Rozlytrek 200 Mg/100 mg Capsules

Solid tumours

Rozlytrek is indicated for the treatment of adult and paediatric patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive locally advanced or metastatic solid tumours, who have progressed following prior therapies, or as initial therapy when there are no acceptable standard therapies.

Non-small cell lung cancer (NSCLC)

Rozlytrek is indicated for the treatment of patients with ROS1-positive, locally advanced or metastatic NSCLC.

General

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 fusion-positive locally advanced or metastatic solid tumours. NTRK fusion-positive status should be established prior to initiation of Rozlytrek therapy.

ROS1-positive non-small cell lung cancer

A validated assay is required for the selection of patients with ROS1-positive locally advanced or metastatic NSCLC. ROS1-positive status should be established prior to initiation of Rozlytrek therapy.

Recommended Dosage

Rozlytrek hard capsules can be taken with or without food, swallowed whole and must not be opened or dissolved.

Adults

The recommended dose of Rozlytrek for adults is 600 mg given orally, once daily (see section 5.2).

Paediatric patients

The recommended dose of Rozlytrek for paediatric patients 12 years and older who have the ability to swallow capsules is 300 mg/m2 orally, once daily (see Table 1). (See section 5.2).

Table 1: Recommended dosing for Paediatric patients

• Body surface area (BSA)
• Once daily dose
• 0.43 - 0.50 m2 100 mg
• 0.51 - 0.80 m2 200 mg
• 0.81 - 1.10 m2 300 mg
• 1.11 - 1.50 m2 400 mg
• u2265 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 events may require temporary interruption, dose reduction, or discontinuation of treatment with Rozlytrek, based on the prescriberu2019s assessment of the patientu2019s safety or tolerability.

Adults

For adults, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability. Table 2 provides general dose reduction advice for adult patients. 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

• Starting Dose: 600 mg once daily
• First dose reduction: 400 mg once daily
• Second dose reduction: 200 mg once daily

Paediatric Patients

Table 3 provides specific dose reduction advice for paediatric patients. For paediatric patients, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability. 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

• Starting Dose once daily
• First dose reduction
• Second dose reduction

100 mg: 100 mg, once/day for 5 days each week *

100 mg, once/day for 3 days each week **

200 mg: 200 mg, once/day for 5 days each week *

100 mg, once/day for 5 days each week*

300 mg: 200 mg once daily

100 mg once daily

400 mg: 300 mg once daily

200 mg, once/day for 5 days each week*

600 mg: 400 mg once daily

200 mg once daily

*5 days each week: Monday, Wednesday, Friday, Saturday, and Sunday

**3 days each week: Monday, Thursday and Saturday

Dose Modifications for Specific Adverse Reactions

Recommendations for Rozlytrek dose modifications for adults and paediatric patients for specific adverse reactions are provided in Table 4. (See section 4.4 and section 4.8).

Table 4: Recommended dose modifications for specified Adverse Drug Reactions for Adult and Paediatric Patients

• Adverse Drug Reaction
• Severity *
• Dose modification

Anemia or Neutropenia Grade 3 or Grade 4

Withhold Rozlytrek until recovery to u2264 Grade 2 or to baseline, then resume treatment at same dose level or reduced dose, as clinically needed.

Cognitive Disorders Grade u2265 2

Withhold Rozlytrek until recovery to u2264 Grade 1 or to baseline, then resume treatment at reduced dose.

If event recurs, further reduce dose.

For prolonged, severe, or intolerable events, discontinue as clinically appropriate.

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 elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis

Permanently discontinue Rozlytrek.

Hyperuricemia Symptomatic or Grade 4

Initiate urate-lowering medication

Withhold Rozlytrek until improvement of signs or symptoms

Resume Rozlytrek at same or reduced dose

Congestive Heart Failure Grade 2 or 3

Withhold Rozlytrek until recovered to less than or equal to Grade 1

Resume at reduced dose

Grade 4

Withhold Rozlytrek until recovered to less than or equal to Grade 1

Resume at reduced dose or discontinue as clinically appropriate

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

Other clinically relevant adverse reactions Grade 3 or 4

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

Rozlytrek is contraindicated in patients with a known hypersensitivity to entrectinib or any of the excipients.

Congestive Heart Failure

Congestive heart failure (CHF) has been reported across clinical trials with Rozlytrek (see Table 5 in 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 dose reduction/interruption of Rozlytrek. 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 edema, 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.

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 should be monitored for signs of cognitive changes. Based on the severity of the cognitive disorder, 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 symptoms of cognitive disorders. (See section 4.7).

Fractures

Rozlytrek increases the risk of fractures (see description of selected ADRs). Patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures should be evaluated promptly. In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area, while in paediatric patientsu2019 fractures occurred in patients with minimal or no trauma. There are no data on the effects of Rozlytrek on healing of known fractures and the risk of occurrence of future fractures. In the majority of paediatric patients treatment was continued with Rozlytrek and the fracture healed.

QTc Interval Prolongation

QT 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 congenital long QT syndrome and in patients taking medications that are known to prolong QT interval. Assessment of ECG at baseline and periodic monitoring of ECGs and electrolytes are recommended. Based on the severity of QTc prolongation, Rozlytrek treatment should be modified as described in Table 4 in section 4.2.

Embryo-foetal toxicity

Based on the findings in animal studies, Rozlytrek may cause foetal harm when administered to a pregnant woman. When administrated to pregnant rats, Rozlytrek caused maternal toxicity and developmental toxicities at exposures 2.3-fold the human exposure by AUC at the recommended dose. (See section 4.6). Female patients receiving Rozlytrek should be advised of the potential harm to the foetus. Female patients of reproductive potential, must use highly effective contraceptive methods during treatment and for 5 weeks following the last dose of Rozlytrek. (See section 4.6).

Drug Abuse and Dependence

Not applicable.

Use in Special Populations

Elderly Use

No differences in safety or efficacy were observed between patients u2265 65 years of age and younger patients. No dose adjustment is required in patients u2265 65 years of age. See section 4.2 and section 5.2.

Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment based on population pharmacokinetic analysis. The safety and efficacy of Rozlytrek in patients with severe renal impairment have not been studied. See section 4.2 and section 5.2.

Hepatic Impairment

The safety and efficacy of Rozlytrek in patients with hepatic impairment have not been studied. See section 4.2 and section 5.2.

Effects of entrectinib on others drugs

CYP substrates

Based on the in vitro studies in human liver microsomes, entrectinib exhibits inhibitory potential toward CYP3A. In vitro studies indicate that entrectinib and its major active metabolite, M5, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 at clinically relevant concentrations. In vitro results indicate entrectinib has weak induction potential toward CYP3A and CYP2C8/9. In a clinical study, co-administration of multiple doses of entrectinib and midazolam, a sensitive CYP3A substrate, increased the systemic exposure of midazolam by approximately 50% indicating a weak inhibitory effect of entrectinib on the metabolism of midazolam (Geometric mean ratio (GMR) with/without entrectinib for AUC inf (90% CI) was 150% (129%, 173%)). Therefore, no dose adjustment is required when Rozlytrek is co-administered with CYP3A substrates.

P-gp substrates

In vitro data suggest that entrectinib has inhibitory potential towards P-gp. In a clinical study, co-administration of a single oral dose of entrectinib with a sensitive P-gp substrate, digoxin, increased the digoxin C max by approximately 28% and overall exposure by approximately 18% (GMR with/without entrectinib for C max (90% CI) was 128% (98.2%, 167%) and AUC inf (90% CI) was 118% (106%, 132%)). 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.

These results indicate that entrectinib is a weak P-gp inhibitor and that no clinically significant interaction exists between digoxin, as a P-gp substrate, and entrectinib. Therefore, no dose adjustment is required when Rozlytrek is co-administered with P-gp substrates.

BCRP substrates

As with P-gp, a mild inhibition of BCRP was observed in in vitro studies. Given that no clinically significant interaction was observed with the P-gp substrate digoxin, an interaction with BCRP is not predicted. No dose adjustment is required when Rozlytrek is co-administered with BCRP substrates.

Other transporter substrates

In vitro data indicate that entrectinib has weak inhibitory potential toward organic anion-transporting polypeptide (OATP) 1B1 and multidrug and toxin extrusion protein 1 (MATE1).

Oral Contraceptive

Physiologically-based pharmacokinetic simulation of the effects of co-administration of multiple oral doses of entrectinib with ethinyl estradiol, an oral contraceptive, predicted no drug-drug interaction. GMR with/without entrectinib for AUC inf (90% CI) of 112% (111%, 113%) and C max (90% CI) was 112% (111%, 113%). Therefore Rozlytrek can be co-administered with an oral contraceptive.

Effects of other drugs 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.

CYP3A inducers

Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose of entrectinib reduced the systemic exposure of entrectinib by 77%. GMR with/without rifampin for AUC inf (90% CI) was 23.3% (18.4%, 29.5%) and C max (90% CI) was 44.4% (35.3%, 55.9%).

Co-administration of Rozlytrek with CYP3A inducers should be avoided (see section 4.2).

CYP3A inhibitors

Co-administration of a single oral dose of entrectinib with multiple oral doses of itraconazole, a strong CYP3A4 inhibitor, increased the systemic exposure of entrectinib by 500%. GMR with/without itraconazole for AUC inf (90% CI) was 604% (454%, 804%) and C max (90% CI) was 173% (137%, 218%). Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, anti-fungal medicines, anti-retroviral medicines) with Rozlytrek should be avoided or limited to 14 days. If concurrent use is unavoidable, dose adjustment of Rozlytrek is required as described in section 2.2 Dosage and Administration.

Medicinal products that increase gastric pH

The aqueous solubility of entrectinib in vitro is pH dependent. In a clinical study, administration of entrectinib with lansoprazole (a proton pump inhibitor (PPI)), resulted in a 25% decrease in entrectinib systemic exposure which is not clinically relevant. GMR with/without lansoprazole for AUC inf (90%CI) was 74.5% (64.7%, 85.9%) and C max (90% CI) was 76.5% (67.6%, 86.6%). Therefore, no dose adjustments are required when Rozlytrek is co administered with PPIs or other medicines that raise gastric pH (e.g., H2 receptor antagonists or antacids).

Effect of transporters on Entrectinib disposition

Based on the in vivo brain-to-plasma concentration ratio (u22650.6) at steady-state in rats and dogs as well as lack of sensitivity to a P-gp inhibitor in vitro in a P-gp expressing cell assay, entrectinib is considered a poor substrate of P-gp. M5 is a substrate of P-gp. Entrectinib is not a substrate of BCRP but M5 is a substrate of BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

Pregnancy

Female patients of reproductive potential must be advised to avoid pregnancy while receiving Rozlytrek (see section 4.4). There is no available data on the use of Rozlytrek in pregnant women. Based on animal studies with entrectinib (see section 5.3) and its mechanism of action, Rozlytrek may cause foetal harm when administered to a pregnant woman. Patients receiving Rozlytrek should be advised of the potential harm to the foetus. Female patients should be advised to contact the medical practitioner, should pregnancy occur.

Breastfeeding

Mothers should not breastfeed their infants when taking Rozlytrek.

Fertility

No fertility studies in animals have been performed to evaluate the effect of entrectinib. With the exception of dose dependent decreases in prostate weight in male dogs, no effects of entrectinib on 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.

Rozlytrek may influence 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 section 4.4 and section 4.8).

Clinical Trials

Summary of the safety profile

For the clinical development program of Rozlytrek, a total of 504 patients have received Rozlytrek in 4 clinical trials (ALKA, STARTRK-1, STARTRK-2 and STARTRK-NG). The safety of Rozlytrek was evaluated as integrated analyses of these 4 clinical trials. The median duration of exposure to Rozlytrek was 5.5 months. The safety of Rozlytrek in adult patients has been evaluated in a total of 475 patients with NTRK-fusion positive, ROS1-positive or ALK-positive solid tumours, in studies ALKA, STARTRK-1, STARTRK-2. The safety of Rozlytrek has been evaluated in 29 paediatric patients with solid tumours (27 patients enrolled in STARTRK-NG, and 2 patients enrolled in STARTRK-2). Of these, 1 patient was less than 1 year old, 21 patients were 2 to 11 years old, 7 patients were 12 to 17 years old.

Tabulated summary of adverse drug reactions from clinical trials

Table 5 summarizes the adverse drug reactions (ADRs) occurring in adult and paediatric patients treated with Rozlytrek. ADRs from clinical trials (Table 5) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1,000 to < 1/100), rare (u2265 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 5 Summary of adverse drug reactions occurring in patients treated with Rozlytrek in clinical trials (integrated safety population)

• System Organ Class
• Adverse Reaction
• Rozlytrek N=504
• Frequency Category (All Grades)
• All Grades (%)
• Grade u2265 3 (%)

General Disorders and Administration Site Conditions

Fatigue 14 45.0 5.0 very common

Edema 6 37.3 1.4 very common

Pain 7 24.4 1.6 very common

Pyrexia 20.0 0.8 very common

Gastrointestinal Disorders

Constipation 42.9 0.4 very common

Diarrhoea 33.5 2.6 very common

Nausea 32.1 0.8 very common

Vomiting 23.2 1.2 very common

Abdominal pain 11.1 0.6 very common

Dysphagia 10.1 0.4 very common

Nervous System Disorders

Dysgeusia 42.3 0.4 very common

Dizziness 5 39.7 1.2 very common

Dysasthesia 3 29.0 0.2 very common

Cognitive Disorders 1 24.2 4.4 very common

Headache 17.5 1.0 very common

Peripheral Sensory Neuropathy 2 15.7 1.0 very common

Ataxia 4 15.7 0.8 very common

Sleep disturbances 16 13.5 0.4 very common

Mood disorders 17 9.1 0.6 common

Syncope 4.6 3.0 common

Respiratory Disorders

Dyspnea 27.0 5.8 * very common

Cough 21.4 0.6 very common

Blood Disorders

Anemia 28.2 9.7 very common

Neutropenia 10 11.3 4.4 very common

Metabolism and Nutritional Disorders

Weight increased 26.4 7.3 very common

Decreased appetite 11.9 0.2 very common

Hyperuricemia 9.1 1.8 common

Dehydration 7.9 1.0 common

Tumour lysis syndrome 0.2 0.2 * uncommon

Renal and urinary disorders

Blood creatinine increased 25.4 0.6 very common

Musculoskeletal Disorders

Myalgia 19.6 0.6 very common

Arthralgia 19.0 0.6 very common

Muscular weakness 12.3 1.2 very common

Fractures 11 6.2 2.4 common

Hepatobiliary Disorders

AST increased 17.5 3.6 very common

ALT increased 16.1 3.4 very common

Infections and Infestations

Lung infection 8 13.1 6.0 * very common

Urinary tract infection 12.7 2.6 very common

Eye Disorders

Vision Blurred 13 11.9 0.4 very common

Skin and Subcutaneous Tissue Disorders

Rash 12 11.5 1.4 very common

Vascular Disorders

Hypotension 15 16.5 2.4 very common

Cardiac Disorders

Congestive Heart Failure 9 3.0 2.2 common

Electrocardiogram QT prolonged 2.0 0.6 common

ALT: Alanine aminotransferase AST: Aspartate aminotransferase

* Grades 3 to 5, inclusive of fatal adverse reactions (including 2 reactions of pneumonia, 2 reactions of dyspnea, and 1 reaction of tumour lysis syndrome)

1 Includes preferred terms: cognitive disorder, confusional state, disturbance in attention, memory impairment, amnesia, mental status changes, hallucination, delirium, u2018hallucination visualu2019 and mental disorder.

2 Includes the preferred terms: neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy

3 Includes the preferred terms: paresthesia, hyperesthesia, hypoesthesia, dysesthesia

4 Includes the preferred terms: ataxia, balance disorder, gait disturbances

5 Includes the preferred terms: dizziness, vertigo, dizziness postural

6 Includes the preferred terms: face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling

7 Includes the preferred terms: back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity

8 Includes the preferred terms: bronchitis, lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection, upper respiratory tract infection

9 Includes the preferred terms: acute right ventricular failure, cardiac failure, cardiac failure congestive, chronic right ventricular failure, ejection fraction decreased, pulmonary edema

10 Includes the preferred terms: neutropenia, neutrophil count decreased

11 Includes the preferred terms: humerus fracture, foot fracture, ankle fracture, femoral neck fracture, stress fracture, fibula fracture, fracture, rib fracture, spinal fracture, wrist fracture, femur fracture, pathological fracture

12 Includes the preferred terms: rash, rash maculopapular, rash pruritic, rash erythematous, rash papular

13 Includes the preferred terms: diplopia, vision blurred, visual impairment

14 Includes the preferred terms: fatigue, asthenia

15 Includes the preferred terms: hypotension, orthostatic hypotension

16 Includes the preferred terms: hypersomnia, insomnia, sleep disorder, somnolence

17 Includes the preferred terms: anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation

There is no experience with overdose in clinical trials with Rozlytrek. Patients who experience overdose should be closely supervised and supportive care instituted. There are no known antidotes for Rozlytrek.