• Who have disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity;
• Who have not received a prior NTRK inhibitor; and
• Who have no satisfactory treatment options.

Rozlytrek is also indicated for the treatment of adult patients with ROS Oncogene 1(ROS1) positive, advanced non-small cell lung cancer (NSCLC), not previously treated with ROS1 inhibitor. Rozyltrek contains a new active substance, entrectinib, which is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC, ROS1, and anaplastic lymphoma kinase (ALK).

Posology

The recommended dose for adults is 600mg entrectinib once daily. The recommended dose for paediatric patients 12 years of age and older is 300mg/m² body surface area once daily. Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment in case of adverse reactions. For adults, the dose may be reduced up to two times, based on tolerability, and should be permanently discontinued if patients are unable to tolerate a dose of 200mg once daily. For paediatric patients 12 years of age and older, the dose of Rozlytrek may be reduced up to two times based on tolerability, and should be permanently discontinued if patients are unable to tolerate the lowest reduced dose.

The capsules should be swallowed whole and not opened or dissolved since their contents are bitter. Rozlytrek can be taken with or without food but should not be taken with grapefruit or grapefruit juice.

Precautions for use

• Patients should be counselled on the potential for cognitive changes and should be instructed not to drive or use machines until symptoms resolve. Confusion, mental status changes, memory impairment, and hallucinations, may occur

• Bone fractures were reported in clinical trials. Patients with signs or symptoms of fractures (for example, pain, abnormal gait, changes in mobility, deformity), should be evaluated promptly;

• Patients should be monitored for signs and symptoms of hyperuricemia. Treatment with urate-lowering medicinal products should be initiated as clinically indicated;

• For patients with symptoms or known risk factors for congestive heart failure, left ventricular ejection fraction should be assessed before starting treatment. Patients 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;

• Use of Rozlytrek should be avoided in patients with a baseline QTc interval longer than 450 ms, inpatients with congenital long QTc syndrome, and in patients taking medicinal products that are knownto 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, andbradyarrhythmia;

• Rozlytrek may cause foetal harm when administered to a pregnant woman. Women of childbearingpotential must use highly effective contraception methods during treatment and up to five weeks after thelast dose of Rozlytrek.Male patients with female partners of childbearing potential must use highly effective contraceptivemethods during treatment with Rozlytrek and for three months after the last dose. Female patients of childbearing potential should have medically supervised pregnancy testing prior toinitiating therapy; and

• Breast-feeding should be discontinued during treatment with Rozlytrek.

Adverse reactions

The most common adverse reactions (≥20%) were fatigue, constipation, dysgeusia, oedema, dizziness, diarrhoea, nausea, dysaesthesia, dyspnoea, anaemia, increased weight, increased blood creatinine, pain, cognitive disorders, vomiting, cough, and pyrexia. The most frequent serious adverse reactions (≥2%) were lung infection, dyspnoea, cognitive impairment, pleural effusion, and fractures. Permanent discontinuation due to an adverse reaction occurred in 4.6% of patients.

Drug-drug interactions

• The concomitant use of strong or moderate CYP3A inhibitors including ketoconazole, itraconazole, voriconazole, and grapefruit should be avoided. For adults, if coadministration is unavoidable, the use of strong or moderate CYP3A inhibitors should be limited to 14 days and the Rozlytrek dose should be reduced as follows:

• • • 100mg once daily for use with strong CYP3A inhibitors; and
    • 200 mg once daily for use with moderate CYP3A inhibitors;

• Co-administration of entrectinib with CYP3A/P-gp inducers (including carbamazepine, phenobarbital, phenytoin, St. John’s Wort) should be avoided;

• Caution is advised when treatment with strong or moderate P-gp inhibitors (for example, verapamil, nifedipine, felodipine, paroxetine) are co-administered with entrectinib;

• Entrectinib is a weak inhibitor of CYP3A4. Caution is advised when entrectinib is administered together with sensitive CYP3A4 substrates with a narrow therapeutic range (for example, cisapride, cyclosporin, fentanyl), due to the increased risk of adverse drug reactions;

• Entrectinib has inhibitory potential towards P-glycoprotein (P-gp). It is unknown whether the effect of entrectinib may be larger to sensitive oral P-gp substrates such as dabigatran etexilate;

• Inhibition of BCRP was observed in in vitro studies. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral BCRP substrates (for example, methotrexate) are co-administered;

• In vitro data indicate that entrectinib has weak inhibitory potential towards organic anion-transporting polypeptide (OATP)1B1. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral OATP1B1 substrates (for example, atorvastatin, pravastatin, rosuvastatin) are co-administered with entrectinib;

• Entrectinib may induce pregnane X receptor (PXR) regulated enzymes. Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (for example, repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure; and

• It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives are advised to add a barrier method.

EU authorisation and pack size details

This medicine is under additional monitoring (black triangle). Pharmacists should report any suspected adverse reactions to the HPRA (Health Products Regulatory Authority). Rozyltrek capsules were first authorised within the EU in July 2020 and were added to the IPU Product File with the June 2022 update, following addition to the High-Tech Medicines Scheme. The capsules should be stored in the original package with the bottle closed to protect from moisture.

High Tech Numbers:

• ROZLYTREK 100MG HARD CAPS     30 capsules 89193
• ROZLYTREK 200MG HARD CAPS      90 capsules 89194