WELIREG

WELIREG- belzutifan tablet, film coated
Merck Sharp & Dohme Corp.

WARNING: EMBRYO-FETAL TOXICITY

1 INDICATIONS AND USAGE

WELIREG is indicated for treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of WELIREG is 120 mg administered orally once daily until disease progression or unacceptable toxicity. WELIREG should be taken at the same time each day and may be taken with or without food.

Advise patients to swallow tablets whole. Do not chew, crush, or split WELIREG prior to swallowing.

If a dose of WELIREG is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for WELIREG the next day. Do not take extra tablets to make up for the missed dose.

If vomiting occurs any time after taking WELIREG, do not retake the dose. Take the next dose on the next day.

2.2 Dosage Modifications for Adverse Reactions

Dosage modifications for WELIREG for adverse reactions are summarized in Table 1.

The recommended dose reductions are:

  • First dose reduction: WELIREG 80 mg orally once daily
  • Second dose reduction: WELIREG 40 mg orally once daily
  • Third dose reduction: Permanently discontinue
Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction Severity Dosage Modification
Anemia [see Warnings and Precautions (5.1)] Hemoglobin <9 g/dL or transfusion indicated
  • Withhold until hemoglobin ≥9g/dL.
  • Resume at reduced dose or discontinue depending on the severity of anemia.
Life-threatening or urgent intervention indicated
  • Withhold until hemoglobin ≥9g/dL.
  • Resume at a reduced dose or permanently discontinue.
Hypoxia [see Warnings and Precautions (5.2)] Decreased oxygen saturation with exercise (e.g., pulse oximeter <88%)
  • Consider withholding until resolved.
  • Resume at the same dose or at a reduced dose depending on the severity of hypoxia.
Decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or urgent intervention indicated
  • Withhold until resolved.
  • Resume at reduced dose or discontinue depending on the severity of hypoxia.
  • Permanently discontinue.
Life-threatening or recurrent symptomatic hypoxia
  • Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6)] Grade 3
  • Withhold dosing until resolved to ≤ Grade 2.
  • Consider resuming at a reduced dose (reduce by 40 mg).
  • Permanently discontinue upon recurrence of Grade 3.
Grade 4
  • Permanently discontinue.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 40 mg, blue, oval shaped, film-coated, debossed with “177” on one side and plain on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anemia

WELIREG can cause severe anemia that can require blood transfusion.

In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia [see Adverse Reactions (6.1)]. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). In another clinical trial [Study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of WELIREG, anemia occurred in 76% of patients and 28% had Grade 3 anemia.

Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia [see Clinical Pharmacology (12.5)].

Transfuse patients as clinically indicated. For patients with hemoglobin <9g/dL, withhold WELIREG until ≥9g/dL, then resume at reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥9g/dL, then resume at a reduced dose or permanently discontinue WELIREG [see Dosage and Administration (2.2)].

The use of erythropoiesis stimulating agents (ESAs) for treatment of anemia is not recommended in patients treated with WELIREG. For patients treated with WELIREG who develop anemia, the safety and effectiveness for use of ESAs have not been established. Randomized controlled trials in patients with cancer receiving myelosuppressive chemotherapy with ESAs have shown that ESAs increased the risks of death and serious cardiovascular reactions, and decreased progression-free survival and/or overall survival. See the prescribing information for ESAs for more information.

5.2 Hypoxia

WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization [see Dosage and Administration (2.2)].

In Study 004, hypoxia occurred in 1.6% of patients [see Adverse Reactions (6.1)]. In another clinical trial [Study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of WELIREG, hypoxia occurred in 29% of patients, including Grade 3 hypoxia in 16%.

Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or Pa O2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same dose or at a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or urgent intervention indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening hypoxia or for recurrent symptomatic hypoxia, permanently discontinue WELIREG [see Dosage and Administration (2.2)].

Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

5.3 Embryo-Fetal Toxicity

Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposures (AUC) at the recommended dose of 120 mg daily.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose, since WELIREG can render some hormonal contraceptives ineffective [see Drug Interactions (7.1)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

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