Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Cognitive disorders

Cognitive disorders, including confusion, mental status changes, memory impairment, and hallucinations, were reported in clinical trials with Rozlytrek (see section 4.8). 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.

Based on the severity of cognitive disorders, Rozlytrek treatment should be modified as described in Table 3 in section 4.2.

Patients should be counselled on the potential for cognitive changes with Rozlytrek treatment. Patients should be instructed not to drive or use machines until symptoms resolve if they experience cognitive disorders (see section 4.7).

Fractures

Fractures have been reported in 25.0% (19/76) paediatric patients treated with Rozlytrek in clinical trials (see section 4.8). 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. Thirteen paediatric patients had more than one occurrence of a fracture and 3 paediatric patients had Rozlytrek treatment interrupted due to a fracture. The majority of fracture events experienced by the paediatric patients resolved. Five paediatric patients discontinued treatment due to fractures.

Patients with signs or symptoms of fractures (e.g., 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.
Rozlytrek dose should be modified based on severity as described in Table 3 in section 4.2.

Congestive heart failure

Congestive heart failure (CHF) has been reported in less than 5% of patients across clinical trials with Rozlytrek (see section 4.8). These reactions were observed in patients with or without a history of cardiac disease and resolved in 70% 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.

Based on the severity of CHF, Rozlytrek treatment should be modified as described in Table 3 in section 4.2.

QTc interval prolongation

QTc interval prolongation has been observed in patients treated with Rozlytrek in clinical trials (see section 4.8).

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.

Based on the severity of QTc prolongation, Rozlytrek treatment should be modified as described in Table 3 in section 4.2.

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.
Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment with Rozlytrek and for 3 months after the last dose (see sections 4.6 and 5.3).

Drug interactions

Co-administration of Rozlytrek with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations (see section 4.5), which could increase the frequency or severity of adverse reactions. In adult patients, co-administration of Rozlytrek with a strong or moderate CYP3A inhibitor should be avoided. For adult patients, if co-administration is unavoidable, the Rozlytrek dose should be reduced (see section 4.2).

During treatment with Rozlytrek, the consumption of grapefruit and grapefruit products should be avoided.

Co-administration of Rozlytrek with a strong or moderate CYP3A or P-gp inducer decreases entrectinib plasma concentrations (see section 4.5), which may reduce efficacy of Rozlytrek, and should be avoided.

Lactose intolerance

Rozlytrek contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sunset yellow FCF (E110)

Rozlytrek 200 mg hard capsules contain sunset yellow FCF (E110), which may cause allergic reactions.

Effects on Driving

4.7    Effects on ability to drive and use machines

Rozlytrek has moderate influence on the ability to drive and use machines. Patients should be instructed not to drive or use machines until the symptoms resolve, if they experience cognitive adverse reactions, syncope, blurred vision, or dizziness, during treatment with Rozlytrek (see sections 4.4 and 4.8).