Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

WINREVAIR (BLA-761363)

(SOTATERCEPT-CSRK)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/21/2026 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

HYPERION

The following data reflect exposure to WINREVAIR in the HYPERION trial. Newly diagnosed adult PAH patients in WHO FC II or III at intermediate or high risk of disease progression (n=320) were randomized in a 1:1 ratio to treatment with WINREVAIR or placebo in combination with background standard of care therapies. The median duration of exposure was longer in the WINREVAIR group (443 days) than in the placebo group (350 days) [see Clinical Studies (14.1)].

The adverse reactions observed in the HYPERION trial were generally consistent with those observed in the STELLAR trial. No severe reductions in platelet count <50,000/mm3 (<50.0 x 109/L) occurred in the WINREVAIR group. Treatment discontinuation due to an adverse event occurred in 3% (epistaxis was the most common reason) and 0% of the WINREVAIR and placebo groups, respectively.

The most common adverse reactions occurring in HYPERION (greater than or equal to 10% for WINREVAIR and at least 5% more than placebo) are shown in Table 5.

Table 5: Adverse Reactions greater than or equal to 10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in HYPERION

Newly added table; please refer to label for complete information.

. . .

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

A total of 257 patients greater than or equal to 65 years of age participated in clinical studies for PAH, of which 167 (65%) were treated with WINREVAIR. No differences in efficacy of WINREVAIR were observed between the <65-year-old and greater than or equal to 65-year-old subgroups.

Bleeding events occurred more commonly in patients greater than or equal to 65 years of age, with a greater imbalance in gastrointestinal bleeding events [see Adverse Reactions (6.1)].

Clinical studies of WINREVAIR did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger patients.

09/21/2026 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Serious Bleeding

Additions and/or revisions underlined:

WINREVAIR increases the risk of bleeding. In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% vs 1% (STELLAR), 7% vs 5% (ZENITH), and 4% vs 2% (HYPERION) of patients taking WINREVAIR vs placebo, respectively [see Clinical Studies (14.1), Adverse Reactions (6.1)].

Post-marketing cases of gastrointestinal bleeding associated with angiodysplasias have been reported in WINREVAIR-treated patients; endoscopic evaluation should be considered in patients with recurrent or unexplained gastrointestinal bleeding [see Adverse Reactions (6.1 and 6.2)].

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 (5.3), Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

ZENITH

. . .

The most common adverse reactions occurring in ZENITH (greater than or equal to 10% for WINREVAIR and at least 5% more than placebo) are shown in Table 4.

Table 4: Adverse Reactions greater than or equal to 10% in Patients Receiving WINREVAIR and at least 5% More Than Placebo in ZENITH

Addition of Gastrointestinal tract bleeding to the adverse reaction section of table, addition of 10 (11.6) to the Winrevair section of tablet, addition of 0 (0.0) to the Placebo section of the table; please refer to label for complete information.

. . .

Additional Controlled Safety Data from Clinical Trials

Gastrointestinal disorders: In a pooled analysis of STELLAR, ZENITH, and HYPERION, gastrointestinal bleeding was observed in 7% of patients in the sotatercept group compared with 2% in the placebo group. Colonic angioectasia was reported in 2% of patients in the sotatercept group compared with 0.2% in the placebo group.

Uncontrolled Long-term Safety Data

. . .

Skin hypopigmentation: In the pooled long-term safety population (n=431), skin hypopigmentation was reported in 5% of patients. Reported manifestations included white or hypochromic spots and hypopigmented macules affecting the extremities or trunk. No events required dose reduction or treatment interruption.

. . .

6.2 Post-marketing Experience

Additions and/or revisions underlined:

. . .

Gastrointestinal disorders: gastrointestinal hemorrhage, gastrointestinal angiodysplasia

General disorders and administration site conditions: injection site reactions

Immune disorders: hypersensitivity reactions (including anaphylaxis and angioedema) [see Warnings and Precautions (5.1)]

. . .

09/21/2026 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Newly added information:

4.1 Hypersensitivity

WINREVAIR is contraindicated in patients with serious hypersensitivity (i.e., anaphylaxis, angioedema) to sotatercept-csrk or any of its excipients [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

Newly added subsection:

5.1 Hypersensitivity

Serious hypersensitivity reactions have been reported in WINREVAIR-treated patients. If a serious hypersensitivity reaction (including anaphylaxis and angioedema) occurs, discontinue WINREVAIR and institute appropriate emergency treatment. Inform patients of the signs and symptoms of hypersensitivity reactions and advise them to seek immediate medical attention if symptoms occur [see Contraindications (4.1) and Adverse Reactions (6.2)].

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity [see Warnings and Precautions (5.1)]

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Hypersensitivity

Advise patients that serious allergic reactions, including anaphylaxis and angioedema, have been reported with WINREVAIR. Instruct patients to seek immediate medical attention if they experience signs or symptoms of a serious allergic reaction, such as hives; swelling of the face, lips, tongue, or throat; or difficulty breathing or swallowing [see Warnings and Precautions (5.1)].

. . .

PATIENT INFORMATION

Additions and/or revisions underlined:

What is WINREVAIR?

. . .

WINREVAIR can:

improve your ability to exercise and perform normal activities with fewer symptoms, and
reduce the risk of your physical condition and symptoms worsening, including lowering your risk of hospitalization for PAH, lung transplant, and death.

It is not known if WINREVAIR is safe and effective in children under 18 years of age.

Who should not take WINREVAIR?

Do not take WINREVAIR if you have had a serious allergic reaction to sotatercept-csrk or any of the other ingredients in WINREVAIR. See the end of this Patient Information leaflet for a complete list of ingredients in WINREVAIR.

What are the possible side effects of WINREVAIR? WINREVAIR may cause serious side effects including: Allergic (hypersensitivity) reactions. Allergic reactions, including anaphylaxis, can happen within hours or days after you use WINREVAIR. Call your healthcare provider or get medical help right away if you have any of these symptoms:

hives
swelling of your face, lips, tongue or throat
sudden trouble breathing or swallowing

Before your next dose of WINREVAIR, tell your healthcare provider if you have had any symptoms of an allergic reaction.

High level of hemoglobin in your blood. High levels of hemoglobin are common with WINREVAIR and can be severe and increase your risk for blood clots. Your healthcare provider will do blood tests to check your hemoglobin levels before starting and regularly during treatment with WINREVAIR.
Severely low number of platelets in your blood. Low platelet counts are common with WINREVAIR and can be severe and increase your risk of bleeding. Your healthcare provider will do blood tests to check your platelet levels before starting and regularly during treatment with WINREVAIR. Tell your healthcare provider if you develop easy bruising or bleeding, bleeding that does not stop, or nosebleeds.
Serious bleeding. Serious bleeding can happen with WINREVAIR. Tell your healthcare provider if you develop any signs or symptoms of bleeding, including:

. . .

The most common side effects of WINREVAIR include:

Infections

. . .

bleeding gums

. . .

08/12/2026 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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.

03/25/2026 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

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

12/08/2025 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Thrombocytopenia

Additions and/or revisions underlined:

WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. In clinical studies, severe thrombocytopenia (platelet count <50,000/mm3 [<50 x 109/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/mm3 [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

Additions and/or revisions underlined:

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)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

A total of 127 patients greater than or equal to 65 years of age participated in clinical studies for PAH, of which 99 (78%) were treated with WINREVAIR. No differences in efficacy of WINREVAIR were observed between the <65-year-old and greater than or equal to 65-year-old subgroups.

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 greater than or equal to 65-year-old subgroups. Bleeding events occurred more commonly in the older WINREVAIR subgroup, but with no imbalance between age subgroups for any specific bleeding event.

Clinical studies of WINREVAIR did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger patients.