Gavreto

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. Posology 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. Missed doses 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. Medicinal product no longer authorised 3 Dose modifications for adverse reactions 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.

Medicinal product no longer authorised 4 Table 1. 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.

0%). 2%). 4%). Based on the data from clinical trials, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures, with a faster time to onset for adverse reactions with increasing pralsetinib exposure.

7% of patients treated with Gavreto. 1%). 6% of patients treated with Gavreto. 2%, respectively). 1. No clinically relevant differences in the safety profile across indications have been observed. Adverse reactions reported in patients treated with Gavreto in the ARROW trial are listed below (Table 3), according to the MedDRA System Organ Class and frequency.

Frequencies are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Within each system organ class, adverse reactions are presented in order of decreasing frequency and severity. Medicinal product no longer authorised 11 Table 3. 5 1 includes pneumonia, pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, atypical pneumonia, lung infection, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, pneumonia streptococcal, pneumonia moraxella, pneumonia staphylococcal, pneumonia pseudomonal, atypical mycobacterial pneumonia, pneumonia legionella 2 most of the cases reported extrapulmonary tuberculosis such as lymph node tuberculosis, peritoneal tuberculosis or renal tuberculosis 3 includes anaemia, haematocrit decreased, red blood cell count decreased, haemoglobin decreased, aplastic anaemia 4 includes neutrophil count decreased, neutropenia 5 includes white blood cell count decreased, leukopenia 6 includes lymphopenia, lymphocyte count decreased 7 includes thrombocytopenia, platelet count decreased 8 includes headache, tension headache 9 includes ageusia, dysgeusia 10 includes hypertension, blood pressure increased 11 includes 39 preferred terms from the SMQ Haemorrhage (excl laboratory terms) narrow, with the exclusion of terms related to invasive drug administration, terms related to rupture, disseminated intravascular coagulopathy, terms related to traumatic haemorrhages, and haemorrhagic terms related to pregnancy, birth or neonatal 12 includes cough, productive cough 13 includes pneumonitis, interstitial lung disease 14 includes abdominal pain, abdominal pain upper 15 includes stomatitis, aphthous ulcer 16 includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, blood bilirubin unconjugated increased 17 includes rash, rash maculo-papular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pustular, rash macular, rash erythematous 18 includes musculoskeletal […]

8). Patients who present with clinically symptomatic pneumonitis or ILD were excluded from clinical trials. Patients should be advised to contact their healthcare provider immediately to report new or worsening respiratory symptoms. , dyspnoea, cough, and fever) should be investigated to exclude other potential causes.

2). 8). Treatment- related hypertension was most commonly managed with anti-hypertensive medicinal products. Treatment with Gavreto should not be initiated in patients with uncontrolled hypertension. Pre- existing hypertension should be adequately controlled before starting Gavreto treatment.

Monitoring of blood pressure is recommended after 1 week, at least monthly thereafter and as clinically indicated. Anti-hypertensive therapy should be initiated or adjusted as appropriate. 2). 8). ALT and AST should be monitored prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated.

2). Medicinal product no longer authorised 7 Haemorrhagic events Severe, including fatal, haemorrhagic events can occur with Gavreto. 2). 8). Therefore, before starting Gavreto treatment, patients should have a QTc interval ≤470 ms and serum electrolytes within normal range.

Hypokalaemia, hypomagnesaemia, and hypocalcaemia should be corrected both prior and during Gavreto treatment. g. intercurrent diarrhoea, vomiting, nausea, concomitant medications). Pralsetinib should be used with caution in patients with medical history of cardiac arrhythmias or QT interval prolongation, as well as in patients on strong CYP 3A4 inhibitors or on medicinal products known to be associated with QT/QTc prolongation.

2). Tuberculosis Tuberculosis, mostly extrapulmonary, has been reported in patients receiving Gavreto. Before starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations.

1.