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warnings and cautions
5 WARNINGS AND PRECAUTIONS Erythrocytosis: If severe, may increase the risk of thromboembolic events and hyperviscosity syndrome. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. ( 5.1 ) Severe Thrombocytopenia: May increase the risk of bleeding. Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. ( 5.2 ) Serious Bleeding: Serious bleeding events were reported and were more likely with concomitant prostacyclin and/or antithrombotic agents, or with low platelet counts. Do not administer WINREVAIR if the patient is experiencing serious bleeding. ( 5.3 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) Impaired Fertility: May impair female and male fertility. ( 5.5 , 8.3 , 13.1 ) 5.1 Erythrocytosis WINREVAIR may increase hemoglobin. Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. In clinical studies, moderate elevations in Hgb (>2 g/dL above ULN) occurred in 15% of patients taking WINREVAIR while no elevations ≥4 g/dL above ULN were observed. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.2 Severe Thrombocytopenia WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. In clinical studies, severe thrombocytopenia (platelet count <50,000/mm 3 [<50 x 10 9 /L]) occurred in 3% to 6% of patients taking WINREVAIR. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Do not initiate treatment if platelet count is <50,000/mm 3 [see Dosage and Administration (2.3) ] . Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required. [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.3 Serious Bleeding In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% vs 1% (STELLAR) and 7% vs 5% (ZENITH) of patients taking WINREVAIR vs placebo, respectively [see Clinical Studies (14.1) ] . Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Evaluate and treat bleeding accordingly. Do not administer WINREVAIR if the patient is experiencing serious bleeding [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) ] . 5.4 Embryo-Fetal Toxicity Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of WINREVAIR to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on area under the curve [AUC]) those occurring at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.5 Impaired Fertility Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertility [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ].
6 ADVERSE REACTIONS 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 6.1 Clinical 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 Pooled long-term safety data are available from 431 patients who participated in multicenter phase 2 (PULSAR, SPECTRA) and phase 3 (STELLAR) clinical trials. A majority of these patients continued in SOTERIA, an ongoing, open-label follow-up study of the long-term safety and efficacy of WINREVAIR. The safety profile with long-term exposure was generally similar to that observed in the STELLAR study. The mean duration of exposure to WINREVAIR was 173 weeks with a maximum exposure of 335 weeks. Intrapulmonary Right-to-Left Shunting: Cases of intrapulmonary right-to-left shunting have been reported in a clinical trial with WINREVAIR. In SOTERIA, right-to-left intrapulmonary shunting has been reported in 3 participants (<0.7%) 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. Additional Adverse Reactions from Clinical Trials The following adverse reactions were reported in at least one adult patient receiving treatment with WINREVAIR. These adverse reactions are presented by system organ class and are ranked by frequency. Skin and Subcutaneous Tissue Disorders: 1% and less than 10%: skin hypopigmentation Gastrointestinal Disorders: 1% and less than 10% : gastrointestinal tract bleeding (including gastrointestinal hemorrhage, upper gastrointestinal hemorrhage, hematemesis, lower gastrointestinal hemorrhage, hematochezia, rectal hemorrhage, melaena, gastritis hemorrhagic), colonic angioectasia 6.2 Post-marketing Experience The following adverse reaction has been reported during post-approval use of WINREVAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: pericardial effusion General disorders and administration site conditions: injection site reactions