WINREVAIR 45mg powder + solvent for injection medication leaflet

Winrevair 45 mg powder and solvent for solution for injection

Winrevair 60 mg powder and solvent for solution for injection

Winrevair 45 mg powder and solvent for solution for injection

Each vial contains 45 mg of sotatercept. After reconstitution, each mL of solution contains 50 mgsotatercept.

Winrevair 60 mg powder and solvent for solution for injection

Each vial contains 60 mg of sotatercept. After reconstitution, each mL of solution contains 50 mgsotatercept.

Sotatercept is a recombinant homodimeric fusion protein consisting of the extracellular domain ofhuman activin receptor type IIA (ActRIIA) linked to the Fc domain of human IgG1, produced in

Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (powder for injection).

Powder: white to off-white powder.

Solvent: clear colourless water for injections.

Winrevair, in combination with other pulmonary arterial hypertension (PAH) therapies, is indicatedfor the treatment of PAH in adult patients with WHO Functional Class (FC) II to III, to improveexercise capacity (see section 5.1).

Winrevair treatment should only be initiated and monitored by a physician experienced in thediagnosis and treatment of PAH.

Winrevair is administered once every 3 weeks as a single subcutaneous injection according to patientweight.

Recommended starting dose

Haemoglobin (Hgb) and platelet count should be obtained prior to the first dose (see section 4.4).

Initiation of treatment is contraindicated if platelet count is consistently < 50 x 109/L (see section 4.3).

Treatment is initiated with a single dose of 0.3 mg/kg (see Table 1).

Table 1: Injection volume for dose of 0.3 mg/kg

Patient weight range (kg) Injection volume Kit type(mL)*30.0 - 40.8 0.240.9 - 57.4 0.357.5 - 74.1 0.474.2 - 90.8 0.5 Kit containing90.9 - 107.4 0.6 1 x 45 mg vial107.5 - 124.1 0.7124.2 - 140.8 0.8140.9 - 157.4 0.9157.5 - 174.1 1.0 Kit containing174.2 - 180.0 1.1 1 x 60 mg vial

*The concentration of the reconstituted solution is 50 mg/mL (see section 6.6)

Recommended target dose

Three weeks after a single starting dose of 0.3 mg/kg, the dose should be escalated to therecommended target dose of 0.7 mg/kg after verifying acceptable Hgb and platelet count (seesection 4.2 “Dose adjustments due to increase in haemoglobin or decreased platelet count”).

Treatment should be continued at 0.7 mg/kg every 3 weeks unless dose adjustments are required.

Table 2: Injection volume for dose of 0.7 mg/kg

Patient weight range (kg) Injection Kit typevolume(mL)*30.0 - 31.7 0.431.8 - 38.9 0.539.0 - 46.0 0.6 Kit containing46.1 - 53.2 0.7 1 x 45 mg vial53.3 - 60.3 0.860.4 - 67.4 0.967.5 - 74.6 1.0

Kit containing74.7 - 81.7 1.11 x 60 mg vial81.8 - 88.9 1.289.0 - 96.0 1.396.1 - 103.2 1.4103.3 - 110.3 1.5 Kit containing110.4 - 117.4 1.6 2 x 45 mg vials117.5 - 124.6 1.7124.7 - 131.7 1.8131.8 - 138.9 1.9139.0 - 146.0 2.0146.1 - 153.2 2.1 Kit containing153.3 - 160.3 2.2 2 x 60 mg vials160.4 - 167.4 2.3167.5 and above 2.4

*The concentration of the reconstituted solution is 50 mg/mL (see section 6.6)

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 ifnecessary (see sections 4.4 and 4.8).

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 shouldbe 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 physicianshould carry out a benefit/risk re-evaluation for the patient before reinitiating treatment.

If a dose is missed, administer as soon as possible. If the missed dose is not taken within 3 days of thescheduled date, adjust the schedule to maintain 3-week dosing intervals.

No dose adjustment is required in elderly patients ≥ 65 years old (see section 5.2).

No dose adjustment is required based on renal impairment (see section 5.2). Sotatercept has not beenstudied in PAH patients with severe renal impairment (estimated glomerular filtration rate (eGFR)<30 mL/min/1.73m2).

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 section 5.2).

The safety and efficacy of Winrevair in children and adolescents below 18 years of age have not yetbeen established. No data are available.

Winrevair is for single use only.

It should be reconstituted before use. The reconstituted medicinal product is a clear to opalescent andcolourless to slightly brownish-yellow solution.

Winrevair should be administered by subcutaneous injection in the abdomen (at least 5 cm away fromnavel), upper arm, or upper thigh. It should not be injected into sites that are scarred, tender, orbruised. 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 ahealthcare professional (HCP). Patients and caregivers may administer the medicinal product whenconsidered 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 ata 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 thedose is adjusted, if the patient requires a different kit, if the patient develops erythrocytosis (seesection 4.4), or at any time at the discretion of the HCP.

Refer to section 6.6 for detailed instructions on the proper preparation and administration of

Winrevair.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with platelet counts consistently < 50 x 109/L before initiating treatment.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Erythrocytosis

Increases in Hgb have been observed in patients during treatment with sotatercept. Severeerythrocytosis may increase the risk of thromboembolic events and hyperviscosity syndrome. Usecaution in patients with erythrocytosis who are at increased risk of thromboembolic events. Hgbshould be monitored before each dose for the first 5 doses, or longer if values are unstable, and every 3to 6 months thereafter to determine if dose adjustments are required (see sections 4.2 and 4.8). If apatient develops erythrocytosis, HCP should consider re-evaluating the patient’s or caregiver’sadministration technique.

Severe thrombocytopenia

Decreased platelet count has been observed in some patients taking sotatercept including severethrombocytopenia (platelet count < 50 x 109/L). Thrombocytopenia was reported more frequently inpatients also receiving prostacyclin infusion (21.5%) compared to patients not receiving prostacyclininfusion (3.1%) (see section 4.8). 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 areunstable, and every 3 to 6 months thereafter to determine whether dose adjustments are required (seesection 4.2).

Serious bleeding

In clinical studies, serious bleeding events (including gastrointestinal, intracranial haemorrhage) havebeen observed in 4.3% of patients during treatment with sotatercept (see section 4.8).

Patients with serious bleeding events were more likely to be on prostacyclin background therapyand/or antithrombotic agents, have low platelet count, or be 65 years of age or older. Patients shouldbe advised about any signs and symptoms of blood loss. A physician should evaluate and treatbleeding events accordingly. Sotatercept should not be administered if the patient is experiencing aserious bleeding event.

Limitation of the clinical data

The clinical studies did not include participants with human immunodeficiency virus (HIV)-, portalhypertension-, schistosomiasis-, or pulmonary veno occlusive disease (PVOD)-associated PAH.

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.

No interaction studies have been performed.

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 least4 months after the last dose if treatment is discontinued (see section 5.3).

There are no data from the use of sotatercept in pregnant women. Studies in animals have shownreproductive toxicity (increases in post-implantation losses, reduction in foetal body weights, anddelays in ossification) (see section 5.3).

Winrevair is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether sotatercept/metabolites are excreted in human milk. A risk to newborns/infantscannot be excluded.

Breast-feeding should be discontinued during treatment and for 4 months after the last dose oftreatment.

Based on findings in animals, sotatercept may impair female and male fertility (see section 5.3).

Sotatercept has no or negligible influence on the ability to drive and use machines.

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.

The safety of sotatercept was evaluated in the pivotal study STELLAR, a placebo-controlled study of163 patients with PAH treated with sotatercept (see section 5.1). The median duration of treatmentwith sotatercept was 313 days.

The adverse reactions reported with sotatercept are listed in the table below by MedDRA system organclass 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).

Table 3: Adverse reactions

System organ class Frequency Adverse reaction

Blood and lymphatic system Very common Thrombocytopenia1,2disorders Increased haemoglobin1

Nervous system disorders Very common Dizziness

Respiratory, thoracic and mediastinal Very common Epistaxisdisorders

Gastrointestinal disorders Very common Diarrhoea

Common Gingival bleeding

Skin and subcutaneous tissue Very common Telangiectasia1disorders Rash

Common Erythema

General disorders and administration Common Injection site pruritussite conditions

Investigations Common Increased blood pressure1,31 See description of selected adverse reactions2 Includes ‘thrombocytopenia’ and ‘platelet count decreased’3 Includes ‘hypertension’, ‘blood pressure diastolic increased’ and ‘blood pressure increased’

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. Increasesin Hgb were managed by dose adjustments (see sections 4.2 and 4.4).

Thrombocytopenia (‘thrombocytopenia’ and ‘platelet count decreased’) was reported in 10.4% ofpatients taking sotatercept. Severe reduction in platelet count < 50 x 109/L occurred in 2.5% of patientstaking sotatercept. Thrombocytopenia was reported more frequently in patients also receivingprostacyclin infusion (21.5%) compared to patients not receiving prostacyclin infusion (3.1%).

Thrombocytopenia was managed by dose adjustments (see sections 4.2 and 4.4).

Telangiectasia

Telangiectasia was observed in 16.6% of patients taking sotatercept. The median time to onset was18.6 weeks. Discontinuations of treatment due to telangiectasia were 1% in the sotatercept group.

Increased blood pressure was reported in 4.3% of patients taking sotatercept. In patients takingsotatercept, mean systolic blood pressure increased from baseline by 2.2 mmHg and diastolic bloodpressure increased by 4.9 mmHg at 24 weeks.

With the exception of bleeding events (a collective group of adverse events of clinical interest), therewere no differences in safety between the < 65-year-old and ≥ 65-year-old subgroups. Bleeding eventsoccurred 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-oldtaking sotatercept.

Long-term safety data

Long-term safety data are available from pooled phase 2 and phase 3 clinical studies (n=431). Themedian duration of exposure was 657 days. The safety profile was generally similar to that observed inthe pivotal STELLAR study.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In a phase 1 healthy volunteer study, one participant dosed at 1 mg/kg of sotatercept experiencedincreased 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 closelymonitored, and supportive care should be provided as appropriate (see sections 4.2 and 4.4).

Sotatercept is not dialyzable during haemodialysis.

Pharmacotherapeutic group: antihypertensives, antihypertensives for pulmonary arterial hypertension.

ATC code: C02KX06

Sotatercept is an activin signalling inhibitor with high selectivity for Activin-A, a dimeric glycoproteinwhich belongs to the transforming growth factor-β (TGF-β) superfamily of ligands. Activin-A binds tothe 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 proliferativesignalling 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 invascular cell hyperproliferation, causing pathological remodelling of the pulmonary arterial wall,narrowing the arterial lumen, increasing pulmonary vascular resistance, and leads to increasedpulmonary artery pressure and right ventricular dysfunction.

Sotatercept consists of a recombinant homodimeric activin receptor type IIA-Fc (ActRIIA-Fc) fusionprotein, which acts as a ligand trap that scavenges excess Activin-A and other ligands for ActRIIA toinhibit 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 vascularproliferation.

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 wassignificantly greater in the sotatercept 0.7 mg/kg and 0.3 mg/kg groups compared with the placebogroup. The placebo-adjusted least squares (LS) mean difference from baselinewas -269.4 dyn*sec/cm5 (95% CI: -365.8, -173.0) for the sotatercept 0.7 mg/kg groupand -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 thepulmonary arterial wall, reduced leucocyte recruitment, inhibited proliferation of endothelial andsmooth muscle cells, and promoted apoptosis in diseased vasculature. These cellular changes wereassociated with thinner vessel walls, reversed arterial and right ventricular remodelling, and improvedhaemodynamics.

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 which323 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) administeredsubcutaneously once every 3 weeks. Patients continued their treatment assignment in the long-termdouble-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 which16.7% were ≥ 65 years of age. Median weight was 68.2 kg (range: 38.0 to 141.3 kg); 89.2% ofparticipants were White, and 79.3% were not Hispanic or Latino; and 79.3% were female. The mostcommon PAH aetiologies were idiopathic PAH (58.5%), heritable PAH (18.3%), and PAH associatedwith connective tissue diseases (14.9%), PAH associated with simple congenital heart disease withrepaired systemic-to-pulmonary shunts (5%), or drug or toxin-induced PAH (3.4%). The mean timesince 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 ofparticipants in WHO FC II was 48.6% and in WHO FC III was 51.4%. The STELLAR study excludedpatients 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 6MWDfrom baseline at Week 24 was 40.8 meters (95% CI: 27.5, 54.1; p < 0.001). The median of theplacebo-adjusted changes in 6MWD at Week 24 were also evaluated in subgroups. The treatmenteffect was consistent across the different subgroups including sex, PAH diagnostic group, backgroundtherapy 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 ofclinical worsening events.

MCI was a pre-defined endpoint measured by the proportion of patients achieving all three of thefollowing 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 worseningevent. 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 thedose 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 bothevents occurring at the same time or different times). Clinical worsening events and death werecaptured until the last patient completed the Week 24 visit (data up to the data cutoff; median durationof exposure 33.6 weeks).

At Week 24, 38.9% of sotatercept-treated patients showed improvement in MCI versus 10.1% in theplacebo group (p < 0.001). The median treatment difference in PVR between sotatercept and placebogroup 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 versus13.8% 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 4). Thetreatment effect of sotatercept versus placebo started by Week 10 and continued for the duration of thestudy.

Table 4: Death or clinical worsening events

Placebo Sotatercept(N=160) (N=163)

Total number of subjects who experienced death or at least 29 (18.1) 7 (4.3)one clinical worsening event, n (%)

Assessment of death or first occurrence of clinical worseningevents*, n (%)

Death 6 (3.8) 2 (1.2)

Worsening-related listing for lung and/or heart transplant 1 (0.6) 1 (0.6)

Need for atrial septostomy 0 (0.0) 0 (0.0)

PAH-specific hospitalisation (≥24 hours) 8 (5.0) 0 (0.0)

Deterioration of PAH† 15 (9.4) 4 (2.5)

* A subject can have more than one assessment recorded for their first event of clinical worsening. There were 2 participantsreceiving placebo and no participant receiving sotatercept who had more than one assessment recorded for their first event ofclinical worsening. This analysis excluded the component “need to initiate rescue therapy with an approved PAH therapy or need toincrease the dose of infusion prostacyclin by 10% or more”.

† Deterioration of PAH is defined by both of the following events occurring at any time, even if they began at different times, ascompared to their baseline values: (a) Worsened WHO functional class (II to III, III to IV, II to IV, etc.); and (b) Decrease in6MWD by ≥ 15% (confirmed by two 6MWTs at least 4 hours apart but no more than one week).

N = number of subjects in FAS population; n = number of subjects in the category. Percentages are calculated as (n/N)*100.

At Week 24 in STELLAR, anti-drug antibodies (ADA) were detected in 44/163 (27%) of patientstaking sotatercept. Among these 44 patients, 12 tested positive for neutralising antibodies againstsotatercept. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Winrevair in one or more subsets of the paediatric population in the treatment of pulmonary arterialhypertension (see section 4.2 for information on paediatric use).

In patients with PAH, the geometric mean (%Coefficient of variation (CV %)) steady-state AUC andsteady-state peak concentration (Cmax) 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 Cmax increase proportionally withdose. Steady state is achieved after approximately 15 weeks of treatment. The accumulation ratio ofsotatercept AUC was approximately 2.2.

The subcutaneous (SC) formulation has an absolute bioavailability of approximately 66% based onpopulation pharmacokinetics analysis. The maximum sotatercept concentration is achieved at amedian time to peak drug concentration (Tmax) of approximately 7 days (range from 2 to 8 days) aftermultiple dosing every 4 weeks.

The central volume of distribution (CV%) of sotatercept is approximately 3.6 L (24.7%). Theperipheral volume of distribution (CV%) is approximately 1.7 L (73.3%).

Sotatercept is catabolised by general protein degradation processes.

Sotatercept clearance is approximately 0.18 L/day. The geometric mean terminal half-life (CV%) isapproximately 21 days (33.8%).

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).

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.

Sotatercept pharmacokinetics was comparable in PAH patients with mild to moderate renalimpairment (eGFR ranging from 30 to 89 mL/min/1.73m2) to those with normal renal function(eGFR ≥90 mL/min/1.73m2). Additionally, sotatercept PK is comparable between non-PAH end-stagerenal disease (ESRD) patients and patients with normal renal function. Sotatercept is not dialyzableduring haemodialysis. Sotatercept has not been studied in PAH patients with severe renal impairment(eGFR <30 mL/min/1.73m2).

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 ismetabolised via cellular catabolism.

No carcinogenicity or mutagenicity studies have been conducted with sotatercept.

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 glandcongestion/necrosis, and membranoproliferative glomerulonephritis and tubulointerstitial nephritis inthe kidneys. Kidney changes were not reversible following a 1-month recovery period. In monkeys,adverse changes included increased interstitial matrix at the corticomedullary junction, decreasedglomerular tuft size, glomerulonephritis and tubulointerstitial nephritis in the kidney. Kidney changesin monkeys partially resolved following a 3-month recovery period. At the no observed adverse effectlevel (NOAEL) in rats and monkeys, sotatercept exposures were ≤2-times the clinical exposure at themaximum recommended human dose (MRHD). Other findings that occurred at clinical exposuremargins in monkeys included hepatic inflammatory infiltrates, lymphoid depletion in spleen, andinflammatory infiltrates in the choroid plexus.

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. Atthe 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 the13-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 clinicalexposure at the MRHD.

In embryo-fetal developmental toxicity studies, effects in rats and rabbits included reductions innumbers of live foetuses and fetal body weights, delays in ossification, and increases in resorptionsand post-implantation losses. In rats only, there were also skeletal variations (increased number ofsupernumerary ribs and changes in the number of thoracic or lumbar vertebrae). At the NOAEL in ratsand 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 observedin 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 correlatedwith delays in sexual maturation. The NOAEL for effects on growth and maturation in pups provides asystemic exposure 0.6-times the clinical exposure at the MRHD.

Citric acid monohydrate (E330)

Sodium citrate (E331)

Polysorbate 80 (E433)

Sucrose

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years

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 longerthan 4 hours after reconstitution.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser.

Store in a refrigerator (2 °C - 8 °C). Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Winrevair 45 mg powder and solvent for solution for injection2 mL capacity, type I glass vial sealed with a bromobutyl rubber stopper with polymer coating andaluminium seal with lime polypropylene flip-off cap containing 45 mg of sotatercept.

Prefilled syringe (type I glass cartridge closed with a bromobutyl rubber stopper) with 1 mL ofsolvent.

Winrevair 60 mg powder and solvent for solution for injection2 mL capacity, type I glass vial sealed with a bromobutyl rubber stopper with polymer coating andaluminium seal with burgundy polypropylene flip-off cap containing 60 mg of sotatercept.

Prefilled syringe (type I glass cartridge closed with a bromobutyl rubber stopper) with 1.3 mL ofsolvent.

Winrevair powder and solvent for solution for injection is available as the following pack sizes:

- Kits containing 1 vial with 45 mg powder, 1 prefilled syringe with 1.0 mL solvent, 1 dosingsyringe with 0.1 mL graduations, 1 vial adaptor (13 mm), 1 needle for injection and 4 alcoholwipes.

- Kits containing 2 vials with 45 mg powder, 2 prefilled syringes with 1.0 mL solvent, 1 dosingsyringe with 0.1 mL graduations, 2 vial adaptors (13 mm), 1 needle for injection and 8 alcoholwipes.

- Kits containing 1 vial with 60 mg powder, 1 prefilled syringe with 1.3 mL solvent, 1 dosingsyringe with 0.1 mL graduations, 1 vial adaptor (13 mm), 1 needle for injection and 4 alcoholwipes.

- Kits containing 2 vials with 60 mg powder, 2 prefilled syringes with 1.3 mL solvent, 1 dosingsyringe with 0.1 mL graduations, 2 vial adaptors (13 mm), 1 needle for injection and 8 alcoholwipes.

Not all pack sizes may be marketed.

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 usedinstead of two 1-vial kit to eliminate the need for multiple injections (see section 6.5).

Reconstitution and administration instructions

Winrevair powder and solvent for solution for injection should be reconstituted before use andadministered as a single injection according to patient weight (see section 4.2).

See the separate Instructions for Use booklet provided in the kit for detailed step by step instructionson how to prepare and administer the medicinal product. An overview of the reconstitution andadministration instructions is provided below.

- Remove the kit from the refrigerator and wait 15 minutes to allow the prefilled syringe(s) andmedicinal 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 tooff-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 analcohol wipe.

- Attach the vial adaptor to the vial.

- Visually inspect the prefilled syringe for any damage or leaks and the sterile water inside toensure 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 1.0 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 medicinalproduct and the 60 mg vial can only provide up to a dose of 1.2 mL of medicinal product. Thefinal 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 solutionshould be clear to opalescent and colourless to slightly brownish-yellow, and should not haveclumps or powder.

- Unscrew the syringe from the vial adaptor and discard the emptied syringe.

- 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. Thereconstituted 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 firstvial 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 medicinalproduct.

- 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.

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 upperarm 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 orupper thigh (see “Instructions for Use” booklet).

- Perform subcutaneous injection.

- Discard the emptied syringe. Do not reuse the syringe.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

See section 4.4 for instructions on the traceability of biological medicinal products.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/24/1850/001

EU/1/24/1850/002

EU/1/24/1850/003

EU/1/24/1850/004

Date of first authorisation: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.