VITRAKVI Hard capsule Ref.[10642] Active ingredients: Larotrectinib

Efficacy across tumour types

The benefit of VITRAKVI has been established in single arm trials encompassing a relatively small sample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of VITRAKVI have been shown on the basis of 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 genetic alterations (see section 5.1). For these reasons, VITRAKVI should only be used if there are no treatment options for which clinical benefit has been established, or where such treatment options have been exhausted (i.e., no satisfactory treatment options).

Neurologic reactions

Neurologic reactions including dizziness, gait disturbance and paraesthesia were reported in patients receiving larotrectinib (see section 4.8). For the majority of neurologic reactions, onset occurred within the first three months of treatment. Withholding, reducing, or discontinuing VITRAKVI dosing should be considered, depending on the severity and persistence of these symptoms (see section 4.2).

Transaminase elevations

ALT and AST increase were reported in patients receiving larotrectinib (see section 4.8). The majority of ALT and AST increases occurred in the first 3 months of treatment. Liver function including ALT and AST assessments should be monitored before the first dose and monthly for the first 3 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase elevations. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, the VITRAKVI dose should be modified when resumed (see section 4.2).

Co-administration with CYP3A4/P-gp inducers

Avoid co-administration of strong or moderate CYP3A4/P-gp inducers with VITRAKVI due to a risk of decreased exposure (see section 4.5).

Contraception in female and male

Women of childbearing potential must use highly effective contraception while taking VITRAKVI and for at least one month after stopping treatment (see sections 4.5 and 4.6). Males of reproductive potential with a non-pregnant woman partner of child bearing potential should be advised to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose (see section 4.6).

Effects of other agents on larotrectinib

Effect of CYP3A, P-gp and BCRP inhibitors on larotrectinib

Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of VITRAKVI with strong CYP3A inhibitors, P-gp and BCRP inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole or grapefruit) may increase larotrectinib plasma concentrations (see section 4.2). Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with itraconazole (a strong CYP3A inhibitor and P-gp and BCRP inhibitor) 200 mg once daily for 7 days increased larotrectinib C_max and AUC by 2.8-fold and 4.3-fold, respectively. Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with a single dose of 600 mg rifampin (a P-gp and BCRP inhibitor) increased larotrectinib C_max and AUC by 1.8-fold and 1.7-fold, respectively.

Effect of CYP3A and P-gp inducers on larotrectinib

Co-administration of VITRAKVI with strong or moderate CYP3A and P-gp inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or St. John’s Wort) may decrease larotrectinib plasma concentrations and should be avoided (see section 4.4). Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with rifampin (a strong CYP3A and P-gp inducer) 600 mg twice daily for 11 days decreased larotrectinib C_max and AUC by 71% and 81%, respectively. No clinical data is available on the effect of a moderate inducer, but a decrease in larotrectinib exposure is expected.

Effects of larotrectinib on other agents

Effect of larotrectinib on CYP3A substrates

Clinical data in healthy adult subjects indicate that co-administration of VITRAKVI (100 mg twice daily for 10 days) increased the C_max and AUC of oral midazolam 1.7-fold compared to midazolam alone, suggesting that larotrectinib is a weak inhibitor of CYP3A. Exercise caution with concomitant use of CYP3A substrates with narrow therapeutic range (e.g. alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus) in patients taking VITRAKVI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking VITRAKVI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Effect of larotrectinib on CYP2B6 substrates

In vitro studies indicate that larotrectinib induces CYP2B6. Co-administration of larotrectinib with CYP2B6 substrates (e.g. bupropion, efavirenz) may decrease their exposure.

Effect of larotrectinib on other transporter substrates

In vitro studies indicate that larotrectinib is an inhibitor of OATP1B1. No clinical studies have been performed to investigate interactions with OATP1B1 substrates. Therefore, it cannot be excluded whether co-administration of larotrectinib with OATP1B1 substrates (e.g. valsartan, statins) may increase their exposure.

Effect of larotrectinib on substrates of PXR regulated enzymes

In vitro studies indicate that larotrectinib is a weak inducer of PXR regulated enzymes (e.g. CYP2C family and UGT). Co-administration of larotrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.

Hormonal contraceptives

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

Women of childbearing potential / Contraception in males and females

Based on the mechanism of action, foetal harm cannot be excluded when administering larotrectinib to a pregnant woman. Women of childbearing potential should have a pregnancy test prior to starting treatment with VITRAKVI.

Women of reproductive potential should be advised to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose. As it is currently unknown whether larotrectinib may reduce the effectiveness of systemically acting hormonal contraceptives, women using systemically acting hormonal contraceptives should be advised to add a barrier method. Males of reproductive potential with a non-pregnant woman partner of child-bearing potential should be advised to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.

Pregnancy

There are no data from the use of larotrectinib in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of VITRAKVI during pregnancy.

Breast-feeding

It is unknown whether larotrectinib/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with VITRAKVI and for 3 days following the final dose.

Fertility

There are no clinical data on the effect of larotrectinib on fertility. No relevant effects on fertility were observed in repeat-dose toxicity studies (see section 5.3).

VITRAKVI has a moderate influence on the ability to drive and use machines. Dizziness and fatigue have been reported in patients receiving larotrectinib, mostly Grade 1 and 2 during the first 3 months of treatment. This may influence the ability to drive and use machines during this time period. Patients should be advised not to drive and use machines, until they are reasonably certain VITRAKVI therapy does not affect them adversely (see section 4.4).

Summary of the safety profile

The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of decreasing frequency were increased ALT (32%), fatigue (30%), constipation (29%), increased AST (27%), dizziness (26%), vomiting (23%), anaemia (23%), and nausea (22%).

The majority of adverse reactions were Grade 1 or 2. Grade 4 was the highest reported grade for adverse reactions neutrophil count decreased (1%), ALT increased (1%), and AST increased (<1%). The highest reported grade was Grade 3 for adverse reactions anaemia, weight increased, fatigue, dizziness, paraesthesia, muscular weakness, nausea, myalgia, gait disturbance, vomiting, and leukocyte count decreased. All the reported Grade 3 adverse reactions occurred in less than 5% of patients, with the exception of anaemia (8%).

Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions, regardless of attribution occurred in 5% of patients (one case each of ALT increased, AST increased, bile duct adenocarcinoma, gait disturbance, intestinal perforation, jaundice, malignant neoplasm progression, neutrophil count decreased, small intestinal obstruction, spinal cord compression, and viral infection). The majority of adverse reactions leading to dose reduction occurred in the first three months of treatment.

Tabulated list of adverse reactions

The safety of VITRAKVI was evaluated in 196 patients with TRK fusion-positive cancer in one of three on-going clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”). The safety population characteristics were comprised of patients with a median age of 37.5 years (range: 0.1, 84) with 37% of patients being paediatric patients. Median time on treatment for the overall safety population (n=196) was 9.3 months (range: 0.10, 51.6). The adverse drug reactions reported in patients (n=196) treated with VITRAKVI are shown in Table 2 and Table 3.

The adverse drug reactions are classified according to the System Organ Class. Frequency groups are defined by the following convention: 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), and not known (cannot be estimated from available data). Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

Table 2. Adverse drug reactions reported in TRK fusion-positive cancer patients treated with VITRAKVI at recommended dose (overall safety population, n=196):

^a Grade 4 reactions were reported
^b ADR dysgeusia includes the preferred terms “dysgeusia” and "taste disorder"

Table 3. Adverse drug reactions reported in TRK fusion-positive paediatric cancer patients treated with VITRAKVI at recommended dose (n=73); all Grades:

^a Infant/toddlers (28 days to 23 months): two Grade 4 Neutrophil count decreased (Neutropenia) reactions reported. Grade 3 reactions included seven cases of Neutrophil count decreased (Neutropenia), three cases of Anaemia, three cases of Weight increased (Abnormal weight gain), and one case each of ALT increased and Vomiting.
^b Children (2 to 11 years): no Grade 4 reactions were reported. Three reported Grade 3 cases of Neutrophil count decreased (Neutropenia), and one case each of Paraesthesia and Myalgia.
^c Adolescents (12 to <18 years): no Grades 3 and 4 reactions were reported.

Description of selected adverse reactions

Neurologic reactions

In the overall safety database (n=196), the maximum grade neurologic reaction observed was Grade 3 which was observed in five (3%) patients and included dizziness (two patients, 1%), paraesthesia (two patients, 1%), and gait disturbance (one patient, <1%). The overall incidence was 26% for dizziness, 8% for paraesthesia and 4% for gait disturbance. Neurologic reactions leading to dose modification included dizziness (2%), paraesthesia (1%), and gait disturbance (<1%). One patient permanently discontinued the treatment due to Grade 3 gait disturbance. In all cases except of one, patients with evidence of anti-tumour activity who required a dose reduction were able to continue dosing at a reduced dose and/or schedule (see section 4.4).

Transaminase elevations

In the overall safety database (n=196), the maximum grade transaminase elevation observed was Grade 4 ALT increase in 2 patients (1%) and AST increase in 1 patient (<1%). Grade 3 ALT and AST increases in 4 (2%) and 2 (1%) of patients, respectively. Majority of Grade 3 elevations were transient appearing in the first or second month of treatment and resolving to Grade 1 by months 3-4. Grade 2 ALT and AST increases were observed in 10 (5%) and 8 (4%) of patients, respectively, and Grade 1 ALT and AST increases were observed in 47 (24%) and 41 (21%) of patients, respectively. ALT and AST increases leading to dose modifications occurred in 10 (5%) patients and 8 (4%) patients, respectively (see section 4.4). No patient permanently discontinued the treatment due to Grade 3-4 ALT and AST increases.

Additional information on special populations

Paediatric patients

Of the 196 patients treated with VITRAKVI, 73 (37%) patients were from 28 days to 18 years of age. Of these 73 patients, 40% were 28 days to <2 years (n=29), 41% were 2 years to < 12 years (n=30), and 19% were 12 years to <18 years (n=14). The safety profile in the paediatric population (<18 years) was consistent in types of reported adverse reactions to those observed in the adult population. The majority of adverse reactions were Grade 1 or 2 in severity (see Table 3) and were resolved without VITRAKVI dose modification or discontinuation. The adverse reactions of vomiting (38% versus 15% in adults), leucocyte count decrease (16% versus 11% in adults), neutrophil count decrease (27% versus 7% in adults), and blood alkaline phosphatase increased (12% versus 4% in adults) were more frequent in paediatric patients compared to adults.

Elderly

Of the 196 patients in the overall safety population who received VITRAKVI, 35 (18%) patients were 65 years or older and 10 (5%) patients were 75 years or older. The safety profile in elderly patients (≥65 years) is consistent with that seen in younger patients. The adverse reaction gait disturbance (11% versus 5% in all adults) was more frequent in patients of 65 years or older.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.