Summary of Product Characteristics (SmPC) - Vitrakvi 100 mg hard capsules

1 NAME OF THE MEDICINAL PRODUCT

VITRAKVI 100 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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).
White opaque hard gelatine capsule, size 0 (22 mm long x 7 mm wide), with blue
printing of BAYER-cross and “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.

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/m²larotrectinib twice daily with a maximum of 100 mg per dose

until disease progression or until unacceptable toxicity occurs.

For paediatric patients from birth to less than 3 months the recommended starting dose is

50 mg/m²twice daily (see section 5.2).

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.

For all grade 3 or 4 adverse reactions not referring to liver function test abnormalities:

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 aged 3 months or older with body surface area less than 1.0 m²	Paediatric patients aged less than 3 months
First	75 mg twice daily	75 mg/m²twice daily	25 mg/m²twice daily
Second	50 mg twice daily	50 mg/m²twice daily	-
Third	100 mg once daily	25 mg/m²twice daily^a	-

^aPaediatric patients on third dose modification at 25 mg/m² twice daily should remain on this dose (25 mg/m²twice daily) even if body surface area increases during the treatment.

VITRAKVI should be permanently discontinued in patients who are unable to tolerate VITRAKVI after three dose modifications.

The recommended dose modifications in case of liver function tests abnormalities during treatment with VITRAKVI are provided in Table 2.

Table 2: Recommended dose modifications and management for VITRAKVI for liver function test abnormalities

Laboratory parameters	Recommended measures
Grade 2 ALT and/or AST (>3x ULN and ≤5x ULN)	Conduct serial laboratory evaluations frequently after the observation of grade 2 toxicity, until resolved, to establish whether a dose interruption or reduction is required.
Grade 3 ALT and/or AST (>5x ULN and ≤20x ULN) or Grade 4 ALT and/or AST (>20x ULN), with bilirubin <2x ULN ≥	Withhold treatment until the adverse reaction resolves or improves to baseline. Monitor liver function frequently until resolution or return to baseline. Permanently discontinue treatment if an adverse reaction does not resolve. Resume at the next dose modification if adverse reactions resolve. Treatment should only be resumed in patients where the benefit outweighs the risk. Permanently discontinue treatment if a grade 4 ALT and/or AST elevation occurs after resuming treatment.
ALT and/or AST 3x ULN with bilirubin ≥2x ULN	Withhold treatment and monitor liver function frequently until resolution or return to baseline. Consider permanent treatment discontinuation. Treatment should only be resumed in patients where the benefit outweighs the risk. If resumed, start at the next lower dose. Monitor liver function frequently upon restart. Permanently discontinue treatment if adverse reaction recurs after resuming treatment.

ALT Alanine aminotransferase
AST Aspartate aminotransferase
ULN upper limit of normal

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.

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 benefi				t
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).

Hepatotoxicity

Abnormalities of liver function tests including increased ALT, AST, a

lkaline phosphatase

(

ALP) and bilirubin have been observed in patients receiving larotrectinib (see section 4.8).

The majority of ALT and AST increases occurred within 3 months of starting treatment.

Cases of hepatotoxicity with increases in ALT and/or AST of grade 2, 3 or 4 severity and

≥

increases in bilirubin 2x ULN have been reported.

In patients with hepatic transaminase elevations, withhold, modify dose or permanentl

discontinue VITRAKVI based on the severity (see section 4.2).

Liver function including ALT, AST, ALP and bilirubin should be monitored before the first

dose, then every 2 weeks during the first month of treatment, then monthly for the next

6 months of treatment, then periodically during treatment. In patients who develop

transaminase elevations, more frequent testing is needed (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 childbearing 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 or moderate CYP3A inhibitors, P-gp and BCRP inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole or grapefruit) may increase larotrectinib plasma concentrations (see section 4.2).

Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with itraconazole (a strong CYP3A inhibitor and P-gp and BCRP inhibitor) 200 mg once daily for 7 days increased larotrectinib C_maxand 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 rifampicin (a P-gp and BCRP inhibitor) increased larotrectinib C_maxand 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 inducers and strong P-gp inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, 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 rifampicin (a strong CYP3A and P-gp inducer) 600 mg once daily for 11 days decreased larotrectinib C_maxand AUC by 71% and 81%, respectively. No clinical data is available on the effect of a moderate inducer, but a decrease in larotrectinib exposure is expected.

Effects of larotrectinib on other agents

Effect of larotrectinib on CYP3A substrates

Clinical data in healthy adult subjects indicate that co-administration of VITRAKVI (100 mg twice daily for 10 days) increased the C_maxand 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.

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 childbearing 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 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).

4.7 Effects on ability to drive and 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 most common adverse drug reactions ( 20%) of VITRAKVI in order of decreasing

frequency were increased ALT (36%), increased AST (33%), vomiting (30%), anaemia

(28%), constipation (28%), diarrhoea (27%), nausea (24%), fatigue (23%), and dizziness

(20%).

The majority of adverse reactions were grade 2 or 3. Grade 4 was the highest reported grade

for adverse reactions neutrophil count decreased (2%), ALT increased (1%), AST increased

leukocyte count decreased, platelet count decreased, muscular weakness and blood alkaline

phosphatase increased (each in < 1%). The highest reported grade was grade 3 for adverse

reactions anaemia (7%), weight increased (6%), diarrhoea (4%), gait disturbance and

vomiting (each 1%), and fatigue, dizziness, paraesthesia, nausea, myalgia, and constipation

(each in < 1%).

Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions occurre

in 2% of patients (2 cases each of neutrophil count decreased, ALT increased, and AST

increased, 1 case each of gait disturbance, and muscular weakness). 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 361 patients with TRK fusion-positive cancer in

one of three on-going clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”) and

post-marketing. The safety population characteristics were comprised of patients with a

median age of 39.0 years (range: 0, 90) with 37% of patients being paediatric patients

Median time on treatment for the overall safety population (n=361) was 16.2 months (range

0.1, 89.1).

The adverse drug reactions reported in patients (n=361) treated with VITRAKVI are shown in

Table 3 and Table 4.

The adverse drug reactions are classified according to the System Organ Class.≥

Frequency groups are defined by the following convention: very common ( 1/10); common ≥ ≥ ≥

( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very

rare (< 1/10,000), and not known (cannot be estimated from available data).

Within each frequency group, undesirable effects are presented in order of decreasing

seriousness.

Table 3: Adverse drug reactions reported in TRK fusion-positive cancer patients treated
with VITRAKVI at recommended dose (overall safety population, n=361) and
post-marketing

System organ class

Frequency

All grades

Grades 3 and 4

Blood and lymphatic

Very common

Anaemia

system disorders

Neutrophil count decreased

(Neutropenia)

Leukocyte count decreased

(Leukopenia)

Common

Platelet count decreased (Thrombocytopenia)

Anaemia

Neutrophil count decreased

(Neutropenia

)^a

Leukocyte count decreased

(Leukopenia

)^a

Uncommon

Platelet count decreased

(Thrombocytopenia)^{a, b}

Nervous system disorders

Very common

Dizziness

Common

Gait disturbance

Paraesthesia

Uncommon

Dizziness

Paraesthesia

Gastrointestinal disorders

Very common

Nausea

Constipation

Vomiting

Diarrhoe

Common

Dysgeusia^c

Diarrhoe

Vomiting

Uncommon

Nausea

Constipation

Hepatobiliary disorders

Not known

Liver injury^d

Musculoskeletal and

Very common

Myalgia

connective tissue

Common

Muscular weakness

disorders

Uncommon

Myalgia

Muscular weakness^{a, b}

General disorders and

Very common

Fatigue

administration site

Uncommon

Fatigue

conditions

Investigations

Very common

Alanine aminotransferase

(ALT) increased

Aspartate aminotransferase

(AST) increased

Weight increased

(Abnormal weight gain)

Common

Blood alkaline phosphatase increased

Alanine aminotransferas

(ALT) increased

Aspartate aminotransferase

(AST) increased

Weight increased (Abnormal

weight gain)

Uncommon

Blood alkaline phosphatase

increased

a, b

^agrade 4 reactions were reported

^beach grade frequency was less than <1%

^cADR dysgeusia includes the preferred terms “dysgeusia” and “taste disorder” ^dincludes cases with ALT/AST ≥3x ULN and bilirubin ≥2x ULN

Table 4: Adverse drug reactions reported in TRK fusion-positive paediatric cance

patients treated with VITRAKVI at recommended dose (n=135); all grades

System organ class

Frequency

Infants and

Children

Adolescents

Paediatric patients

toddlers

(n=43)^a

(n=67)^b

(n=25)^c

(n=135)

Blood and

Very

Anaemia

Anaemi

lymphatic

common

Neutrophil count

system

decreased

decrease

disorders

(Neutropenia)

Leukocyte count

decreased

(Leukopenia)

Platelet count

decreased

decrease

(Thrombocytopenia)

Common

Platelet count

decrease

(Thrombocytopenia)

Very

Dizzines

common

Nervous system
disorders

Common

Dizziness

Dizzines

Paraesthesia

Dizzines

Paraesthesia

Gait disturbance

Paraesthesia

Gait disturbance

Very

Nausea

common

Constipation

Vomiting

Vomitin

Diarrhoea

Diarrhoe

Gastrointestina		l
disorders

Common

Dysgeusi

Dysgeus

Very

Myalgia

common

Musculoskeleta	l
and connective
tissue disorder	s

Common

Muscular weakness

General
disorders and
administration
site conditions

Very

Fatigue

common

Investigations

Very

Alanine

common

aminotransferase

(ALT) increased

Aspartate

Aspartat

aminotransferase

(AST) increased

Weight increased

(Abnormal weight

gain)

Blood alkaline

phosphatase

increased

^aInfant/toddlers (28 days to 23 months): 5 grade 4 Neutrophil count decreased (Neutropenia) reactions and 2 Blood alkaline phosphatase increased reported. Grade 3 reactions included 11 cases of Neutrophil count decreased (Neutropenia), 4 cases of ALT increased, 3 cases each of Anaemia, Diarrhoea, and Weight increased (Abnormal weight gain), and 2 cases each of Blood alkaline phosphatase increased, and Vomiting and 1 case of AST increased.

^bChildren (2 to 11 years): 1 grade 4 Leukocytes count decreased reported. 9 reported grade 3 cases of Neutrophil

count decreased (Neutropenia), 4 cases of Weight increased (Abnormal weight gain), 2 cases each of ALT

increased, Anaemia, Diarrhoea, and Vomiting and 1 case each of AST increased, Gait disturbance, Paraesthesia

and Myalgia.

^cAdolescents (12 to <18 years): no grade 4 reactions were reported. Grade 3 reactions were reported in 1 case

each of ALT increased, AST increased, Fatigue, Gait disturbance, and Muscular weakness.

Description of selected adverse reactions

Neurologic reactions

In the overall safety database (n=361), the maximum grade neurologic adverse reaction

observed was grade 3 or 4 which was observed in 10 (3%) patients and included gait

disturbance (4 patients, 1%), dizziness (3 patients, <1%), and paraesthesia (3 patients, <1%

The overall incidence was 20% for dizziness, 7% for paraesthesia and 5% for gait

disturbance. Neurologic reactions leading to dose modification or interruptions included

dizziness (1%), gait disturbance (<1%), and paraesthesia (<1%). One patient permanently

discontinued the treatment due to grade 3 gait disturbance. In all cases except of one, patien

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).

Hepatotoxicity

Abnormalities of liver function tests including ALT, AST, ALP and bilirubin have been

observed in patients treated with VITRAKVI.

In the overall safety database (n=361), the maximum grade transaminase elevation observe

was grade 4 ALT increase in 7 patients (2%) and AST increase in 4 patients (1%). Grade 3

ALT and AST increases in 26 (7%) and 22 (6%) of patients, respectively. Majority of grad

e 3

elevations were transient appearing in the first three months of treatment and resolving to

grade 1 by months 3-4. Grade 2 ALT and AST increases were observed in 37 (10%) and 33

(9%) of patients, respectively, and grade 1 ALT and AST increases were observed in 173

(48%) and 177 (49%) of patients, respectively.

ALT and AST increases leading to dose modifications or interruptions occurred in 25 (7%)

patients and 21 (6%) patients, respectively (see section 4.4). Two patients permanently

discontinued the treatment with 1 patient due to grade 3 ALT and grade 3 AST increases.

Cases of hepatotoxicity with increases in ALT and/or AST of grade 2, 3 or 4 severity and

≥

increases in bilirubin 2x ULN have been reported. In some cases, the dose of VITRAKVI

was withheld and restarted at a reduced dose, while in other cases treatment was permanent

discontinued (see section 4.4).

Additional information on special populations

Paediatric patients

Of the 361 patients treated with VITRAKVI, 135 (37%) patients were from birth to

≥

< 18 years of age (n=13 from birth to < 3 months, n=4 3 months to < 6 months, n=17 ≥ ≥ ≥

6 months to < 12 months, n=9 12 months to < 2 years, n=30 2 years to < 6 years, n=3 ≥ ≥

6 years to < 12 years, n=25 12 years to < 18 years). The majority of adverse reactions

were grade 1 or 2 in severity and were resolved without VITRAKVI dose modification or

discontinuation. Adverse reactions of grade 3 or 4 in severity were generally observed mor

frequently in patients < 6 years of age. They were reported in 77% of patients from birt

≥

to < 3 months and in 47% of patients 3 months to < 6 years. Decreased neutrophil count h

been reported to have led to study drug discontinuation, dose modification and dose

interruption.

Elderly
Of the 361 patients in the overall safety population who received VITRAKVI, 69 (19%)
patients were 65 years or older and 22 (6%) patients were 75 years or older. The safety profile ≥
in elderly patients ( 65 years) is consistent with that seen in younger patients. The adverse
reaction dizziness (30% versus 28% in all adults), anaemia (36% versus 28% in all adults),
diarrhoea (25% versus 23% in all adults), muscular weakness (13% versus 11% in all adults),
platelet count decreased (12% versus 6% in all adults), gait disturbance (9% versus 5% in all
adults), and dysgeusia (9% versus 6% in all adults) 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
https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or
Apple App Store		.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic
agents, protein kinase inhibitors, ATC code:	L01EX12	.
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 constitutiv			e
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 effects

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 (C_max) 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

C_max, 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 5). Two studies are

still ongoing.

Patients with and without documented NTRK gene fusion were allowed to participate i

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

364 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 2024. 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 committe

(BIRC).

In addition, 60 patients with primary CNS tumours and measurable disease at baseline were

treated in Study 2 (“NAVIGATE”) and in Study 3 (“SCOUT”). Fifty-seven of the 60 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 on tissue samples for the molecular test methods:

next generation sequencing (NGS) used in 327 patients, polymerase chain reaction (PCR)

used in 14 patients, fluorescence in situ hybridization (FISH) used in 18 patients, and other

testing methods (Sequencing, Nanostring, Sanger sequencing, or Chromosome Microarray)

used in 5 patients.

Table 5: Clinical studies contributing to the efficacy analyses in solid and primary CNS

tumours

Study name, design and patient

Dose and

Tumour types included in

population

formulation

efficacy analysis

Study 1

Doses up to 200 mg

Thyroid (n=4)

Salivary gland (n=3) GIST (n=2)^a

Soft tissue sarcoma (n=2) NSCLC (n=1)^{b, c}

Unknown primary cancer (n=1)

NCT02122913

once or twice daily

(25 mg, 100 mg

•

Phase 1, open-label, dose escalation

capsules or 20 mg/mL

and expansion study; expansion

oral solution)

phase required tumours with an

NTRK gene fusion≥

•

Adult patients ( 18 years) with

advanced solid tumours with an

NTRK gene fusion

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

NSCLC (n=29)^b,

210

(25 mg, 100 mg

Soft tissue sarcoma (n=28)

capsules or 20 mg/mL

Thyroid (n=26)^b

oral solution)

Colon (n=25)

Salivary gland (n=24)

Primary CNS (n=19)

Melanoma (n=10)^b

Breast, non-secretory

(n=10)^b

Pancreas (n=7)

Breast, secretory (n=5

)

Cholangiocarcinoma (

n=4)

GIST (n=3)^a

Gastric (n=3)

Prostate (n=2)

Appendix, Atypical

carcinoid lung cancer

Bone sarcoma, Cervix

Hepatic^e, Duodenal,

External auditory canal^b,

Oesophageal, SCLC^b,

Rectal, Testes^b, Thymus,

Unknown primary cancer,

Urothelial, Uterus (n=

each)

Study 3 “SCOUT”

Doses up to

Infantile fibrosarcoma (n=49)

Soft tissue sarcoma (n=42)^bPrimary CNS (n=41) Congenital mesoblastic nephroma (n=2)

Bone sarcoma (n=2) Breast secretory, Cervix, Lipofibromatosis,

Melanoma, Thyroid (n=1 each)

141

NCT02637687

100 mg/m²twice daily

(25 mg, 100 mg

•

Phase 1/2 multinational, open-label,

capsules or 20 mg/mL

dose escalation and expansion study

;

oral solution)

Phase 2 expansion cohort required

advanced solid tumours with an

NTRK gene fusion, including locally

advanced infantile fibrosarcoma

•

Paediatric patients from birth to

21 years with advanced cancer or

with primary CNS tumours

Total number of patients (n)^*

364

* consist of 304 patients with IRC tumour response assessment and 60 patients with primary CNS tumours (including astrocytoma, ganglioglioma,

glioblastoma, glioma, glioneuronal tumours, neuronal and mixed neuronal-glial tumours, oligodendroglioma, and primitive neuro-ectodermal

tumour, not specified) with investigator tumour response assessment

^aGIST: gastrointestinal stromal tumour

^bbrain metastases were observed in some patients in the following tumour types: lung (NSCLC, SCLC), thyroid

melanoma, breast (non-secretory), external auditory canal, soft tissue sarcoma and testes

^cNSCLC: non-small cell lung cancer

^dSCLC: small cell lung cancer

^ehepatocellular carcinoma

Baseline characteristics for the pooled 304 patients with solid tumours with an NTRK gen

fusion were as follows: median age 44.5 years (range 0-90 years); 33% < 18 years of age, and

≥

67% 18 years; 55% white and 47% male; and ECOG PS 0-1 (88%), 2 (10%), or 3 (2%).

Ninety-one percent of patients had received prior treatment for their cancer, defined as

surgery, radiotherapy, or systemic therapy. Of these, 72% had received prior systemic therapy

with a median of 1 prior systemic treatment regimen. Twenty-eight percent of all patients had

received no prior systemic therapy. Of those 304 patients the most common tumour types

represented were soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung cancer (11%),

thyroid cancer (10%), salivary gland tumour (9%) and colon cancer (8%).

Baseline characteristics for the 60 patients with primary CNS tumours with an NTRK gene

fusion assessed by investigator were as follows: median age 9.1 years (range 0-79 years);

≥

43 patients < 18 years of age, and 17 patients 18 years, and 39 patients white and

28 patients male; and ECOG PS 0-1 (52 patients), or 2 (5 patients). Fifty-seven (95%) 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=304) and with post-hoc addition of primary

CNS tumours (n=60) resulting in the pooled population (n=364), are presented in Table 6 and

Table 7.

Table 6: Pooled efficacy results in solid tumours including and excluding primary CNS

tumours

Efficacy parameter

Analysis in solid

tumours excluding

tumours including

primary CNS tumours

(n=304)^a

(n=364)^{a, b}

Overall response rate (ORR) ^{% (n)}

65% (198)

60% (219)

[95% CI]

[59, 70]

[55, 65]

Complete response (CR)

22% (66)

20% (71)

Pathological complete response^c

7% (20)

5% (20)

Partial response (PR)

37% (112)

35% (128)

Time to first response (median, months)

1.84

[range]

[0.89, 22.90]

[0.89, 49.87]

Duration of response (median, months)

43.3

[range]

≥

[0.0+, 84.7+]

% with duration 12 months

≥

80%

79%

% with duration 24 months

≥

66%

65%

% with duration 36 months

≥

57%

54%

% with duration 48 months

48%

47%

+ denotes ongoing

^aIndependent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours

(304 patients).

^bEvaluated using either RANO or RECIST v1.1 criteria for primary CNS tumours (60 patients).
^cA pathological CR was a CR achieved by patients who were treated with larotrectinib and subsequently
	underwent surgical resection with no viable tumour cells and negative margins on post-surgical pathology
	evaluation. The pre-surgical best response for these patients was reclassified pathological CR after surgery
	following RECIST v.1.1	.

Table 7: Overall response rate and duration of response by tumour type*

Tumour type	Patients (n=364)	ORR^a		DOR
		%	95% CI	months ≥ ≥ ≥						Range (months)
					12		24		36
Soft tissue sarcoma	72	68%	56%, 79%	80%		72%		60%		0.03+, 84.7+
Primary CNS	60	35%	23%, 48%	66%		50%		50%		2.8, 70.9+
Infantile fibrosarcoma	49	94%	83%, 99%	83%		66%		60%		1.6+, 73.7+
Lung	32	69%	50%, 84%	75%		52%		45%		1.9+, 67.2+
Thyroid	31	65%	45%, 81%	85%		63%		47%		3.7, 83.9+
Salivary gland	27	85%	66%, 96%	91%		86%		76%		2.7, 81.1+
Colon	25	48%	28%, 69%	83%		62%		31%		3.9, 56.3+
Breast	16
Non-secretory^c	10	30%	7%, 65%	67%		0%		0%		7.4, 15.3+
Secretory^b	6	83%	36%, 100%	80%		80%		80%		11.1, 69.2+
Melanoma	11	45%	17%, 77%	50%		NR		NR		1.9+, 23.2+
Pancreas	7	14%	0%, 58%	0%		0%		0%		5.8, 5.8
Gastrointestinal stromal tumour	5	80%	28%, 99%	75%		38%		38%		9.5, 50.4+
Bone sarcoma	3	33%	1%, 91%	0%		0%		0%		9.5, 9.5
Congenital mesoblastic nephroma	2	100%	16%, 100%	100%		100%		50%		32.9, 44.5
Cervix	2	50%	1%, 99%	100%		NR		NR		18.7+, 18.7+
Unknown primary cancer	2	100%	16%, 100%	0		0		0		5.6, 7.4
External auditory canal	1	100%	3%, 100%	100%		100%		100%		45.1+, 45.1+
Lipofibromatosis	1	100%	3%, 100%	100%		NR		NR		17.7+, 17.7+

DOR: duration of response

NE: not evaluable

NR: not reached

* no data are available for the following tumour types: cholangiocarcinoma (n=4); gastric (n=3); prostate (n=2); appendix, hepatic, duodenal, oesophageal, rectal, testes, thymus, urothelial, uterus (n=1 each) + denotes ongoing response

^{a evaluated}per independent review committee analysis by RECIST v1.1 for all tumour types except ^{patients with a}
	^{primary CNS tumour who were evaluated}using either RANO or RECIST v1.1 criteria
^bwith 2 complete, 2 partial response
^cwith 1 complete, 2 partial response
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=222), the ORR was 51%. In the paediatric sub-population
(n=142), the ORR was 74%.
In 257 patients with wide molecular characterisation before larotrectinib treatment, the ORR
in 120 patients who had other genomic alterations in addition to NTRK gene fusion was 53%,
and in 137 patients without other genomic alterations ORR was 68%.

Pooled primary analysis set
The pooled primary analysis set consisted of 304 patients and did not include primary CNS
tumours. Median time on treatment before disease progression was 15.9 months (range: 0.1 to
99.4 months) based on July 2024 cut-off. Fifty-five percent of patients had received
VITRAKVI for 12 months or more, 37% had received VITRAKVI 24 months or more, and
28% had received VITRAKVI 36 months or more. Follow-up was ongoing at the time of the
analysis for 27% of patients.
At the time of analysis, the median duration of response is 43.3 months (range: 0.0+ to
84.7+), an estimated 80% [95% CI: 74, 86] of responses lasted 12 months or longer, 66%
[95% CI: 59, 74] of responses lasted 24 months or longer, and 57% [95% CI: 49, 64] of
responses lasted 36 months or longer. Eighty-three percent (83%) [95% CI: 79, 88] of patients
treated were alive one year after the start of therapy, 73% [95% CI: 68, 78] after two year			s
after the start of therapy, and 68% [95% CI: 63, 74] after three years with the median for
overall survival not yet being reached. Median progression free survival was 28.0 months at
the time of the analysis, with a progression free survival rate of 63% [95% CI: 57, 69] after
1 year, 54% [95% CI: 48, 60] after 2 years, and 44% [95% CI: 38, 50] after 3 years.
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, of the 60 patients with primary CNS tumours confirmed response
was observed in 21 patients (35%) with 5 of the 60 patients (8%) being complete responders
and 16 patients (27%) being partial responders. Further 24 patients (40%) had stable disease.
13 patients (22%) had progressive disease.		At the time of data cut-off, time on treatment
ranged from 1.2 to 67.3 months	and was ongoing in 20 out of 60 patients, with all 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 Medicines and Healthcare products Regulatory Agency (MHRA) 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 (C_max) of larotrectinib were
achieved at approximately 1 hour after dosing. Half-life (t_½) 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) C_maxand 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 C_max36% higher with the oral solution

formulation

Larotrectinib C_maxwas reduced by approximately 35% and there was no effect on AUC i

healthy subjects administered VITRAKVI after a high-fat and high-calorie meal compared t

the C_maxand 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 followin

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 radiolabelled 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 radiolabelled 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% wa

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 (C_max) 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 (C_maxand AUC) in paediatric
patients at the recommended dose of 100 mg/m²with a maximum of 100 mg BID was higher ≥
than in adults ( 18 years of age) given the dose of 100 mg BID (see Table 8).
Data defining exposure in small children (1 month to < 2 years of age) at the recommended
dose is limited (n=46).

Table 8: Exposure (C_maxand AUC^a) in patients grouped by age group at the recommended dose of 100 mg/m²with a maximum of 100 mg BID

Fold difference compared to patients

≥

Age group

n=438^b

18 years of age

Cmax

AUC^a

1 to < 3 months

3.2

4.5

3 to < 6 months

3.0

3.2

6 to < 12 months

2.1

1.7

1 to < 2 years

1.6

1.1

2 to < 6 years

1.6

1.1

6 to < 12 years

1.3

1.2

12 to < 18 years ≥

0.9

0.8

18 years

285

1.0

^aarea under the plasma concentration-time curve at steady-state

^bnumber of patients from 23 September 2024 data cut-off

≥

^cfold difference is the ratio of stated age group to 18 years group. A fold-difference of 1 equates to no

difference.

Simulations have shown that the dose of 50 mg/m²BID in patients aged less than 3 months

results in exposures comparable to patients aged 3 months to less than 2 years at a dose of

100 mg/m²BID, without the exposure metrics (C_max, AUC, C_trough) falling below the simulated

exposure in patients aged 3 months to less than 2 years. There is no clinical data with a dose

of 50 mg/m²BID in patients aged less than 3 months.

Elderly

There is no clinically meaningful difference in larotrectinib exposure in patients > 65 years

compared to those in younger patients (< 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 AUC_0-infwas

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. C_maxwas 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 C_maxand AUC_0-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 and race have no effect on the systemic exposure of larotrectinib based on population
pharmacokinetic analysis.

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.

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 (C_max) which are approximately 6-fold the human therapeutic exposures. Larotrectinib had no neurobehavioural findings in adult animals (rats, mice, cynomolgus monkeys) at exposure (C_max) at least 7-fold higher than the human exposure. Larotrectinib had no effect on respiratory function in rats; at exposures (C_max) 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, bleached dewaxed
Indigo carmine aluminium lake (E 132)
T	itanium dioxide (E 171)
Propylene glycol (E 1520)
Dimeticone 1000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 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) screw
cap with a polyethylene (PE) heat seal layer.
Each carton contains one bottle of 56 hard capsules.

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 plc
400 South Oak Way
Reading
RG2 6AD

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00010/0743

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

06/10/2026

10 DATE OF REVISION OF THE TEXT

06/10/2026

Prescription needed?	Yes, prescription-only medicine (POM)
Active substance	Larotrectinib
Strength	100 mg
Pharmaceutical form	Oral capsule
How is it taken	Oral
Pack sizes	56 capsule
Is it available?	Listed as available (NHS Dictionary of Medicines and Devices – not a record of current supplies)
Shelf life	4 years.
Drug group (ATC)	L Antineoplastic and immunomodulating agents L01 Antineoplastic agents L01E Protein kinase inhibitors, antineoplastic and immunomodulating agents L01EX Other protein kinase inhibitors L01EX12 larotrectinib
Additional monitoring	Yes ▼ – new safety information is collected quickly. Report any side effect to the Yellow Card scheme.
Marketing authorisation	PLGB 00010/0743 (first authorised 6 October 2026)
Codes	GTIN 4057598027595

VITRAKVI 100 mg hard capsules – Summary of Product Characteristics (SmPC) for healthcare professionals

Summary of Product Characteristics (SmPC) - Vitrakvi 100 mg hard capsules

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

3 PHARMACEUTICAL FORM

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

4.2 Posology and method of administration

Table 1: Recommended dose modifications for VITRAKVI for adverse reactions

Table 2: Recommended dose modifications and management for VITRAKVI for liver function test abnormalities

4.3 Contraindications

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of interaction

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

Effect of CYP3A and P-gp inducers on larotrectinib

Effect of larotrectinib on CYP3A substrates

Effect of larotrectinib on CYP2B6 substrates

Effect of larotrectinib on other transporter substrates

Effect of larotrectinib on substrates of PXR regulated enzymes

Hormonal contraceptives

4.6 Fertility, pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Investigations

4.9 Overdose

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Table 7: Overall response rate and duration of response by tumour type*

5.2 Pharmacokinetic properties

Table 8: Exposure (Cmax and AUCa) in patients grouped by age group at the recommended dose of 100 mg/m2 with a maximum of 100 mg BID

5.3 Preclinical safety data

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Special precautions for disposal

7 MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10 DATE OF REVISION OF THE TEXT

About this document

Facts about Vitrakvi 100 mg hard capsules

Table 8: Exposure (C_maxand AUC^a) in patients grouped by age group at the recommended dose of 100 mg/m²with a maximum of 100 mg BID