Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Gavreto is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor.
Therapy should be initiated by a physician experienced in the administration of anticancer medicinal products.
Patient selection for treatment of RET fusion-positive advanced NSCLC should be based on a validated test method.
The recommended dose is 400 mg pralsetinib once daily on an empty stomach (see method of administration). Treatment should be continued until disease progression or unacceptable toxicity.
If vomiting occurs after taking a dose of pralsetinib, the patient should not take an additional dose but continue with the next scheduled dose.
If a dose of pralsetinib is missed, the patient should make up for the missed dose as soon as possible on the same day. The regular daily dose schedule for pralsetinib should be resumed the next day.
Interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.
Patients may have their dose reduced by 100 mg decrements to a minimum dose of 100 mg once daily. Gavreto should be permanently discontinued in patients who are unable to tolerate 100 mg orally once daily.
Recommended dose modifications for adverse reactions are indicated in Table 1.
Table 1. Recommended dose modifications for Gavreto for adverse reactions:
| Adverse reaction | Severitya | Dose modification |
|---|---|---|
| Pneumonitis/Interstitial lung disease (ILD) (see section 4.4) | Grade 1 or 2 | Interrupt treatment with Gavreto until resolution. Resume at a reduced dose. Permanently discontinue Gavreto for recurrent pneumonitis/ILD. |
| Grade 3 or 4 | Permanently discontinue for pneumonitis/ILD. | |
| Hypertension | Grade 3 | Interrupt treatment with Gavreto for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. |
| Grade 4 | Permanently discontinue Gavreto. | |
| Transaminase elevations | Grade 3 or 4 | Interrupt treatment with Gavreto and monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) once weekly until resolution to Grade 1 or baseline. Resume at a reduced dose. If the transaminase elevation recurs at Grade 3 or higher, permanently discontinue treatment with Gavreto. |
| Haemorrhagic events | Grade 3 or 4 | Interrupt treatment with Gavreto until resolution to Grade 1. Resume at a reduced dose. Permanently discontinue Gavreto for life-threatening or recurrent severe haemorrhagic events. |
| QT prolongation | Grade 3 | Interrupt treatment with Gavreto for QTc intervals >500 ms until QTc interval returns to <470 ms. Resume at the same dose if risk factors that cause QT prolongation are identified and corrected. Resume treatment at a reduced dose if other risk factors that cause QT prolongation are not identified. |
| Grade 4 | Permanently discontinue Gavreto if the patient has life-threatening arrhythmia. | |
| Other clinically significant adverse reactions (see section 4.8) | Grade 3 or 4 | Interrupt treatment with Gavreto until improvement to ≤Grade 2. Resume at a reduced dose. Permanently discontinue for recurrent Grade 4 adverse reactions. |
a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
Concomitant use of pralsetinib with known strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided (see section 4.4 and section 4.5). If co-administration with a strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor cannot be avoided, the current dose of pralsetinib should be reduced as recommended in Table 2. After the strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor have been discontinued for 3 to 5 elimination half-lives, the pralsetinib dose that was taken prior to the use of the inhibitor should be resumed.
Table 2. Recommended dose modifications for Gavreto for co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors:
| Current Gavreto dose | Recommended Gavreto dose |
|---|---|
| 400 mg orally once daily | 200 mg orally once daily |
| 300 mg orally once daily | 200 mg orally once daily |
| 200 mg orally once daily | 100 mg orally once daily |
Concomitant use of pralsetinib with strong CYP3A4 inducers should be avoided (see section 4.4 and section 4.5). If concomitant use with a strong CYP3A4 inducer cannot be avoided, the dose of pralsetinib should be increased to double the current pralsetinib dose starting on Day 7 of co-administration of pralsetinib with the strong CYP3A4 inducer. After the strong CYP3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose that was taken prior to the use of the inducer should be resumed.
No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLCR] 30 to 89 mL/min estimated by Cockcroft-Gault). Pralsetinib has not been studied in patients with severe renal impairment (CLCR 15 to 29 mL/min) or end-stage renal disease (CLCR <15 mL/min). Since pralsetinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment or end-stage renal disease (see section 5.2).
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST). Pralsetinib has not been studied in patients with moderate or severe hepatic impairment, therefore its use in patients with moderate or severe hepatic impairment is not recommended (see section 5.2).
No dose adjustment is recommended for patients aged 65 years and above (see section 5.1).
The safety and efficacy of pralsetinib in paediatric patients below 18 years of age with RET fusion-positive advanced NSCLC have not been established. No data are available.
Gavreto is for oral use. Patients should swallow the hard capsules whole with a glass of water, on an empty stomach. They should not eat for at least two hours before and at least one hour after taking pralsetinib (see section 5.2).
No cases of overdose have been reported in clinical trials with pralsetinib. The maximum dose of pralsetinib studied clinically is 600 mg orally once daily. Adverse reactions observed at this dose were consistent with the safety profile at 400 mg once daily (see section 4.8).
There is no known antidote for Gavreto overdose. In the event of suspected overdose, Gavreto should be interrupted and supportive care instituted. Based on the large volume of distribution of pralsetinib and extensive protein binding, dialysis is unlikely to result in significant removal of pralsetinib.
2 years.
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
High density polyethylene (HDPE) bottle with child-resistant closure (polypropylene) and foiled induction seal liner and desiccant sachet (silica gel).
Pack sizes: 60, 90 or 120 capsules.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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