Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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, 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 3 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 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 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 3 in section 4.2.
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 3 in section 4.2.
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 3 in section 4.2.
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).
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. 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.
Rozlytrek contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rozlytrek 200 mg hard capsules contain sunset yellow FCF (E110), which may cause allergic reactions.
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.
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.
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.
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.
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.
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).
Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib and formation of its major active metabolite M5.
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.
Co-administration of itraconazole, a strong CYP3A4 inhibitor, with a single oral dose of entrectinib increased AUCinf by 600% and Cmax by 173%. Based on physiologically based pharmacokinetic (PBPK) modelling, a similar magnitude of the effect is expected in children as young as 2 years old.
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).
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).
Interaction studies have only been performed in adults.
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).
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.
It is unknown whether entrectinib or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with Rozlytrek.
No fertility studies in animals have been performed to evaluate the effect of entrectinib (see section 5.3).
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).
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.
Table 4 summarises the adverse drug reactions (ADRs) occurring in 762 adult 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 adult and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 months.
Table 5 includes paediatric patients from three clinical studies; STARTRK-NG, STARTRK-2 and TAPISTRY. The median duration of exposure was 11.1 months. Paediatric data in the description of selected adverse reactions reflect exposure to Rozlytrek in this expanded paediatric safety population (n=91). The safety profile observed in the expanded paediatric population was consistent with the known paediatric safety profile from the integrated safety population in Table 4 below.
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 4. 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 | |
| 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 fracture, 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 5. 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%), Electro- cardiogram QT prolonged (9.5%) | Congestive heart failure (5.5%), Electro- cardiogram QT prolonged (5.5%) | Congestive heart failure (5.5%), Electro- cardiogram QT 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
1 Infant/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
2 Children (≥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
3 Adolescents (≥12 to <18 years of age): Grade ≥3 reactions reported were neutropenia, weight increased, fracture, lung infection, and headache
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 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 (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 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.
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 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 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.
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.
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 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.
Not applicable.
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