Rozlytrek

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rozlytrek 100 mg hard capsules 
Rozlytrek 200 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Rozlytrek 100 mg hard capsules 
 
Each hard capsule contains 100 mg of entrectinib. 
 
Excipients with known effect 
Each hard capsule contains 65 mg lactose. 
 
Rozlytrek 200 mg hard capsules 
 
Each hard capsule contains 200 mg of entrectinib. 
 
Excipients with known effect 
Each hard capsule contains 130 mg lactose, and 0.6 mg of the azo colouring agent sunset yellow FCF 
(E110). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
 
Rozlytrek 100 mg hard capsules 
 
Size 2 (18 mm in length), hard capsule with yellow opaque body and cap with ENT 100 imprinted in 
blue on the body. 
 
Rozlytrek 200 mg hard capsules 
 
Size 0 (21.7 mm in length), hard capsule with orange opaque body and cap with ENT 200 imprinted in 
blue on the body. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age 
and older with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,  
• who have a disease that is locally advanced, metastatic or where surgical resection is likely to 

result in severe morbidity, and 
• who have not received a prior NTRK inhibitor 



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• who have no satisfactory treatment options (see sections 4.4 and 5.1).  
 
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.  
 
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. 
 
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).  
 
Table 1: Recommended dosing for paediatric patients 
 

Body surface area (BSA) Once daily dose 

1.11 m2 to 1.50 m2 400 mg 

≥ 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. 
 



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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.  
 
Table 3: Dose reduction schedule for paediatric patients 
 
Action BSA of 1.11 m2 to1.50 m2 

(once/day) 
BSA ≥ 1.51 m2 

(once/day) 
Recommended dose  400 mg 600 mg 
First dose reduction  300 mg 400 mg 
Second dose reduction  200 mg, for 5 days each week* 200 mg 
*5 days each week: Monday, Wednesday, Friday, Saturday, and Sunday 

 
Recommendations for Rozlytrek dose modifications for adult and paediatric patients in case of 
specific adverse reactions are provided in Table 4 (see sections 4.4 and 4.8). 
 
Table 4: 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 



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Adverse 
reaction Severity* 

Dosage modification 

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 



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Adverse 
reaction Severity* 

Dosage modification 

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 

 
Strong or moderate CYP3A inhibitors 
The concomitant use of strong or moderate CYP3A inhibitors in adults and paediatric patients 
12 years and older, should be avoided (see section 4.4). 
 
For adults, if coadministration 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: 
• 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 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). 
 
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 hepatic impairment. Entrectinib has not 
been studied in patients with moderate and severe hepatic impairment (see section 5.2). 
 
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 
The safety and efficacy of entrectinib in children below 12 years of age 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.  
 
Method of administration 
 
Rozlytrek is for oral use. The hard capsules should be swallowed whole and must not be opened 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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 



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4.4 Special warnings and precautions for use 
 
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. 
The effect may be quantitatively different depending on tumour type, as well as on concomitant 
genomic alterations (see section 5.1). For these reasons, Rozlytrek should only be used if there are no 
satisfactory treatment options (i.e., for which clinical benefit has not been established, or where such 
treatment options have been exhausted). 
 
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 4 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 21.9% (7/32) paediatric patients treated with Rozlytrek in clinical 
trials (see section 4.8). Bone fractures were reported in patients less than 12  years of age and were 
localised in the lower extremity (with a predilection for hip, femur and tibia). Bone fractures in 
paediatric patients generally occurred with minimal or no trauma. Three patients had more than one 
occurrence of a fracture and 3  patients had Rozlytrek treatment interrupted due to a fracture. All 
patients continued Rozlytrek treatment and all but one event of fracture recovered. 
 
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 4 in section 4.2. 
 
Congestive heart failure 
 
Congestive heart failure (CHF) has been reported 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 
upon treatment with diuretics 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.  



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Based on the severity of CHF, Rozlytrek treatment should be modified as described in Table 4 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 4 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 and paediatric patients 12  years and older, 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. 
 



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Sunset yellow FCF (E110) 
 
Rozlytrek 200 mg hard capsules contain sunset yellow FCF (E110), which may cause allergic 
reactions. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of entrectinib on other medicinal products 
 
Effect of entrectinib on CYP substrates 
Entrectinib is a weak inhibitor of CYP3A4. Co-administration of entrectinib 600 mg once daily with 
oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but 
reduced midazolam Cmax by 21%. Caution is advised when entrectinib is administered together with 
sensitive CYP3A4 substrates with a narrow therapeutic range (e.g., cisapride, cyclosporin, ergotamine, 
fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus), due to the increased risk of 
adverse drug reactions. 
 
Effect of entrectinib on P-gp substrates 
In vitro data suggest that entrectinib has inhibitory potential towards P-glycoprotein (P-gp). 
 
Co-administration of a single 600 mg dose of entrectinib with digoxin (a sensitive P-gp substrate) 
increased digoxin Cmax by 28% and AUC by 18%. The renal clearance of digoxin was similar between 
treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of 
entrectinib on renal clearance of digoxin. 
 
The effect of entrectinib on digoxin absorption is not considered clinically relevant, but it is unknown 
whether the effect of entrectinib may be larger on more sensitive oral P-gp substrates such as 
dabigatran etexilate. 
 
Effect of entrectinib on BCRP substrates 
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 (e.g. methotrexate, mitoxantrone, topotecan, lapatinib) are co-administered with entrectinib, 
due to the risk of increased absorption. 
 
Effect of entrectinib on other transporter substrates 
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 (e.g. atorvastatin, pravastatin, rosuvastatin repaglinide, 
bosentan) are co-administered with entrectinib, due to the risk of increased absorption. 
 
Effect of entrectinib on substrates of PXR regulated enzymes 
In vitro studies indicate that entrectinib may induce pregnane X receptor (PXR) regulated enzymes 
(e.g. CYP2C family and UGT). Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19 
substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure. 
 
Oral contraceptives 
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 (see section 4.6). 
 
Effects of other medicinal products on entrectinib 
 
Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib 
and formation of its major active metabolite M5. 
 



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Effect of CYP3A or P-gp inducers on entrectinib 
Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose 
of entrectinib reduced entrectinib AUCinf by 77% and Cmax by 56%. 
 
Co-administration of entrectinib with CYP3A/P-gp inducers (including, but not limited to, 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's Wort -Hypericum 
perforatum-, apalutamide, ritonavir) should be avoided. 
 
Effect of CYP3A or P-gp inhibitors on entrectinib 
Co-administration of itraconazole, a strong CYP3A4 inhibitor, with a single oral dose of entrectinib 
increased AUCinf by 600% and Cmax by 173%. 
 
Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, ritonavir, 
saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit or Seville oranges) 
should be avoided. If concurrent use of strong or moderate inhibitors of CYP3A4 is unavoidable, dose 
adjustment of entrectinib is required (see section 4.2). 
 
Although, a marked effect of inhibitory P-gp medicinal products on entrectinib pharmacokinetics is 
not expected, caution is advised when treatment with strong or moderate P-gp inhibitors (e.g. 
verapamil, nifedipine, felodipine, fluvoxamine, paroxetine) are co-administered with entrectinib due to 
risk of increased entrectinib exposure (see section 5.2). 
 
Effect of medicinal products that increase gastric pH on entrectinib 
Co-administration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg entrectinib 
dose reduced entrectinib AUC by 25% and Cmax by 23%. 
 
No dose adjustments are required when entrectinib is co-administered with PPIs or other drugs that 
raise gastric pH (e.g., H2 receptor antagonists or antacids). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in males and females 
 
Female patients of childbearing potential should have medically supervised pregnancy testing prior to 
initiating Rozlytrek therapy. 
 
Female patients of childbearing potential must use highly effective contraceptive methods during 
treatment and for at least 5 weeks following the last dose of Rozlytrek. 
It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting 
hormonal contraceptives (see section 4.5). Therefore, women using systemically acting hormonal 
contraceptives should be advised to add a barrier method. 
 
Male patients with female partners of childbearing potential must use highly effective contraceptive 
methods during treatment and for at least 3 months following the last dose of Rozlytrek (see section 
5.3). 
 
Pregnancy 
 
There are no available data from the use of entrectinib in pregnant women. Based on animal studies 
and its mechanism of action, entrectinib may cause foetal harm when administered to a pregnant 
woman (see sections 4.4 and 5.3). 
 
Rozlytrek is not recommended during pregnancy and in women of childbearing potential not using 
contraception. 
 
Female patients receiving Rozlytrek should be advised of the potential harm to the foetus. Female 
patients should be advised to contact the doctor, should pregnancy occur. 



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Breast-feeding 
 
It is unknown whether entrectinib or its metabolites are excreted in human milk. 
A risk to the breast-fed children cannot be excluded. 
Breast-feeding should be discontinued during treatment with Rozlytrek. 
 
Fertility 
 
No fertility studies in animals have been performed to evaluate the effect of entrectinib (see 
section 5.3). 
 
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). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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 (5.2%), dyspnoea (4.6%), cognitive impairment (3.8%), and pleural effusion 
(2.4%). Permanent discontinuation due to an adverse reaction occurred in 4.4% of patients. 
 
Tabulated list of adverse reactions 
 
Tables 5 and 6 summarise the adverse drug reactions (ADRs) occurring in adult and paediatric patients 
treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, STARTRK-2) and one 
clinical trial in pediatric patients (STARTRK-NG). The median duration of exposure was 5.5 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 <1/1000), very rare (<1/10,000). Within each system organ class, the 
adverse reactions are presented in order of decreasing frequency. 
 



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Table 5: Adverse drug reactions occurring in adult and paediatric patients treated with 
Rozlytrek in clinical trials (N=504) 
 

System organ class Adverse reaction All grades (%) 
Frequency category 

(all grades) 
Grade ≥3 

(%) 
Infections and 
infestations 

Lung infection1 13.1 Very common 6.0* 
Urinary tract infection 12.7 Very common 2.6 

Blood and 
lymphatic system 
disorders 

Anaemia 28.2 Very common 9.7 

Neutropenia2 11.3 Very common 4.4 

Metabolism and 
nutritional 
disorders 

Weight increased 26.4 Very common 7.3 
Decreased appetite 11.9 Very common 0.2 
Hyperuricemia 9.1  Common 1.8 
Dehydration 7.9 Common 1.0 
Tumour lysis syndrome 0.2 Uncommon 0.2* 

Nervous system 
disorders 

Dysgeusia 42.3 Very common 0.4 
Dizziness3 39.7 Very common 1.2 
Dysaesthesia4 29.0 Very common 0.2 
Cognitive disorders5 24.2 Very common 4.4 
Headache 17.5 Very common 1.0 
Peripheral sensory 
neuropathy6 15.7 Very common 1.0 

Ataxia7 15.7 Very common 0.8 
Sleep disturbances8 13.5 Very common 0.4 
Mood disorders9 9.1 Common 0.6 
Syncope 4.6 Common 3.0 

Eye disorders Vision blurred10 11.9 Very common 0.4 

Cardiac disorders 

Congestive heart 
failure11 3.0 Common 2.2 

Electrocardiogram QTc 
prolonged 2.0 Common 0.6 

Vascular disorders Hypotension12 16.5 Very common 2.4 
Respiratory, 
thoracic and 
mediastinal 
disorders 

Dyspnoea 27.0 Very common 5.8* 
Cough 21.4 Very common 0.6 
Pleural effusion 6.9 Common 2.8 

Gastrointestinal 
disorders 

Constipation 42.9 Very common 0.4 
Diarrhoea 33.5 Very common 2.6 
Nausea 32.1 Very common 0.8 
Vomiting 23.2 Very common 1.2 
Abdominal pain 11.1 Very common 0.6 
Dysphagia 10.1 Very common 0.4 

Hepatobiliary 
disorders 

AST increased 17.5 Very common 3.6 
ALT increased 16.1 Very common 3.4 

Skin and 
subcutaneous 
tissue disorders 

Rash13 11.5 Very common 1.4 

Photosensitivity reaction 2.8 Common 0 

Musculoskeletal 
and connective 
tissue disorders 

Myalgia 19.6 Very common 0.6 
Arthralgia 19.0 Very common 0.6 
Muscular weakness 12.3 Very common 1.2 
Fractures14 6.2 Common 2.4 

Renal and urinary 
disorders 

Blood creatinine 
increased 25.4 Very common 0.6 

Urinary retention15 10.9 Very common 0.6 



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System organ class Adverse reaction All grades (%) 
Frequency category 

(all grades) 
Grade ≥3 

(%) 
General disorders 
and 
administration site 
conditions 

Fatigue16 45.0 Very common 5.0 
Oedema17 37.3 Very common 1.4 
Pain18 24.4 Very common 1.6 
Pyrexia 20.0 Very common 0.8 

* Grades 3 to 5, inclusive of fatal adverse reactions (including 2 reactions of pneumonia, 2 reactions of dyspnoea, 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, disturbance in attention, memory impairment, amnesia, mental 
status changes, hallucination, delirium, ‘visual hallucination’ and 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) 
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 (ankle fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, fracture, humerus fracture, 
jaw fracture, lower limb fracture, pathological fracture, rib fracture, spinal compression fracture, spinal fracture, stress 
fracture, tibia fracture, wrist fracture) 
15 Urinary retention (urinary retention, urinary incontinence, urinary hesitation, micturition disorder, micturition urgency) 
16 Fatigue (fatigue, asthenia) 
17 Oedema (face oedema, fluid retention, generalised oedema, localized oedema, oedema, oedema peripheral, peripheral 
swelling) 
18 Pain (back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity) 



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Table 6: Adverse drug reactions occurring in paediatric patients treated with Rozlytrek in 
clinical trials 
 

System organ class Frequency Adolescents
1 

 (N=7) 
All paediatric patients 

(N=32) 

Infections and 
infestations Very common  

Urinary tract infection 
(18.8%),  
Lung infection (12.5%),  

Blood and lymphatic 
system disorders Very common 

Anaemia (57.1%), 
Neutropenia (42.9%) 

Anaemia (59.4%), 
Neutropenia (43.8%) 

Metabolism and 
nutritional disorders Very common 

Weight increased (57.1%), 
Decreased appetite 
(14.3%) 

Weight increased (50%), 
Decreased appetite (31.3%), 
Dehydration (25%) 

Nervous system 
disorders Very common 

Dysgeusia (42.9%), 
Dysaesthesia (28.6%),  
Mood disorders (28.6%), 
Cognitive disorders 
(14.3%), Headache 
(14.3%),  
Syncope (14.3%), 
Peripheral sensory 
neuropathy (14.3%),  
Sleep disturbances 
(14.3%) 

Headache (31.3%),  
Dysgeusia (21.9%),  
Mood disorders (28.1%), 
Ataxia (15.6%),  
Sleep disturbances (13.3%), 
Dizziness (12.5%),  
Peripheral sensory 
neuropathy (12.5%), 

Eye disorders Very common Vision blurred (14.3%)  
Vascular disorders Very common Hypotension (14.3%) Hypotension (18.8%) 
Respiratory, 
thoracic and 
mediastinal 
disorders 

Very common Dyspnoea (28.6%),  Cough (28.6%) 

Dyspnoea (18.8%),  
Cough (50%),  
Pleural effusion (12.5%) 

Gastrointestinal 
disorders Very common 

Nausea (71.4%),  
Abdominal pain (28.6%), 
Constipation (28.6%) 

Nausea (46.9%),  
Abdominal pain (28.1%), 
Constipation (43.8%), 
Vomiting (34.4%),  
Diarrhoea (37.5%) 

Hepatobiliary 
disorders Very common 

AST increased (57.1%), 
ALT increased (42.9%)  

AST increased (50%),  
ALT increased (50%)  

Skin and 
subcutaneous tissue 
disorders 

Very common  Rash (25%) 

Musculoskeletal and 
connective tissue 
disorders 

Very common Arthralgia (14.3%),  Myalgia (14.3%) Fractures (21.9%) 

Very common Muscular weakness (28.6%) Muscular weakness (18.8%) 

Renal and urinary 
disorders Very common 

Blood creatinine increased 
(57.1%) 

Blood creatinine increased 
(43.8%),  
Urinary retention (21.9%) 

General disorders 
and administration 
site conditions 

Very common 
Fatigue (42.9%),  
Pain (57.1%),  
Pyrexia (57.1%) 

Fatigue (43.8%),  
Pain (46.9%),  
Pyrexia (56.3%),  
Oedema (18.8%) 

% refers to all grades 
1Adolescents (12 to <18 years of age): Grade ≥3 reactions reported were neutropenia and headache 

 



15 

Description of selected adverse reactions 
 
Cognitive disorders 
A variety of cognitive symptoms was reported across clinical trials (section 4.4). These included 
events reported as cognitive disorders (6.3%), confusional state (7.3%), disturbance in attention 
(3.8%), memory impairment (4.2%), amnesia (2.8%), mental status changes (1.2%), hallucination 
(1.0%), delirium (0.8%), visual hallucination (0.4%) and mental disorder (0.2%). Grade 3 cognitve 
disorders were reported in 4.4% of patients. Adult patients who had CNS disease at baseline had a 
higher frequency of these adverse reactions (29.7%) compared to those without CNS disease (23.1%). 
The median time to onset for cognitive disorders was 0.92 months. 
 
Fractures 
Fractures were experienced by 5.3% (25/475) of adult patients and 21.8% (7/32) of paediatric patients. 
In general, there was inadequate assessment for tumour involvement at the site of fracture; however, 
radiologic abnormalities possibly indicative of tumour involvement were reported in some adult 
patients. In 2 paediatric patients, bilateral femoral neck fractures occurred. In both adult and paediatric 
patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). No 
patients discontinued Rozlytrek due to fractures. 
 
In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area. 
The median time to fracture was 3.4 months (range: 0.26 months to 18.5 months) in adults. Rozlytrek 
was interrupted in 36.0% of adults that experienced fractures. 
 
In paediatric patients all fractures occurred in patients with minimal or no trauma. A total of 
11 adverse reactions of fractures were reported in the 7 paediatric patients. The median time to fracture 
was 4.3 months (range: 2.46 months to 7.39 months) in paediatric patients. Rozlytrek was interrupted 
in 42.9% (3/7) of paediatric patients that experienced fractures. Three of the fractures were Grade 2 
and 4 fractures were Grade 3. Three of the Grade 3 fractures were serious. There were no reports of 
tumour involvement at the site of the fracture. All but one event of fracture recovered. 
 
Ataxia 
Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.7% of 
patients. The median time to onset for ataxia was 0.4 months (range: 0.03 months to 28.19 months) 
and the median duration was 0.7 months (range: 0.03 months to 11.99 months). The majority of 
patients (67.1%) recovered from ataxia. Ataxia related adverse reactions were observed more 
frequently in elderly patients (23.8%) compared to patients below 65  years of age (12.8%). 
 
Syncope 
Syncope was reported in 4.6% of patients. In some patients, syncope was reported with concurrent 
hypotension, dehydration, or QTc prolongation and in other patients no other concurrent related 
conditions were reported. 
 
QTc interval prolongation 
Among the 504  patients who received entrectinib across clinical trials, 17 (4.0%) patients with at least 
one post-baseline ECG assessment experienced QTcF interval prolongation of >60 ms after starting 
entrectinib, and 12 (2.8%) patients had a QTcF interval of ≥500 ms (section 4.4). 
 
Peripheral sensory neuropathy 
Peripheral sensory neuropathy was reported in 15.7% of patients. The median time to onset was 
0.49 months (range 0.03 months to 20.93 months) and the median duration was 0.8 months (range: 
0.07 months to 6.01 months). The majority of patients (55.7%) recovered from peripheral neuropathy. 
 
Eye disorders 
Eye disorders reported across clinical trials included vision blurred (8.5%), diplopia (2.6%), and visual 
impairment (1.6%). The median time to onset for eye disorders was 1.9 months (range: 0.03 months to 
21.59 months). The median duration of eye disorders was 1 month (range 0.03 months to 14.49 
months). The majority of patients (61.7%) recovered from the eye disorder adverse reactions. 



16 

 
Paediatric population 
 
The overall safety profile of Rozlytrek in the paediatric population is similar to the safety profile in 
adults. 
 
The safety of Rozlytrek in paediatric patients was established based on extrapolation of data from 
three open-label, single-arm clinical trials in adult patients with solid tumours harbouring an NTRK 
gene fusion (ALKA, STARTRK-1 and STARTRK-2), and data from 32 paediatric patients 
(30 patients enrolled in STARTRK-NG, and 2 patients enrolled in STARTRK-2). Of these, 2 patients 
were less than 2 years old, 23 patients were 2 to 11 years old, 7 patients were 12 to 17 years old. 
 
Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (at 
least a 5% increased incidence) in paediatric patients compared to adult patients were neutropenia 
(28.1% vs. 3.4%), weight increased (21.9% vs 6.9%), headache (6.3% vs 0.6%) and bone fractures 
(12.5% vs 1.9%). 
 
There are limited safety data in adolescents, however, the safety profile in adolescents is similar to the 
overall safety profile of Rozlytrek. Adverse reactions Grade ≥3 reported in adolescents were 
neutropenia and headache. 
 
Elderly 
Among the 504 patients who received entrectinib across clinical trials, 130 (25.8%) patients were 
65 years or older and 34 (6.7%) were 75 years or older. The overall safety profile of entrectinib in the 
elderly patients is similar to the safety profile observed in patients younger than 65 years of age. 
Adverse reactions occurring more frequently in the elderly compared to patients less than 65 years old 
were dizziness (48.5% vs 36.6%), blood creatinine increased (31.5% vs 23.3%), and hypotension (21.5% 
vs 14.7%), ataxia (23.8% vs 12.8%). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Patients who experience overdose should be closely supervised and supportive care instituted. There 
are no known antidotes for entrectinib. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE56 
 
Mechanism of action 
 
Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC 
(encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, 
respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase 
(ALK), with IC50 values of 0.1 to 2 nM. The major active metabolite of entrectinib, M5, showed 
similar in vitro potency and activity against TRK, ROS1, and ALK. 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


17 

Fusion proteins that include TRK, ROS1 or ALK kinase domains drive tumourigenic potential through 
hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. 
Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple 
tumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALK 
fusion genes. 
 
Prior treatments with other drugs that inhibit the same kinases may confer resistance to entrectinib. 
Resistance mutations in the TRK kinase domain identified following entrectinib discontinuation 
include NTRK1 (G595R, G667C) and NTRK3 (G623R, G623E and G623K). Resistance mutations in 
the ROS1 kinase domain identified following entrectinib discontinuation include G2032R, F2004C 
and F2004I. 
 
The molecular causes for primary resistance to entrectinib are not known. It is therefore not known if 
the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy 
of TRK inhibition. 
 
Clinical efficacy and safety 
 
NTRK gene fusion-positive solid tumours 
 
Efficacy in adult patients 
The efficacy of Rozlytrek was evaluated in a pooled sub-group of adult patients with unresectable or 
metastatic solid tumours with a NTRK gene fusion enrolled in one of three multicentre single-arm, 
open-label clinical trials (ALKA, STARTRK-1 and STARTRK-2). To be included in the pooled 
subgroup, patients were required to have confirmed NTRK gene fusion-positive solid tumours; 
measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1; at least 
6 months of follow-up after the first dose of Rozlytrek and no prior therapy with a TRK inhibitor 
(patients with concomitant driver mutations, where known, were excluded). Patients with primary 
CNS tumours were assessed separately using Response Assessment in Neuro-Oncology Criteria 
(RANO). Patients received Rozlytrek 600 mg orally once daily until unacceptable toxicity or disease 
progression. The primary efficacy endpoints were objective response rate (ORR) and duration of 
response (DOR) as evaluated by by Blinded Independent Central Review (BICR) according to 
RECIST v1.1. 
 
Efficacy was assessed in 74 adult patients with solid tumours with an NTRK gene fusion enrolled in 
these trials. The baseline demographic and disease characteristics were: 47.3% males, median age of 
57 years (range 21 years to 83 years), 35% and 14.9% were older than 65 years and 75 years of age, 
respectively, 70% white Caucasian, 17.6% Asian, 5.5% Hispanic or Latino and 59.7% never smokers. 
The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (40.5%), 
1 (45.9%), or 2 (13.5%). Most patients (97.3%) had metastatic disease [most common sites being lung 
(60.8%), lymph nodes (52.7%) and brain (25.7%)], 2.7% patients had locally advanced disease. 86.5% 
patients had received prior treatment for their cancer including surgery (82.4%), radiotherapy (63.5%), 
chemotherapy (81.1%) and 27% patients had no prior systemic therapies for metastatic disease. The 
most common cancers were sarcoma (21.6%), lung cancer (17.6%), salivary gland tumours (17.6%), 
thyroid cancer (9.5%) colorectal cancer (9.5%) and breast cancer (8.1%). Most patients (97.3%) had 
an NTRK gene fusion detected by next-generation sequencing (NGS) and 2.7% had a NTRK gene 
fusion detected by other nucleic acid-based tests. The overall median duration of follow-up from 
receipt of first dose was 14.2  months. 
 
Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in 
Table 7. 
 



18 

Table 7: Overall efficacy by BICR in adults with NTRK-fusion positive solid tumours 
 

Efficacy endpoint Rozlytrek N = 74 

Primary endpoints (BICR assessed; RECIST 1.1) 

Objective Response Rate  
Number of Responses 47/74  
ORR% (95% CI) 63.5% (51.5, 74.4) 

Complete Response, n (%) 5 (6.8%) 
Partial Response, n (%) 42 (56.8%) 
Duration of Response*   

Number (%) of patients with events 21/47 (44.7%) 
Median, months (95% CI) 12.9 (9.3, NE) 

6-month durable response % (95% CI) 71% (58, 85) 
9-month durable response % (95% CI) 65% (51,80)  
12-month durable response % (95% CI) 55% (39,72) 
NE = not estimable. 
Confidence Intervals (CI) calculated using the Clopper-Pearson method. 
*Median and percentiles based on Kaplan-Meier estimates 

 
Objective response rate and duration of response by tumour type in adult patients with NTRK gene 
fusion-positive solid tumours is presented in Table 8 below. 
 
Table 8: Efficacy by tumour type, in adults with NTRK gene fusion-positive solid tumours 
 

Tumour type Patients (N = 74) 

ORR DOR 

n (%) 95% CI Range (months) 
Sarcoma 16 9 (56.3) (29.9, 80.3) 2.8, 15.1 
Non-small cell lung cancer 13 9 (69.2) (38.6, 90.9) 1.4*, 25.9* 
Salivary (MASC) 13 12 (92.3) (64.0, 99.8) 2.8, 22.1* 
Breast cancer (secretory) 4 4 (100) (39.8, 100) 5.5, 20.2* 
Breast cancer (non-secretory) 2 NE, PR NA 4.2 
Thyroid cancer 7 3 (42.9) (9.9, 81.6) 5.6, 10.9* 
Colorectal cancer 7 2 (28.6) (3.7, 71) 7.9*, 15.2 
Neuroendocrine cancers 4 2 (50.0) (6.8, 93.2) 1.9*, 9.2* 
Pancreatic cancer 3 2 (66.7) (9.4, 99.2) 7.1, 12.9 
Ovarian cancer 1 Non CR/PD NA 26.0* 
Endometrial carcinoma 1 PR NA 26.0* 
Cholangiocarcinoma  1 PR NA 9.3 
Gastrointestinal cancer (other) 1 PR NA 5.6* 
Neuroblastoma 1 NE NA NA 

*Censored 
ORR: Objective Response Rate; DOR: Duration of Response; MASC: mammary analogue secretory carcinoma; NA: not 
applicable due to small number or lack of response; CR: complete response; PR: partial response; PD: progressive disease; 
NE: not estimable. 

 
Due to the rarity of NTRK gene fusion-positive cancers, patients were studied across multiple tumour 
types with a limited number of patients in some tumour types, causing uncertainty in the ORR 
estimate per tumour type. The ORR in the total population may not reflect the expected response in a 
specific tumour type. 
 
The ORR in 30 patients that had broad molecular characterisation before Rozlytrek treatment was 
56.7% [37.4, 74.5]; of those, the ORR in 24 patients who had other genomic alterations in addition to 
NTRK gene fusion was 50% [29.1, 70.9] and the ORR in 6 patients without other genomic alterations 
was 83.3% [35.9, 99.6]. 
 



19 

Intracranial response 
A BICR assessment resulted in a subgroup of 16 adult patients with CNS metastases at baseline, 
including 8 patients with measureable CNS lesions. Intracranial (IC) response assessed by BICR 
according to RECIST v1.1 was reported in 5 out of these 8 patients (1 CR and 4 PR), for an ORR of 
62.5% (95%  CI: 24.5, 91.5) and DOR of NE (5.0, NE). Four of these 8 patients had received 
intracranial radiotherapy to the brain within 2 months prior to starting Rozlytrek treatment. 
 
Primary CNS tumour  
Across the three trials, seven adult patients with CNS primary tumours were treated with Rozlytrek 
with a minimum of 6 months of follow-up. One out of the seven adult patients had an objective 
response assessed by BICR according to RANO. 
 
Efficacy in paediatric patients 
The efficacy of Rozlytrek in paediatric patients 12 years and older was based on extrapolation of data 
from three open-label, single-arm clinical trials in adult patients with solid tumours harbouring a 
NTRK gene fusion (ALKA, STARTRK-1 and STARTRK-2), and efficacy and pharmacokinetic data 
in paediatric patients enrolled in STARTRK-NG. The best overall response as evaluated by BICR in 
5 paediatric patients, (all patients were less than 12 years of age and had more than 6 months of follow 
up; 3 patients had solid tumours and 2 patients had primary CNS tumours) showed 2 complete 
responses (epithelioid glioblastoma and infantile fibrosarcoma) and 3 partial responses (high-grade 
glioma, infantile fibrosarcoma and metastatic melanoma). The responses in 4 out of 5  paediatric 
patients were ongoing at the time of data cut-off (see section 4.2). 
 
ROS1-positive NSCLC 
 
The efficacy of Rozlytrek was evaluated in a pooled sub-group of patients with ROS1-positive 
metastatic NSCLC who received Rozlytrek 600 mg orally once daily and were enrolled in one of three 
multicentre single-arm, open label clinical trials (ALKA, STARTRK-1 and STARTRK-2). To be 
included in the pooled sub-group, patients were required to have histologically confirmed, recurrent or 
metastatic, ROS1-positive NSCLC, ECOG performance status ≤2, measurable disease per RECIST 
v1.1, ≥6 months of follow-up, and no prior therapy with a ROS1 inhibitor. All patients were assessed 
for CNS lesions at baseline. 
 
The primary efficacy endpoints were ORR and DOR, as evaluated by BICR according to RECIST 
v1.1. The secondary efficacy endpoints included PFS, OS, and in patients presenting with CNS 
metastases at baseline - IC-ORR and IC-DOR, (also evaluated by BICR using RECIST v1.1). 
 
Efficacy was assessed in 161 patients with ROS1-positive NSCLC. The baseline demographic and 
disease characteristics were: 35.4% males, median age of 54 years (range 20 years to 86 years), 24.2% 
and 4.3% were older than 65 years and 75 years of age, respectively, 44.1% white Caucasian, 45.3% 
Asian, 4.3%, Black, 2.6% Hispanic or Latino and 62.7% never smokers. The ECOG (Eastern 
Cooperative Oncology Group) performance status at baseline was 0 (41%), 1 (49.1%), or 2 (9.9%). 
Most patients (98.1%) had metastatic disease [most common sites being lymph nodes (69.6%), lung 
(50.3%) and brain (32.9%)], 1.9% patients had locally advanced disease and 37.3% patients had no 
prior systemic therapies for metastatic disease. ROS1 positivity was determined by NGS in 83% of 
patients, by FISH in 9% of patients, and by RT-PCR in 8% of patients. The overall median duration of 
follow-up from receipt of the first dose was 15.8 months. 
 
Efficacy results from patients with ROS1-positive NSCLC are summarised in Table 9. 
 



20 

Table 9: Overall efficacy by BICR in patients with ROS1-positive NSCLC 
 

Efficacy endpoint Rozlytrek N = 161 

Primary endpoints (BICR-assessed, RECIST 1.1) 

Objective Response Rate   
Number of Responses 108/161 
ORR% (95% CI) 67.1% (59.25, 74.27) 

Complete Response, n (%) 14 (8.7%) 
Partial Response, n (%) 94 (58.4%) 
Duration of Response*   

Number (%) of patients with events 48/108 (44.4%) 
Range (months) 1.8**, 42.3** 

6-month durable response % (95% CI) 83% (76, 90) 
9-month durable response % (95% CI) 75% (67, 84) 
12-month durable response % (95% CI) 63% (53, 73) 

Secondary endpoints (BICR-assessed, RECIST 1.1) 

PFS  
Number (%) of patients with events 82/161 (50.9%) 
6-month PFS % (95% CI) 77% (70, 84) 
9-month PFS % (95% CI) 66% (58, 74) 
12-month PFS % (95% CI) 55% (47, 64) 

Overall Survival*  
Number (%) of patients with events 38/161 (23.6%) 
6-month OS % (95% CI) 91% (87, 96) 
9-month OS % (95% CI) 86% (81, 92) 
12-month OS % (95% CI) 81% (74, 87) 

NE = not estimable. 
Confidence Intervals (CI) calculated using the Clopper-Pearson method. 
* Event-free rates based on Kaplan-Meier estimates 
** Censored 

 
In the ROS1 positive NSCLC efficacy evaluable patients with ≥12 months of follow-up (N = 94), the 
ORR was 73.4% (95% CI: 63.3, 82), the median DoR was 16.5 months (95% CI: 14.6, 28.6) and 
median PFS was 16.8 months (95% CI: 12, 21.4). 
 
Intracranial response 
A BICR assessment resulted in a subgroup of 46 ROS1-positive NSCLC patients with CNS metastases 
at baseline including 24 patients with measureable CNS lesions. Intracranial response assessed by 
BICR according to RECIST v1.1 was reported in 19 of these 24 patients (3 CR and 16 PR) for an 
ORR of 79.2% (95% CI: 57.8, 92.9). The percentage of patients (95% CI) with DOR ≥6 months, 
≥9 months and ≥12 months was 76% (56, 97), 62% (38, 86), and 55% (29, 80), respectively (Kaplan-
Meier estimates). Nine of these 24 patients had received intracranial radiotherapy to the brain within 
2 months of starting Rozlytrek treatment. 
 
Conditional approval 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 



21 

Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Rozlytrek in one or more subsets of the paediatric population in the treatment with NTRK gene 
fusion-positive locally advanced or metastatic solid tumours (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetic parameters for entrectinib and its major active metabolite (M5), have been 
characterized in patients with NTRK gene fusion-positive solid tumours and ROSI-positive NSCLC 
and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not 
dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two 
weeks for M5 following daily administration of Rozlytrek. 
 
Entrectinib is a weak P-gp substrate based on in vitro data. The exact in vivo contribution of P-gp is 
unknown. M5 is a P-gp substrate. Entrectinib is not a substrate of BCRP but M5 is a substrate of 
BCRP. Entrectinib and M5 are not substrates of OATP 1B1 or OATP1B3. 
 
Absorption 
 
Following a single 600 mg oral administration of Rozlytrek to patients with NTRK gene 
fusion-positive and ROS1-positive NSCLC under fed conditions, entrectinib was rapidly absorbed 
reaching time-to-maximum plasma concentration (Tmax) after approximately 4 to 6 hours. Based on 
population pharmacokinetic analysis, steady-state was achieved within 5 days for entrectinib with 
600 mg once daily dosing. 
 
No clinically significant effect of food on entrectinib bioavailability was observed. 
 
Distribution 
 
Entrectinib and its major active metabolite M5 are highly bound to human plasma proteins 
independent of drug concentrations. In human plasma, entrectinib and M5 had similar protein binding 
with >99% bound at a clinically relevant concentration. 
 
After a single oral dose of entrectinib, the geometric mean volume of distribution (Vz/F) was 600 L, 
suggesting extensive distribution of the drug. Entrectinib demonstrated steady-state brain-to-plasma 
concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs) at clinically relevant 
systemic exposures. 
 
Biotransformation 
 
Entrectinib is metabolised predominantly by CYP3A4 (~76%). Minor contributions from several other 
CYPs and UGT1A4 were estimated at <25% in total. The active metabolite M5 (formed by CYP3A4) 
and the direct N-glucuronide conjugate, M11, (formed by UGT1A4) are the two major circulating 
metabolites identified. 
 
Elimination 
 
The population PK model estimated mean accumulation at steady-state following 600 mg once daily 
administration of entrectinib was 1.89 (±0.381) and 2.01 (±0.437) for M5. Following administration of 
a single dose of [14C]-labelled entrectinib, 83% radioactivity was excreted in faeces (36% of the dose 
as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%). 
 
Entrectinib and M5 account for approximately 73% of radioactivity in systemic circulation at Cmax, 
and approximately half of total radioactivity AUCINF. 
 



22 

Population PK analysis estimated apparent clearance CL/F was 19.6 L/h and 52.4 L/h for entrectinib 
and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 hours 
and 40 hours, respectively. 
 
Linearity/Non-linearity 
 
Entrectinib has linear pharmacokinetics in the dose range of 100 mg to 600 mg. 
 
Pharmacokinetics in special populations 
 
Paediatric population 
 
Data obtained from population pharmacokinetic analyses show that in paediatric patients 12 years and 
older, a dose of 400 mg Rozlytrek once daily for BSA range 1.11 m2 to 1.50 m2, and a dose of 600 mg 
Rozlytrek once daily for BSA range ≥1.51 m2 results in a similar systemic exposure attained in adults 
treated with 600 mg of Rozlytrek, once daily. 
 
Elderly 
 
No differences in entrectinib exposure were noted in patients older than 65 years and younger adults 
based on pharmacokinetic analysis. 
 
Renal impairment 
 
Negligible amounts of entrectinib and the active metabolite M5 are excreted unchanged in urine 
(~3% of the dose) indicating that renal clearance plays a minor role in the elimination of entrectinib. 
Based on population pharmacokinetic analyses, the pharmacokinetics of entrectinib are not 
significantly affected in renal impairment. The impact of severe renal impairment on the 
pharmacokinetics of entrectinib is unknown. 
 
Hepatic impairment 
 
As elimination of entrectinib is predominantly through metabolism in the liver, hepatic impairment 
may increase the plasma concentration of entrectinib and/or its major active metabolite M5. Limited 
clinical data is available in patients with hepatic impairment. 
 
No clinically significant differences in the pharmacokinetics of entrectinib were observed based on 
mild hepatic impairment. The impact of moderate to severe hepatic impairment on the 
pharmacokinetics of entrectinib is unknown. 
 
Effects of age, body weight, race and gender 
 
No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age 
(4 years to 86 years), sex, race (Asian, Black and White) and body weight (32 kg to 130 kg). 
 
5.3 Preclinical safety data 
 
Carcinogenicity 
 
No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib. 
 
Genotoxicity 
 
Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but 
demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human 
peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo 
micronucleus assay in rats and did not induce DNA damage in a comet assay in rats. 



23 

Impairment of fertility 
 
Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. No 
adverse effects of entrectinib on male and female reproductive organs were observed in the 
repeat-dose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, 
the human exposure by AUC at the recommended human dose. 
 
Reproductive toxicity 
 
In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and 
food consumption) and foetal malformations (including body closure defects and malformations of the 
vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib which represents approximately 
2-fold the human exposure by AUC at the recommended dose. Dose-response dependent reduced 
foetal body weight (low, middle and high dose) and reduced skeletal ossification (middle and high 
dose) were observed at exposures equivalent to <2 times the human exposure by AUC at the 
recommended dose. 
 
Repeat dose toxicity studies 
 
Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were 
observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax 
at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human 
exposure by AUC at the recommended dose. In adult rats and dogs, effects on liver (increased ALT 
and hepatocellular necrosis) were observed at ≥0.6 times the human exposure by AUC at the 
recommended dose. In dogs, diarrhoea at ≥0.1 times the human exposure by AUC at the recommended 
dose and prolongations of QT/QTc interval at ≥0.1 times the human exposure by Cmax at the 
recommended dose were also observed. 
 
Juvenile rat toxicology study 
 
In a 13-week juvenile rat toxicology study animals were dosed daily from post-natal day 7 to day 97 
(approximately equivalent to neonate to adulthood in humans). In addition to CNS effects, ptosis and 
skin effects, decreased RBC parameters and effects on growth and development were observed in the 
dosing and recovery phases including decreased body weight gain and delayed sexual maturation (at 
≥4 mg/kg/day, approximately 0.1 times the human exposure by AUC at the recommended dose). 
Deficits in neurobehavioral assessments including functional observational battery (decreased landing 
foot splay, decreased fore and hind limb grip strength that seemed to manifest later in age) and 
learning and memory (at ≥8mg/kg/day, approximately 0.2 times the human exposure by AUC at the 
recommended dose), and decreased femur length (at ≥16 mg/kg/day, approximately 0.3 times the 
human exposure by AUC at the recommended dose) were observed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
 
Tartaric acid 
Lactose  
Hypromellose  
Crospovidone 
Microcrystalline cellulose 
Colloidal anhydrous silica 
Magnesium stearate 
 



24 

Capsule shell 
 
Hypromellose 
Titanium dioxide (E171) 
Yellow iron oxide (E172 – 100 mg hard capsule) 
Sunset yellow FCF (E110 – 200 mg hard capsule) 
 
Printing ink 
 
Shellac 
Propylene glycol 
Indigo carmine aluminium lake (E132) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions 
 
6.5 Nature and contents of container 
 
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. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1460/001 
EU/1/20/1460/002 
 



25 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
  

http://www.ema.europa.eu/


26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE 

POST-AUTHORISATION MEASURES FOR THE 
CONDITIONAL MARKETING AUTHORISATION 

  



27 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measure: 
 
Description Due date 
Post-authorisation efficacy study (PAES): In order to further characterise the 
efficacy of entrectinib in patients with baseline CNS disease, the MAH should 
conduct and submit the results of a randomised controlled trial versus crizotinib in 
treatment naïve ROS1 NSCLC patients. The primary endpoint will be PFS in the 
subgroup of patients with CNS metastases at baseline. The clinical study report 
should be submitted by: 

31 December 
2027 

 
 



28 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE CONDITIONAL MARKETING AUTHORISATION 

 
This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 
Description Due date 
In order to further confirm the histology-independent efficacy of entrectinib in adult 
and paediatric patients, the MAH should submit a pooled analysis for an increased 
sample size of NTRK fusion-positive patients from the ongoing studies 
STARTRK-2, STARTRK-NG and any additional clinical trial conducted according 
to an agreed protocol. 
The MAH should submit the results of an interim safety and efficacy analysis of the 
NTRK efficacy-evaluable adult and paediatric patients including adolescents that 
are available as per integrated statistical analysis plan. 

31 March 
2027 
 
 
 

In order to further investigate the impact of the presence/absence of other molecular 
alteration on the efficacy of entrectinib, the MAH should submit the results from 
tumour genomic profiling by plasma and/or tissue when possible at baseline and 
progression together with clinical outcomes association per tumour histology for the 
patients from the updated pooled analysis. 

31 March 
2027 

  



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 



31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rozlytrek 100 mg hard capsules 
entrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg entrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
30 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



32 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1460/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rozlytrek 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
 
  



33 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rozlytrek 100 mg hard capsules 
entrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg entrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
30 capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



34 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rozlytrek 200 mg hard capsules 
entrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 200 mg entrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose and azo colouring agent sunset yellow FCF (E110). See package leaflet for further 
information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
90 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1460/002  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
rozlytrek 200 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



37 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rozlytrek 200 mg hard capsules 
entrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 200 mg entrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose and azo colouring agent sunset yellow FCF (E110). See package leaflet for further 
information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
90 capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



38 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
B. PACKAGE LEAFLET 

  



40 

Package leaflet: Information for the patient 
 

Rozlytrek 100 mg hard capsules 
Rozlytrek 200 mg hard capsules 

entrectinib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again.  
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Rozlytrek is and what it is used for 
2. What you need to know before you take Rozlytrek 
3. How to take Rozlytrek 
4. Possible side effects 
5. How to store Rozlytrek 
6. Contents of the pack and other information 
 
 
1. What Rozlytrek is and what it is used for 
 
What Rozlytrek is 
 
Rozlytrek is a cancer medicine that contains the active substance entrectinib. 
 
What Rozlytrek is used for 
 
Rozlytrek is used to treat either: 
• adults and children 12 years of age and older with solid tumour (cancer) in various parts of the 

body that is caused by a change in the neurotrophic tyrosine receptor kinase (NTRK) gene, or 
• adults with a type of lung cancer called ‘non-small cell lung cancer’ (NSCLC) that is caused by 

a change in the ROS1 gene. 
 
NTRK gene fusion-positive solid tumour cancer 
 
It is used when: 
• a test has shown that your cancer cells have a change in genes called ‘NTRK’ and has spread 

within the affected organ or to other organs in your body or if surgery to remove the cancer is 
likely to result in severe complications (see ‘How Rozlytrek works’ below), and 

• you have not received treatment with medicines called NTRK inhibitors 
• other treatments have not worked or are not suitable for you. 
 



41 

ROS1-positive non -small cell lung cancer (NSCLC) 
 
It is used if your lung cancer: 
• is ‘ROS1-positive’ – this means that your cancer cells have a change in a gene called ‘ROS1’ 

(see ‘How Rozlytrek works’ below), 
• has spread to other parts of your body (metastatic), and 
• you have not received treatment with medicines called ROS1 inhibitors. 
 
How Rozlytrek works 
 
Rozlytrek works by blocking the action of abnormal enzymes caused by a change in the NTRK or 
ROS1 genes that make them. The faulty enzymes encourage the cancer cells to grow. 
 
Rozlytrek may slow down or stop the cancer growing. It may also help to shrink your cancer. 
 
 
2. What you need to know before you take Rozlytrek 
 
Do not take Rozlytrek 
 
• if you are allergic to entrectinib or any of the other ingredients of this medicine (listed in 

section 6). 
If you are not sure, talk to your doctor, pharmacist or nurse before taking Rozlytrek. 
 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before taking Rozlytrek if: 
• you have recently experienced memory loss, confusion, hallucinations, or mental status changes 
• you have a history of fractured bones, or conditions which may increase your risk of breaking 

bones, called ‘osteoporosis’ or ‘osteopaenia’ 
• you take medication to lower the levels of uric acid in your blood 
• you have heart failure (an inability for your heart to adequately pump blood to supply oxygen to 

the body) – signs can include cough, shortness of breath, and swelling in your legs or arms 
• you have or had heart disorders or a heart conduction problem called ‘prolonged QTc interval’ – 

this is shown on an ‘electro-cardiogram’ (ECG), or low levels of electrolytes (potassium, 
magnesium, calcium or phosphorus) in your blood 

• you have an inherited problem called ‘galactose intolerance’, ‘congenital lactase deficiency’ or 
‘glucose-galactose malabsorption’. 

 
Other medicines and Rozlytrek 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
This is because Rozlytrek can affect the way some other medicines work. Also, some other medicines 
can affect the way Rozlytrek works. 
 
In particular, tell your doctor or pharmacist if you are taking any of the following medicines: 
• medicines for fungal infections (anti-fungals) – such as ketoconazole, itraconazole, voriconazole, 

posaconazole 
• medicines to treat Acquired Immune Deficiency Syndrome (AIDS)/Human immunodeficiency 

virus (HIV) infection – such as ritonavir or saquinavir 
• a herbal medicine for depression – St. John’s Wort 
• medicines to stop seizures or fits (anti-epileptics) – such as phenytoin, carbamazepine, or 

phenobarbital 
• medicines for tuberculosis – such as rifampicin, rifabutin 
• medicines to treat solid cancers and blood cancer – topotecan, lapatinib, mitoxantrone, 

apalutamide, methotrexate 



42 

• a medicine for inflammation of joints or joint autoimmune disease (rheumatoid arthritis) – 
methotrexate 

• a medicine for migraine-type headaches – ergotamine 
• a medicine for relief of severe pain – fentanyl 
• a medicine for mental illness (psychoses) or involuntary movements and sounds, also called 

Tourette Syndrome – pimozide 
• a medicine for irregular heart rate –quinidine 
• medicines to prevent formation of blood clots – warfarin, dabigatran etexilate 
• medicines for gastric reflux (heartburn) – cisapride, omeprazole 
• medicines to reduce blood cholesterol – atorvastatin, pravastatin, rosuvastatin 
• medicines to suppress your body’s immune system, or prevent the body from rejecting an organ 

transplant – sirolimus, tacrolimus, cyclosporin, 
• medicines for depression – paroxetine, fluvoxamine 
• medicines to reduce blood sugar levels – repaglinide, tolbutamide 
• medicines for high blood pressure – bosentan, felodipine, nifedipine, verapamil. 
 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
Rozlytrek. 
 
Rozlytrek with food and drink 
 
Do not drink grapefruit juice or eat grapefruit or Seville oranges during your treatment with Rozlytrek. 
It may increase the amount of the medicine in your blood to a harmful level. 
 
Pregnancy, breast-feeding and fertility 
 
Women and contraception 
 
You should not become pregnant while taking this medicine because it could harm the baby. If you are 
able to become pregnant, you must use highly effective contraception while on treatment and for at 
least 5 weeks after stopping treatment. 
 
It is not known if Rozlytrek can reduce the effect of birth control medicines (pills or implanted 
hormonal contraceptives). You should use another reliable method of birth control such as a barrier 
method (e.g. condom) so you do not become pregnant while you are taking Rozlytrek and for 5 weeks 
after you stop treatment. 
 
Talk to your doctor about the right methods of contraception for you and your partner. 
 
Men and contraception 
 
Your female partner should not become pregnant while you are taking this medicine because it could 
harm the baby. If your female partner is able to become pregnant, you must use highly effective 
contraception while on treatment and for at least 3 months after stopping treatment. Talk to your 
doctor about the right methods of contraception for you and your partner. 
 
Pregnancy 
 
• Do not take Rozlytrek if you are pregnant. This is because it may harm your baby. 
• If you become pregnant when taking the medicine or during the 5 weeks after taking your last 

dose, tell your doctor straight away. 
 
Breast-feeding  
 
Do not breast-feed while taking this medicine. This is because it is not known if Rozlytrek can pass 
over into breast milk and could therefore harm your baby. 



43 

 
Driving and using machines 
 
Rozlytrek may affect your ability to drive or use machines. Rozlytrek may cause you to: 
• have blurred vision 
• feel dizzy 
• pass out (lose consciousness) 
• feel tired 
• have changes in your mental status, feel confused or see things that are not there (hallucinations). 
If this happens, you should not drive, use a bicycle, or operate heavy machinery until your symptoms 
resolve. Talk to your doctor or pharmacist about whether it is okay for you to drive or use machines. 
 
Rozlytrek contains: 
 
• lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to 

some sugars, contact your doctor before taking this medicine. 
• sunset yellow FCF (E110) in 200 mg hard capsules only. This is a colouring agent, which 

may cause allergic reactions. 
 
 
3. How to take Rozlytrek 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
How much to take 
 
Adults 
 
• The recommended dose is 3 capsules of 200 mg once a day (total amount 600 mg). 
• If you feel unwell, sometimes your doctor may lower your dose, stop treatment for a short time 

or stop treatment completely. 
 
Children  
 
• Rozlytrek can be used in children 12 years of age and older. 
• Your doctor will work out the correct dose to use – this will depend on the height and weight of 

the child. 
 
How to take 
 
Take Rozlytrek by mouth – with or without food. Swallow each capsule whole. Do not open or 
dissolve the capsules since the contents of the capsule are very bitter. 
 
If you vomit after taking Rozlytrek 
 
If you vomit immediately after taking a dose of Rozlytrek, take another dose. 
 
If you take more Rozlytrek than you should 
 
If you take more Rozlytrek than you should, talk to a doctor or go to hospital straight away. Take the 
medicine pack and this leaflet with you. 
 
If you forget to take Rozlytrek 
 
• If your next dose is more than 12 hours later, take the missed dose as soon as you remember. 



44 

• If there are less than 12 hours until your next dose, do not take the missed dose. Then take your 
next dose at the usual time. 

• Do not take a double dose to make up for a missed dose. 
 
If you stop taking Rozlytrek 
 
Do not stop taking this medicine without talking to your doctor first. It is important to take Rozlytrek 
every day for as long as your doctor prescribes it for you. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine. 
 
Serious side effects 
Tell your doctor straight away if you notice any of the following after having taken Rozlytrek. Your 
doctor may lower your dose, stop your treatment for a short time or stop your treatment completely: 
• you have cough, shortness of breath, and swelling in your legs or arms (fluid retention). These can 

be signs of heart problems 
• you feel confused, have changes in mood, memory problems or hallucinations (see things that are 

not there) 
• you feel dizzy or light-headed, or feel your heart beating irregularly or fast, as this may be a sign 

of an abnormal heart rhythm 
• you notice any joint pain, bone pain, deformities or changes in your ability to move 
• you have kidney problems or arthritis, as this may be the result of high uric acid levels in your 

blood. 
 
Other side effects  
 
Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 
 
Very common: may affect more than 1 in 10 people: 
• feeling tired 
• constipation 
• changes in taste 
• feeling unsteady or dizzy 
• swelling  
• diarrhoea  
• feeling sick 
• abnormal sense of touch which feels like itching, tingling or burning sensation 
• lack of enough red blood cells (anaemia) 
• shortness of breath 
• weight gain 
• increased blood level of creatinine (a substance normally eliminated by the kidneys into the urine) 
• pain including back pain, neck pain, musculoskeletal pain, pain in limbs 
• vomiting 
• cough 
• fever 
• muscle pain 
• joint pain 
• headache 



45 

• low blood pressure 
• increased blood levels of certain liver enzymes (AST/ALT) 
• abnormal unpleasant sensation in your arms or legs 
• loss of muscle coordination, being unsteady when walking 
• disturbance in normal sleep patterns 
• lung infection  
• urinary tract infection 
• muscle weakness 
• decreased appetite  
• blurred vision 
• rash  
• decreased number of a type of white blood cell called neutrophils 
• stomach pain  
• inability to empty your bladder completely 
• difficulty swallowing. 
 
Common: may affect up to 1 in 10 people: 
• mood disorders 
• dehydration 
• fluid in your lungs 
• fainting 
 
Uncommon: may affect less than 1 in 100 people: 
• changes in certain chemicals in your blood caused by rapid breakdown of tumour cells, which may 

cause damage to organs, including the kidneys, heart, and liver. 
 
Tell your doctor, pharmacist or nurse if you notice any of the side effects above. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rozlytrek 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the carton and the bottle after 

EXP. The expiry date refers to the last day of that month. 
• This medicine does not require any special storage conditions 
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 
environment. 

 
 
6. Contents of the pack and other information 
 
What Rozlytrek contains 
 
The active substance is entrectinib. 
Rozlytrek 100 mg: each capsule contains 100 mg entrectinib 
Rozlytrek 200 mg: each capsule contains 200 mg entrectinib 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


46 

 
The other ingredients are: 
• Capsule content: tartaric acid, lactose (see section 2 ‘Rozlytrek contains lactose’), hypromellose, 

crospovidone, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate.  
• Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172; for Rozlytrek 

100 mg capsule), sunset yellow FCF (E110; for Rozlytrek 200 mg capsule). See section 2 
‘Rozlytrek contains sunset yellow FCF (E110)’. 

• Printing ink: shellac, propylene glycol, indigo carmine aluminium lake (E132). 
 
What Rozlytrek looks like and contents of the pack 
 
Rozlytrek 100 mg hard capsules are opaque yellow with ENT 100 imprinted in blue on the body. 
 
Rozlytrek 200 mg hard capsules are opaque orange with ENT 200 imprinted in blue on the body. 
 
The capsules are provided in bottles containing either: 
• 30 hard capsules of Rozlytrek 100 mg, or 
• 90 hard capsules of Rozlytrek 200 mg. 
 
Marketing Authorisation Holder 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A.  
Tél/Tel: +32 (0) 2 525 82 11 

Lietuva 
UAB “Roche Lietuva”  
Tel: +370 5 2546799 
 

България 
Рош България ЕООД  
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 

Česká republika 
Roche s. r. O.  
Tel: +420 - 2 20382111 

Magyarország 
Roche (Magyarország) Kft.  
Tel: +36 - 23 446 800 

Danmark 
Roche a/s  
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 
 

Deutschland 
Roche Pharma AG  
Tel: +49 (0) 7624 140  

Nederland 
Roche Nederland B.V.  
Tel: +31 (0) 348 438050 
 



47 

Eesti 
Roche Eesti OÜ  
Tel: + 372 - 6 177 380  

Norge 
Roche Norge AS  
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH  
Tel: +43 (0) 1 27739 

España 
Roche Farma S.A.  
Tel: +34 - 91 324 81 00 

Polska 
Roche Polska Sp.z o.o.  
Tel: +48 - 22 345 18 88 
 

France 
Roche  
Tél: +33 (0) 1 47 61 40 00  

Portugal 
Roche Farmacêutica Química, Lda  
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o.  
Tel: +385 1 4722 333  
 
Ireland 
Roche Products (Ireland) Ltd.  
Tel: +353 (0) 1 469 0700 
 

România 
Roche România S.R.L.  
Tel: +40 21 206 47 01  
 
Slovenija 
Roche farmacevtska družba d.o.o.  
Tel: +386 - 1 360 26 00 

Ísland 
Roche a/s c/o Icepharma hf  
Sími: +354 540 8000 

Slovenská republika 
Roche Slovensko, s.r.o.  
Tel: +421 - 2 52638201  
 

Italia 
Roche S.p.A.  
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500  
 

Κύπρος 
Γ.Α.Σταμάτης & Σια Λτδ.  
Τηλ: +357 - 22 76 62 76  

Sverige 
Roche AB  
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA  
Tel: +371 - 6 7039831  

United Kingdom 
Roche Products Ltd.  
Tel: +44 (0) 1707 366000 
 

  
This leaflet was last revised in  
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
  

http://www.ema.europa.eu/


48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

CONCLUSIONS ON THE GRANTING OF THE CONDITIONAL MARKETING 
AUTHORISATION PRESENTED BY THE EUROPEAN MEDICINES AGENCY 



49 

Conclusions presented by the European Medicines Agency on: 
 
• Conditional marketing authorisation 
 
The CHMP having considered the application is of the opinion that the risk-benefit balance is 
favourable to recommend the granting of the conditional marketing authorisation as further explained 
in the European Public Assessment Report. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET
	CONCLUSIONS ON THE GRANTING OF THE CONDITIONAL MARKETING AUTHORISATION PRESENTED BY THE EUROPEAN MEDICINES AGENCY