GAVRETO Capsule (2020)

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Blueprint Medicines Corporation

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1. Indications and Usage

GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. This indication is approved ...

2. Dosage and Administration

2.1 Patient Selection Select patients for treatment with GAVRETO based on the presence of a RET gene fusion [see Clinical Studies (14)]. 2.2 Recommended Dosage The recommended dosage ...

3. Dosage Forms and Strengths

Capsules: 100 mg, light blue, opaque, hard hydroxypropyl methylcellulose (HPMC) capsule printed with BLU-667 on the capsule shell body and 100 mg on the capsule shell cap.

4. Contraindications

None.

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 10% of patients ...

6. Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Hypertension [see ...

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 ...

7. Drug Interactions

7.1 Effects of Other Drugs on GAVRETO Strong CYP3A Inhibitors Avoid coadministration with strong CYP3A inhibitors. Coadministration of GAVRETO with a strong CYP3A inhibitor increases pralsetinib exposure, ...

8.1. Pregnancy

Risk Summary Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are ...

8.2. Lactation

Risk Summary There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious ...

8.3. Females and Males of Reproductive Potential

Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily [see Use in Specific Populations ...

8.4. Pediatric Use

The safety and effectiveness of GAVRETO have not been established in pediatric patients. Animal Toxicity Data In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur ...

8.5. Geriatric Use

Of the 438 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 30% were 65 years or older. No overall differences in pharmacokinetics (PK), safety or efficacy were observed ...

8.6. Hepatic Impairment

GAVRETO has not been studied in patients with moderate hepatic impairment (total bilirubin >1.5 to 3.0 × upper limit of normal [ULN] and any aspartate aminotransferase [AST]) or severe hepatic impairment ...

11. Description

Pralsetinib is an oral receptor tyrosine kinase inhibitor. The chemical name for pralsetinib is (cis)N((S)1(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1 ...

12.1. Mechanism of Action

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s ...

12.2. Pharmacodynamics

Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized. Cardiac Electrophysiology The QT interval prolongation potential of GAVRETO ...

12.3. Pharmacokinetics

At 400 mg once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (Cmax) and area under the concentration-time ...

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 ...

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 ≥1.1 times and ≥2.6 ...

14. Clinical Studies

The efficacy of GAVRETO was evaluated in patients with RET fusion-positive metastatic NSCLC in a multicenter, non-randomized, open-label, multi-cohort clinical trial (ARROW, NCT03037385). The ...

16.1. How Supplied

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 ...

16.2. Storage and Handling

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 ...