The following clinically significant adverse reactions are described elsewhere in the labeling: Erythrocytosis [see Warnings and Precautions (5.1) ] Severe Thrombocytopenia [see Warnings and Precautions (5.2) ] Serious Bleeding [see Warnings and Precautions (5.3) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ] Impaired Fertility [see Warnings and Precautions (5.5) ] The most common (≥10% in patients receiving WINREVAIR and 5% more than placebo) adverse reactions were infections, epistaxis, telangiectasia, diarrhea, headache, rash, increased hemoglobin, dizziness, erythema, and gingival bleeding.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. STELLAR The following data reflect exposure to WINREVAIR in the STELLAR trial. Adult PAH patients with WHO FC II or III (n=323) were randomized in a 1:1 ratio to receive WINREVAIR or placebo in combination with background standard of care therapies.
Patients received a starting dose of 0.3 mg/kg via SC injection and the dose was increased to the target dose of 0.7 mg/kg administered once every 3 weeks for 24 weeks. After completing the primary 24-week treatment phase, patients continued into a long-term double-blind (LTDB) treatment period, maintaining their randomized treatment assignment, until all patients completed the primary treatment period. The median duration of treatment was 273 days in the placebo group and 313 days in the WINREVAIR group [see Clinical Studies (14.1) ].
The most common adverse reactions occurring in STELLAR (≥10% for WINREVAIR and at least 5% more than placebo) are shown in Table 3 . Table 3: Adverse Reactions ≥10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in STELLAR Double-blind placebo-controlled period + Long-term double-blind period of STELLAR Adverse reaction WINREVAIR N=163 Placebo N=160 Headache 40 (24.5) 28 (17.5) Epistaxis 36 (22.1) 3 (1.9) Rash 33 (20.2) 13 (8.1) Telangiectasia 27 (16.6) 7 (4.4) Diarrhea 25 (15.3) 16 (10.0) Dizziness 24 (14.7) 10 (6.3) Erythema 22 (13.5) 5 (3.1) Increased Hemoglobin Increases in Hgb were managed by dose delays (10%), dose reductions (6%), or both (5%).
Shifts in Hgb from normal to above normal levels occurred in 87 (53%) patients receiving WINREVAIR and in 23 (14%) patients receiving placebo. Thrombocytopenia Decreases in platelets were managed by dose delays (2%), dose reductions (2%), or both (2%). Shifts in platelet count from normal to below normal occurred in 40 (25%) patients receiving WINREVAIR and in 26 (16%) patients receiving placebo. Telangiectasia In patients exposed to WINREVAIR who experienced telangiectasia, the median time to onset was 36.1 weeks.
Increased Blood Pressure In patients taking WINREVAIR, mean systolic/diastolic blood pressure increased from baseline by 2.2/4.9 mmHg at 24 weeks. In patients taking placebo, the change from baseline in mean blood pressure was -1.6/-0.6 mmHg. Treatment Discontinuation The incidences of treatment discontinuations due to an adverse reaction were 4% in the WINREVAIR group and 7% in the placebo group. No specific adverse reactions causing treatment discontinuations occurred with a frequency greater than 1% and more often in the WINREVAIR group.
ZENITH The following data reflect exposure to WINREVAIR in the ZENITH trial. Adult PAH patients with WHO FC III or IV at high risk of mortality (n=172) were randomized in a 1:1 ratio to treatment with WINREVAIR or placebo in combination with background standard of care therapies. Patients who did not experience a primary endpoint event remained in the Double-Blind Placebo-Controlled (DBPC) Treatment Period, while patients who experienced an event of PAH worsening-related hospitalization of ≥24 hours were eligible to enroll into the open-label, long-term follow-up (LTFU) study SOTERIA.
The median duration of exposure was longer in the WINREVAIR group (435 days) than in the placebo group (268 days) [see Clinical Studies (14.1) ]. The overall incidences of adverse reactions in both arms were higher in the ZENITH trial than in the STELLAR trial. Severe reduction in platelet count <50,000/mm 3 (<50.0 x 10 9 /L) occurred in 6% of patients taking WINREVAIR. In the WINREVAIR group, 1 patient (1%) discontinued study intervention due to an adverse event, compared with 4 patients (5%) in the placebo group.
Table 4: Adverse Reactions ≥10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in ZENITH Adverse reaction WINREVAIR N=86 Placebo N=86 Infections 58 (67.4) 38 (44.2) Epistaxis 39 (45.3) 8 (9.3) Diarrhea 22 (25.6) 15 (17.4) Telangiectasia 22 (25.6) 3 (3.5) Increased hemoglobin 13 (15.1) 1 (1.2) Rash 9 (10.5) 4 (4.7) Erythema 9 (10.5) 3 (3.5) Gingival bleeding 9 (10.5) 2 (2.3) Uncontrolled Long-term Safety Data PULSAR was a multicenter, randomized, double-blind, phase 2 trial that included a 24-week placebo-controlled treatment period, followed by an 18-month active-drug extension period.
The safety profile in the long-term uncontrolled extension period of the PULSAR study was generally similar to that observed in the STELLAR study. Patients were treated with WINREVAIR 0.3 mg/kg or 0.7 mg/kg (n=104) and had a mean duration of exposure of 151 weeks (maximum 218 weeks). Intrapulmonary Right-to-Left Shunting: Cases of intrapulmonary right-to-left shunting have been reported in a clinical trial with WINREVAIR.
In SOTERIA, an ongoing open-label study of the long-term safety and efficacy of WINREVAIR, right-to-left intrapulmonary shunting has been reported in 2 participants (<0.5%) who developed worsening hypoxemia despite improved PAH hemodynamics. Post-marketing cases have also been reported. Partial to complete improvement in oxygenation has been observed following discontinuation of WINREVAIR.
