercept 0.7 mg/kg group and -151.1 dyn*sec/cm⁵ (95% CI: -249.6,-52.6) for the sotatercept 0.3 mg/kg group.
In rat models of PAH, a sotatercept analogue reduced expression of pro-inflammatory markers at the pulmonary arterial wall, reduced leucocyte recruitment, inhibited proliferation of endothelial and smooth muscle cells, and promoted apoptosis in diseased vasculature. These cellular changes were associated with thinner vessel walls, reversed arterial and right ventricular remodelling, and improved haemodynamics.
Clinical efficacy and safety: The efficacy of sotatercept was evaluated in adult patients with PAH in the pivotal STELLAR study. STELLAR was a double-blind, placebo-controlled, multicentre, parallel-group clinical study in which 323 patients with PAH (WHO Group 1 Functional Class II or III) were randomised 1:1 to sotatercept (starting dose 0.3 mg/kg escalated to target dose 0.7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks. Patients continued their treatment assignment in the long-term double-blind treatment period until all patients completed Week 24.
Participants in this study were adults with a median age of 48.0 years (range: 18 to 82 years), of which 16.7% were ≥65 years of age. Median weight was 68.2 kg (range: 38.0 to 141.3 kg); 89.2% of participants were White, and 79.3% were not Hispanic or Latino; and 79.3% were female. The most common PAH aetiologies were idiopathic PAH (58.5%), heritable PAH (18.3%), and PAH associated with connective tissue diseases (14.9%), PAH associated with simple congenital heart disease with repaired systemic-to-pulmonary shunts (5%), or drug or toxin-induced PAH (3.4%). The mean time since PAH diagnosis to screening was 8.76 years.
Most participants were receiving either triple (61.3%) or double (34.7%) background PAH therapy, and more than one-third (39.9%) were receiving prostacyclin infusions. The proportions of participants in WHO FC II was 48.6% and in WHO FC III was 51.4%. The STELLAR study excluded patients diagnosed with HIV-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and PVOD.
The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6MWD). In the sotatercept treatment group, the median of the placebo-adjusted change in 6MWD from baseline at Week 24 was 40.8 meters (95% CI: 27.5, 54.1; p <0.001). The median of the placebo-adjusted changes in 6MWD at Week 24 were also evaluated in subgroups. The treatment effect was consistent across the different subgroups including sex, PAH diagnostic group, background therapy at baseline, prostacyclin infusion therapy at baseline, WHO FC, and baseline PVR.
The secondary endpoints included improvements in multicomponent improvement (MCI), PVR, N-terminal pro-B-type natriuretic peptide (NT-proBNP), WHO FC, time to death or first occurrence of clinical worsening events.
MCI was a pre-defined endpoint measured by the proportion of patients achieving all three of the following criteria at Week 24 relative to baseline: improvement in 6MWD (increase ≥30 m), improvement in NT-proBNP (decrease in NT-proBNP ≥30% or maintenance/achievement of NT-proBNP level <300 ng/L), and improvement in WHO FC or maintenance of WHO FC II.
Disease progression was measured by the time to death or first occurrence of a clinical worsening event. Clinical worsening events included worsening-related listing for lung and/or heart transplant, need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by ≥10%, need for atrial septostomy, hospitalisation for worsening PAH (≥24 hours), or deterioration of PAH (worsened WHO FC and decrease in 6MWD ≥15% with both events occurring at the same time or different times). Clinical worsening events and death were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks).
At Week 24, 38.9% of sotatercept-treated patients showed improvement in MCI versus 10.1% in the placebo group (p <0.001). The median treatment difference in PVR between sotatercept and placebo group was -234.6 dyn*sec/cm⁵ (95% CI: -288.4, -180.8; p <0.001). The median treatment difference in NT-proBNP between the sotatercept and placebo groups was -441.6 pg/mL (95% CI: -573.5, -309.6; p <0.001). Improvement in WHO FC from baseline occurred in 29% of patients in sotatercept versus 13.8% in placebo (p <0.001).
Treatment with sotatercept resulted in an 82% reduction (HR 0.182, 95% CI: 0.075, 0.441; p <0.001) in the occurrence of death or clinical worsening events compared to placebo (see Table 1). The treatment effect of sotatercept versus placebo started by Week 10 and continued for the duration of the study.

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Immunogenicity: At Week 24 in STELLAR, anti-drug antibodies (ADA) were detected in 44/163 (27%) of patients taking sotatercept. Among these 44 patients, 12 tested positive for neutralising antibodies against sotatercept. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
Pharmacokinetics: In patients with PAH, the geometric mean (%Coefficient of variation (CV%)) steady-state AUC and steady-state peak concentration (C_max) at the dose of 0.7 mg/kg every 3 weeks were 171.3 mcg×d/mL (34.2%) and 9.7 mcg/mL (30%), respectively. Sotatercept AUC and C_max increase proportionally with dose. Steady state is achieved after approximately 15 weeks of treatment. The accumulation ratio of sotatercept AUC was approximately 2.2.
Absorption: The subcutaneous (SC) formulation has an absolute bioavailability of approximately 66% based on population pharmacokinetics analysis. The maximum sotatercept concentration is achieved at a median time to peak drug concentration (T_max) of approximately 7 days (range from 2 to 8 days) after multiple dosing every 4 weeks.
Distribution: The central volume of distribution (CV%) of sotatercept is approximately 3.6 L (24.7%). The peripheral volume of distribution (CV%) is approximately 1.7 L (73.3%).
Biotransformation: Sotatercept is catabolised by general protein degradation processes.
Elimination: Sotatercept clearance is approximately 0.18 L/day. The geometric mean terminal half-life (CV%) is approximately 21 days (33.8%).
Specific populations: Age, sex, and ethnic origin: No clinically significant differences in sotatercept pharmacokinetics (PK) were observed based on age (18 to 81 years of age), sex, or ethnic origin (82.9% Caucasian, 3.1% Black, 7.1% Asian, and 6.9% other).
Body weight: The clearance and central volume of distribution of sotatercept increase with increasing body weight. The recommended weight-based dosing regimen results in consistent sotatercept exposures.
Renal impairment: Sotatercept pharmacokinetics was comparable in PAH patients with mild to moderate renal impairment (eGFR ranging from 30 to 89 mL/min/1.73 m²) to those with normal renal function (eGFR ≥90 mL/min/1.73 m²). Additionally, sotatercept PK is comparable between non-PAH end-stage renal disease (ESRD) patients and patients with normal renal function. Sotatercept is not dialysable during haemodialysis. Sotatercept has not been studied in PAH patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).
Hepatic impairment: Sotatercept has not been studied in PAH patients with hepatic impairment (Child-Pugh Classification A to C). Hepatic impairment is not expected to influence sotatercept metabolism since sotatercept is metabolised via cellular catabolism.
Toxicology: Preclinical safety data: No carcinogenicity or mutagenicity studies have been conducted with sotatercept.
Repeat dose toxicity: In rats and monkeys, the longest SC toxicity studies were 3 months and 9 months in duration, respectively. In rats, adverse findings included efferent duct/testicular degeneration, adrenal gland congestion/necrosis, and membranoproliferative glomerulonephritis and tubulointerstitial nephritis in the kidneys. Kidney changes were not reversible following a 1-month recovery period. In monkeys, adverse changes included increased interstitial matrix at the corticomedullary junction, decreased glomerular tuft size, glomerulonephritis and tubulointerstitial nephritis in the kidney. Kidney changes in monkeys partially resolved following a 3-month recovery period. At the no observed adverse effect level (NOAEL) in rats and monkeys, sotatercept exposures were ≤2-times the clinical exposure at the maximum recommended human dose (MRHD). Other findings that occurred at clinical exposure margins in monkeys included hepatic inflammatory infiltrates, lymphoid depletion in spleen, and inflammatory infiltrates in the choroid plexus.
Reproductive toxicity: In a female fertility study, oestrous cycle duration was increased, pregnancy rates were decreased, there were increases in pre-implantation and post-implantation loss and reductions in live litter size. At the NOAEL for female fertility endpoints, sotatercept exposure was 2-times the clinical AUC at the MRHD.
In males, there were non-reversible histologic changes in the efferent ducts, testes, and epididymides. Histomorphologic changes in rat testes correlated to decreased fertility index that reversed during the 13-week treatment-free period. A NOAEL for testicular histologic changes was not established and the NOAEL for male fertility functional changes provides a systemic exposure 2-times the clinical exposure at the MRHD.
In embryo-foetal developmental toxicity studies, effects in rats and rabbits included reductions in numbers of live foetuses and foetal body weights, delays in ossification, and increases in resorptions and post-implantation losses. In rats only, there were also skeletal variations (increased number of supernumerary ribs and changes in the number of thoracic or lumbar vertebrae). At the NOAEL in rats and rabbits, sotatercept exposures were 2-times and 0.4-times, respectively, the clinical exposure at the MRHD.
In a pre- and postnatal development study in rats, no sotatercept related adverse effects were observed in first filial generation (F1) pups from dams dosed during gestation at estimated exposures up to 2-times the MRHD. In F1 pups from dams dosed during lactation, decreases in pup weight correlated with delays in sexual maturation. The NOAEL for effects on growth and maturation in pups provides a systemic exposure 0.6-times the clinical exposure at the MRHD.

Winrevair, in combination with other pulmonary arterial hypertension (PAH) therapies, is indicated for the treatment of PAH in adult patients with WHO Functional Class (FC) II to III, to improve exercise capacity (see Pharmacology: Pharmacodynamics under Actions).

Winrevair treatment should only be initiated and monitored by a physician experienced in the diagnosis and treatment of PAH.
Posology: Winrevair is administered once every 3 weeks as a single subcutaneous injection according to patient weight.
Recommended starting dose: Haemoglobin (Hgb) and platelet count should be obtained prior to the first dose (see Precautions). Initiation of treatment is contraindicated if platelet count is consistently <50 x 10⁹/L (see Contraindications).
Treatment is initiated with a single dose of 0.3 mg/kg (see Table 2).

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Recommended target dose: Three weeks after a single starting dose of 0.3 mg/kg, the dose should be escalated to the recommended target dose of 0.7 mg/kg after verifying acceptable Hgb and platelet count (see Dose adjustments due to increase in haemoglobin or decreased platelet count as follows). Treatment should be continued at 0.7 mg/kg every 3 weeks unless dose adjustments are required. (See Table 3.)

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Dose adjustments due to increase in haemoglobin or decreased platelet count: Hgb and platelet count should be monitored for the first 5 doses, or longer if values are unstable. Thereafter, Hgb and platelet count should be verified every 3 to 6 months and the dose adjusted if necessary (see Precautions and Adverse Reactions).
Treatment should be delayed for 3 weeks (i.e., one dose delay) if any of the following occur: Hgb increases >1.24 mmol/L (2 g/dL) from the previous dose and is above the ULN; Hgb increases >2.48 mmol/L (4 g/dL) from baseline; Hgb increases >1.24 mmol/L (2 g/dL) above ULN; Platelet count decreases <50 x 10⁹/L.
Hgb and platelet count should be obtained again before reinitiating treatment.
For treatment delays lasting >9 weeks, treatment should be restarted at 0.3 mg/kg, and the dose should be escalated to 0.7 mg/kg after verifying acceptable Hgb and platelet count.
For treatment delays lasting >9 weeks due to platelet counts consistently <50 x 10⁹/L, the physician should carry out a benefit/risk re-evaluation for the patient before reinitiating treatment.
Missed dose: If a dose is missed, administer as soon as possible. If the missed dose is not taken within 3 days of the scheduled date, adjust the schedule to maintain 3-week dosing intervals.
Elderly: No dose adjustment is required in elderly patients ≥65 years old (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is required based on renal impairment (see Pharmacology: Pharmacokinetics under Actions). Sotatercept has not been studied in PAH patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²).
Hepatic impairment: No dose adjustment is required based on hepatic impairment (Child-Pugh Classification A to C). Sotatercept has not been studied in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of Winrevair in children and adolescents below 18 years of age have not yet been established. No data are available (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Method of administration: Winrevair is for single use only.
It should be reconstituted before use. The reconstituted medicinal product is a clear to opalescent and colourless to slightly brownish-yellow solution.
Winrevair should be administered by subcutaneous injection in the abdomen (at least 5 cm away from navel), upper arm, or upper thigh. It should not be injected into sites that are scarred, tender, or bruised. The same injection site should not be used on two consecutive injections.
Winrevair powder and solvent for solution for injection is intended for use under the guidance of a healthcare professional (HCP). Patients and caregivers may administer the medicinal product when considered appropriate and when they receive training from a HCP in how to reconstitute, prepare, measure and inject Winrevair powder and solvent for solution for injection. A HCP should confirm at a subsequent visit, soon after training, that the patient or caregiver can perform these steps correctly. A HCP should also consider reconfirming the patient's or caregiver's administration technique if the dose is adjusted, if the patient requires a different kit, if the patient develops erythrocytosis (see Precautions), or at any time at the discretion of the HCP.
Refer to Special precautions for disposal and other handling under Cautions for Usage for detailed instructions on the proper preparation and administration of Winrevair.

In a phase 1 healthy volunteer study, one participant dosed at 1 mg/kg of sotatercept experienced increased Hgb associated with symptomatic hypertension that improved with phlebotomy.
In the event of overdose in a patient with PAH, increases in Hgb and blood pressure should be closely monitored, and supportive care should be provided as appropriate (see Dosage & Administration and Precautions). Sotatercept is not dialysable during haemodialysis.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Patients with platelet counts consistently <50 x 10⁹/L before initiating treatment.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Erythrocytosis: Increases in Hgb have been observed in patients during treatment with sotatercept. Severe erythrocytosis may increase the risk of thromboembolic events and hyperviscosity syndrome. Use caution in patients with erythrocytosis who are at increased risk of thromboembolic events. Hgb should be monitored before each dose for the first 5 doses, or longer if values are unstable, and every 3 to 6 months thereafter to determine if dose adjustments are required (see Dosage & Administration and Adverse Reactions). If a patient develops erythrocytosis, HCP should consider re-evaluating the patient's or caregiver's administration technique.
Severe thrombocytopenia: Decreased platelet count has been observed in some patients taking sotatercept including severe thrombocytopenia (platelet count <50 x 10⁹/L). Thrombocytopenia was reported more frequently in patients also receiving prostacyclin infusion (21.5%) compared to patients not receiving prostacyclin infusion (3.1%) (see Adverse Reactions). Severe thrombocytopenia may increase the risk of bleeding events. Platelet count should be monitored before each dose for the first 5 doses, or longer if values are unstable, and every 3 to 6 months thereafter to determine whether dose adjustments are required (see Dosage & Administration).
Serious bleeding: In clinical studies, serious bleeding events (including gastrointestinal, intracranial haemorrhage) have been observed in 4.3% of patients during treatment with sotatercept (see Adverse Reactions).
Patients with serious bleeding events were more likely to be on prostacyclin background therapy and/or antithrombotic agents, have low platelet count, or be 65 years of age or older. Patients should be advised about any signs and symptoms of blood loss. A physician should evaluate and treat bleeding events accordingly. Sotatercept should not be administered if the patient is experiencing a serious bleeding event.
Limitation of the clinical data: The clinical studies did not include participants with human immunodeficiency virus (HIV)-, portal hypertension-, schistosomiasis-, or pulmonary veno occlusive disease (PVOD)-associated PAH.
Excipients with known effect: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium free'.
This medicinal product contains 0.20 mg of polysorbate 80 in each mL of reconstituted solution. Polysorbates may cause allergic reactions.
Effects on ability to drive and use machines: Sotatercept has no or negligible influence on the ability to drive and use machines.

Women of childbearing potential: Pregnancy testing is recommended for women of childbearing potential before starting treatment. Women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose if treatment is discontinued (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Pregnancy: There are no data from the use of sotatercept in pregnant women. Studies in animals have shown reproductive toxicity (increases in post-implantation losses, reduction in foetal body weights, and delays in ossification) (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Winrevair is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding: It is unknown whether sotatercept/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment and for 4 months after the last dose of treatment.
Fertility: Based on findings in animals, sotatercept may impair female and male fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of safety profile: The most frequently reported adverse reactions were headache (24.5%), epistaxis (22.1%), telangiectasia (16.6%), diarrhoea (15.3%), dizziness (14.7%), rash (12.3%), and thrombocytopenia (10.4%).
The most frequently reported serious adverse reactions were thrombocytopenia (<1%) and epistaxis (<1%).
The most common adverse reactions leading to discontinuation were epistaxis and telangiectasia.
Tabulated list of adverse reactions: The safety of sotatercept was evaluated in the pivotal study STELLAR, a placebo-controlled study of 163 patients with PAH treated with sotatercept (see Pharmacology: Pharmacodynamics under Actions). The median duration of treatment with sotatercept was 313 days.
The adverse reactions reported with sotatercept are listed in the table as follows by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), and very rare (<1/10 000). (See Table 4.)

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Description of selected adverse reactions: Increased haemoglobin: In STELLAR, adverse reactions of increased Hgb ('haemoglobin increased' and 'polycythaemia') were reported in 8.6% of patients taking sotatercept. Based on laboratory data, moderate elevations in Hgb (>1.24 mmol/L (2 g/dL) above ULN) occurred in 15.3% of patients taking sotatercept. Increases in Hgb were managed by dose adjustments (see Dosage & Administration and Precautions).
Thrombocytopenia: Thrombocytopenia ('thrombocytopenia' and 'platelet count decreased') was reported in 10.4% of patients taking sotatercept. Severe reduction in platelet count <50 x 10⁹/L occurred in 2.5% of patients taking sotatercept. Thrombocytopenia was reported more frequently in patients also receiving prostacyclin infusion (21.5%) compared to patients not receiving prostacyclin infusion (3.1%). Thrombocytopenia was managed by dose adjustments (see Dosage & Administration and Precautions).
Telangiectasia: Telangiectasia was observed in 16.6% of patients taking sotatercept. The median time to onset was 18.6 weeks. Discontinuations of treatment due to telangiectasia were 1% in the sotatercept group.
Increased blood pressure: Increased blood pressure was reported in 4.3% of patients taking sotatercept. In patients taking sotatercept, mean systolic blood pressure increased from baseline by 2.2 mmHg and diastolic blood pressure increased by 4.9 mmHg at 24 weeks.
Elderly: 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 subgroup (52% vs 31.9% in patients <65-year-old); however, there was no notable imbalance between age categories for any specific bleeding event. Serious bleeding occurred in 3.6% of patients <65-year-old and in 8.0% of patients ≥65-year-old taking sotatercept.
Long-term safety data: Long-term safety data are available from pooled phase 2 and phase 3 clinical studies (n=431). The median duration of exposure was 657 days. The safety profile was generally similar to that observed in the pivotal STELLAR study.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

No interaction studies have been performed.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned as follows.
Special precautions for disposal and other handling: Selecting the appropriate product kit: If a patient's weight requires the use of two 45 mg or two 60 mg vials, a 2-vial kit should be used instead of two 1-vial kit to eliminate the need for multiple injections.
Reconstitution and administration instructions: Winrevair powder and solvent for solution for injection should be reconstituted before use and administered as a single injection according to patient weight (see Dosage & Administration).
See the separate Instructions for Use under Cautions for Usage for detailed step by step instructions on how to prepare and administer the medicinal product. An overview of the reconstitution and administration instructions is provided as follows.
Reconstitution: Remove the kit from the refrigerator and wait 15 minutes to allow the prefilled syringe(s) and medicinal product to come to room temperature prior to preparation.
Check the vial to ensure the medicinal product is not expired. The powder should be white to off-white and may look like a whole or broken up cake.
Remove the lid from the vial containing the powder and swab the rubber stopper with an alcohol wipe.
Attach the vial adaptor to the vial.
Visually inspect the prefilled syringe for any damage or leaks and the sterile water inside to ensure there are no visible particles.
Break off the cap of the prefilled syringe and attach the syringe to the vial adaptor.
Inject all of the sterile water from the attached syringe into the vial containing the powder: The prefilled syringe provided with the vial 45 mg contains 1 mL of sterile water; The prefilled syringe provided with the vial 60 mg contains 1.3 mL of sterile water.
After reconstitution, the 45 mg vial can only provide up to a dose of 0.9 mL of medicinal product and the 60 mg vial can only provide up to a dose of 1.2 mL of medicinal product. The final concentration after reconstitution is 50 mg/mL.
Gently swirl the vial to reconstitute the medicinal product. Do not shake or vigorously agitate.
Allow the vial to stand for up to 3 minutes to allow bubbles to disappear.
Visually inspect the reconstituted solution. When properly mixed, the reconstituted solution should be clear to opalescent and colourless to slightly brownish-yellow, and should not have clumps or powder.
Unscrew the syringe from the vial adaptor and discard the emptied syringe into a sharps container.
If prescribed a 2-vial kit, repeat the steps within this section to prepare the second vial.
Use the reconstituted solution as soon as possible, but no later than 4 hours after reconstitution.
Dosing syringe preparation: Before preparing the dosing syringe, visually inspect the reconstituted solution. The reconstituted solution should be clear to opalescent and colourless to slightly brownish-yellow, and should not have clumps or powder.
Swab the vial adaptor with an alcohol wipe.
Remove the dosing syringe from its packaging and attach the syringe to the vial adaptor.
Turn the syringe and vial upside-down and withdraw the appropriate volume for injection, based on the patient's weight.
If the dose amount requires the use of two vials, withdraw the entire contents of the first vial and slowly transfer the entire contents into the second vial, to ensure dose accuracy.
Turn the syringe and vial upside-down and withdraw the required amount of medicinal product.
If necessary, push the plunger in to remove excess medicinal product or air from the syringe.
Remove the syringe from the vial adaptor and attach the needle.
Administration: Winrevair is to be administered as a single subcutaneous injection.
Select the injection site on the abdomen (at least 5 cm away from navel), upper thigh, or upper arm and swab with an alcohol wipe. Select a new site for each injection that is not scarred, tender, or bruised.
For administration by the patient or caregiver, train them to inject only in the abdomen or upper thigh (see Instructions for Use as follows).
Perform subcutaneous injection.
Discard the emptied syringe into a sharps container. Do not reuse the syringe.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
See Precautions for instructions on the traceability of biological medicinal products.
Instructions for Use: Any patient or caregiver who is to prepare and inject Winrevair must first be trained and deemed capable of independent administration of Winrevair by a healthcare professional.
1. Check Winrevair product and expiry date.
Remove the Winrevair kit from the refrigerator.
Check the expiry date and look for any signs of damage on the kit or in the supplies. If expired or damaged, do not use. Patients must be advised to talk to the doctor or pharmacist immediately to get a new kit.
Check that the medicine is what the doctor prescribed.
2. Let the kit come to room temperature, gather supplies, and wash hands.
Wait 15 minutes to allow the kit to warm to room temperature. Cold medicine is more painful to inject.
Along with the kit, gather these items and find a clean, flat surface where the dose will be prepared and injected: Sharps disposal container; Gauze, cotton ball or bandage.
Wash hands with soap and water.
Mix powdered medicine into liquid form: Start with the top tray (use items from the top tray).
3. Remove vial, prefilled syringe, and vial adaptor from the kit.
4a. Check the medicine and the vial.
Check the vial label to confirm the medicine is not expired.
Visually inspect the medicine powder. It should be white to off-white and may look like a whole or broken up cake. Do not use if expired, damaged, or if there are particles in it.
4b. Remove plastic cap and clean the vial.
Flip off the plastic cap and clean the rubber stopper on top of the vial with an alcohol wipe. Do not use if vial cap is missing. Do not touch the cleaned rubber stopper.
Set vial aside on a clean, flat surface.
5a. Align vial adaptor to vial.
Peel open the vial adaptor package and remove it from its package.
Hold the blue neck of the adaptor and align the vial adaptor on top of the vial. Do not touch the inside of the vial adaptor to keep it clean and avoid sharps.
To attach the vial adaptor: Hold the blue neck of vial adaptor. Do not hold bottom of the adaptor.
5b. Attach vial adaptor to vial.
Hold the vial with one hand. Push the vial adaptor down firmly so it snaps in place. (There may be a feeling of some resistance.)
5c. Clean vial adaptor.
Clean the top of the vial adaptor with an alcohol wipe.
6. Check prefilled syringe.
Confirm the product is not expired. Visually inspect that the sterile water inside the prefilled syringe is clear. Do not use if there are any clumps, particles, discolouration, or if product is expired.
7. Break off prefilled syringe white cap.
Break off the prefilled syringe cap along the perforation. Do not touch the tip of the prefilled syringe. Do not push the plunger; it may spill the sterile water.
8. Connect prefilled syringe to vial adaptor.
Now, pick up the medicine vial with the vial adaptor attached.
Align the prefilled syringe tip on the blue circle of the vial adaptor.
Push and twist the prefilled syringe onto the vial adaptor until it cannot be turned further. While twisting, be sure to hold onto the vial adaptor. Do not push the plunger; it may spill the sterile water.
9. Transfer sterile water from prefilled syringe to vial.
Slowly push the plunger all the way down to transfer all the sterile water into the vial. (The plunger will move up; this is normal.)
Make sure all sterile water is transferred to the vial.
10. Swirl to mix medicine.
Do not shake the vial. Hold the prefilled syringe and gently swirl the vial in a circular motion until the powder is fully dissolved. This may take up to 2 minutes. Do not shake or agitate vigorously.
When the medicine is mixed well, it should be clear. If not, repeat this step until it is clear.
Press the plunger down again to make sure all the liquid is in the vial since some liquid could have moved back into the syringe. (The plunger will move up; this is normal.)
11. Wait for the bubbles to go away.
Set the vial aside for bubbles to go away. This may take up to 3 minutes.
Before continuing, make sure the medicine in the vial: Is clear to opalescent; Is colourless to slightly brownish-yellow; Does not have clumps or powder; Does not have large bubbles.
It is okay to have slight foam (small bubbles) around the edges of the vial.
12. Prepare vial by removing extra air.
While the vial oriented upright, gently pull the plunger upwards to the top of the barrel but be careful not to pull the plunger out of the syringe.
Tip: This step only pulls extra air out of the vial to reduce the pressure in the vial and prevent medicine from spilling during the syringe removal.
13. Remove prefilled syringe from vial.
Hold the vial adaptor and unscrew the syringe from the vial.
Throw away the syringe in the sharps container.
A vial of medicine should be prepared and ready to be used in the next steps.
Withdraw the prescribed dose: For the next steps, the following will be needed: Mixed vial of medicine; Items from the bottom tray (use items from the bottom tray).
14. Clean top of vial adaptor.
With a new alcohol wipe from the bottom tray, clean the top of the vial adaptor.
15. Remove empty dosing syringe from its package.
Find the empty dosing syringe in the bottom tray and remove it from its package.
This dosing syringe will be used to measure out the medicine needed (based on the prescribed dose). Do not touch tip of the dosing syringe.
16. Pull air into the dosing syringe.
This must be done to make sure pressure in the vial is even and to get an accurate dose.
Hold the dosing syringe upright and pull down the plunger to draw air into the dosing syringe. Stop when the amount in 'mL' listed in the prescription is reached.
Top rim of plunger should be at the prescribed dose.
Tip: Each line on the dosing syringe is 0.1 mL.
17. Connect dosing syringe to the vial.
While holding the vial adaptor, screw the dosing syringe on until it stops.
Dosing syringe should contain amount of air matching the prescription.
18. Push air into vial, then flip upside down.
Push the plunger all the way down to transfer all the air into the vial.
Then hold the plunger in place with the thumb and flip the vial upside down.
19. Pull plunger back to withdraw the dose.
With the vial and dosing syringe upside down, slowly pull the plunger back.
Stop when the amount in 'mL' listed on the prescription is reached.
Top rim of the plunger should line up with the prescribed dose.
Tip: Each line on the dosing syringe is 0.1 mL.
20. Check for air bubbles and air pockets.
Check to see if there are large air bubbles or an air pocket in the syringe. Extra air will be removed in the next steps.
21. Remove air bubbles and air pockets.
If there are air bubbles or an air pocket, tap the side of the dosing syringe to move the air to the top. Slowly push the plunger up to remove extra air.
Large bubbles and air pockets must be removed to get an accurate dose (1 or 2 small bubbles are okay).
22. Compare amount to prescribed dose.
After removing all extra air, compare the amount to the prescribed dose.
If the prescribed amount in the syringe is not reached, slowly pull the plunger back again to withdraw more medicine.
Repeat Steps 19 to 21 until the prescribed dose is reached and no large bubbles are visible.
23. Confirm the prescribed dose.
Before continuing, check to make sure the prescribed dose is reached in the dosing syringe.
The top rim of the plunger should line up with the prescribed dose.
If the amount does not match the prescribed dose, repeat Steps 19 to 22.
24. Remove the dosing syringe from the vial and set the dosing syringe aside.
Hold the plunger in place with one hand. With the other hand, hold the vial adaptor and unscrew the filled dosing syringe from the vial.
Throw away the vial into the sharps container.
Place the filled dosing syringe on a clean, flat surface.
Do not touch the dosing syringe tip or let it touch any surfaces.
25. Attach the injection needle.
Do not touch the connection hub of the needle.
Find the needle in the bottom tray and open its package.
With the needle still in the package, grip the base of the needle and twist on the dosing syringe until it stops. Remove the needle package.
Move the safety shield away from the needle and toward the syringe. Place the dosing syringe on a clean, flat surface. Do not uncap the needle.
26. Choose and clean the injection site.
Select an injection site on the stomach (abdomen) or the upper thigh. If injecting on the stomach area, avoid a 5 cm area around the belly button.
Choose a different site for every injection. Do not inject into skin that is damaged, sore, bruised, or has red patches. Do not inject through clothes.
Clean the injection site with a new alcohol wipe. Do not touch the cleaned injection site again.
Now, the medicine is ready to be injected.
27. Inject the medicine.
Pull the cap straight off the needle.
Throw away the cap. Do not touch the plunger until ready to inject so no medicine will be lost.
Gently pinch and hold a fold of skin where it will be injected. Insert the needle with a dartlike motion at a 45° to 90° angle. This helps to inject directly under the skin (subcutaneous injection).
Push the plunger with slow, steady pressure all the way down until the dosing syringe is empty. Confirm all the medicine has been injected.
Let go of the skin fold now. Keep the fingers away from the needle at all times.
While keeping the plunger pushed in, remove the needle from the skin at the same angle it was inserted.
To reapply the safety shield, push the shield against a flat surface until a "click" can be heard and the needle is covered.
Throw away the dosing syringe and used items in a sharps disposal container. Do not remove the needle from the dosing syringe.
How to throw away Winrevair: Throw away any used vial (including any remaining Winrevair liquid), needle, vial and needle caps, and used syringes in a sharps disposal container.
Do not throw away the Winrevair vials, syringes, or needle in the household waste.
Do not reuse any of the supplies. This product is disposable and should only be used one time.
If there is no sharps disposal container, a household container may be used that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharp objects being able to come out, upright and stable during use, leak resistant, and properly labelled to warn of hazardous waste inside the container.
When the sharps disposal container is almost full, the local guidelines should be followed for the right way to throw away the sharps disposal container. Do not throw away any medicines, vials, loose needles, or syringes via household waste. Ask the pharmacist how to throw away medicines no longer used. These measures will help protect the environment.
Do not recycle used sharps container.

Shelf life: Unopened vial: 3 years.
After reconstitution: Biochemical and biophysical in-use stability has been demonstrated for 4 hours at 30°C.
From a microbiological point of view, the medicinal product should be used immediately or no longer than 4 hours after reconstitution.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Special precautions for storage: Store in a refrigerator (2°C-8°C). Do not freeze.
Store in the original package in order to protect from light.

What should you do if you're bleeding from the injection site: Place a cotton ball or bandage on your skin right away and apply a small amount of pressure. If the bleeding does not stop, call your doctor or pharmacist right away.
Where can you find your prescription amount: Your prescription amount in 'mL' is on your prescription. Contact your doctor or pharmacist if you can't find your prescription amount.
What should you do if you accidentally get some medicine on your skin or your work surface: Wash the area thoroughly with soap and water right away.
What should you do if you're not sure you administered your prescribed dose correctly: Call your doctor or pharmacist.
What should you do if the plunger of your dosing syringe moves automatically when you try to withdraw medicine from the vial: Don't worry if your plunger moves slightly on its own when you are filling your dosing syringe with medicine.
With one hand, hold the plunger in place to stop the plunger from moving.
With the other hand, unscrew the vial from the dosing syringe. Once unscrewed, it is safe to let go of the plunger.
You can avoid this automatic plunger movement by pushing air into the vial before filling your dosing syringe with medicine.
What should you do if your kit parts are damaged or compromised (for example, discoloured, cloudy, or has particles): If your kit parts are damaged or compromised, do not use it. Call your doctor or pharmacist to get a new kit.
What should you do if your medicine does not turn clear after mixing and swirling: Do not use the medicine if you have swirled the medicine vial for about 2 minutes and let it stand for another 3 minutes, but your medicine vial remains cloudy or has clumps, powder, or foreign particles. Call your doctor or pharmacist to get a new kit.
What should you do if the sterile water won't come out of the prefilled syringe: Check that the vial adaptor is attached to the vial securely. If not, hold the vial and press the vial adaptor down firmly to make sure the vial adaptor punctures the vial rubber stopper.
What should you do if you dropped your kit components: Do not use if any items are damaged. If you are unsure, call your doctor or pharmacist to get a new kit.
Can you use your kit that has been left out of the refrigerator: If the unused kit has been out of the refrigerator for an extended period of time, contact your doctor or pharmacist before proceeding.
Do you need to use mixed medicine right away: We recommend you inject the medicine right after mixing but no later than 4 hours after mixing. If it has been more than 4 hours, throw away unused mixed medicine. If you have questions or are unsure about the process, contact your doctor or pharmacist.
How can you get help preparing and giving your injection: If you have questions about how to give Winrevair the correct way or need more information, you can call your doctor or pharmacist.
For any other information about this medicine, contact your doctor or pharmacist.

Other Antihypertensives

C02KX06 - sotatercept ; Belongs to the class of other antihypertensives. Used in the treatment of pulmonary arterial hypertension.

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