5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3)].

5.2 Hypertension

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1)]. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment- emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3)].

5.3 Hepatoxicity

Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years).

Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3)].

5.4 Hemorrhagic Events

Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event.

Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3)].

5.5 Tumor Lysis Syndrome

Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

5.6 Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing.

Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on GAVRETO

Strong or Moderate CYP3A and/or P-gp Inhibitors

Concomitant use with a strong or moderate CYP3A inhibitor and/or a P-gp inhibitor increases pralsetinib exposure [Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to GAVRETO. Avoid coadministration of GAVRETO with a strong or moderate CYP3A and/or P-gp inhibitor. If coadministration with any of the above inhibitors cannot be avoided, reduce the GAVRETO dose [see Dosage and Administration (2.4)].

Strong or Moderate CYP3A Inducers

Concomitant use with a strong CYP3A inducer decreases pralsetinib exposure [see Clinical Pharmacology (12.3)], which may decrease efficacy of GAVRETO. Avoid concomitant use of GAVRETO with strong or moderate CYP3A inducers. If coadministration of GAVRETO with strong or moderate CYP3A inducers cannot be avoided, increase the GAVRETO dose [see Dosage and Administration (2.5)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with pralsetinib have not been conducted. Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay with or without metabolic activation and was not clastogenic in either an in vitro micronucleus assay in TK6 cells or an in vivo bone marrow micronucleus assay in rats.

In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats, although pralsetinib did not have clear effects on male or female mating performance or ability to become pregnant, at the 20 mg/kg dose level (approximately 2.9 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions); post- implantation loss occurred at doses as low as 5 mg/kg (approximately 0.35 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). In a separate fertility and early embryonic development study in which male rats administered 20 mg/kg pralsetinib were mated to untreated female rats, there were no clear pralsetinib-related effects on intrauterine survival of embryos or on male reproductive performance at a dose approximately 1.7 times the human exposure (AUC) at the clinical dose of 400 mg. In a 13-week repeat-dose toxicology study, male rats exhibited histopathological evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥ 10 mg/kg/day, approximately 1 times the human exposure based on AUC at the clinical dose of 400 mg.

13.2 Animal Toxicology and/or Pharmacology

In 28-day rat and monkey toxicology studies, once daily oral administration of pralsetinib resulted in histologic necrosis and hemorrhage in the heart of preterm decedents at exposures ≥ 1.3 times and ≥ 3.1 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg. Pralsetinib induced hyperphosphatemia (rats) and multi-organ mineralization (rats and monkeys) in 13-week toxicology studies at exposures approximately 2.8 times and ≥ 0.13 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg.

16 HOW SUPPLIED/STORAGE AND HANDLING

GAVRETO (pralsetinib) 100 mg, light blue, opaque, immediate release, hydroxypropyl methylcellulose (HPMC) hard capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap are supplied as follows:

• Bottles of 60 capsules (NDC 50242-210-60).
• Bottles of 90 capsules (NDC 50242-210-90).
• Bottles of 120 capsules (NDC 50242-210-12).

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

ILD/Pneumonitis

Advise patients to contact their healthcare provider if they experience new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].

Hypertension

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions (5.2)].

Hepatotoxicity

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.3)].

Hemorrhagic Events

Advise patients that GAVRETO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [see Warnings and Precautions (5.4)].

Tumor Lysis Syndrome

Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.5)].

Risk of Impaired Wound Healing

Advise patients that GAVRETO may impair wound healing. Advise patients that temporary interruption of GAVRETO is recommended prior to any elective surgery [see Warnings and Precautions (5.6)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective non-hormonal contraception during the treatment with GAVRETO and for 2 weeks after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential that GAVRETO may impair fertility [See Use in Specific Populations (8.3)].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7.1)].

Administration

Advise patients to take GAVRETO on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO) [see Dosage and Administration (2.2)].