Posology : מינונים

4.2   Posology and method of administration

Treatment with Rozlytrek should be initiated by a physician experienced in the use of anticancer medicinal products.

Patient selection

NTRK gene fusion-positive solid tumours
A validated assay is required for the selection of patients with NTRK gene fusion-positive solid tumours. NTRK gene fusion-positive status must be established prior to initiation of Rozlytrek therapy (see section 5.1).

ROS1-positive non-small cell lung cancer
A validated assay is required for the selection of patients with ROS1-positive NSCLC. ROS1-positive status must be established prior to initiation of Rozlytrek therapy (see section 5.1).

Posology

Adults
The recommended dose for adults is 600 mg entrectinib once daily.
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 3) 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 
Recommendations for Rozlytrek dose modifications for adult patients in case of specific adverse reactions are provided in Table 3 (see sections 4.4 and 4.8).

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

Adverse
Severity*                                Dosage modification reaction
• 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          Permanently discontinue Rozlytrek 1.5 times ULN (in the absence of cholestasis or haemolysis)
• Withhold Rozlytrek until recovery to less
Anaemia or                                                    than or equal to Grade 2 Grade 3 or 4 neutropenia                                                 • Resume at the same dose or reduced dose, as clinically needed
•     Withhold Rozlytrek until improvement or
Vision                                                            stabilization.
Disorders             Grade 2 or above
•      Resume at same dose or reduced dose, as clinically appropriate.
Other clinically      Grade 3 or 4                          • Withhold Rozlytrek until adverse reaction relevant                                                      resolves or improves to recovery or adverse                                                       improvement to Grade 1 or baseline reactions
• Resume at the same or 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
* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0

Strong or moderate CYP3A inhibitors
The concomitant use of strong or moderate CYP3A inhibitors in adults patients, should be avoided (see section 4.4).

For adults, if coadministration is unavoidable, the Rozlytrek dose should be reduced as follows:
•     100 mg once daily for use with strong CYP3A inhibitors (see section 4.5)
•     200 mg once daily for use with moderate CYP3A inhibitors.

After discontinuation of a strong or moderate CYP3A inhibitor for 3 to 5 elimination half-lives, resume the Rozlytrek dose that was taken prior to initiating the CYP3A inhibitor (see section 4.5).

Special populations

Elderly
No dose adjustment is required in patients ≥ 65 years of age (see section 5.2).


Hepatic impairment
No dose adjustment is recommended for patients with mild (total bilirubin ≤ 1.5 times ULN) hepatic impairment. Rozlytrek has not been studied in patients with moderate (total bilirubin  1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment.

Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment. Entrectinib has not been studied in patients with severe renal impairment (see section 5.2).

Paediatric population
Rozlytrek is not indicated for patients less than 18 years of age.

Method of administration
Rozlytrek is for oral use. The hard capsules should be swallowed whole and must not be opened, crushed, chewed or dissolved since the contents of the capsule are very bitter. Rozlytrek can be taken with or without food (see section 5.2) but should not be taken with grapefruit or grapefruit juice (see section 4.5).