Vitrakvi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 25 mg hard capsules 
VITRAKVI 100 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
VITRAKVI 25 mg hard capsules 
Each hard capsule contains larotrectinib sulfate equivalent to 25 mg of larotrectinib. 
 
VITRAKVI 100 mg hard capsules 
Each hard capsule contains larotrectinib sulfate equivalent to 100 mg of larotrectinib. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
VITRAKVI 25 mg hard capsules 
White opaque hard gelatine capsule, size 2 (18 mm long x 6 mm wide), with blue printing of 
BAYER-cross and “LARO 25 mg” on body of capsule. 
 
VITRAKVI 100 mg hard capsules 
White opaque hard gelatine capsule, size 0 (22 mm long x 7 mm wide), with blue printing of 
BAYER-cross and “LARO 100 mg” on body of capsule. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
VITRAKVI as monotherapy is indicated for the treatment of adult and paediatric patients with solid 
tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, 
- who have a disease that is locally advanced, metastatic or where surgical resection is likely to 

result in severe morbidity, and 
- who have no satisfactory treatment options (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Treatment with VITRAKVI should be initiated by physicians experienced in the administration of 
anticancer therapies. 
 
The presence of an NTRK gene fusion in a tumour specimen should be confirmed by a validated test 
prior to initiation of treatment with VITRAKVI. 
 



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Posology 
 
Adults 
The recommended dose in adults is 100 mg larotrectinib twice daily, until disease progression or until 
unacceptable toxicity occurs. 
 
Paediatric population 
Dosing in paediatric patients is based on body surface area (BSA). The recommended dose in 
paediatric patients is 100 mg/m2 larotrectinib twice daily with a maximum of 100 mg per dose until 
disease progression or until unacceptable toxicity occurs. 
 
Missed dose 
If a dose is missed, the patient should not take two doses at the same time to make up for a missed 
dose. Patients should take the next dose at the next scheduled time. If the patient vomits after taking a 
dose, the patient should not take an additional dose to make up for vomiting. 
 
Dose modification 
For all Grade 2 adverse reactions, continued dosing may be appropriate, though close monitoring to 
ensure no worsening of the toxicity is advised. Patients with Grade 2 ALT and/or AST increases, 
should be followed with serial laboratory evaluations every one to two weeks after the observation of 
Grade 2 toxicity until resolved to establish whether a dose interruption or reduction is required. 
 
For Grade 3 or 4 adverse reactions: 
- VITRAKVI should be withheld until the adverse reaction resolves or improves to baseline or 

Grade 1. Resume at the next dose modification if resolution occurs within 4 weeks. 
- VITRAKVI should be permanently discontinued if an adverse reaction does not resolve within 

4 weeks. 
 
The recommended dose modifications for VITRAKVI for adverse reactions are provided in Table 1. 
 
Table 1: Recommended dose modifications for VITRAKVI for adverse reactions 

Dose modification 
Adult and 

paediatric patients with body 
surface area of at least 1.0 m2 

Paediatric patients with body 
surface area less than 1.0 m2 

First 75 mg twice daily 75 mg/m2 twice daily 

Second 50 mg twice daily 50 mg/m2 twice daily 

Third 100 mg once daily 25 mg/m2 twice daily 

 
VITRAKVI should be permanently discontinued in patients who are unable to tolerate VITRAKVI 
after three dose modifications. 
 
Special populations 
 
Elderly 
No dose adjustment is recommended in elderly patients (see section 5.2). 
 
Hepatic impairment 
The starting dose of VITRAKVI should be reduced by 50% in patients with moderate (Child-Pugh B) 
to severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with 
mild hepatic impairment (Child-Pugh A) (see section 5.2). 
 



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Renal impairment 
No dose adjustment is required for patients with renal impairment (see section 5.2). 
 
Co-administration with strong CYP3A4 inhibitors 
If co-administration with a strong CYP3A4 inhibitor is necessary, the VITRAKVI dose should be 
reduced by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, 
VITRAKVI should be resumed at the dose taken prior to initiating the CYP3A4 inhibitor (see 
section 4.5). 
 
Method of administration 
 
VITRAKVI is for oral use. 
 
VITRAKVI is available as a capsule or oral solution with equivalent oral bioavailability and may be 
used interchangeably. 
 
The patient should be advised to swallow the capsule whole with a glass of water. Due to the bitter 
taste, the capsule should not be opened, chewed or crushed. 
 
The capsules can be taken with or without food but should not be taken with grapefruit or grapefruit 
juice. 
 
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 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). 
 



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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). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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 Cmax 
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 Cmax 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 Cmax 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. 
 



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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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 



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4.7 Effects on ability to drive or use machines 
 
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). 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The safety of VITRAKVI was evaluated in 125 patients with TRK fusion-positive cancer in one of 
three clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”). Median time on treatment for the 
overall safety population was 7.4 months (range: 0.03 to 40.7). The safety population characteristics 
were comprised of patients with a median age of 45 years (range: 0.1, 80) with 30% of patients being 
paediatric patients. The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of 
decreasing frequency were fatigue (32%), increased ALT (31%), dizziness (30%), increased AST 
(29%), constipation (29%), nausea (26%), anaemia (24%), and vomiting (20%). 
The majority of adverse reactions were Grade 1 or 2. Grade 4 was the highest reported grade for 
adverse reactions neutrophil count decreased (1.6%) and ALT increased (< 1%). The highest reported 
grade was Grade 3 for adverse reactions anaemia, weight increased, fatigue, increased AST, dizziness, 
paraesthesia, nausea, myalgia, and leukocyte count decreased. All the reported Grade 3 adverse 
reactions occurred in less than 5% of patients, with the exception of anaemia (7%). 
Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions, regardless of 
attribution occurred in 3% of patients (one case each of ALT increase, AST increase, intestinal 
perforation, jaundice, small intestinal obstruction). The majority of adverse reactions leading to dose 
reduction occurred in the first three months of treatment. 
 
Tabulated list of adverse reactions  
 
The adverse drug reactions reported in patients 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. 
 



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Table 2: Adverse drug reactions reported in TRK fusion-positive cancer patients treated with 
VITRAKVI at recommended dose (n=125) 

System organ class Frequency All grades Grades 3 and 4 
Blood and lymphatic 
system disorders 

Very common Anaemia 
Neutrophil count decreased 
(Neutropenia) 
Leukocyte count decreased 
(Leukopenia) 

 

Common  Anaemia 
Neutrophil count 
decreased (Neutropenia)a 
Leukocyte count 
decreased (Leukopenia) 

Nervous system 
disorders 

Very common Dizziness 
Paraesthesia 

 

Common Gait disturbance 
 

Dizziness 
Paraesthesia 

Gastrointestinal 
disorders 

Very common Nausea 
Constipation 
Vomiting 

 

Common Dysgeusia Nausea 
Musculoskeletal and 
connective tissue 
disorders 

Very common Myalgia 
Muscular weakness 

 

Common  Myalgia 
General disorders 
and administration 
site conditions 

Very common Fatigue  

Common  Fatigue 

Investigations Very common Alanine aminotransferase 
(ALT) increased 
Aspartate aminotransferase 
(AST) increased 
Weight increased 
(Abnormal weight gain) 

 

Common Blood alkaline phosphatase 
increased 

Alanine aminotransferase 
(ALT) increaseda 
Aspartate 
aminotransferase (AST) 
increased 
Weight increased 
(Abnormal weight gain) 

a Grade 4 reactions were reported 
 



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Table 3: Adverse drug reactions reported in TRK fusion-positive paediatric cancer patients 
treated with VITRAKVI at recommended dose (n=37); all Grades 
System organ 
class 

Frequency Infants and 
toddlers 
(n=14)a 

Children 
 
(n=15)b 

Adolescents 
 
(n=8)c 

Paediatric 
patients 
(n=37) 

Blood and 
lymphatic 
system 
disorders 

Very 
common 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Nervous system 
disorders 

Very 
common 

  Dizziness 
Paraesthesia 

 

Common  Paraesthesia 
Gait disturbance 

 Dizziness 
Paraesthesia 
Gait disturbance 

Gastrointestinal 
disorders 

Very 
common 

Nausea 
Constipation 
Vomiting 

Nausea 
Constipation 
Vomiting 

Nausea 
Vomiting 

Nausea 
Constipation 
Vomiting 

Common  Dysgeusia  Dysgeusia 
Musculoskeletal 
and connective 
tissue disorders 

Very 
common 

  Myalgia 
Muscular 
weakness 

 

Common  Myalgia  Myalgia 
Muscular 
weakness 

General 
disorders and 
administration 
site conditions 

Very 
common 

Fatigue Fatigue  Fatigue 

Investigations Very 
common 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 
Blood alkaline 
phosphatase 
increased 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Blood alkaline 
phosphatase 
increased 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 
Blood alkaline 
phosphatase 
increased 

Common Blood alkaline 
phosphatase 
increased 

   

a Infant/toddlers (28 days to 23 months): one Grade 4 Neutrophil count decreased (Neutropenia) reaction reported. Grade 3 
reactions included two cases Neutrophil count decreased (Neutropenia) and one case of anaemia. 

b Children (2 to 11 years): no Grade 4 reactions were reported. One reported Grade 3 case each of Neutrophil count 
decreased (Neutropenia), Paraesthesia, Myalgia, Weight increased (Abnormal weight gain). 

c Adolescents (12 to <18 years): no Grades 3 and 4 reactions were reported. 
 



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Description of selected adverse reactions 
 
Neurologic reactions 
In the overall safety database (n=125), the maximum grade neurologic reaction observed was Grade 3 
which was observed in three (2%) patients and included dizziness (one patient, <1%) and paraesthesia 
(two patients, 1.6%). The overall incidence was 30% for dizziness, 10% for paraesthesia and 3% for 
gait disturbance. Neurologic reactions leading to dose modification included dizziness (2%). None of 
these adverse reactions led to treatment discontinuation. In all cases, 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=125), the maximum grade transaminase elevation observed was 
Grade 4 ALT increase in 1 patient (<1%). Grade 3 ALT and AST increases in 3 (2%) and 2 (2%) 
patients, respectively. Majority of Grade 3 elevations were transient appearing in first or second month 
of treatment and resolving to Grade 1 by months 3-4. Grade 2 ALT and AST increases were observed 
in 9 (7%) and 6 (5%) of patients, respectively, and Grade 1 ALT and AST increases were observed in 
26 (21%) and 28 (22%) of patients, respectively. 
ALT and AST increases leading to dose modifications occurred in 7 (6%) patients and 6 (5%) 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 125 patients treated with VITRAKVI, 37 (30%) patients were from 28 days to 18 years of age. Of 
these 37 patients, 38% were 28 days to < 2 years (n=14), 41% were 2 years to < 12 years (n=15), and 
22% were 12 years to < 18 years (n=8). 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 (35% versus 
14% in adults), leucocyte count decrease (22% versus 9% in adults), neutrophil count decrease (30% 
versus 7% in adults), blood alkaline phosphatase increased (14% versus 2% in adults) and 
transaminase elevations (ALT 41% versus 27% in adults and AST 35% versus 26% in adults) were 
more frequent in paediatric patients compared to adults. 
 
Elderly 
Of 125 patients in the overall safety population who received VITRAKVI, 28 (22%) patients were 
65 years or older and 8 (6%) patients were 75 years or older. The safety profile in elderly patients 
(≥ 65 years) is consistent with that seen in younger patients (< 65 years). The adverse reactions gait 
disturbance (17% versus 3% in under 65 years), and blood alkaline phosphatase increased (4% versus 
2% in under 65 years) were 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. 
 
4.9 Overdose 
 
There is limited experience of overdose with VITRAKVI. Symptoms of overdose are not established. 
In the event of overdose, physicians should follow general supportive measures and treat 
symptomatically. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, 
protein kinase inhibitors, ATC code: L01XE53. 
 
Mechanism of action 
 
Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor 
kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target 
for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded 
by NTRK1, NTRK2 and NTRK3 genes, respectively. In a broad panel of purified enzyme assays, 
larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. The only other 
kinase activity occurred at 100-fold higher concentrations. In in vitro and in vivo tumour models, 
larotrectinib demonstrated anti-tumour activity in cells with constitutive activation of TRK proteins 
resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein 
overexpression. 
 
In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, 
NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel 
chimeric oncogenic proteins are aberrantly expressed, driving constitutive kinase activity subsequently 
activating downstream cell signalling pathways involved in cell proliferation and survival leading to 
TRK fusion-positive cancer. 
 
Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib 
had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the 
clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain 
with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L. 
 
The molecular causes for primary resistance to larotrectinib are not known. It is therefore not known if 
the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy 
of TRK inhibition. The measured impact of any concomitant genomic alterations on larotrectinib 
efficacy is provided below (see clinical efficacy). 
 
Pharmacodynamic effect 
 
Cardiac electrophysiology 
In 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg, VITRAKVI did 
not prolong the QT interval to any clinically relevant extent. 
The 200 mg dose corresponds to a peak exposure (Cmax) similar to that observed with larotrectinib 
100 mg BID at steady state. A shortening of QTcF was observed with VITRAKVI dosing, with a 
maximum mean effect observed between 3 and 24 hours after Cmax, with a geometric mean decrease in 
QTcF from baseline of -13.2 msec (range -10 to -15.6 msec). Clinical relevance of this finding has not 
been established.  
 
Clinical efficacy 
 
Overview of studies 
The efficacy and safety of VITRAKVI were studied in three multicentre, open-label, single-arm 
clinical studies in adult and paediatric cancer patients (Table 4). The studies were ongoing at the time 
of approval. 
Patients with and without documented NTRK gene fusion were allowed to participate in Study 1 and 
Study 3 (“SCOUT”). Patients enrolled to Study 2 (“NAVIGATE”) were required to have TRK 
fusion-positive cancer. The pooled primary analysis set of efficacy includes 93 patients with TRK 
fusion-positive cancer enrolled across the three studies that had measurable disease assessed by 
RECIST v1.1, a non-CNS primary tumour and received at least one dose of larotrectinib. These 



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patients were required to have received prior standard therapy appropriate for their tumour type and 
stage of disease or who, in the opinion of the investigator, would have had to undergo radical surgery 
(such as limb amputation, facial resection, or paralysis causing procedure), or were unlikely to 
tolerate, or derive clinically meaningful benefit from available standard of care therapies in the 
advanced disease setting. The major efficacy outcome measures were overall response rate (ORR) and 
duration of response (DOR), as determined by a blinded independent review committee (BIRC). 
In addition, 9 patients with primary CNS tumours and measurable disease at baseline were treated in 
Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). All primary CNS tumour patients had received 
prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy). Tumour responses 
were assessed by the investigator using RANO or RECIST v1.1 criteria. 
 
Identification of NTRK gene fusions relied upon the molecular test methods: next generation 
sequencing (NGS) used in 98 patients, reverse transcription-polymerase chain reaction (RT-PCR) used 
in 1 patient and fluorescence in situ hybridization (FISH) used in 6 patients as routinely performed at 
certified laboratories. 
 



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Table 4: Clinical studies contributing to the efficacy analyses in solid and primary CNS tumours 
Study name, design and patient 
population 

Dose and 
formulation 

Tumour types included in 
efficacy analysis 

n 

Study 1 
NCT02122913 
 
• Phase 1, open-label, dose escalation 

and expansion study; expansion 
phase required tumours with an 
NTRK gene fusion 

• Adult patients (≥ 18 years) with 
advanced solid tumours with an 
NTRK gene fusion 

Doses up to 200 mg 
once or twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Salivary gland (n=3) 
GIST (n=2)a 
NSCLC (n=1)c 
Soft tissue sarcoma (n=1) 
Thyroid (n=1) 

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Study 2 “NAVIGATE” 
NCT02576431 
 
• Phase 2 multinational, open label, 

tumour “basket” study 
• Adult and paediatric patients 

≥ 12 years with advanced solid 
tumours with an NTRK gene fusion 

100 mg twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Salivary gland (n=14) 
Thyroid (n=9)b 
Soft tissue sarcoma (n=9) 
Colorectal (n=6) 
Melanoma (n=6) 
NSCLC (n=5)b, c 
Primary CNS (n=4) 
GIST (n=2)a 
Biliary (n=2) 
SCLC (n=1)b, d 
Appendix (n=1) 
Breast (n=1) 
Bone sarcoma (n=1) 
Pancreas (n=1) 

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Study 3 “SCOUT” 
NCT02637687 
 
• Phase 1/2 multinational, open-label, 

dose escalation and expansion study; 
Phase 2 expansion cohort required 
advanced solid tumours with an 
NTRK gene fusion, including locally 
advanced infantile fibrosarcoma 

• Paediatric patients ≥ 1 month to 
21 years with advanced cancer or 
with primary CNS tumours 

Doses up to 
100 mg/m2 twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Infantile fibrosarcoma 
(n=13) 
Soft tissue sarcoma (n=11) 
Primary CNS (n=5) 
Bone sarcoma (n=1) 
Congenital mesoblastic 
nephroma (n=1) 
Melanoma (n=1) 

32 

Total number of patients (n)* 102 
*  consist of 93 patients with IRC tumour response assessment and 9 patients with primary CNS tumours (including glioma, 

glioblastoma and astrocytoma) with investigator tumour response assessment 
a GIST: gastrointestinal stromal tumour 
b brain metastases observed in one thyroid, one NSCLC, and one SCLC patient 
c NSCLC: non-small cell lung cancer 
d SCLC: small cell lung cancer 
 
Baseline characteristics for the pooled 93 patients with solid tumours with an NTRK gene fusion were 
as follows: median age 41 years (range 0.1-78 years); 30% < 18 years of age, and 70% ≥ 18 years; 
70% white and 53% male; and ECOG PS 0-1 (89%), or 2 (11%). Ninety-seven percent of patients had 
received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. Of 
these, 77% had received prior systemic therapy with a median of 1 prior systemic treatment regimen. 
Twenty-three percent of all patients had received no prior systemic therapy. The most common tumour 
types represented were soft tissue sarcoma (23%), salivary gland tumour (18%), infantile fibrosarcoma 
(14%), thyroid cancer (11%), lung and melanoma cancer (8% for each), and colon cancer (6%). 



14 

Baseline characteristics for the 9 patients with primary CNS tumours with an NTRK gene fusion 
assessed by investigator were as follows: median age 12 years (range 2-79 years); 6 patients 
< 18 years of age, and 3 patients ≥ 18 years, and 8 patients white and 5 patients male; and ECOG PS 
0-1 (8 patients), or 2 (1 patient). All patients had received prior treatment for their cancer, defined as 
surgery, radiotherapy, or systemic therapy. There was a median of 1 prior systemic treatment regimen 
received. 
 
Efficacy results 
The pooled efficacy results for overall response rate, duration of response and time to first response, in 
the primary analysis population (n=93) and with post-hoc addition of primary CNS tumours (n=9) 
resulting in the pooled population (n=102), are presented in Table 5 and Table 6.  
 
Table 5: Pooled efficacy results in solid tumours including and excluding primary CNS tumours 

Efficacy parameter Analysis in solid 
tumours excluding 
primary CNS tumours 
(n=93)a 

Analysis in solid  
tumours including 
primary CNS tumours 
(n=102)a, b 

Overall response rate (ORR) % (n) 
[95% CI] 

72% (67) 
[62, 81] 

67% (68) 
[57, 76] 

Complete response (CR) 16% (15) 15% (15) 
Surgical complete responsec 1% (1) 1% (1) 
Partial response (PR) 55% (51) 51% (52) 
Time to first response (median, months) 
[range] 

1.81 
[0.95, 14.55] 

1.81 
[0.95, 14.55] 

Duration of response (median, months) 
[range] 
% with duration ≥ 6 months 
% with duration ≥ 12 months 

NR 
[1.6+, 38.7+] 
88% 
75% 

NR 
[1.6+, 38.7+] 
88% 
75% 

 

NR: not reached 
+ denotes ongoing 
a Independent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours (93 patients).  
b Investigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (9 patients). 
c Paediatric patient (6 months old at enrolment) with locally advanced unresectable infantile fibrosarcoma with complete 

surgical response.  
 



15 

Table 6: Overall response rate and duration of response by tumour type 

Tumour type Patients (n=102) 
ORR DOR 

% 95% CI ≥ 12 months Range (months) 
Soft tissue sarcomaa 21 81% 58%, 95% 78% 1.9+, 38.7+ 
Salivary glanda 17 88% 64%, 99% 91% 3.7+, 33.7+ 
Infantile 
fibrosarcomaa 13 92% 64%, 100% 60% 1.6+, 17.3+ 

Thyroida 10 70% 35%, 93% 86% 3.7, 29.8+ 
Primary CNSb 9 11% 0%, 48% NR 2.0+ 
Lunga 7 71% 29%, 96% 75% 7.4+, 25.8+ 
Melanomaa 7 43% 10%, 82% 50% 1.9+, 23.2+ 
Colona 6 33% 4%, 78% NR 5.6, 9.2+ 
Gastrointestinal 
stromal tumoura 4 100% 40%, 100% 67% 7.4+, 20.0+ 

Bone sarcomaa 2 50% 1%, 99% 0% 9.5 
Cholangiocarcinomaa 2 SD, NE NA NA NA 
Congenital 
mesoblastic 
nephromaa 

1 100% 3%, 100% NR 9.8+ 

Appendixa 1 SD NA NA NA 
Breasta, c 1 PD NA NA NA 
Pancreasa 1 SD NA NA NA 

DOR: duration of response 
NA: not applicable due to small numbers or lack of response 
NE: not evaluable 
NR: not reached 
PD: progressive disease 
SD: stable disease 
+ denotes ongoing response 
a independent review committee analysis by RECIST v1.1 
b patients with a primary CNS tumour were evaluated per investigator assessment using either RANO or RECIST v1.1 

criteria 
c non-secretory 
 
Due to the rarity of TRK fusion-positive cancer, patients were studied across multiple tumour types 
with a limited number of patients in some tumour types, causing uncertainty in the ORR estimate per 
tumour type. The ORR in the total population may not reflect the expected response in a specific 
tumour type. 
 
In the adult sub-population (n=65), the ORR was 68%. In the paediatric sub-population (n=28), the 
ORR was 82%. 
 
In 85 patients with wide molecular characterisation before larotrectinib treatment, the ORR in 
48 patients who had other genomic alterations in addition to NTRK gene fusion was 58%, and in 
37 patients without other genomic alterations ORR was 84%. 
 
Pooled primary analysis set 
 
The pooled primary analysis set consisted of 93 patients and did not include primary CNS tumours. 
Median time on treatment was 12.1 months (range: 0.66 to 40.7 months) based on July 2018 cut-off. 
Fifty-two percent of patients had received VITRAKVI for 12 months or more and 30% had received 
VITRAKVI 18 months or more, with follow-up ongoing at the time of the analysis. 
At the time of analysis, the median duration of response had not been reached, 75% patients had 
responses which were ongoing with an estimated 88% of responses lasting 6 months or longer and 
75% of responses lasting 12 months or longer. Eighty-eight percent (88%) [95% CI: 81, 95] of patients 



16 

treated were alive one year after the start of therapy. Median progression free survival had not been 
reached at the time of analysis. 
The median change in tumour size in the pooled primary analysis set was a decrease of 66%. 
 
Patients with primary CNS tumours 
 
At the time of data cut-off, 8 of 9 enrolled patients with primary CNS tumours were evaluable for 
response by investigator assessment. A partial response was observed in 1 patient. At the time of data 
cut-off, time on treatment ranged from 2.8 to 9.2 months and was ongoing in 6 out of 9 patients. 
 
Conditional approval 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
In cancer patients given VITRAKVI capsules, peak plasma levels (Cmax) of larotrectinib were achieved 
at approximately 1 hour after dosing. Half-life (t½) is approximately 3 hours and steady state is reached 
within 8 days with a systemic accumulation of 1.6 fold. At the recommended dose of 100 mg taken 
twice daily, steady-state arithmetic mean (± standard deviation) Cmax and daily AUC in adults were 
914 ± 445 ng/mL and 5410 ± 3813 ng*h/mL, respectively. In vitro studies indicate that larotrectinib is 
not a substrate for either OATP1B1 or OATP1B3. 
 
In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 at clinically relevant concentrations and is unlikely to affect clearance of 
substrates of these CYPs. 
In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, 
OCT1, OCT2, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations and is 
unlikely to affect clearance of substrates of these transporters. 
 
Absorption 
 
VITRAKVI is available as a capsule and oral solution formulation. 
The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 
100 mg oral dose. In healthy adult subjects, the AUC of larotrectinib in the oral solution formulation 
was similar to the capsule, with Cmax 36% higher with the oral solution formulation. 
Larotrectinib Cmax was reduced by approximately 35% and there was no effect on AUC in healthy 
subjects administered VITRAKVI after a high-fat and high-calorie meal compared to the Cmax and 
AUC after overnight fasting. 
 
Effect of gastric pH-elevating agents on larotrectinib 
Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the 
gastrointestinal (GI) tract larotrectinib is fully soluble over entire pH range of the GI tract. Therefore, 
larotrectinib is unlikely to be affected by pH-modifying agents. 
 
Distribution 
 
The mean volume of distribution of larotrectinib in healthy adult subjects was 48 L following 
intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose, indicating 
moderate distribution into tissues from the plasma. Binding of larotrectinib to human plasma proteins 
in vitro was approximately 70% and was independent of drug concentration. The blood-to-plasma 
concentration ratio was approximately 0.9. 
 



17 

Biotransformation 
 
Larotrectinib was metabolised predominantly by CYP3A4/5 in vitro. Following oral administration of 
a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib 
(19%) and an O-glucuronide that is formed following loss of the hydroxypyrrolidine-urea moiety 
(26%) were the major circulating radioactive drug components. 
 
Elimination 
 
The half-life of larotrectinib in plasma of cancer patients given 100 mg twice daily of VITRAKVI was 
approximately 3 hours. Mean clearance (CL) of larotrectinib was approximately 34 L/h following 
intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose of 
VITRAKVI. 
 
Excretion 
 
Following oral administration of 100 mg radiolabeled larotrectinib to healthy adult subjects, 58% of 
the administered radioactivity was recovered in faeces and 39% was recovered in urine and when an 
IV microtracer dose was given in conjunction with a 100 mg oral dose of larotrectinib, 35% of the 
administered radioactivity was recovered in faeces and 53% was recovered in urine. The fraction 
excreted as unchanged drug in urine was 29% following IV microtracer dose, indicating that direct 
renal excretion accounted for 29% of total clearance. 
 
Linearity / non-linearity 
 
The area under the plasma concentration-time curve (AUC) and maximum plasma concentration 
(Cmax) of larotrectinib after a single dose in healthy adult subjects were dose proportional up to 400 mg 
and slightly greater than proportional at doses of 600 to 900 mg. 
 
Special populations 
 
Paediatric patients 
Based on population pharmacokinetic analyses exposure (Cmax and AUC) in paediatric patients 
(1 month to <3 months of age) at the recommended dose of 100 mg/m2 with a maximum of 100 mg 
BID was 3-fold higher than in adults (≥18 years of age) given the dose of 100 mg BID. At the 
recommended dose, the Cmax in paediatric patients (≥3 months to <12 years of age) was higher than in 
adults, but the AUC was similar to that in adults. For paediatric patients older than 12 years of age, the 
recommended dose is likely to give similar Cmax and AUC as observed in adults. 
Data defining exposure in small children (1 month to <6 years of age) at the recommended dose is 
limited (n=33). 
 
Elderly 
There are limited data in elderly. PK data is available only in 2 patients over 65 years. 
 
Patients with hepatic impairment 
A pharmacokinetic study was conducted in subjects with mild (Child-Pugh A), moderate 
(Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, and in healthy adult control subjects 
with normal hepatic function matched for age, body mass index and sex. All subjects received a single 
100 mg dose of larotrectinib. An increase in larotrectinib AUC0-inf was observed in subjects with mild, 
moderate and severe hepatic impairment of 1.3, 2 and 3.2-fold respectively versus those with normal 
hepatic function. Cmax was observed to increase slightly by 1.1, 1.1 and 1.5-fold respectively. 
 



18 

Patients with renal impairment 
A pharmacokinetic study was conducted in subjects with end stage renal disease requiring dialysis, 
and in healthy adult control subjects with normal renal function matched for age, body mass index and 
sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib Cmax and 
AUC0-inf, of 1.25 and 1.46-fold respectively was observed in renally impaired subjects versus those 
with normal renal function. 
 
Other special populations 
Gender did not appear to influence larotrectinib pharmacokinetics to a clinically significant extent. 
There was not enough data to investigate the potential influence of race on the systemic exposure of 
larotrectinib. 
 
5.3 Preclinical safety data 
 
Systemic toxicity 
 
Systemic toxicity was assessed in studies with daily oral administration up to 3 months in rats and 
monkeys. Dose limiting skin lesions were only seen in rats and were primarily responsible for 
mortality and morbidity. Skin lesions were not seen in monkeys. 
Clinical signs of gastrointestinal toxicity were dose limiting in monkeys. In rats, severe toxicity 
(STD10) was observed at doses corresponding to 1- to 2-times the human AUC at the recommended 
clinical dose. No relevant systemic toxicity was observed in monkeys at doses which correspond to 
> 10-times the human AUC at the recommended clinical dose. 
 
Embryotoxicity / Teratogenicity  
 
Larotrectinib was not teratogenic and embryotoxic when dosed daily during the period of 
organogenesis to pregnant rats and rabbits at maternotoxic doses, i.e. corresponding to 32-times (rats) 
and 16-times (rabbits) the human AUC at the recommended clinical dose. Larotrectinib crosses the 
placenta in both species. 
 
Reproduction toxicity 
 
Fertility studies with larotrectinib have not been conducted. In 3-months toxicity studies, larotrectinib 
had no histological effect on the male reproductive organs in rats and monkeys at the highest tested 
doses corresponding to approximately 7-times (male rats) and 10-times (male monkeys) the human 
AUC at the recommended clinical dose. In addition, larotrectinib had no effect on spermatogenesis in 
rats. 
 
In a 1-month repeat-dose study in rats, fewer corpora lutea, increased incidence of anestrus and 
decreased uterine weight with uterine atrophy were observed and these effects were reversible. No 
effects on female reproductive organs were seen in the 3-months toxicity studies in rats and monkeys 
at doses corresponding to approximately 3-times (female rats) and 17-times (female monkeys) the 
human AUC at the recommended clinical dose. 
Larotrectinib was administered to juvenile rats from postnatal day (PND) 7 to 70. Pre-weaning 
mortality (before PND 21) was observed at the high dose level corresponding to 2.5- to 4-times the 
AUC at the recommended dose. Growth and nervous system effects were seen at 0.5- to 4-times the 
AUC at the recommended dose. Body weight gain was decreased in pre-weaning male and female 
pups, with a post-weaning increase in females at the end of exposure whereas reduced body weight 
gain was seen in males also post-weaning without recovery. The male growth reduction was 
associated with delayed puberty. Nervous system effects (i.e. altered hindlimb functionality and, 
likely, increases in eyelid closure) demonstrated partial recovery. A decrease in pregnancy rate was 
also reported despite normal mating at the high-dose level. 
 



19 

Genotoxicity and carcinogenicity 
 
Carcinogenicity studies have not been performed with larotrectinib. 
Larotrectinib was not mutagenic in bacterial reverse mutation (Ames) assays and in in vitro 
mammalian mutagenesis assays. Larotrectinib was negative in the in vivo mouse micronucleus test at 
the maximum tolerated dose of 500 mg/kg. 
 
Safety pharmacology 
 
The safety pharmacology of larotrectinib was evaluated in several in vitro and in vivo studies that 
assessed effects on the CV, CNS, respiratory, and GI systems in various species. Larotrectinib had no 
adverse effect on haemodynamic parameters and ECG intervals in telemetered monkeys at exposures 
(Cmax) which are approximately 6-fold the human therapeutic exposures. Larotrectinib had no 
neurobehavioural findings in adult animals (rats, mice, cynomolgus monkeys) at exposure (Cmax) at 
least 7-fold higher than the human exposure. Larotrectinib had no effect on respiratory function in rats; 
at exposures (Cmax) at least 8-times the human therapeutic exposure. In rats, larotrectinib accelerated 
intestinal transit and increased gastric secretion and acidity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
 
Printing ink 
Shellac 
Indigo carmine aluminium lake (E 132) 
Titanium dioxide (E 171) 
Propylene glycol (E 1520) 
Dimeticone 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE)-bottles with a child-resistant polypropylene (PP) cap with a 
polyethylene (PE) heat seal layer. 
 
Each carton contains one bottle of 56 hard capsules. 
 



20 

6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1385/001 – VITRAKVI 25 mg 
EU/1/19/1385/002 – VITRAKVI 100 mg 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

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


21 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 20 mg/mL oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of oral solution contains larotrectinib sulfate equivalent to 20 mg of larotrectinib. 
 
Excipients with known effect: 
Each mL of oral solution contains 295 mg sucrose, 22 mg sorbitol, 1.6 mg propylene glycol and 
0.2 mg methyl parahydroxybenzoate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral solution. 
 
Clear yellow to orange solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
VITRAKVI as monotherapy is indicated for the treatment of adult and paediatric patients with solid 
tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, 
- who have a disease that is locally advanced, metastatic or where surgical resection is likely to 

result in severe morbidity, and 
- who have no satisfactory treatment options (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Treatment with VITRAKVI should be initiated by physicians experienced in the administration of 
anticancer therapies. 
 
The presence of an NTRK gene fusion in a tumour specimen should be confirmed by a validated test 
prior to initiation of treatment with VITRAKVI. 
 
Posology 
 
Adults 
The recommended dose in adults is 100 mg larotrectinib twice daily, until disease progression or until 
unacceptable toxicity occurs. 
 
Paediatric population 
Dosing in paediatric patients is based on body surface area (BSA). The recommended dose in 
paediatric patients is 100 mg/m2 larotrectinib twice daily with a maximum of 100 mg per dose until 
disease progression or until unacceptable toxicity occurs. 
 



22 

Missed dose 
If a dose is missed, the patient should not take two doses at the same time to make up for a missed 
dose. Patients should take the next dose at the next scheduled time. If the patient vomits after taking a 
dose, the patient should not take an additional dose to make up for vomiting. 
 
Dose modification 
For all Grade 2 adverse reactions, continued dosing may be appropriate, though close monitoring to 
ensure no worsening of the toxicity is advised. Patients with Grade 2 ALT and/or AST increases, 
should be followed with serial laboratory evaluations every one to two weeks after the observation of 
Grade 2 toxicity until resolved to establish whether a dose interruption or reduction is required. 
 
For Grade 3 or 4 adverse reactions: 
- VITRAKVI should be withheld until the adverse reaction resolves or improves to baseline or 

Grade 1. Resume at the next dose modification if resolution occurs within 4 weeks. 
- VITRAKVI should be permanently discontinued if an adverse reaction does not resolve within 

4 weeks. 
 
The recommended dose modifications for VITRAKVI for adverse reactions are provided in Table 1. 
 
Table 1: Recommended dose modifications for VITRAKVI for adverse reactions 

Dose modification 
Adult and 

paediatric patients with body 
surface area of at least 1.0 m2 

Paediatric patients with body 
surface area less than 1.0 m2 

First 75 mg twice daily 75 mg/m2 twice daily 

Second 50 mg twice daily 50 mg/m2 twice daily 

Third 100 mg once daily 25 mg/m2 twice daily 

 
VITRAKVI should be permanently discontinued in patients who are unable to tolerate VITRAKVI 
after three dose modifications. 
 
Special populations 
 
Elderly 
No dose adjustment is recommended in elderly patients (see section 5.2). 
 
Hepatic impairment 
The starting dose of VITRAKVI should be reduced by 50% in patients with moderate (Child-Pugh B) 
to severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with 
mild hepatic impairment (Child-Pugh A) (see section 5.2). 
 
Renal impairment 
No dose adjustment is required for patients with renal impairment (see section 5.2). 
 
Co-administration with strong CYP3A4 inhibitors 
If co-administration with a strong CYP3A4 inhibitor is necessary, the VITRAKVI dose should be 
reduced by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, 
VITRAKVI should be resumed at the dose taken prior to initiating the CYP3A4 inhibitor (see 
section 4.5). 
 
Method of administration 
 
VITRAKVI is for oral use. 
 



23 

VITRAKVI is available as a capsule or oral solution with equivalent oral bioavailability and may be 
used interchangeably. 
 
The oral solution should be administered by mouth using an oral syringe of 1 mL or 5 mL volume or 
enterally by using a nasogastric feeding tube. 
- For doses below 1 mL a 1 mL oral syringe should be used. The calculated dose volume should 

be rounded to the nearest 0.1 mL. 
- For doses of 1 mL and higher a 5 mL oral syringe should be used. The dose volume should be 

calculated to the nearest 0.2 mL. 
- VITRAKVI should not be mixed with feeding formulas, if administered via nasogastric feeding 

tube. Mixing with the feeding formulas could lead to tube blockages. 
- For instructions for use of oral syringes and feeding tubes see section 6.6. 
 
The oral solution can be taken with or without food but should not be taken with grapefruit or 
grapefruit juice. 
 
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 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). 
 



24 

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). 
 
Important information about some of the ingredients 
 
Sucrose: may be harmful to the teeth. Patients with rare hereditary problems of fructose intolerance, 
glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicinal 
product. 
Sorbitol: patients with hereditary fructose intolerance (HFI) should not take this medicinal product. 
Sodium: this medicine contains less than 1 mmol sodium (23 mg) per 5 mL, that is to say essentially 
‘sodium-free’. 
Propylene glycol: co-administration with any substrate for alcohol dehydrogenase such as ethanol may 
induce serious adverse effects in neonates. 
Parahydroxybenzoate: may cause allergic reactions (possibly delayed). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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 Cmax 
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 Cmax 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 Cmax 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. 



25 

 
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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 



26 

4.7 Effects on ability to drive or use machines 
 
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). 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The safety of VITRAKVI was evaluated in 125 patients with TRK fusion-positive cancer in one of 
three clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”). Median time on treatment for the 
overall safety population was 7.4 months (range: 0.03 to 40.7). The safety population characteristics 
were comprised of patients with a median age of 45 years (range: 0.1, 80) with 30% of patients being 
paediatric patients. The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of 
decreasing frequency were fatigue (32%), increased ALT (31%), dizziness (30%), increased AST 
(29%), constipation (29%), nausea (26%), anaemia (24%), and vomiting (20%). 
The majority of adverse reactions were Grade 1 or 2. Grade 4 was the highest reported grade for 
adverse reactions neutrophil count decreased (1.6%) and ALT increased (< 1%). The highest reported 
grade was Grade 3 for adverse reactions anaemia, weight increased, fatigue, increased AST, dizziness, 
paraesthesia, nausea, myalgia, and leukocyte count decreased. All the reported Grade 3 adverse 
reactions occurred in less than 5% of patients, with the exception of anaemia (7%). 
Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions, regardless of 
attribution occurred in 3% of patients (one case each of ALT increase, AST increase, intestinal 
perforation, jaundice, small intestinal obstruction). The majority of adverse reactions leading to dose 
reduction occurred in the first three months of treatment. 
 
Tabulated list of adverse reactions  
 
The adverse drug reactions reported in patients 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. 
 



27 

Table 2: Adverse drug reactions reported in TRK fusion-positive cancer patients treated with 
VITRAKVI at recommended dose (n=125) 

System organ class Frequency All grades Grades 3 and 4 
Blood and lymphatic 
system disorders 

Very common Anaemia 
Neutrophil count decreased 
(Neutropenia) 
Leukocyte count decreased 
(Leukopenia) 

 

Common  Anaemia 
Neutrophil count 
decreased (Neutropenia)a 
Leukocyte count 
decreased (Leukopenia) 

Nervous system 
disorders 

Very common Dizziness 
Paraesthesia 

 

Common Gait disturbance 
 

Dizziness 
Paraesthesia 

Gastrointestinal 
disorders 

Very common Nausea 
Constipation 
Vomiting 

 

Common Dysgeusia Nausea 
Musculoskeletal and 
connective tissue 
disorders 

Very common Myalgia 
Muscular weakness 

 

Common  Myalgia 
General disorders 
and administration 
site conditions 

Very common Fatigue  

Common  Fatigue 

Investigations Very common Alanine aminotransferase 
(ALT) increased 
Aspartate aminotransferase 
(AST) increased 
Weight increased 
(Abnormal weight gain) 

 

Common Blood alkaline phosphatase 
increased 

Alanine aminotransferase 
(ALT) increaseda 
Aspartate 
aminotransferase (AST) 
increased 
Weight increased 
(Abnormal weight gain) 

a Grade 4 reactions were reported 
 



28 

Table 3: Adverse drug reactions reported in TRK fusion-positive paediatric cancer patients 
treated with VITRAKVI at recommended dose (n=37); all Grades 
System organ 
class 

Frequency Infants and 
toddlers 
(n=14)a 

Children 
 
(n=15)b 

Adolescents 
 
(n=8)c 

Paediatric 
patients 
(n=37) 

Blood and 
lymphatic 
system 
disorders 

Very 
common 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Anaemia 
Neutrophil count 
decreased 
(Neutropenia) 
Leukocyte count 
decreased 
(Leukopenia) 

Nervous system 
disorders 

Very 
common 

  Dizziness 
Paraesthesia 

 

Common  Paraesthesia 
Gait disturbance 

 Dizziness 
Paraesthesia 
Gait disturbance 

Gastrointestinal 
disorders 

Very 
common 

Nausea 
Constipation 
Vomiting 

Nausea 
Constipation 
Vomiting 

Nausea 
Vomiting 

Nausea 
Constipation 
Vomiting 

Common  Dysgeusia  Dysgeusia 
Musculoskeletal 
and connective 
tissue disorders 

Very 
common 

  Myalgia 
Muscular 
weakness 

 

Common  Myalgia  Myalgia 
Muscular 
weakness 

General 
disorders and 
administration 
site conditions 

Very 
common 

Fatigue Fatigue  Fatigue 

Investigations Very 
common 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 
Blood alkaline 
phosphatase 
increased 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Blood alkaline 
phosphatase 
increased 

Alanine 
aminotransferase 
(ALT) increased 
Aspartate 
aminotransferase 
(AST) increased 
Weight increased 
(Abnormal 
weight gain) 
Blood alkaline 
phosphatase 
increased 

Common Blood alkaline 
phosphatase 
increased 

   

a Infant/toddlers (28 days to 23 months): one Grade 4 Neutrophil count decreased (Neutropenia) reaction reported. Grade 3 
reactions included two cases Neutrophil count decreased (Neutropenia) and one case of anaemia. 

b Children (2 to 11 years): no Grade 4 reactions were reported. One reported Grade 3 case each of Neutrophil count 
decreased (Neutropenia), Paraesthesia, Myalgia, Weight increased (Abnormal weight gain). 

c Adolescents (12 to <18 years): no Grades 3 and 4 reactions were reported. 
 



29 

Description of selected adverse reactions 
 
Neurologic reactions 
In the overall safety database (n=125), the maximum grade neurologic reaction observed was Grade 3 
which was observed in three (2%) patients and included dizziness (one patient, <1%) and paraesthesia 
(two patients, 1.6%). The overall incidence was 30% for dizziness, 10% for paraesthesia and 3% for 
gait disturbance. Neurologic reactions leading to dose modification included dizziness (2%). None of 
these adverse reactions led to treatment discontinuation. In all cases, 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=125), the maximum grade transaminase elevation observed was 
Grade 4 ALT increase in 1 patient (<1%). Grade 3 ALT and AST increases in 3 (2%) and 2 (2%) 
patients, respectively. Majority of Grade 3 elevations were transient appearing in first or second month 
of treatment and resolving to Grade 1 by months 3-4. Grade 2 ALT and AST increases were observed 
in 9 (7%) and 6 (5%) of patients, respectively, and Grade 1 ALT and AST increases were observed in 
26 (21%) and 28 (22%) of patients, respectively. 
ALT and AST increases leading to dose modifications occurred in 7 (6%) patients and 6 (5%) 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 125 patients treated with VITRAKVI, 37 (30%) patients were from 28 days to 18 years of age. Of 
these 37 patients, 38% were 28 days to < 2 years (n=14), 41% were 2 years to < 12 years (n=15), and 
22% were 12 years to < 18 years (n=8). 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 (35% versus 
14% in adults), leucocyte count decrease (22% versus 9% in adults), neutrophil count decrease (30% 
versus 7% in adults), blood alkaline phosphatase increased (14% versus 2% in adults) and 
transaminase elevations (ALT 41% versus 27% in adults and AST 35% versus 26% in adults) were 
more frequent in paediatric patients compared to adults. 
 
Elderly  
Of 125 patients in the overall safety population who received VITRAKVI, 28 (22%) patients were 
65 years or older and 8 (6%) patients were 75 years or older. The safety profile in elderly patients 
(≥ 65 years) is consistent with that seen in younger patients (< 65 years). The adverse reactions gait 
disturbance (17% versus 3% in under 65 years), and blood alkaline phosphatase increased (4% versus 
2% in under 65 years) were 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. 
 
4.9 Overdose 
 
There is limited experience of overdose with VITRAKVI. Symptoms of overdose are not established. 
In the event of overdose, physicians should follow general supportive measures and treat 
symptomatically. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, 
protein kinase inhibitors, ATC code: L01XE53. 
 
Mechanism of action 
 
Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor 
kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target 
for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded 
by NTRK1, NTRK2 and NTRK3 genes, respectively. In a broad panel of purified enzyme assays, 
larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. The only other 
kinase activity occurred at 100-fold higher concentrations. In in vitro and in vivo tumour models, 
larotrectinib demonstrated anti-tumour activity in cells with constitutive activation of TRK proteins 
resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein 
overexpression. 
 
In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, 
NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel 
chimeric oncogenic proteins are aberrantly expressed, driving constitutive kinase activity subsequently 
activating downstream cell signalling pathways involved in cell proliferation and survival leading to 
TRK fusion-positive cancer. 
 
Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib 
had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the 
clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain 
with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L. 
 
The molecular causes for primary resistance to larotrectinib are not known. It is therefore not known if 
the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy 
of TRK inhibition. The measured impact of any concomitant genomic alterations on larotrectinib is 
efficacy provided below (see clinical efficacy). 
 
Pharmacodynamic effect 
 
Cardiac electrophysiology 
In 36 healthy adult subjects receiving single doses ranging from 100 mg to 900 mg, VITRAKVI did 
not prolong the QT interval to any clinically relevant extent. 
The 200 mg dose corresponds to a peak exposure (Cmax) similar to that observed with larotrectinib 
100 mg BID at steady state. A shortening of QTcF was observed with VITRAKVI dosing, with a 
maximum mean effect observed between 3 and 24 hours after Cmax, with a geometric mean decrease in 
QTcF from baseline of -13.2 msec (range -10 to -15.6 msec). Clinical relevance of this finding has not 
been established.  
 
Clinical efficacy 
 
Overview of studies 
The efficacy and safety of VITRAKVI were studied in three multicentre, open-label, single-arm 
clinical studies in adult and paediatric cancer patients (Table 4). The studies were ongoing at the time 
of approval. 
Patients with and without documented NTRK gene fusion were allowed to participate in Study 1 and 
Study 3 (“SCOUT”). Patients enrolled to Study 2 (“NAVIGATE”) were required to have TRK 
fusion-positive cancer. The pooled primary analysis set of efficacy includes 93 patients with TRK 
fusion-positive cancer enrolled across the three studies that had measurable disease assessed by 
RECIST v1.1, a non-CNS primary tumour and received at least one dose of larotrectinib. These 



31 

patients were required to have received prior standard therapy appropriate for their tumour type and 
stage of disease or who, in the opinion of the investigator, would have had to undergo radical surgery 
(such as limb amputation, facial resection, or paralysis causing procedure), or were unlikely to 
tolerate, or derive clinically meaningful benefit from available standard of care therapies in the 
advanced disease setting. The major efficacy outcome measures were overall response rate (ORR) and 
duration of response (DOR), as determined by a blinded independent review committee (BIRC). 
In addition, 9 patients with primary CNS tumours and measurable disease at baseline were treated in 
Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). All primary CNS tumour patients had received 
prior cancer treatment (surgery, radiotherapy and/or previous systemic therapy). Tumour responses 
were assessed by the investigator using RANO or RECIST v1.1 criteria. 
 
Identification of NTRK gene fusions relied upon the molecular test methods: next generation 
sequencing (NGS) used in 98 patients, reverse transcription-polymerase chain reaction (RT-PCR) used 
in 1 patient and fluorescence in situ hybridization (FISH) used in 6 patients as routinely performed at 
certified laboratories. 
 



32 

Table 4: Clinical studies contributing to the efficacy analyses in solid and primary CNS tumours 
Study name, design and patient 
population 

Dose and 
formulation 

Tumour types included in 
efficacy analysis 

n 

Study 1 
NCT02122913 
 
• Phase 1, open-label, dose escalation 

and expansion study; expansion 
phase required tumours with an 
NTRK gene fusion 

• Adult patients (≥ 18 years) with 
advanced solid tumours with an 
NTRK gene fusion 

Doses up to 200 mg 
once or twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Salivary gland (n=3) 
GIST (n=2)a 
NSCLC (n=1)c 
Soft tissue sarcoma (n=1) 
Thyroid (n=1) 

8 

Study 2 “NAVIGATE” 
NCT02576431 
 
• Phase 2 multinational, open label, 

tumour “basket” study 
• Adult and paediatric patients 

≥ 12 years with advanced solid 
tumours with an NTRK gene fusion 

100 mg twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Salivary gland (n=14) 
Thyroid (n=9)b 
Soft tissue sarcoma (n=9) 
Colorectal (n=6) 
Melanoma (n=6) 
NSCLC (n=5)b, c 
Primary CNS (n=4) 
GIST (n=2)a 
Biliary (n=2) 
SCLC (n=1)b, d 
Appendix (n=1) 
Breast (n=1) 
Bone sarcoma (n=1) 
Pancreas (n=1) 

62 

Study 3 “SCOUT” 
NCT02637687 
 
• Phase 1/2 multinational, open-label, 

dose escalation and expansion study; 
Phase 2 expansion cohort required 
advanced solid tumours with an 
NTRK gene fusion, including locally 
advanced infantile fibrosarcoma 

• Paediatric patients ≥ 1 month to 
21 years with advanced cancer or 
with primary CNS tumours 

Doses up to 
100 mg/m2 twice daily 
(25 mg, 100 mg 
capsules or 20 mg/mL 
oral solution) 

Infantile fibrosarcoma 
(n=13) 
Soft tissue sarcoma (n=11) 
Primary CNS (n=5) 
Bone sarcoma (n=1) 
Congenital mesoblastic 
nephroma (n=1) 
Melanoma (n=1) 

32 

Total number of patients (n)* 102 
* consist of 93 patients with IRC tumour response assessment and 9 patients with primary CNS tumours (including glioma, 

glioblastoma and astrocytoma) with investigator tumour response assessment 
a GIST: gastrointestinal stromal tumour 
b brain metastases observed in one thyroid, one NSCLC, and one SCLC patient 
c NSCLC: non-small cell lung cancer 
d SCLC: small cell lung cancer 
 
Baseline characteristics for the pooled 93 patients with solid tumours with an NTRK gene fusion were 
as follows: median age 41 years (range 0.1-78 years); 30% < 18 years of age, and 70% ≥ 18 years; 
70% white and 53% male; and ECOG PS 0-1 (89%), or 2 (11%). Ninety-seven percent of patients had 
received prior treatment for their cancer, defined as surgery, radiotherapy, or systemic therapy. Of 
these, 77% had received prior systemic therapy with a median of 1 prior systemic treatment regimen. 
Twenty-three percent of all patients had received no prior systemic therapy. The most common tumour 
types represented were soft tissue sarcoma (23%), salivary gland tumour (18%), infantile fibrosarcoma 
(14%), thyroid cancer (11%), lung and melanoma cancer (8% for each), and colon cancer (6%). 
Baseline characteristics for the 9 patients with primary CNS tumours with an NTRK gene fusion 
assessed by investigator were as follows: median age 12 years (range 2-79 years); 6 patients 



33 

< 18 years of age, and 3 patients ≥ 18 years, and 8 patients white and 5 patients male; and ECOG PS 
0-1 (8 patients), or 2 (1 patient). All patients had received prior treatment for their cancer, defined as 
surgery, radiotherapy, or systemic therapy. There was a median of 1 prior systemic treatment regimen 
received. 
 
Efficacy results 
The pooled efficacy results for overall response rate, duration of response and time to first response, in 
the primary analysis population (n=93) and with post-hoc addition of primary CNS tumours (n=9) 
resulting in the pooled population (n=102), are presented in Table 5 and Table 6.  
 
Table 5: Pooled efficacy results in solid tumours including and excluding primary CNS tumours 

Efficacy parameter Analysis in solid 
tumours excluding 
primary CNS tumours 
(n=93)a 

Analysis in solid 
tumours including 
primary CNS tumours 
(n=102)a, b 

Overall response rate (ORR) % (n) 
[95% CI] 

72% (67) 
[62, 81] 

67% (68) 
[57, 76] 

Complete response (CR) 16% (15) 15% (15) 
Surgical complete responsec 1% (1) 1% (1) 
Partial response (PR) 55% (51) 51% (52) 
Time to first response (median, months) 
[range] 

1.81 
[0.95, 14.55] 

1.81 
[0.95, 14.55] 

Duration of response (median, months) 
[range] 
% with duration ≥ 6 months 
% with duration ≥ 12 months 

NR 
[1.6+, 38.7+] 
88% 
75% 

NR 
[1.6+, 38.7+] 
88% 
75% 

 

NR: not reached 
+ denotes ongoing 
a Independent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours (93 patients).  
b Investigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (9 patients). 
c Paediatric patient (6 months old at enrolment) with locally advanced unresectable infantile fibrosarcoma with complete 

surgical response. 
 



34 

Table 6: Overall response rate and duration of response by tumour type 

Tumour type Patients (n=102) 
ORR DOR 

% 95% CI ≥ 12 months Range (months) 
Soft tissue sarcomaa 21 81% 58%, 95% 78% 1.9+, 38.7+ 
Salivary glanda 17 88% 64%, 99% 91% 3.7+, 33.7+ 
Infantile 
fibrosarcomaa 13 92% 64%, 100% 60% 1.6+, 17.3+ 

Thyroida 10 70% 35%, 93% 86% 3.7, 29.8+ 
Primary CNSb 9 11% 0%, 48% NR 2.0+ 
Lunga 7 71% 29%, 96% 75% 7.4+, 25.8+ 
Melanomaa 7 43% 10%, 82% 50% 1.9+, 23.2+ 
Colona 6 33% 4%, 78% NR 5.6, 9.2+ 
Gastrointestinal 
stromal tumoura 4 100% 40%, 100% 67% 7.4+, 20.0+ 

Bone sarcomaa 2 50% 1%, 99% 0% 9.5 
Cholangiocarcinomaa 2 SD, NE NA NA NA 
Congenital 
mesoblastic 
nephromaa 

1 100% 3%, 100% NR 9.8+ 

Appendixa 1 SD NA NA NA 
Breasta, c 1 PD NA NA NA 
Pancreasa 1 SD NA NA NA 
DOR: duration of response 
NA: not applicable due to small numbers or lack of response 
NE: not evaluable 
NR: not reached 
PD: progressive disease 
SD: stable disease 
+ denotes ongoing response 
a independent review committee analysis by RECIST v1.1 
b patients with a primary CNS tumour were evaluated per investigator assessment using either RANO or RECIST v1.1 

criteria 
c non-secretory 
 
Due to the rarity of TRK fusion-positive cancer, patients were studied across multiple tumour types 
with a limited number of patients in some tumour types, causing uncertainty in the ORR estimate per 
tumour type. The ORR in the total population may not reflect the expected response in a specific 
tumour type. 
 
In the adult sub-population (n=65), the ORR was 68%. In the paediatric sub-population (n=28), the 
ORR was 82%. 
 
In 85 patients with wide molecular characterisation before larotrectinib treatment, the ORR in 
48 patients who had other genomic alterations in addition to NTRK gene fusion was 58%, and in 
37 patients without other genomic alterations ORR was 84%. 
 
Pooled primary analysis set 
 
The pooled primary analysis set consisted of 93 patients and did not include primary CNS tumours. 
Median time on treatment was 12.1 months (range: 0.66 to 40.7 months) based on July 2018 cut-off. 
Fifty-two percent of patients had received VITRAKVI for 12 months or more and 30% had received 
VITRAKVI 18 months or more, with follow-up ongoing at the time of the analysis. 
At the time of analysis, the median duration of response had not been reached, 75% patients had 
responses which were ongoing with an estimated 88% of responses lasting 6 months or longer and 
75% of responses lasting 12 months or longer. Eighty-eight percent (88%) [95% CI: 81, 95] of patients 



35 

treated were alive one year after the start of therapy. Median progression free survival had not been 
reached at the time of analysis. 
The median change in tumour size in the pooled primary analysis set was a decrease of 66%. 
 
Patients with primary CNS tumours 
 
At the time of data cut-off, 8 of 9 enrolled patients with primary CNS tumours were evaluable for 
response by investigator assessment. A partial response was observed in 1 patient. At the time of data 
cut-off, time on treatment ranged from 2.8 to 9.2 months and was ongoing in 6 out of 9 patients. 
 
Conditional approval 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
In cancer patients given VITRAKVI capsules, peak plasma levels (Cmax) of larotrectinib were achieved 
at approximately 1 hour after dosing. Half-life (t½) is approximately 3 hours and steady state is reached 
within 8 days with a systemic accumulation of 1.6 fold. At the recommended dose of 100 mg taken 
twice daily, steady-state arithmetic mean (± standard deviation) Cmax and daily AUC in adults were 
914 ± 445 ng/mL and 5410 ± 3813 ng*h/mL, respectively. In vitro studies indicate that larotrectinib is 
not a substrate for either OATP1B1 or OATP1B3. 
 
In vitro studies indicate that larotrectinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 at clinically relevant concentrations and is unlikely to affect clearance of 
substrates of these CYPs. 
In vitro studies indicate that larotrectinib does not inhibit the transporters BCRP, P-gp, OAT1, OAT3, 
OCT1, OCT2, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations and is 
unlikely to affect clearance of substrates of these transporters. 
 
Absorption 
 
VITRAKVI is available as a capsule and oral solution formulation. 
The mean absolute bioavailability of larotrectinib was 34% (range: 32% to 37%) following a single 
100 mg oral dose. In healthy adult subjects, the AUC of larotrectinib in the oral solution formulation 
was similar to the capsule, with Cmax 36% higher with the oral solution formulation. 
Larotrectinib Cmax was reduced by approximately 35% and there was no effect on AUC in healthy 
subjects administered VITRAKVI after a high-fat and high-calorie meal compared to the Cmax and 
AUC after overnight fasting. 
 
Effect of gastric pH-elevating agents on larotrectinib 
Larotrectinib has pH-dependent solubility. In vitro studies show that in liquid volumes relevant to the 
gastrointestinal (GI) tract larotrectinib is fully soluble over entire pH range of the GI tract. Therefore, 
larotrectinib is unlikely to be affected by pH-modifying agents. 
 
Distribution 
 
The mean volume of distribution of larotrectinib in healthy adult subjects was 48 L following 
intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose, indicating 
moderate distribution into tissues from the plasma. Binding of larotrectinib to human plasma proteins 
in vitro was approximately 70% and was independent of drug concentration. The blood-to-plasma 
concentration ratio was approximately 0.9. 
 



36 

Biotransformation 
 
Larotrectinib was metabolised predominantly by CYP3A4/5 in vitro. Following oral administration of 
a single 100 mg dose of radiolabeled larotrectinib to healthy adult subjects, unchanged larotrectinib 
(19%) and an O-glucuronide that is formed following loss of the hydroxypyrrolidine-urea moiety 
(26%) were the major circulating radioactive drug components. 
 
Elimination 
 
The half-life of larotrectinib in plasma of cancer patients given 100 mg twice daily of VITRAKVI was 
approximately 3 hours. Mean clearance (CL) of larotrectinib was approximately 34 L/h following 
intravenous administration of an IV microtracer in conjunction with a 100 mg oral dose of 
VITRAKVI. 
 
Excretion 
 
Following oral administration of 100 mg radiolabeled larotrectinib to healthy adult subjects, 58% of 
the administered radioactivity was recovered in faeces and 39% was recovered in urine and when an 
IV microtracer dose was given in conjunction with a 100 mg oral dose of larotrectinib, 35% of the 
administered radioactivity was recovered in faeces and 53% was recovered in urine. The fraction 
excreted as unchanged drug in urine was 29% following IV microtracer dose, indicating that direct 
renal excretion accounted for 29% of total clearance. 
 
Linearity / non-linearity 
 
The area under the plasma concentration-time curve (AUC) and maximum plasma concentration 
(Cmax) of larotrectinib after a single dose in healthy adult subjects were dose proportional up to 400 mg 
and slightly greater than proportional at doses of 600 to 900 mg. 
 
Special populations 
 
Paediatric patients 
Based on population pharmacokinetic analyses exposure (Cmax and AUC) in paediatric patients 
(1 month to <3 months of age) at the recommended dose of 100 mg/m2 with a maximum of 100 mg 
BID was 3-fold higher than in adults (≥18 years of age) given the dose of 100 mg BID. At the 
recommended dose, the Cmax in paediatric patients (≥3 months to <12 years of age) was higher than in 
adults, but the AUC was similar to that in adults. For paediatric patients older than 12 years of age, the 
recommended dose is likely to give similar Cmax and AUC as observed in adults. 
Data defining exposure in small children (1 month to <6 years of age) at the recommended dose is 
limited (n=33). 
 
Elderly 
There are limited data in elderly. PK data is available only in 2 patients over 65 years. 
 
Patients with hepatic impairment 
A pharmacokinetic study was conducted in subjects with mild (Child-Pugh A), moderate 
(Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, and in healthy adult control subjects 
with normal hepatic function matched for age, body mass index and sex. All subjects received a single 
100 mg dose of larotrectinib. An increase in larotrectinib AUC0-inf was observed in subjects with mild, 
moderate and severe hepatic impairment of 1.3, 2 and 3.2-fold respectively versus those with normal 
hepatic function. Cmax was observed to increase slightly by 1.1, 1.1 and 1.5-fold respectively. 
 



37 

Patients with renal impairment 
A pharmacokinetic study was conducted in subjects with end stage renal disease requiring dialysis, 
and in healthy adult control subjects with normal renal function matched for age, body mass index and 
sex. All subjects received a single 100 mg dose of larotrectinib. An increase in larotrectinib Cmax and 
AUC0-inf, of 1.25 and 1.46-fold respectively was observed in renally impaired subjects versus those 
with normal renal function. 
 
Other special populations 
Gender did not appear to influence larotrectinib pharmacokinetics to a clinically significant extent. 
There was not enough data to investigate the potential influence of race on the systemic exposure of 
larotrectinib. 
 
5.3 Preclinical safety data 
 
Systemic toxicity 
 
Systemic toxicity was assessed in studies with daily oral administration up to 3 months in rats and 
monkeys. Dose limiting skin lesions were only seen in rats and were primarily responsible for 
mortality and morbidity. Skin lesions were not seen in monkeys. 
Clinical signs of gastrointestinal toxicity were dose limiting in monkeys. In rats, severe toxicity 
(STD10) was observed at doses corresponding to 1- to 2-times the human AUC at the recommended 
clinical dose. No relevant systemic toxicity was observed in monkeys at doses which correspond to 
> 10-times the human AUC at the recommended clinical dose. 
 
Embryotoxicity / Teratogenicity  
 
Larotrectinib was not teratogenic and embryotoxic when dosed daily during the period of 
organogenesis to pregnant rats and rabbits at maternotoxic doses, i.e. corresponding to 32-times (rats) 
and 16-times (rabbits) the human AUC at the recommended clinical dose. Larotrectinib crosses the 
placenta in both species. 
 
Reproduction toxicity 
 
Fertility studies with larotrectinib have not been conducted. In 3-months toxicity studies, larotrectinib 
had no histological effect on the male reproductive organs in rats and monkeys at the highest tested 
doses corresponding to approximately 7-times (male rats) and 10-times (male monkeys) the human 
AUC at the recommended clinical dose. In addition, larotrectinib had no effect on spermatogenesis in 
rats. 
 
In a 1-month repeat-dose study in rats, fewer corpora lutea, increased incidence of anestrus and 
decreased uterine weight with uterine atrophy were observed and these effects were reversible. No 
effects on female reproductive organs were seen in the 3-months toxicity studies in rats and monkeys 
at doses corresponding to approximately 3-times (female rats) and 17-times (female monkeys) the 
human AUC at the recommended clinical dose. 
Larotrectinib was administered to juvenile rats from postnatal day (PND) 7 to 70. Pre-weaning 
mortality (before PND 21) was observed at the high dose level corresponding to 2.5- to 4-times the 
AUC at the recommended dose. Growth and nervous system effects were seen at 0.5- to 4-times the 
AUC at the recommended dose. Body weight gain was decreased in pre-weaning male and female 
pups, with a post-weaning increase in females at the end of exposure whereas reduced body weight 
gain was seen in males also post-weaning without recovery. The male growth reduction was 
associated with delayed puberty. Nervous system effects (i.e. altered hindlimb functionality and, 
likely, increases in eyelid closure) demonstrated partial recovery. A decrease in pregnancy rate was 
also reported despite normal mating at the high-dose level. 
 



38 

Genotoxicity and carcinogenicity 
 
Carcinogenicity studies have not been performed with larotrectinib. 
Larotrectinib was not mutagenic in bacterial reverse mutation (Ames) assays and in in vitro 
mammalian mutagenesis assays. Larotrectinib was negative in the in vivo mouse micronucleus test at 
the maximum tolerated dose of 500 mg/kg. 
 
Safety pharmacology 
 
The safety pharmacology of larotrectinib was evaluated in several in vitro and in vivo studies that 
assessed effects on the CV, CNS, respiratory, and GI systems in various species. Larotrectinib had no 
adverse effect on haemodynamic parameters and ECG intervals in telemetered monkeys at exposures 
(Cmax) which are approximately 6-fold the human therapeutic exposures. Larotrectinib had no 
neurobehavioural findings in adult animals (rats, mice, cynomolgus monkeys) at exposure (Cmax) at 
least 7-fold higher than the human exposure. Larotrectinib had no effect on respiratory function in rats; 
at exposures (Cmax) at least 8-times the human therapeutic exposure. In rats, larotrectinib accelerated 
intestinal transit and increased gastric secretion and acidity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Purified water 
Sucrose 
Hydroxypropylbetadex 
Glycerol (E 422) 
Sorbitol (E 420) 
Sodium citrate (E 331) 
Sodium dihydrogen phosphate dihydrate (E 339) 
Citric acid (E 330) 
Propylene glycol (E 1520) 
Potassium sorbate (E 202) 
Methyl parahydroxybenzoate (E 218) 
Citrus fruit flavour 
Natural flavour 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
After first opening: 30 days. 
Store in a refrigerator (2 °C - 8 °C). 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C - 8 °C). 
Do not freeze. 
 
For storage conditions after first opening of the medicinal product, see section 6.3. 
 



39 

6.5 Nature and contents of container 
 
Amber glass (type III) bottle with a child-resistant polypropylene (PP) cap with a polyethylene (PE) 
seal liner. 
 
Each carton contains one bottle of 100 mL oral solution. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for use: 
 
Oral syringe 
- Use a suitable oral syringe with CE marking and bottle adapter (28 mm diameter) if applicable. 

-  For volumes less than 1 mL use a 1 mL oral syringe with 0.1 mL graduation. 
-  For volumes of 1 mL and higher use a 5 mL oral syringe with 0.2 mL graduation. 

- Open the bottle: press the bottle cap and turn it counter clockwise. 
- Insert the bottle adapter into the bottle neck and ensure it is well fixed. 
- Take the oral syringe and ensure that the plunger is fully depressed. Put the oral syringe in the 

adapter opening. Turn the bottle upside down. 
- Fill the oral syringe with small amount of solution by pulling the plunger down, then push the 

plunger upwards to remove any bubbles. 
- Pull the plunger down to the graduation mark equal to the quantity in mL as prescribed. 
- Turn the bottle the right way up and remove the oral syringe from the bottle adapter. 
- Slowly depress the plunger, directing the liquid towards the inside cheek to allow for natural 

swallowing. 
- Close the bottle with the original bottle cap (leaving the adapter in place). 
 
Nasogastric feeding tube 
- Use a suitable nasogastric feeding tube. The outer diameter of the nasogastric feeding tube 

should be selected based on the patient characteristics. Typical tube diameter, tube lengths and 
derived prime volumes are presented in Table 7. 

- The feeding should be stopped and the tube flushed with at least 10 mL water. NOTE: See 
exceptions regarding neonates and patients with fluid restrictions in the sub-point directly 
below. 

- A suitable syringe should be used to administer VITRAKVI to the nasogastric feeding tube. 
 The tube should be flushed again with at least 10 mL water to ensure VITRAKVI is delivered 

and to clear the tube. 
 Neonates and children with fluid restrictions may require minimal flushing volume of 0.5 to 

1 mL or flushing with air to deliver VITRAKVI. 
- Restart the feeding. 
 
Table 7: Recommended tube dimensions per age group 
Patient Tube diameter for 

standard feeds 
Tube diameter for 
high density feeds 

Tube length (cm) Tube prime 
volume (mL) 

Neonate 4-5 FR 6 FR 40-50 0.25-0.5 
Children 6 FR 8 FR 50-80 0.7-1.4 
Adult 8 FR 10 FR 80-120 1.4-4.2 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 



40 

 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1385/003 – VITRAKVI 20 mg/mL oral solution 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

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


41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION 

MEASURES FOR THE CONDITIONAL MARKETING 
AUTHORISATION 

 
 
 



42 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

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

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

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

 
 



43 

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

 
This being a conditional marketing authorisation and pursuant to Article 14a of Regulation (EC) 
No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 

Description Due date 

In order to further confirm the histology-independent efficacy of larotrectinib 
and to investigate the primary and secondary resistance mechanisms, the MAH 
should submit a pooled analysis for the increased sample size including the 
final report of study LOXO-TRK-15002 (NAVIGATE). 

30 June 2024 

In order to further investigate the long-term toxicity and developmental effects 
of larotrectinib in paediatric patients, with particular focus on 
neurodevelopment including cognitive function, the MAH should submit the 
final report of study LOXO-TRK-15003 (SCOUT) including 5 year follow up 
data. 

31 March 2027 

In order to further confirm the appropriate dose recommended in paediatric 
patients, the MAH should submit an updated pop PK model based on 
additional PK sampling in patients aged 1 month to 6 years from study 
LOXO-TRK-15003 (SCOUT). 

30 September 2021 

 



44 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



46 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 25 mg hard capsules 
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains larotrectinib sulfate, equivalent to 25 mg of larotrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Swallow whole. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



47 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
VITRAKVI 25 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



48 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 25 mg hard capsules 
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains larotrectinib sulfate, equivalent to 25 mg of larotrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Swallow whole. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



49 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



50 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 100 mg hard capsules 
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains larotrectinib sulfate, equivalent to 100 mg of larotrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Swallow whole. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



51 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
VITRAKVI 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



52 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 100 mg hard capsules 
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains larotrectinib sulfate, equivalent to 100 mg of larotrectinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Swallow whole. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



53 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



54 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 20 mg/mL oral solution  
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of oral solution contains larotrectinib sulfate, equivalent to 20 mg of larotrectinib.  
 
 
3. LIST OF EXCIPIENTS 
 
Contains: sucrose, E 420, E 1520, E 218. Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 mL oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
Use within 30 days of opening. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
 



55 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
VITRAKVI 20 mg/mL  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



56 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
VITRAKVI 20 mg/mL oral solution  
larotrectinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of oral solution contains larotrectinib sulfate, equivalent to 20 mg of larotrectinib.  
 
 
3. LIST OF EXCIPIENTS 
 
Contains: sucrose, E 420, E 1520, E 218. Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 mL oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
Use within 30 days of opening. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze. 
 
 



57 

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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/19/1385/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 



58 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



59 

Package leaflet: Information for the patient 
 

VITRAKVI 25 mg hard capsules 
VITRAKVI 100 mg hard capsules 

larotrectinib 
 

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

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

side effects not listed in this leaflet. See section 4. 
- This leaflet has been written as though the person taking the medicine is reading it. If you are 

giving this medicine to your child, please replace “you” with “your child” throughout. 
 
 
What is in this leaflet: 
 
1. What VITRAKVI is and what it is used for 
2. What you need to know before you take VITRAKVI 
3. How to take VITRAKVI 
4. Possible side effects 
5. How to store VITRAKVI 
6. Contents of the pack and other information 
 
 
1. What VITRAKVI is and what it is used for 
 
What VITRAKVI is used for 
VITRAKVI contains the active substance larotrectinib.  
 
It is used in adults, adolescents and children to treat solid tumours (cancer) in various parts of the body 
that are caused by a change in the NTRK gene (neurotrophic tyrosine receptor kinase). 
VITRAKVI is only used when 
- these cancers are advanced or have spread to other parts of the body or if a surgery to remove 

the cancer is likely to cause severe complications and 
- there are no satisfactory treatment options. 
 
Before you are given VITRAKVI, your doctor will do a test to check if you have the change in the 
NTRK gene. 
 
How VITRAKVI works 
In patients whose cancer is due to an altered NTRK gene, the change in the gene causes the body to 
make an abnormal protein called TRK fusion protein, which can lead to uncontrolled cell growth and 
cancer. VITRAKVI blocks the action of TRK fusion proteins and so may slow or stop the growth of 
the cancer. It may also help to shrink the cancer. 
 
If you have any questions on how VITRAKVI works or why it has been prescribed for you, ask your 
doctor, pharmacist or nurse. 
 
 



60 

2. What you need to know before you take VITRAKVI 
 
Do not take VITRAKVI if 
- you are allergic to larotrectinib or any of the other ingredients of this medicine (listed in 

section 6). 
 
Tests and checks 
VITRAKVI can increase the amount of the liver enzymes ALT and AST in your blood. Your doctor 
will do blood tests before and during treatment to check the level of ALT and AST and check how 
well your liver is working. 
 
Other medicines and VITRAKVI 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This is because some medicines may affect the way VITRAKVI works or VITRAKVI may 
affect how other medicines work.  
In particular, tell your doctor, pharmacist or nurse if you are taking any of the following medicines: 
- medicines used to treat fungal or bacterial infections called itraconazole, voriconazole, 

clarithromycin, telithromycin, troleandomycin 
- a medicine used to treat Cushing’s syndrome called ketoconazole 
- medicines used to treat HIV infection called atazanavir, indinavir, nelfinavir, ritonavir, 

saquinavir, rifabutin, efavirenz 
- a medicine used to treat depression called nefazodone 
- medicines used to treat epilepsy called phenytoin, carbamazepine, phenobarbital 
- a herbal medicine used to treat depression called St. John’s wort 
- a medicine used to treat tuberculosis called rifampicin 
- a medicine used for strong pain relief called alfentanil 
- medicines used to prevent organ rejection after an organ transplant called ciclosporin, sirolimus, 

tacrolimus 
- a medicine used to treat an abnormal heart rhythm called quinidine 
- medicines used to treat migraines called dihydroergotamine, ergotamine 
- a medicine used to treat long-term pain called fentanyl 
- a medicine used to control involuntary movements or sounds called pimozide 
- a medicine to help you stop smoking called bupropion 
- medicines to reduce blood sugar levels called repaglinide, tolbutamide 
- a medicine that prevents blood clots called warfarin 
- a medicine used to reduce the amount of acid produced in the stomach called omeprazole 
- a medicine used to help control high blood pressure called valsartan 
- a group of medicines used to help lower cholesterol called statins 
- hormonal medicines used for contraception, see section “contraception – for men and women” 

below. 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse. 
 
Taking VITRAKVI with food and drink 
Do not eat grapefruit or drink grapefruit juice while taking VITRAKVI. This is because it may 
increase the amount of VITRAKVI in your body. 
 
Pregnancy and breast-feeding 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
You should not use VITRAKVI during pregnancy since the effect of VITRAKVI on the unborn is not 
known. 
 
Breast-feeding 
Do not breast-feed while taking this medicine and for 3 days after the last dose. This is because it is 
not known if VITRAKVI passes into breast milk. 
 



61 

Contraception – for men and women 
You should avoid getting pregnant while taking this medicine. 
If you are able to become pregnant, your doctor should do a pregnancy test before you start treatment. 
You must use effective methods of contraception while taking VITRAKVI and for at least 1 month 
after the last dose, if  
- you are able to become pregnant. If you use hormonal contraceptives, you should also use a 

barrier method, such as a condom. 
- you have sex with a woman able to become pregnant. 
Ask your doctor about the best method of contraception for you. 
 
Driving, cycling and using machines 
VITRAKVI may make you feel dizzy or tired. If this happens, do not drive, cycle or use any tools or 
machines. 
 
 
3. How to take VITRAKVI 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor, 
pharmacist or nurse if you are not sure. 
 
How much to take 
Adults (from 18 years) 
- The recommended dose of VITRAKVI is 100 mg (1 capsule of 100 mg or 4 capsules of 25 mg), 

two times a day. 
- Your doctor will review your dose and change it as needed.  
 
Children and adolescents 
- Your child’s doctor will work out the right dose for your child based on their height and weight.  
- The maximum recommended dose is 100 mg (1 capsule of 100 mg or 4 capsules of 25 mg), two 

times a day. 
- Your child’s doctor will review the dose and change it as needed.  
 
An oral solution of VITRAKVI is available for patients who cannot swallow the capsules. 
 
How to take this medicine 
- VITRAKVI can be taken with or without food.  
- Do not eat grapefruit or drink grapefruit juice while taking this medicine. 
- Swallow the VITRAKVI capsules whole with a glass of water. Do not open, chew or crush the 

capsule as it has a very bitter taste. 
 
If you take more VITRAKVI than you should 
Talk to your doctor, pharmacist or nurse or go to a hospital straight away. Take the medicine pack and 
this leaflet with you. 
 
If you miss a dose of VITRAKVI 
Do not take a double dose to make up for a forgotten dose or if you vomit after taking this medicine. 
Take your next dose at the usual time. 
 
If you stop taking VITRAKVI 
Do not stop taking this medicine without talking to your doctor first. It is important to take 
VITRAKVI for as long as your doctor tells you. 
If you are not able to take the medicine as your doctor prescribed talk to your doctor straight away. 
If you have further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 



62 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
You should immediately contact your doctor if you experience any of the following serious side 
effects: 
- feeling dizzy, tingling, feeling numb, or a burning feeling in your hands and feet (very common 

side effect, may affect more than 1 in 10 people), difficulty walking normally (common side 
effect, may affect up to 1 in 10 people). This could be symptoms of nervous system problems. 

Your doctor may decide to lower the dose, or pause or stop the treatment. 
 
Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 
Very common (may affect more than 1 in 10 people): 
- you may look pale and feel your heart pumping, which could be symptoms of low red blood 

cells (anaemia) 
- flu like symptoms including fever, which could be symptoms of low white blood cells 

(neutropenia, leukopenia) 
- feeling or being sick (nausea or vomiting) 
- constipation 
- muscle pain (myalgia) 
- muscle weakness 
- feeling tired (fatigue) 
- increased amount of liver enzymes in blood tests 
- weight increase. 
 
Common (may affect up to 1 in 10 people): 
- change in how things taste (dysgeusia) 
- increased amount of “alkaline phosphatase” in blood tests (very common in children). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store VITRAKVI 
 
- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton and the bottle label 

after EXP. The expiry date refers to the last day of that month. 
- This medicine does not require any special storage conditions. 
- Do not use this medicine if you notice that capsules look damaged. 
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

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

 
 
6. Contents of the pack and other information 
 
What VITRAKVI contains 
The active substance is larotrectinib.  
Each VITRAKVI 25 mg capsule contains 25 mg of larotrectinib (as sulfate). 
Each VITRAKVI 100 mg capsule contains 100 mg of larotrectinib (as sulfate). 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


63 

The other ingredients are: 
Capsule shell: 
- Gelatin 
- Titanium dioxide (E 171) 
Printing ink: 
- Shellac 
- Indigo carmine aluminium lake (E 132) 
- Titanium dioxide (E 171) 
- Propylene glycol (E 1520) 
- Dimeticone 
 
What VITRAKVI looks like and the contents of the bottle 
- VITRAKVI 25 mg is supplied as white opaque hard gelatine capsule, (18 mm long x 6 mm 

wide), with blue printing of BAYER-cross and “LARO 25 mg” on the body of the capsule  
- VITRAKVI 100 mg is supplied as white opaque hard gelatine capsule, (22 mm long x 7 mm 

wide), with blue printing of BAYER-cross and “LARO 100 mg” on the body of the capsule  
 
Each carton contains 1 child-resistant plastic bottle containing 56 hard gelatine capsules. 
 
Marketing Authorisation Holder  
Bayer AG 
51368 Leverkusen  
Germany 
 
Manufacturer 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen  
Germany  
 



64 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel. +37 05 23 36 868 

България 
Байер България ЕООД 
Tел.: +359 02 4247280 

Luxembourg/Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420 266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel:+36 14 87-41 00 

Danmark 
Bayer A/S 
Tlf: +45 45 23 50 00 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +35 621 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49 (0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31-(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372 655 8565 

Norge 
Bayer AS 
Tlf: +47 23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-61 87 500 

Österreich 
Bayer Austria Ges.m.b.H. 
Tel: +43-(0)1-711 46-0 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel: +48 22 572 35 00 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351 21 416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: +385-(0)1-6599 900 

România 
SC Bayer SRL 
Tel: +40 21 529 59 00 

Ireland 
Bayer Limited 
Tel: +353 1 2999313 

Slovenija 
Bayer d. o. o. 
Tel: +386 (0)1 58 14 400 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Bayer spol. s r.o. 
Tel. +421 2 59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39 02 397 8 1 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358- 20 785 21 

Κύπρος 
NOVAGEM Limited 
Tηλ: +357 22 48 38 58 

Sverige 
Bayer AB 
Tel: +46 (0) 8 580 223 00 

Latvija 
SIA Bayer 
Tel: +371 67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44-(0)118 206 3000 

 
This leaflet was last revised in <{MM/YYYY}. 
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 



65 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 



66 

Package leaflet: Information for the patient 
 

VITRAKVI 20 mg/mL oral solution 
larotrectinib 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

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

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

side effects not listed in this leaflet. See section 4. 
- This leaflet has been written as though the person taking the medicine is reading it. If you are 

giving this medicine to your child, please replace “you” with “your child” throughout. 
 
 
What is in this leaflet: 
 
1. What VITRAKVI is and what it is used for 
2. What you need to know before you take VITRAKVI 
3. How to take VITRAKVI 
4. Possible side effects 
5. How to store VITRAKVI 
6. Contents of the pack and other information 
 
 
1. What VITRAKVI is and what it is used for 
 
What VITRAKVI is used for 
VITRAKVI contains the active substance larotrectinib.  
 
It is used in adults, adolescents and children to treat solid tumours (cancer) in various parts of the body 
that are caused by a change in the NTRK gene (neurotrophic tyrosine receptor kinase). 
VITRAKVI is only used when 
- these cancers are advanced or have spread to other parts of the body or if a surgery to remove 

the cancer is likely to cause severe complications and 
- there are no satisfactory treatment options. 
 
Before you are given VITRAKVI, your doctor will do a test to check if you have the change in the 
NTRK gene. 
 
How VITRAKVI works 
In patients whose cancer is due to an altered NTRK gene, the change in the gene causes the body to 
make an abnormal protein called TRK fusion protein, which can lead to uncontrolled cell growth and 
cancer. VITRAKVI blocks the action of TRK fusion proteins and so may slow or stop the growth of 
the cancer. It may also help to shrink the cancer. 
 
If you have any questions on how VITRAKVI works or why it has been prescribed for you, ask your 
doctor, pharmacist or nurse. 
 
 



67 

2. What you need to know before you take VITRAKVI 
 
Do not take VITRAKVI if 
- you are allergic to larotrectinib or any of the other ingredients of this medicine (listed in 

section 6).  
 
Tests and checks 
VITRAKVI can increase the amount of the liver enzymes ALT and AST in your blood. Your doctor 
will do blood tests before and during treatment to check the level of ALT and AST and check how 
well your liver is working. 
 
Other medicines and VITRAKVI 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This is because some medicines may affect the way VITRAKVI works or VITRAKVI may 
affect how other medicines work.  
In particular, tell your doctor, pharmacist or nurse if you are taking any of the following medicines: 
- medicines used to treat fungal or bacterial infections called itraconazole, voriconazole, 

clarithromycin, telithromycin, troleandomycin 
- a medicine used to treat Cushing’s syndrome called ketoconazole 
- medicines used to treat HIV infection called atazanavir, indinavir, nelfinavir, ritonavir, 

saquinavir, rifabutin, efavirenz 
- a medicine used to treat depression called nefazodone 
- medicines used to treat epilepsy called phenytoin, carbamazepine, phenobarbital 
- a herbal medicine used to treat depression called St. John’s wort 
- a medicine used to treat tuberculosis called rifampicin 
- a medicine used for strong pain relief called alfentanil 
- medicines used to prevent organ rejection after an organ transplant called ciclosporin, sirolimus, 

tacrolimus 
- a medicine used to treat an abnormal heart rhythm called quinidine 
- medicines used to treat migraines called dihydroergotamine, ergotamine 
- a medicine used to treat long-term pain called fentanyl 
- a medicine used to control involuntary movements or sounds called pimozide 
- a medicine to help you stop smoking called bupropion 
- medicines to reduce blood sugar levels called repaglinide, tolbutamide 
- a medicine that prevents blood clots called warfarin 
- a medicine used to reduce the amount of acid produced in the stomach called omeprazole 
- a medicine used to help control high blood pressure called valsartan 
- a group of medicines used to help lower cholesterol called statins 
- hormonal medicines used for contraception, see section “contraception – for men and women” 

below. 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse. 
 
Taking VITRAKVI with food and drink 
Do not eat grapefruit or drink grapefruit juice while taking VITRAKVI. This is because it may 
increase the amount of VITRAKVI in your body. 
 
Pregnancy and breast-feeding 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. 
You should not use VITRAKVI during pregnancy since the effect of VITRAKVI on the unborn is not 
known. 
 
Breast-feeding 
Do not breast-feed while taking this medicine and for 3 days after the last dose. This is because it is 
not known if VITRAKVI passes into breast milk. 
 



68 

Contraception – for men and women 
You should avoid getting pregnant while taking this medicine. 
If you are able to become pregnant, your doctor should do a pregnancy test before you start treatment. 
You must use effective methods of contraception while taking VITRAKVI and for at least 1 month 
after the last dose, if 
- you are able to become pregnant. If you use hormonal contraceptives, you should also use a 

barrier method, such as a condom. 
- you have sex with a woman able to become pregnant. 
Ask your doctor about the best method of contraception for you.  
 
Driving, cycling and using machines 
VITRAKVI may make you feel dizzy or tired. If this happens, do not drive, cycle or use any tools or 
machines. 
 
VITRAKVI contains: 
- sucrose: it may be harmful to the teeth. If you have been told by your doctor that you have an 

intolerance to some sugars, contact your doctor before taking this medicinal product. 
- 22 mg sorbitol in 1 mL. Sorbitol is a source of fructose. If your doctor has told you that you or 

your child have an intolerance to some sugars or if you have been diagnosed with hereditary 
fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down 
fructose, talk to your doctor before you or your child take or receive this medicine. 

- less than 1 mmol (or 23 mg) of sodium per 5 mL, that is to say essentially ‘sodium free’. 
- 1.6 mg propylene glycol in 1 mL. If your baby is less than 4 weeks old, talk to your doctor or 

pharmacist before giving them this medicine, in particular if the baby is given other medicines 
that contain propylene glycol or alcohol. 

- parahydroxybenzoate: it may cause allergic reactions (possibly delayed). 
 
 
3. How to take VITRAKVI 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor, 
pharmacist or nurse if you are not sure. 
 
How much to take 
Adults (from 18 years) 
- The recommended dose of VITRAKVI is 100 mg (5 mL), two times a day. 
- Your doctor will review your dose and change it as needed.  
 
Children and adolescents 
- Your child’s doctor will work out the right dose for your child based on their height and weight.  
- The maximum recommended dose is 100 mg (5 mL), two times a day. 
- Your child’s doctor will review the dose and change it as needed.  
 



69 

How to take this medicine 
- VITRAKVI can be taken with or without food.  
- Do not eat grapefruit or drink grapefruit juice while taking this medicine. 
- Along with this medicine you need a bottle adapter (28 mm diameter) and a syringe that can be 

used to give medicines by mouth. Use a 1 mL syringe with 0.1 mL marks for doses less than 
1 mL. Use a 5 mL syringe with 0.2 mL marks for doses of 1 mL or more. 
-  Press the bottle cap and turn it anti-clockwise to open the bottle. 
-  Put the bottle adapter into the bottle neck and make sure it is well fixed. 
-  Push the plunger fully into the syringe and then put the syringe in the adapter opening. 

Turn the bottle upside down. 
-  Fill the syringe with a small amount of solution by pulling the plunger down, then push 

the plunger upwards to remove any large bubbles that are in the syringe. 
-  Pull the plunger down to the mark equal to the dose in mL prescribed by your doctor. 
-  Turn the bottle the right way up and take the syringe out of the adapter. 
-  Put the syringe in the mouth, pointing towards the inside of the cheek – this will help you 

swallow the medicine naturally. Slowly press the plunger in. 
-  Put the bottle cap on and tightly close the bottle - leave the adapter in the bottle. 
If necessary, VITRAKVI may be administered via a nasogastric feeding tube. For details how to 
do so, please ask your doctor, pharmacist or nurse. 

 
If you take more VITRAKVI than you should 
Talk to your doctor, pharmacist or nurse or go to a hospital straight away. Take the medicine pack and 
this leaflet with you. 
 
If you miss a dose of VITRAKVI 
Do not take a double dose to make up for a forgotten dose or if you vomit after taking this medicine. 
Take your next dose at the usual time. 
 
If you stop taking VITRAKVI 
Do not stop taking this medicine without talking to your doctor first. It is important to take 
VITRAKVI for as long as your doctor tells you. 
If you are not able to take the medicine as your doctor prescribed talk to your doctor straight away. 
If you have further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
You should immediately contact your doctor if you experience any of the following serious side 
effects: 
- feeling dizzy, tingling, feeling numb, or a burning feeling in your hands and feet (very common 

side effect, may affect more than 1 in 10 people), difficulty walking normally (common side 
effect, may affect up to 1 in 10 people). This could be symptoms of nervous system problems. 

Your doctor may decide to lower the dose, or pause or stop the treatment. 
 



70 

Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 
Very common (may affect more than 1 in 10 people): 
- you may look pale and feel your heart pumping, which could be symptoms of low red blood 

cells (anaemia) 
- flu like symptoms including fever, which could be symptoms of low white blood cells 

(neutropenia, leukopenia) 
- feeling or being sick (nausea or vomiting) 
- constipation 
- muscle pain (myalgia) 
- muscle weakness  
- feeling tired (fatigue) 
- increased amount of liver enzymes in blood tests 
- weight increase. 
 
Common (may affect up to 1 in 10 people): 
- change in how things taste (dysgeusia) 
- increased amount of “alkaline phosphatase” in blood tests (very common in children). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store VITRAKVI 
 
- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton and the bottle label 

after EXP. The expiry date refers to the last day of that month. 
- Store in a refrigerator (2 °C - 8 °C). 
- Do not freeze. 
- Once the bottle is open, you must use your medicine within 30 days of opening. 
- Do not take the medicine if the bottle or bottle cap looks damaged or like it has leaked.  
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

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

 
 
6. Contents of the pack and other information 
 
What VITRAKVI contains 
The active substance is larotrectinib.  
Each mL of oral solution contains 20 mg of larotrectinib (as sulfate). 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
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71 

The other ingredients are: 
- Purified water 
- Sucrose 
- Hydroxypropylbetadex 
- Glycerol (E 422) 
- Sorbitol (E 420) 
- Sodium citrate (E 331) 
- Sodium dihydrogen phosphate dihydrate (E 339) 
- Citric acid (E 330) 
- Propylene glycol (E 1520) 
- Potassium sorbate (E 202) 
- Methyl parahydroxybenzoate (E 218) 
- Citrus fruit flavour 
- Natural flavour 
 
See “VITRAKVI contains” in section 2 for more information. 
 
What VITRAKVI looks like and the contents of the bottle 
VITRAKVI is a clear yellow to orange oral solution. 
 
Each carton contains 1 child-resistant glass bottle containing 100 mL oral solution. 
 
Marketing Authorisation Holder  
Bayer AG 
51368 Leverkusen  
Germany 
 
Manufacturer 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen  
Germany  
 



72 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel. +37 05 23 36 868 

България 
Байер България ЕООД 
Tел.: +359 02 4247280 

Luxembourg/Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420 266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel:+36 14 87-41 00 

Danmark 
Bayer A/S 
Tlf: +45 45 23 50 00 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +35 621 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49 (0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31-(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372 655 8565 

Norge 
Bayer AS 
Tlf: +47 23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-61 87 500 

Österreich 
Bayer Austria Ges.m.b.H. 
Tel: +43-(0)1-711 46-0 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel: +48 22 572 35 00 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351 21 416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: +385-(0)1-6599 900 

România 
SC Bayer SRL 
Tel: +40 21 529 59 00 

Ireland 
Bayer Limited 
Tel: +353 1 2999313 

Slovenija 
Bayer d. o. o. 
Tel: +386 (0)1 58 14 400 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Bayer spol. s r.o. 
Tel. +421 2 59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39 02 397 8 1 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358- 20 785 21 

Κύπρος 
NOVAGEM Limited 
Tηλ: +357 22 48 38 58 

Sverige 
Bayer AB 
Tel: +46 (0) 8 580 223 00 

Latvija 
SIA Bayer 
Tel: +371 67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44-(0)118 206 3000 

 
This leaflet was last revised in <{MM/YYYY}. 
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 



73 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


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