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).

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.
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.

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.

Efficacy across tumour types
The benefit of VITRAKVI has been established in single arm trials encompassing a relatively small
sample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of VITRAKVI have
been shown on the basis of overall response rate and response duration in a limited number of tumour
types. The effect may be quantitatively different depending on tumour type, as well as on concomitant
genetic alterations (see section 5.1). For these reasons, VITRAKVI should only be used if there are no
treatment options for which clinical benefit has been established, or where such treatment options have
been exhausted (i.e., no satisfactory treatment options).
Neurologic reactions
Neurologic reactions including dizziness, gait disturbance and paraesthesia were reported in patients
receiving larotrectinib (see section 4.8). For the majority of neurologic reactions, onset occurred
within the first three months of treatment. Withholding, reducing, or discontinuing VITRAKVI dosing
should be considered, depending on the severity and persistence of these symptoms (see section 4.2).
Transaminase elevations
ALT and AST increase were reported in patients receiving larotrectinib (see section 4.8). The majority
of ALT and AST increases occurred in the first 3 months of treatment.
Liver function including ALT and AST assessments should be monitored before the first dose and
monthly for the first 3 months of treatment, then periodically during treatment, with more frequent
testing in patients who develop transaminase elevations. Withhold or permanently discontinue
VITRAKVI based on the severity. If withheld, the VITRAKVI dose should be modified when
resumed (see section 4.2).

Co-administration with CYP3A4/P-gp inducers
Avoid co-administration of strong or moderate CYP3A4/P-gp inducers with VITRAKVI due to a risk
of decreased exposure (see section 4.5).
Contraception in female and male
Women of childbearing potential must use highly effective contraception while taking VITRAKVI
and for at least one month after stopping treatment (see sections 4.5 and 4.6).
Males of reproductive potential with a non-pregnant woman partner of child bearing potential should
be advised to use highly effective contraception during treatment with VITRAKVI and for at least one
month after the final dose (see section 4.6).

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

Effect of larotrectinib on other transporter substrates
In vitro studies indicate that larotrectinib is an inhibitor of OATP1B1. No clinical studies have been
performed to investigate interactions with OATP1B1 substrates. Therefore, it cannot be excluded
whether co-administration of larotrectinib with OATP1B1 substrates (e.g. valsartan, statins) may
increase their exposure.
Effect of larotrectinib on substrates of PXR regulated enzymes
In vitro studies indicate that larotrectinib is a weak inducer of PXR regulated enzymes (e.g. CYP2C
family and UGT). Co-administration of larotrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates
(e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.
Hormonal contraceptives
It is currently unknown whether larotrectinib may reduce the effectiveness of systemically acting
hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should
be advised to add a barrier method.

Women of childbearing potential / Contraception in males and females
Based on the mechanism of action, foetal harm cannot be excluded when administering larotrectinib to
a pregnant woman. Women of childbearing potential should have a pregnancy test prior to starting
treatment with VITRAKVI.
Women of reproductive potential should be advised to use highly effective contraception during
treatment with VITRAKVI and for at least one month after the final dose. As it is currently unknown
whether larotrectinib may reduce the effectiveness of systemically acting hormonal contraceptives,
women using systemically acting hormonal contraceptives should be advised to add a barrier method.
Males of reproductive potential with a non-pregnant woman partner of child-bearing potential should
be advised to use highly effective contraception during treatment with VITRAKVI and for at least one
month after the final dose.
Pregnancy
There are no data from the use of larotrectinib in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
(see section 5.3).
As a precautionary measure, it is preferable to avoid the use of VITRAKVI during pregnancy.
Breast-feeding
It is unknown whether larotrectinib/metabolites are excreted in human milk.
A risk to the newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment with VITRAKVI and for 3 days following the
final dose.
Fertility
There are no clinical data on the effect of larotrectinib on fertility. No relevant effects on fertility were
observed in repeat-dose toxicity studies (see section 5.3).

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

Summary of the safety profile
The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of decreasing frequency
were increased ALT (32%), fatigue (30%), constipation (29%), increased AST (27%), dizziness
(26%), vomiting (23%), anaemia (23%), and nausea (22%).
The majority of adverse reactions were Grade 1 or 2. Grade 4 was the highest reported grade for
adverse reactions neutrophil count decreased (1%), ALT increased (1%), and AST increased (< 1%).
The highest reported grade was Grade 3 for adverse reactions anaemia, weight increased, fatigue,
dizziness, paraesthesia, muscular weakness, nausea, myalgia, gait disturbance, vomiting, and
leukocyte count decreased. All the reported Grade 3 adverse reactions occurred in less than 5% of
patients, with the exception of anaemia (8%).
Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions, regardless of
attribution occurred in 5% of patients (one case each of ALT increased, AST increased, bile duct
adenocarcinoma, gait disturbance, intestinal perforation, jaundice, malignant neoplasm progression,
neutrophil count decreased, small intestinal obstruction, spinal cord compression, and viral infection).
The majority of adverse reactions leading to dose reduction occurred in the first three months of
treatment.

Tabulated list of adverse reactions
The safety of VITRAKVI was evaluated in 196 patients with TRK fusion-positive cancer in one of
three on-going clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”). The safety population
characteristics were comprised of patients with a median age of 37.5 years (range: 0.1, 84) with 37%
of patients being paediatric patients. Median time on treatment for the overall safety population
(n=196) was 9.3 months (range: 0.10, 51.6).
The adverse drug reactions reported in patients (n=196) treated with VITRAKVI are shown in Table 2
and Table 3.
The adverse drug reactions are classified according to the System Organ Class.
Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100
to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000),
and not known (cannot be estimated from available data).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness

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.

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 are still ongoing.
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 164 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 as of July
2019. These 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, 24 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 166 patients, reverse transcription-polymerase chain reaction (RT-PCR)
used in 9 patients, fluorescence in situ hybridization (FISH) used in 12 patients, and Nanostring in
1 patient as routinely performed at certified laboratories.

Pooled primary analysis set
The pooled primary analysis set consisted of 164 patients and did not include primary CNS tumours.
Median time on treatment before disease progression was 14.7 months (range: 0.10 to 51.6 months)
based on July 2019 cut-off. Forty-four percent of patients had received VITRAKVI for 12 months or
more and 21% had received VITRAKVI 24 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, an estimated 76% [95%
CI: 67, 85] of responses lasted 12 months or longer, and 67% [95% CI: 55, 78] of responses lasted
24 months or longer. Ninety percent (90%) [95% CI: 85, 95] of patients treated were alive one year
after the start of therapy and 82% [95% CI: 75, 90] after two years with the median for overall survival
not yet being reached. Median progression free survival was 33.4 months at the time of the analysis,
with a progression free survival rate of 66% [95% CI: 58, 74] after 1 year and 58% [95% CI: 48, 67]
after 2 years.
The median change in tumour size in the pooled primary analysis set was a decrease of 68%.
Patients with primary CNS tumours
At the time of data cut-off, of the 24 patients with primary CNS tumours confirmed response was
observed in 5 patients (21%) with 2 of the 24 patients (8%) being complete responders and 3 patients
(12.5%) being partial responders. In 2 additional patients (8%) a not yet confirmed partial response
was observed. Further 15 patients (63%) had stable disease. Two patients (8%) had progressive
disease. At the time of data cut-off, time on treatment ranged from 1.2 to 21.4 months and was
ongoing in 15 out of 24 patients, with one of these patients receiving post-progression treatment.
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.

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. 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.
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.
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.

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.
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.

6.1 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

Not applicable.

Store below 30°C.

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.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.