4.1. Therapeutic indications

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, III, and IV (see section 5.1).

4.2. Posology and method of administration

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 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 (mL)*

Kit type

30.0 – 40.8

0.2

Kit containing

1 x 45 mg vial

40.9 – 57.4

0.3

57.5 – 74.1

0.4

74.2 – 90.8

0.5

90.9 – 107.4

0.6

107.5 – 124.1

0.7

124.2 – 140.8

0.8

140.9 – 157.4

0.9

157.5 – 174.1

1.0

Kit containing

1 x 60 mg vial

174.2 – 180.0

1.1

*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 the recommended target dose of 0.7 mg/kg after verifying acceptable Hgb and platelet count (see section 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 volume (mL)*

Kit type

30.0 – 31.7

0.4

Kit containing

1 x 45 mg vial

31.8 – 38.9

0.5

39.0 – 46.0

0.6

46.1 – 53.2

0.7

53.3 – 60.3

0.8

60.4 – 67.4

0.9

67.5 – 74.6

1.0

Kit containing

1 x 60 mg vial

74.7 – 81.7

1.1

81.8 – 88.9

1.2

89.0 – 96.0

1.3

Kit containing

2 x 45 mg vials

96.1 – 103.2

1.4

103.3 – 110.3

1.5

110.4 – 117.4

1.6

117.5 – 124.6

1.7

124.7 – 131.7

1.8

131.8 – 138.9

1.9

Kit containing

2 x 60 mg vials

139.0 – 146.0

2.0

146.1 – 153.2

2.1

153.3 – 160.3

2.2

160.4 – 167.4

2.3

167.5 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 if necessary (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 upper limit of normal (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 section 5.2).

Renal impairment

No dose adjustment is required based on renal impairment (see section 5.2). Limited data are available on the use of sotatercept in PAH patients with severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2).

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 section 5.2).

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.

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 section 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.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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 sections 4.2 and 4.8). 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% to 24.5%) compared to patients not receiving prostacyclin infusion (0.0% to 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 are unstable, and every 3 to 6 months thereafter to determine whether dose adjustments are required (see section 4.2).

Serious bleeding

In clinical studies, serious bleeding events (including gastrointestinal, intracranial haemorrhage) have been observed in 4.3% to 7.0% of patients during treatment with sotatercept (see section 4.8).

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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

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 section 5.3).

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 section 5.3).

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 section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The most frequently reported adverse reactions in either STELLAR or ZENITH were epistaxis (45.3%), headache (26.7%), telangiectasia (25.6%), diarrhoea (25.6%), increased haemoglobin (15.1%), thrombocytopenia (15.1%), dizziness (14.7%), back pain (14%), rash (12.3%), and gingival bleeding (10.5%).

The most frequently reported serious adverse reactions were thrombocytopenia (< 1.2%), epistaxis (< 1.2%) and dizziness (< 1.2%).

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 placebo-controlled studies STELLAR and ZENITH, which included 163 and 86 patients with PAH treated with sotatercept, respectively (see section 5.1). The median duration of treatment with sotatercept was 313 days in STELLAR and 434.5 days in ZENITH.

The adverse reactions reported with sotatercept are listed in the table below 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).

Table 3: Adverse reactions

System organ class

Frequency

Adverse reaction

Infections and infestations

Common

Urinary tract infections

Blood and lymphatic system disorders

Very common

Thrombocytopenia1,2

Increased haemoglobin1

Nervous system disorders

Very common

Dizziness

Headache

Respiratory, thoracic and mediastinal disorders

Very common

Epistaxis

Uncommon

Intrapulmonary shunt3

Gastrointestinal disorders

Very common

Diarrhoea

Gingival bleeding4

Skin and subcutaneous tissue disorders

Very common

Telangiectasia1

Rash

Common

Erythema

Musculoskeletal and connective tissue disorders

Very common

Back pain4

General disorders and administration site conditions

Common

Injection site pruritus

Investigations

Common

Increased blood pressure1,5

1 See description of selected adverse reactions

2 Includes 'thrombocytopenia' and 'platelet count decreased'

3 See 'Long-term satety data'

4 The frequency category is based on ZENITH

5 Includes 'hypertension', 'blood pressure diastolic increased' and 'blood pressure increased'

Description of selected adverse reactions

Increased haemoglobin

In STELLAR, increased Hgb ('haemoglobin increased' and 'polycythaemia') was 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.

In ZENITH, increased Hgb was reported in 15.1% of patients taking sotatercept. Based on laboratory data, moderate elevations in Hgb occurred in 7.1% of patients taking sotatercept.

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

Thrombocytopenia

In STELLAR, 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%).

In ZENITH, thrombocytopenia was reported in 15.1% of patients taking sotatercept. Severe reduction in platelet count < 50 x 109/L occurred in 6.0% of patients taking sotatercept. Thrombocytopenia was reported only in patients also receiving prostacyclin infusion (24.5%).

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

Telangiectasia

In STELLAR, 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.

In ZENITH, telangiectasia was observed in 25.6% of patients taking sotatercept. The median time to onset was 12.8 weeks. There were no discontinuations of treatment due to telangiectasia in the sotatercept group.

Increased blood pressure

In STELLAR, 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.

In ZENITH, increased blood pressure was reported in 2.3% of patients taking sotatercept. In patients taking sotatercept, mean systolic blood pressure increased from baseline by 3.1 mmHg and diastolic blood pressure increased by 5.1 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.

In STELLAR, bleeding events occurred more commonly in the older sotatercept subgroup (52% versus 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.

In ZENITH, bleeding events occurred more commonly in the older sotatercept subgroup (73.3% versus 60.7% in patients < 65-year-old). Serious bleeding occurred in 3.6% of patients < 65-year-old and in 13.3% of patients ≥ 65-year-old taking sotatercept.

Long-term safety data

Pooled long-term safety data are available from 431 patients who participated in phase 2 and phase 3 clinical studies (PULSAR, SPECTRA, and STELLAR). A majority of these patients continued into SOTERIA, an ongoing open-label follow-up study of the long-term safety and efficacy of sotatercept. The mean duration of exposure was 173 weeks, with a maximum exposure of 355 weeks. The safety profile was generally similar to that observed in the pivotal STELLAR study. Right-to-left intrapulmonary shunting has been reported in participants who developed worsening hypoxemia despite improved PAH haemodynamics

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 sections 4.2 and 4.4). Sotatercept is not dialyzable during haemodialysis.