4.1. Therapeutic indications

Neurotrophic tyrosine receptor kinase (NTRK) gene fusion

Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age and older with solid tumours that have a 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

• who have no satisfactory treatment options (see sections 4.4 and 5.1).

ROS1 gene fusion

Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1‑positive, advanced non‑small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

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

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 gene fusion

A validated assay is required for the selection of adult patients with ROS1‑positive NSCLC. ROS1‑positive status must be established prior to initiation of Rozlytrek therapy (see section 5.1).

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.

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

Hyperuricemia

Symptomatic or Grade 4

• Initiate urate‑lowering medication

• Withhold Rozlytrek until improvement of signs or symptoms

• Resume Rozlytrek at same or reduced dose

QT interval prolongation

QTc 481 to 500 ms

• Withhold Rozlytrek until recovered to baseline

• Resume treatment at same dose

QTc greater than 500 ms

• Withhold Rozlytrek until QTc interval recovers to baseline

• Resume at same dose if factors that cause QT prolongation are identified and corrected

• Resume at reduced dose if other factors that cause QT prolongation are not identified

Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia

• Permanently discontinue Rozlytrek

Transaminase elevations

Grade 3

• Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline

• Resume at same dose if resolution occurs within 4 weeks

• Permanently discontinue if adverse reaction does not resolve within 4 weeks

• Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks

Grade 4

• Withhold Rozlytrek until recovery to less than or equal to Grade 1 or to baseline

• Resume at reduced dose if resolution occurs within 4 weeks

• Permanently discontinue if adverse reaction does not resolve within 4 weeks

• Permanently discontinue for recurrent Grade 4 events

ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 2 times ULN (in the absence of cholestasis or haemolysis)

• Permanently discontinue Rozlytrek

Anaemia or neutropenia

Grade 3 or 4

• Withhold Rozlytrek until recovery to less than or equal to Grade 2 or to baseline

• Resume at the same dose or reduced dose, as clinically needed

Other clinically relevant adverse reactions

Grade 3 or 4

• Withhold Rozlytrek until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline

• Resume at the same or reduced dose, if resolution occurs within 4 weeks

• Consider permanent discontinuation if adverse reaction does not resolve within 4 weeks

• Permanently discontinue for recurrent Grade 4 events

* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

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 co-administration is unavoidable, the use of strong or moderate CYP3A inhibitors with Rozlytrek should be limited to 14 days and the Rozlytrek dose should be reduced as follows:

• 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 (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment (see section 5.2). Patients with severe hepatic impairment should be carefully monitored for hepatic function and adverse reactions (see Table 4).

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, grapefruit juice, or Seville Oranges (see section 4.5).

The hard capsules should be swallowed whole. Do not crush or chew the capsules.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 29.7% (27/91) of paediatric patients treated with Rozlytrek in clinical trials (see section 4.8). Bone fractures mostly occurred in paediatric patients less than 12 years of age and were localised in the lower extremity (with a predilection for femur, tibia, foot and fibula). In both adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area. Fourteen paediatric patients had more than one occurrence of a fracture. Fractures resolved in the majority of paediatric patients (see section 4.8). Five paediatric patients had Rozlytrek treatment interrupted due to a fracture. Six paediatric patients discontinued treatment due to fractures.

Patients with signs or symptoms of fractures (e.g., pain, abnormal gait, changes in mobility, deformity) should be evaluated promptly.

Hyperuricemia

Hyperuricemia has been observed in patients treated with entrectinib. Serum uric acid levels should be assessed prior to initiating Rozlytrek and periodically during treatment. Patients should be monitored for signs and symptoms of hyperuricemia. Treatment with urate‑lowering medicinal products should be initiated as clinically indicated and Rozlytrek withheld for signs and symptoms of hyperuricemia. Rozlytrek dose should be modified based on severity as described in Table 4 in section 4.2.

Congestive heart failure

Congestive heart failure (CHF) has been reported in 5.4% of patients across clinical trials with Rozlytrek (see section 4.8). These reactions were observed in patients with or without a history of cardiac disease and resolved in 63.0% of those patients upon institution of appropriate clinical management and/or Rozlytrek dose reduction/interruption.

For patients with symptoms or known risk factors of CHF, left ventricular ejection fraction (LVEF) should be assessed prior to initiation of Rozlytrek treatment. Patients receiving Rozlytrek should be carefully monitored and those with clinical signs and symptoms of CHF, including shortness of breath or oedema, should be evaluated and treated as clinically appropriate.

Based on the severity of CHF, Rozlytrek treatment should be modified as described in Table 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, grapefruit products, and Seville oranges should be avoided.

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

Lactose intolerance

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

Sunset yellow FCF (E110)

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

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.

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, dexamethasone) should be avoided.

If co-administration of Rozlytrek with dexamethasone cannot be avoided, dexamethasone dose recommendations should be determined by the healthcare professional.

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 medicines that raise gastric pH (e.g., H2 receptor antagonists or antacids).

Paediatric population

Interaction studies have only been performed in adults.

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.

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, diarrhoea, dizziness, dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain, vomiting, pyrexia, arthralgia, increased aspartate aminotransferase and dyspnoea, cognitive disorders, cough, and increased alanine aminotransferase. The most frequent serious adverse reactions (≥2%) were lung infection (5.3%), fractures (4.1%), dyspnoea (3.6%), cognitive impairment (2.9%), pleural effusion (2.5%) and pyrexia (2.5%). Permanent discontinuation due to an adverse reaction occurred in 6.0% of patients.

Tabulated list of adverse reactions

Tables 5 and 6 summarise the adverse drug reactions (ADRs) occurring in 762 adults and 91 paediatric patients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK‑1, and STARTRK‑2) and one clinical trial in paediatric patients (STARTRK‑NG) and one clinical trial in adults and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 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 <1/1 000), very rare (<1/10 000). Within each system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 5: Adverse drug reactions occurring in adult and paediatric patients treated with Rozlytrek in clinical trials (n=853)

System organ class

Adverse reaction

All grades

(%)

Frequency category

(all grades)

Grade ≥3

(%)

Infections and infestations

Urinary tract infection

15.7

Very common

2.7

Lung infection1

14.4

Very common

6.1*

Blood and lymphatic system disorders

Anaemia

33.4

Very common

9.7

Neutropenia2

15.8

Very common

6.1

Metabolism and nutritional disorders

Weight increased

34.1

Very common

10.6

Hyperuricemia

16.4

Very common

2.3

Decreased appetite

13.0

Very common

0.7

Dehydration

6.6

Common

1.1

Tumour lysis syndrome

0.2

Uncommon

0.2*

Nervous system disorders

Dizziness3

36.5

Very common

1.9

Dysgeusia

35.8

Very common

0.2

Dysaesthesia4

24.9

Very common

0.4

Cognitive disorders5

23.3

Very common

3.6

Peripheral sensory neuropathy6

16.2

Very common

1.1

Headache

16.1

Very common

0.6

Ataxia7

15.1

Very common

1.5

Sleep disturbances8

12.8

Very common

0.4

Mood disorders9

9.4

Common

0.6

Syncope

5.0

Common

3.5

Eye disorders

Vision blurred10

11.7

Very common

0.2

Cardiac disorders

Congestive heart failure11

5.4

Common

2.5*

Electrocardiogram QTc prolonged

3.6

Common

0.9

Myocarditis

0.2

Uncommon

0.1

Vascular disorders

Hypotension12

15.9

Very common

2.3

Respiratory, thoracic and mediastinal disorders

Dyspnoea

23.8

Very common

4.9*

Cough

21.1

Very common

0.4

Pleural effusion

6.0

Common

2.2

Gastrointestinal disorders

Constipation

42.3

Very common

0.4

Diarrhoea

37.9

Very common

2.2

Nausea

30.0

Very common

0.6

Vomiting

25.1

Very common

1.1

Abdominal pain

11.6

Very common

0.6

Dysphagia

10.7

Very common

0.6

Hepatobiliary disorders

AST increased

21.1

Very common

2.9

ALT increased

20.2

Very common

3.2

Skin and subcutaneous tissue disorders

Rash13

13.4

Very common

1.2

Photosensitivity reaction

1.9

Common

0

Musculoskeletal and connective tissue disorders

Arthralgia

21.0

Very common

0.7

Myalgia

19.7

Very common

0.8

Fractures14

11.3

Very common

3.4

Muscular weakness

10.4

Very common

1.3

Renal and urinary disorders

Blood creatinine increased

31.5

Very common

1.2

Urinary retention15

10.4

Very common

0.6

General disorders and administration site conditions

Fatigue16

43.5

Very common

5.0

Oedema17

34.3

Very common

1.8

Pain18

25.6

Very common

1.5

Pyrexia

23.8

Very common

0.9

* Grades 3 to 5, inclusive of fatal adverse reactions (including 4 reactions of pneumonia, 3 reactions of dyspnoea, 1 reaction of cardiac failure, 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, memory impairment, disturbance in attention, amnesia, mental status changes, hallucination, delirium, disorientation, brain fog, attention deficit hyperactivity disorder, 'visual hallucination', 'auditory hallucination', mental impairment, 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 (acetabulum fracture, ankle fracture, avulsion fracture, bursitis, cartilage injury, clavicle fracture, compression fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, fracture, fractured sacrum, hand fracture, hip fracture, humerus fracture, ilium fracture, jaw fracture, joint injury, limb fracture, lower limb fracture, lumbar vertebral fracture, osteoporotic fracture, pathological fracture, pelvic fracture, rib fracture, spinal compression fracture, spinal fracture, spondylolisthesis, sternal fractures, stress fracture, synovial rupture, thoracic vertebral fracture, tibia fracture, ulna 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, localised oedema, oedema, oedema peripheral, peripheral swelling)

18 Pain (back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity)

Table 6: Adverse drug reactions occurring in paediatric patients treated with Rozlytrek in clinical trials (n=91)

System organ class

Frequency

Infants and toddlers1

(n=21)

Children2

(n=55)

Adolescents3

(n=15)

All paediatric patients

(n=91)

Infections and infestations

Very common

Lung infection (28.6%), Urinary tract infection (23.8%)

Urinary tract infection (23.6%), Lung infection (16.4%)

Urinary tract infection (19.8%), Lung infection (17.6%)

Common

Lung infection (6.7%)

Blood and lymphatic system disorders

Very common

Anaemia (61.9%), Neutropenia (47.6%)

Anaemia (34.5%), Neutropenia (27.3%)

Anaemia (33.3%), Neutropenia (33.3%)

Anaemia (40.7%), Neutropenia (33.0%)

Metabolism and nutritional disorders

Very common

Weight increased (23.8%), Decreased appetite (14.3%)

Weight increased (38.5%), Decreased appetite (29.1%), Dehydration (12.7%)

Weight increased (53.3%), Decreased appetite (13.3%), Hyperuricemia (13.3%)

Weight increased (38.5%), Decreased appetite (23.1%)

Common

Dehydration (4.8%), Hyperuricemia (4.8%)

Hyperuricemia (3.6%)

Dehydration (8.8%), Hyperuricemia (5.5%)

Nervous system disorders

Very common

Headache (32.7%), Mood disorders (16.4%), Sleep disturbances (16.4%), Dizziness (14.5%), Ataxia (10.9%)

Dysgeusia (20%), Mood disorders (13.3%), Cognitive disorders (13.3%), Dysaesthesia (13.3%)

Headache (20.9%), Mood disorders (14.3%), Sleep disturbances (13.2%)

Common

Mood disorders (9.5%), Sleep disturbances (9.5%), Cognitive disorders (9.5%), Ataxia (4.8%), Peripheral sensory neuropathy (4.8%), Syncope (4.8%)

Cognitive disorders (9.1%), Dysgeusia (9.1%), Dysaesthesia (5.5%), Syncope (5.5%), Peripheral sensory neuropathy (5.5%)

Headache (6.7%), Sleep disturbances (6.7%), Peripheral sensory neuropathy (6.7%), Syncope (6.7%)

Cognitive disorders (9.9%), Dizziness (8.8%), Dysgeusia (8.8%), Ataxia (7.7%), Dysaesthesia (5.5%), Peripheral sensory neuropathy (5.5%), Syncope (5.5%)

Eye disorders

Common

Vision blurred (7.3%)

Vision blurred (6.7%)

Vision blurred (5.5%)

Cardiac disorders

Common

Congestive heart failure (9.5%), Electrocardiogram QTc prolonged (9.5%)

Congestive heart failure (5.5%), Electrocardiogram QTc prolonged (5.5%)

Congestive heart failure (5.5%), Electrocardiogram QTc prolonged (5.5%)

Vascular disorders

Common

Hypotension (9.5%)

Hypotension (7.3%)

Hypotension (6.7%)

Hypotension (7.7%)

Respiratory, thoracic and mediastinal disorders

Very common

Cough (42.9%)

Cough (40%)

Cough (20%), Dyspnoea (13.3%)

Cough (37.4%)

Common

Dyspnoea (4.8%)

Dyspnoea (9.1%), Pleural effusion (5.5%)

Pleural effusion (6.7%)

Dyspnoea (8.8%), Pleural effusion (4.4%)

Gastrointestinal disorders

Very common

Vomiting (47.6%), Diarrhoea (42.9%), Constipation (42.9%)

Vomiting (43.6%), Diarrhoea (43.6%), Constipation (36.4%), Nausea (34.5%), Abdominal pain (25.5%)

Nausea (40%), Constipation (33.3%), Vomiting (20%), Diarrhoea (20%), Abdominal pain (13.3%)

Vomiting (40.7%),

Diarrhoea (39.6%)

Constipation (37.4%),

Nausea (28.6%),

Abdominal pain (19.8%)

Common

Abdominal pain (9.5%), Nausea (4.8%)

Hepatobiliary disorders

Very common

ALT increased (47.6%), AST increased (42.9%)

AST increased (29.1%), ALT increased (25.5%)

AST increased (53.3%), ALT increased (46.7%)

AST increased (36.3%), ALT increased (34.1%)

Skin and subcutaneous tissue disorders

Very common

Rash (38.1%)

Rash (21.8%)

Rash (22%)

Musculo-skeletal and connective tissue disorders

Very common

Fractures (40%), Arthralgia (16.4%)

Fractures (20%), Muscular weakness (13.3%), Myalgia (13.3%)

Fractures (29.7%), Arthralgia (11.0%)

Common

Fractures (9.5%)

Muscular weakness (7.3%), Myalgia (7.3%)

Arthralgia (6.7%)

Muscular weakness (6.6%), Myalgia (6.6%)

Renal and urinary disorders

Very common

Blood creatinine increased (19%)

Blood creatinine increased (34.5%), Urinary retention (18.2%)

Blood creatinine increased (46.7%)

Blood creatinine increased (33%), Urinary retention (14.3%)

Common

Urinary retention (9.5%)

Urinary retention (6.7%)

General disorders and administration site conditions

Very common

Pyrexia (61.9%)

Pyrexia (50.9%), Fatigue (40%), Pain (30.9%), Oedema (14.5%)

Pain (33.3%), Pyrexia (33.3%), Fatigue (20%)

Fatigue (28.6%), Pain (26.4%), Pyrexia (50.5%), Oedema (11%)

Common

Pain (9.5%), Oedema (9.5%), Fatigue (4.8%)

% refers to all grades

1Infants/ toddlers (≥ 28 days to < 24 months): Grade ≥3 reactions reported were neutropenia, weight increased, lung infection, anaemia, AST increased, abdominal pain and urinary tract infection

2Children (≥24 months to < 12 years): Grade ≥3 reactions reported were neutropenia, weight increased, fractures, lung infection, anaemia, ALT increased, syncope, AST increased, ataxia, dyspnoea, abdominal pain congestive heart failure, fatigue, headache, pain, pyrexia, urinary tract infection, arthralgia, cognitive disorders, constipation, cough, decreased appetite. dehydration, hypotension, muscular weakness, oedema and vomiting

3Adolescents (≥12 to <18 years of age): Grade ≥3 reactions reported were neutropenia, weight increased, fracture, lung infection and headache

Description of selected adverse reactions

Cognitive disorders

A variety of cognitive symptoms was reported across clinical trials (see section 4.4). These included events reported as cognitive disorders (6.4%), confusional state (6.2%), memory impairment (4.9%), disturbance in attention (4.1%), amnesia (2.3%), mental status changes (0.9%), hallucination (0.8%), delirium (0.8%), disorientation (0.5%), brain fog (0.4%), attention deficit hyperactivity disorder (0.2%), visual hallucination (0.2%), auditory hallucination (0.1%), mental impairment (0.1%) and mental disorder (0.1%). Grade 3 cognitive disorders were reported in 3.6% of patients. Adult patients who had central nervous system (CNS) disease at baseline had a higher frequency of these adverse reactions (30%) compared to those without CNS disease (22.6%). The median time to onset for cognitive disorders was 0.95 months. In the paediatric population, 2.2% (2/91) of patients experienced disturbance in attention of Grade 1 severity and 2.2% (2/91) of patients experienced disturbance in attention of Grade 2 severity.

Fractures

Fractures were experienced by 9.1% (69/762) of adult patients and 29.7% (27/91) 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 both adult and paediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft) and some fractures occurred in the setting of a fall or other trauma.

The median time to fracture was 8.11 months (range: 0.26 months to 45.34 months) in adults. Rozlytrek was interrupted in 26.1% of adults that experienced fractures. Eighteen adult patients had Rozlytrek treatment interrupted and 2 adult patients discontinued Rozlytrek due to fractures. Rozlytrek dose was reduced for 2 adult patients due to fractures.

A total of 52 fracture events were reported in 27 paediatric patients, with 14 patients who experienced more than one occurrence of fracture. In paediatric patients, fractures mostly occurred in patients less than 12 years of age. Fractures resolved in 85.2% (23/27) of paediatric patients. The median time to fracture was 4.3 months (range: 2.0 months to 28.65 months) in paediatric patients. Twelve patients experienced Grade 2 fractures and 10 patients experienced Grade 3 fractures. Seven of the Grade 3 fractures were serious. Rozlytrek was interrupted in 18.5% (5/27) of paediatric patients who experienced fractures. Six paediatric patients discontinued Rozlytrek due to fractures. Rozlytrek dose was reduced for one paediatric patient.

Ataxia

Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.1% of patients. The median time to onset for ataxia was 0.5 months (range: 0.03 months to 65.48 months) and the median duration was 0.7 months (range: 0.03 months to 11.99 months). The majority of patients (55.8%) recovered from ataxia. Ataxia related adverse reactions were observed more frequently in elderly patients (24.2%) compared to patients below 65 years of age (11.8%).

Syncope

Syncope was reported in 5.0% 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 853 patients who received entrectinib across clinical trials, 47 (7.2%) patients with at least one post‑baseline ECG assessment experienced QTcF interval prolongation of >60 ms after starting entrectinib, and 27 (4.1%) patients had a QTcF interval of > 500 ms (see section 4.4).

Peripheral sensory neuropathy

Peripheral sensory neuropathy was reported in 16.2% of patients. The median time to onset was 0.71 months (range 0.03 months to 81.97 months) and the median duration was 0.9 months (range: 0.07 months to 41 months). 48.6% of patients recovered from peripheral neuropathy.

Eye disorders

Eye disorders reported across clinical trials included vision blurred (9%), visual impairment (1.9%), and diplopia (1.8%). The median time to onset for eye disorders was 1.9 months (range: 0.03 months to 49.61 months). The median duration of eye disorders was 1.2 months (range 0.03 months to 14.98 months). 54% of patients recovered from the eye disorder adverse reactions.

Paediatric population

The overall safety profile of Rozlytrek in the paediatric population is generally similar to the safety profile in adults.

The safety of Rozlytrek in paediatric patients was established based on data from 91 paediatric patients across 3 clinical trials (STARTRK-NG, STARTRK-2, and TAPISTRY). Of these, 21 patients were 28 days to < 2 years old, 55 patients were ≥ 2 to < 12 years old, 15 patients were ≥ 12 to < 18 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 (19.8% vs. 4.5%), weight increased (18.7% vs 9.6%), bone fractures (11% vs 2.5%) and lung infection (11% vs 5.5%). No Grade 5 events were observed in the 91 patients in the expanded paediatric safety population. Grade 3 to 4 events that occurred at a frequency ≥5% were neutropenia (19.8%), weight increased (18.7%), fractures (11%), lung infection (11%), and anaemia (8.8%).

The safety profile in each age group (infants and toddlers, children and adolescents) is similar to the overall safety profile of Rozlytrek in paediatric patients.

Elderly

Among the 853 patients who received entrectinib across clinical trials, 227 (26.6%) patients were 65 years or older and 53 (6.2%) were 75 years or older. The overall safety profile of entrectinib in elderly patients is similar to the safety profile observed in patients younger than 65 years of age. Adverse reactions occurring more frequently (at least a 5% increased incidence) in the elderly compared to patients less than 65 years old were dizziness (44.9% vs 33.4%), blood creatinine increased (35.7% vs 30%), hypotension (19.8% vs 14.5%), and ataxia (24.2% vs 11.8%).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Patients who experience overdose should be closely supervised and supportive care instituted. There are no known antidotes for entrectinib.