Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients older than 1 month with solid tumours that have a NTRK gene fusion,
Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.
Treatment with Rozlytrek should be initiated by a physician experienced in the use of anticancer medicinal products.
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).
A validated assay is required for the selection of adult patients with ROS1-positive NSCLC. ROS1-positive status must be established prior to initiation of Rozlytrek therapy (see section 5.1).
Rozlytrek is available as hard capsules or film-coated granules.
The physician should prescribe the most appropriate pharmaceutical form according to the dose required and patient needs.
The recommended dose for adults is 600 mg entrectinib once daily.
The recommended dose for paediatric patients >6 months of age is based on body surface area (BSA) (see Table 1). Patients who have difficulty or are unable to swallow capsules but can swallow soft food, may receive treatment with Rozlytrek film-coated granules. Refer to the Rozlytrek film-coated granules SmPC for prescribing information.
Table 1. Recommended dosing for paediatric patients >6 months:
| Body surface area (BSA)* | Once daily dose |
|---|---|
| ≤0.42 m² | 250 mg/m²** |
| 0.43 m² to 0.50 m² | 100 mg |
| 0.51 m² to 0.80 m² | 200 mg |
| 0.81 m² to 1.10 m² | 300 mg |
| 1.11 m² to 1.50 m² | 400 mg |
| ≥1.51 m² | 600 mg |
* BSA categories and recommended dosing in Table 1 are based on closely matching exposures to a target dose of 300 mg/m²
** To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used. Refer to the Method of Administration section below and section 6.6.
The recommended dose for paediatric patients >1 month to ≤6 months of age is 250 mg/m² BSA entrectinib once daily, using capsules prepared as an oral suspension.
Capsules administered as an oral suspension (oral or enteral use) enable dosing increments of 10 mg. The daily dose to be administered should be rounded to the nearest 10 mg increment as described in the Method of administration section below and section 6.6.
It is recommended that patients are treated with Rozlytrek until disease progression or unacceptable toxicity.
If a planned dose of Rozlytrek is missed, patients can make up that dose unless the next dose is due within 12 hours.
For whole capsules, if vomiting occurs immediately after taking a dose of Rozlytrek, patients may repeat that dose.
For capsules administered as an oral suspension by individuals other than the healthcare professional (e.g., caregivers or parents) and partial or total vomiting/spitting occurs immediately after taking an administered dose, caregivers should consult the healthcare professional for the next steps.
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.
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.
For paediatric patients older than 1 month, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability (see Table 2).
Table 2. Dose reduction schedule for adult and paediatric patients:
| Starting dose once daily | First dose reduction | Second dose reduction | |
|---|---|---|---|
| 250 mg/m² | Reduce the once daily dose to two thirds of the starting dose* | Reduce the once daily dose to one third of the starting dose* | Permanently discontinue Rozlytrek in patients who are unable to tolerate Rozlytrek after two dose reductions. |
| 100 mg | 50 mg or 100 mg once daily, according to schedule** | 50 mg once daily | |
| 200 mg | 150 mg once daily | 100 mg once daily | |
| 300 mg | 200 mg once daily | 100 mg once daily | |
| 400 mg | 300 mg once daily | 200 mg once daily | |
| 600 mg | 400 mg once daily | 200 mg once daily |
* To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used. Refer to the Method of administration section below and section 6.6.
** Monday (100 mg), Tuesday (50 mg), Wednesday (100 mg), Thursday (50 mg), Friday (100 mg), Saturday (50 mg), and Sunday (100 mg).
Recommendations for Rozlytrek dose modifications for adult and paediatric 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 and paediatric patients:
| Adverse reaction | Severity* | Dosage modification |
|---|---|---|
| Congestive heart failure | 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 |
| 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 | |
| Cognitive disorders | 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 | |
| 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 |
| QT interval prolongation | 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 | |
| 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 • 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 recovery or improvement to Grade 1 or baseline • Resume at the same or reduced dose, if resolution occurs within 4 weeks • Consider permanent discontinuation 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.
The concomitant use of strong or moderate CYP3A inhibitors in adult and paediatric patients older than 1 month should be avoided (see section 4.4).
For adults, if co-administration is unavoidable, the use of strong or moderate CYP3A inhibitors with Rozlytrek should be limited to 14 days and the Rozlytrek dose should be reduced as follows:
After discontinuation of the concomitant strong or moderate CYP3A inhibitors, the Rozlytrek dose that was taken prior to initiating the strong or moderate CYP3A inhibitor can be resumed. A wash-out period may be required for CYP3A4 inhibitors with a long half-life (see section 4.5).
No dose adjustment is required in patients ≥65 years of age (see section 5.2).
No dose adjustment is recommended for patients with mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment (see section 5.2). Patients with severe hepatic impairment should be carefully monitored for hepatic function and adverse reactions (see Table 3).
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).
The safety and efficacy of entrectinib in paediatric patients 1 month of age and younger have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.
Rozlytrek is for oral use or enteral use (e.g., gastric or nasogastric).
Rozlytrek can be taken with or without food (see section 5.2) but should not be taken with grapefruit, grapefruit juice, or Seville oranges (see section 4.5).
The hard capsules should be swallowed whole. Do not crush or chew the capsules.
For details on preparation of capsules as an oral suspension, see section 6.6.
Rozlytrek should be taken immediately after preparation as an oral suspension. Discard the suspension if not used within 2 hours (see section 6.4).
The patient should drink water after taking the oral suspension to ensure the medicinal product has been completely swallowed. If enteral (e.g., gastric or nasogastric) administration is required, administer the oral suspension via the tube. The tube should be flushed with water or milk after delivering Rozlytrek. Follow the manufacturer’s instructions for the enteral tube to administer the medicine, see section 6.6.
Detailed instructions on the administration of the capsules prepared as an oral suspension are given in the Instructions for Use (IFU) at the end of the package leaflet.
Patients who experience overdose should be closely supervised and supportive care instituted. There are no known antidotes for entrectinib.
4 years.
Following preparation as an oral suspension, use immediately. Discard the oral suspension if not used within 2 hours.
Store in the original package and keep the bottle tightly closed in order to protect from moisture.
Following preparation as an oral suspension, do not store above 30°C and use within 2 hours.
Rozlytrek 100 mg hard capsules:
HDPE bottles containing 30 hard capsules with a child-resistant, tamper-evident closure and silica gel desiccant integrated in the cap.
Rozlytrek 200 mg hard capsules:
HDPE bottles containing 90 hard capsules with a child-resistant, tamper-evident closure and silica gel desiccant integrated in the cap.
The capsule(s) should be opened carefully and the contents mixed with room temperature drinking water or milk to prepare an oral suspension (see Table 11). Do not touch your eyes, nose or mouth during the preparation of the oral suspension.
Prior to administration of the first dose, the HCP should indicate to the patient or caregiver the exact volume of water or milk to be added to the capsule(s) content to prepare the oral suspension and the exact volume of the oral suspension to withdraw for reaching the recommended dose based on section 4.2 and Table 11.
Provide the patient or caregiver with a measuring device (e.g., oral syringe). The syringe (with 0.5 mL graduation marks) and a cup (empty and clean) with adequate capacity to contain the suspension volume to be prepared should be available. The syringe and cup are not included in the package.
The syringe and cup could be reused according to the manufacturer’s guidelines. The HCP should indicate to the patient or caregiver that the syringe and cup should be exclusively used for Rozlytrek suspension preparation and should be keep out of the sight and reach of children or other persons that are not caregivers or parents.
The oral suspension should be taken immediately. Discard the suspension if not used within 2 hours.
Table 11. Preparation of Rozlytrek capsules as an oral suspension:
| Prescribed dose of Rozlytrek to be given | Number of 100 mg or 200 mg capsules needed | Amount of water or milk to be mixed with the content of the capsule(s) to prepare the suspension | Amount of suspension to withdraw in order to reach the prescribed dose |
|---|---|---|---|
| 20 mg | One 100 mg | 5 mL | 1 mL |
| 30 mg | One 100 mg | 5 mL | 1.5 mL |
| 40 mg | One 100 mg | 5 mL | 2 mL |
| 50 mg | One 100 mg | 5 mL | 2.5 mL |
| 60 mg | One 100 mg | 5 mL | 3 mL |
| 70 mg | One 100 mg | 5 mL | 3.5 mL |
| 80 mg | One 100 mg | 5 mL | 4 mL |
| 90 mg | One 100 mg | 5 mL | 4.5 mL |
| 100 mg | One 100 mg | 5 mL | 5 mL |
| 110 mg | One 200 mg | 10 mL | 5.5 mL |
| 120 mg | One 200 mg | 10 mL | 6 mL |
| 130 mg | One 200 mg | 10 mL | 6.5 mL |
| 140 mg | One 200 mg | 10 mL | 7 mL |
| 150 mg | One 200 mg | 10 mL | 7.5 mL |
| 200 mg | One 200 mg | 10 mL | 10 mL |
| 300 mg | Three 100 mg | 15 mL | 15 mL |
| 400 mg | Two 200 mg | 20 mL | 20 mL |
| 600 mg | Three 200 mg | 30 mL | 30 mL |
Detailed instructions on preparation and administration of the capsules as an oral suspension are given in the IFU at the end of the package leaflet.
Any unused medicinal product or waste material, including the remaining suspension (not administered) should be disposed of in accordance with local requirements. The remaining suspension (not administered) should not be discarded in wastewater. These measures will help protect the environment.
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