ROZLYTREK

Treatment with Rozlytrek should be initiated by a physician experienced in the use of anticancer medicinal products. Patient selection NTRK gene fusion A validated assay is required for the selection of patients with NTRK gene fusion-positive solid tumours.

1). ROS1 gene fusion A validated assay is required for the selection of adult patients with ROS1-positive NSCLC. 1). Posology Adults The recommended dose for adults is 600 mg entrectinib once daily. Paediatric population The recommended dose for paediatric patients 12 years of age and older is 300 mg/m2 body surface area (BSA) entrectinib once daily (see Table 1).

51m2 600 mg Duration of treatment It is recommended that patients are treated with Rozlytrek until disease progression or unacceptable toxicity. Delayed or missed doses If a planned dose of Rozlytrek is missed, patients can make up that dose unless the next dose is due within 12 hours.

If vomiting occurs immediately after taking a dose of Rozlytrek, patients may repeat that dose. Dose modifications Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with Rozlytrek, in case of specified adverse reactions (see Table 4) or based on the prescriber’s assessment of the patient’s safety or tolerability.

Adults For adults, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability (see Table 2). Rozlytrek treatment should be permanently discontinued if patients are unable to tolerate a dose of 200 mg once daily.

Table 2:

Dose reduction schedule for adult patients Dose reduction schedule Dose level Recommended dose 600 mg once daily First dose reduction 400 mg once daily Second dose reduction 200 mg once daily Paediatric population For paediatric patients 12 years of age and older, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability (see Table 3).

For some patients an intermittent dosing schedule is required to achieve the recommended reduced total weekly paediatric dose. Rozlytrek treatment should be permanently discontinued if patients are unable to tolerate the lowest reduced dose.

8).

Table 4:

Recommended Rozlytrek dose modifications for adverse reactions in adult and paediatric patients Adverse reaction Severity* Dosage modification Symptomatic with middle to moderate activity or exertion, including where intervention is indicated (Grade 2 or 3) • Withhold Rozlytrek until recovered to less than or equal to Grade 1 • Resume at reduced dose Congestive heart failure Severe with symptoms at rest, minimal activity, or exertion or where intervention is indicated (Grade 4) • Withhold Rozlytrek until recovered to less than or equal to Grade 1 • Resume at reduced dose or discontinue as clinically appropriate Intolerable, but moderate changes interfering with activities of daily living (Intolerable Grade 2) • Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose or reduced dose, as clinically needed Severe changes limiting activities of daily living (Grade 3) • Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose Cognitive disorders Urgent intervention indicated for event (Grade 4) • For prolonged, severe, or intolerable events, discontinue Rozlytrek as clinically appropriate Hyperuricemia Symptomatic or Grade 4 • Initiate urate-lowering medication • Withhold Rozlytrek until improvement of signs or symptoms • Resume Rozlytrek at same or reduced dose QTc 481 to 500 ms • Withhold Rozlytrek until recovered to baseline • Resume treatment at same dose QTc greater than 500 ms • Withhold Rozlytrek until QTc interval recovers to baseline • Resume at same dose if factors that cause QT prolongation are identified and corrected • Resume at reduced dose if other factors that cause QT prolongation are not identified QT interval prolongation Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia • Permanently discontinue Rozlytrek Transaminase elevations Grade 3 • Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks Adverse reaction Severity* Dosage modification • Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks Grade 4 • Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks • Permanently discontinue for recurrent Grade 4 events ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 2 times ULN (in the absence of cholestasis or haemolysis) • Permanently discontinue Rozlytrek Anaemia or neutropenia Grade 3 or 4 • Withhold Rozlytrek until recovery to less than or equal to Grade 2 or to baseline • Resume at the same dose or reduced dose, as clinically needed Other clinically relevant adverse reactions Grade 3 or 4 • Withhold Rozlytrek until adverse reaction resolves or improves to […]

Summary of the safety profile The most common adverse reactions (≥20%) were fatigue, constipation, diarrhoea, dizziness, dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain, vomiting, pyrexia, arthralgia, increased aspartate aminotransferase and dyspnoea, cognitive disorders, cough, and increased alanine aminotransferase.

5%). 0% of patients. Tabulated list of adverse reactions Tables 5 and 6 summarise the adverse drug reactions (ADRs) occurring in 762 adults and 91 paediatric patients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, and STARTRK-2) and one clinical trial in paediatric patients (STARTRK-NG) and one clinical trial in adults and paediatric patients (TAPISTRY).

6 months. Adverse drug reactions are listed by MedDRA system organ class. The following categories of frequency have been used: 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).

Within each system organ class, the adverse reactions are presented in order of decreasing frequency. 9 * Grades 3 to 5, inclusive of fatal adverse reactions (including 4 reactions of pneumonia, 3 reactions of dyspnoea, 1 reaction of cardiac failure, and 1 reaction of tumour lysis syndrome).

1 Lung infection (bronchitis, lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection, upper respiratory tract infection) 2 Neutropenia (neutropenia, neutrophil count decreased) 3 Dizziness (dizziness, vertigo, dizziness postural) 4 Dysaesthesia (paresthesia, hyperesthesia, hypoesthesia, dysesthesia) 5 Cognitive disorders (cognitive disorder, confusional state, memory impairment, disturbance in attention, amnesia, mental status changes, hallucination, delirium, disorientation, brain fog, attention deficit hyperactivity disorder, ‘visual hallucination’, ‘auditory hallucination’, mental impairment, mental disorder) 6 Periphery sensory neuropathy (neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy) 7 Ataxia (ataxia, balance disorder, gait disturbances) 8 Sleep disturbances (hypersomnia, insomnia, sleep disorder, somnolence) 9 Mood disorders (anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation) System organ class Adverse reaction All grades (%) Frequency category (all grades) Grade ≥3 (%) 10 Vision blurred (diplopia, vision blurred, visual impairment) 11 Congestive heart failure (acute right ventricular failure, cardiac failure, cardiac failure congestive, chronic right ventricular failure, ejection fraction decreased, pulmonary oedema) 12 Hypotension (hypotension, orthostatic hypotension) 13 Rash (rash, rash maculopapular, rash pruritic, rash erythematous, rash papular) 14 Fractures (acetabulum fracture, ankle fracture, avulsion fracture, bursitis, cartilage injury, clavicle fracture, compression fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, fracture, fractured sacrum, hand fracture, hip fracture, humerus fracture, ilium fracture, jaw fracture, joint injury, limb fracture, lower limb fracture, lumbar vertebral fracture, osteoporotic fracture, […]

Efficacy across tumour types The benefit of Rozlytrek has been established in single-arm trials encompassing a relatively small sample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of Rozlytrek have been shown based on overall response rate and response duration in a limited number of tumour types.

1). , for which clinical benefit has not been established, or where such treatment options have been exhausted). 8). Patients over the age of 65 years experienced a higher incidence of these events than younger patients. Patients should be monitored for signs of cognitive changes.

2. Patients should be counselled on the potential for cognitive changes with Rozlytrek treatment. 7). 8). Bone fractures mostly occurred in paediatric patients less than 12 years of age and were localised in the lower extremity (with a predilection for femur, tibia, foot and fibula).

In both adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area. Fourteen paediatric patients had more than one occurrence of a fracture. 8). Five paediatric patients had Rozlytrek treatment interrupted due to a fracture.

Six paediatric patients discontinued treatment due to fractures. , pain, abnormal gait, changes in mobility, deformity) should be evaluated promptly. Hyperuricemia Hyperuricemia has been observed in patients treated with entrectinib.

Serum uric acid levels should be assessed prior to initiating Rozlytrek and periodically during treatment. Patients should be monitored for signs and symptoms of hyperuricemia. Treatment with urate-lowering medicinal products should be initiated as clinically indicated and Rozlytrek withheld for signs and symptoms of hyperuricemia.

2. 8). 0% of those patients upon institution of appropriate clinical management and/or Rozlytrek dose reduction/interruption. For patients with symptoms or known risk factors of CHF, left ventricular ejection fraction (LVEF) should be assessed prior to initiation of Rozlytrek treatment.

Patients receiving Rozlytrek should be carefully monitored and those with clinical signs and symptoms of CHF, including shortness of breath or oedema, should be evaluated and treated as clinically appropriate. 2. 8). Use of Rozlytrek should be avoided in patients with a baseline QTc interval longer than 450 ms, in patients with congenital long QTc syndrome, and in patients taking medicinal products that are known to prolong the QTc interval.

Rozlytrek should be avoided in patients with electrolyte imbalances or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias. If in the opinion of the treating physician, the potential benefits of Rozlytrek in a patient with any of these conditions outweigh the potential risks, additional monitoring should be performed and a specialist consultation should be considered.

Assessment of ECG and electrolytes at baseline and after 1 month of treatment with Rozlytrek are recommended. Periodic monitoring of ECGs and electrolytes as clinically indicated throughout Rozlytrek treatment, are also recommended.

2. Women of childbearing potential Rozlytrek may cause foetal harm when administered to a pregnant woman. Women of childbearing potential must use highly effective contraception methods during treatment and up to 5 weeks after the last dose of Rozlytrek.

3). 5), which could increase the frequency or severity of adverse reactions. In adult and paediatric patients 12 years and older, co-administration of Rozlytrek with a strong or moderate CYP3A inhibitor should be avoided. 2). During treatment with Rozlytrek, the consumption of grapefruit, grapefruit products, and Seville oranges should be avoided.

Co-administration of Rozlytrek with a strong or moderate CYP3A or P-gp inducer decreases entrectinib plasma concentrations (see […]

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