Gavreto
(pralsetinib)Dosage & Administration
Select patients for treatment with GAVRETO based on the presence of a RET gene fusion.
The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO).
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Gavreto Prescribing Information
Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
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.
RET Fusion-Positive Thyroid Cancer
GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Patient Selection
Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) [see Clinical Studies (14)].
Information on FDA-approved tests for RET gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics.
An FDA-approved test for the detection of RET gene fusion (thyroid cancer) is not currently available.
Recommended Dosage
The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO) [see Clinical Pharmacology (12.3)]. Continue treatment until disease progression or until unacceptable toxicity.
If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day.
Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.
Dosage Modifications for Adverse Reactions
The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2.
| Dose Reduction | Recommended Dosage |
|---|---|
| First | 300 mg once daily |
| Second | 200 mg once daily |
| Third | 100 mg once daily |
Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.
The recommended dosage modifications for adverse reactions are provided in Table 2.
| Adverse Reaction | Severity * | Dosage Modification |
|---|---|---|
| ||
| ILD/Pneumonitis [see Warnings and Precautions (5.1)] | Grade 1 or 2 | Withhold GAVRETO until resolution. Resume by reducing the dose as shown in Table 1. |
| Permanently discontinue GAVRETO for recurrent ILD/pneumonitis. | ||
| Grade 3 or 4 | Permanently discontinue for confirmed ILD/pneumonitis. | |
| Hypertension [see Warnings and Precautions (5.2)] | Grade 3 | Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. |
| Grade 4 | Discontinue GAVRETO. | |
| Hepatotoxicity [see Warnings and Precautions (5.3)] | Grade 3 or 4 | Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. |
| Resume at reduced dose . | ||
| For recurrent events at Grade 3 or higher, discontinue GAVRETO. | ||
| Hemorrhagic Events [see Warnings and Precautions (5.4)] | Grade 3 or 4 | Withhold GAVRETO until recovery to baseline or Grade 0 or 1. |
| Discontinue GAVRETO for severe or life-threatening hemorrhagic events. | ||
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 or 4 | Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose . |
| Permanently discontinue for recurrent Grade 4 adverse reactions. | ||
Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors
Avoid coadministration of GAVRETO with any of the following:
- Strong CYP3A inhibitors
- Moderate CYP3A inhibitors
- P-gp inhibitors
- Combined P-gp and strong CYP3A inhibitors
- Combined P-gp and moderate CYP3A inhibitors
If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
| Current GAVRETO Dosage | Recommended GAVRETO Dosage when Coadministered with: | |
|---|---|---|
| Combined P-gp and Strong CYP3A Inhibitors |
| |
| 400 mg orally once daily | 200 mg orally once daily | 300 mg orally once daily |
| 300 mg orally once daily | 200 mg orally once daily | 200 mg orally once daily |
| 200 mg orally once daily | 100 mg orally once daily | 100 mg orally once daily |
Dose Modification for Use with CYP3A Inducers
Avoid coadministration of GAVRETO with any of the following:
- Strong CYP3A inducers
- Moderate CYP3A inducers
If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
| Current GAVRETO Dosage | Recommended GAVRETO Dosage when Coadministered with: | |
|---|---|---|
| Strong CYP3A Inducers | Moderate CYP3A Inducers | |
| 400 mg orally once daily | 800 mg orally once daily | 600 mg orally once daily |
| 300 mg orally once daily | 600 mg orally once daily | 500 mg orally once daily |
| 200 mg orally once daily | 400 mg orally once daily | 300 mg orally once daily |
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.
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 no available data on GAVRETO use in pregnant women to inform drug-associated risk. 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 (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In an embryo-fetal development study, once daily oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at dose levels ≥ 20 mg/kg (approximately 1.8 times the human exposure based on area under the curve [AUC] at the clinical dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose level (approximately 0.6 times the human exposure based on AUC at the clinical dose of 400 mg). Once daily oral administration of pralsetinib at dose levels ≥ 5 mg/kg (approximately 0.2 times the human AUC at the clinical dose of 400 mg) resulted in an increase in visceral malformations and variations (absent or small kidney and ureter, absent uterine horn, malpositioned kidney or testis, retroesophageal aortic arch) and skeletal malformations and variations (vertebral and rib anomalies and reduced ossification).
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 adverse reactions in breastfed children, advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose.
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 (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating GAVRETO [see Use in Specific Populations (8.1)].
Contraception
GAVRETO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. GAVRETO may render hormonal contraceptives ineffective.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.
Infertility
Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, GAVRETO may impair fertility [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for RET fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of RET fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
The safety and effectiveness of GAVRETO have not been established in pediatric patients with RET fusion-positive NSCLC or in pediatric patients younger than 12 years old with RET fusion-positive thyroid cancer.
Animal Toxicity Data
In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur occurred at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. In rats there were findings of increased physeal thickness in the femur and sternum as well as tooth (incisor) abnormalities (fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) in both 4- and 13-week studies at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. Recovery was not assessed in the 13-week toxicology study, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.
Monitor growth plates in adolescent patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.
Geriatric Use
Of the 540 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years and over.
No overall differences in pharmacokinetics (PK), safety or effectiveness were observed between patients aged 65 years or older and younger patients.
Hepatic Impairment
No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Clinical Pharmacology (12.3)].
None.
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)].
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)].
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)].
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)].
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.
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.
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)].