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3rd PartyAHFS DI® Essentials™
AHFS DI® Essentials™
AHFS DI® Essentials™ Module
Specific guidance to safely and effectively monitor and prescribe drug therapy.
AHFS DI® Essentials™ Sample Monograph
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<!DOCTYPE dif SYSTEM "dif.dtd">
<dif extraction-date='20220215'>
<ahfs>
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<ahfs-mono unit-id='a318064e' cpyrt-date='20181217' cx-date='20190930' mono-type='essential'>
<unit-num>
318064
</unit-num>
<intro-info>
<print-class>
<class-num class-code-ref='10:00' class-text='Antineoplastic Agents'/>
</print-class>
<print-title>
Larotrectinib (Systemic)
</print-title>
<full-title>
Larotrectinib Sulfate
</full-title>
<short-title>
Larotrectinib
</short-title>
<drug-name-info>
<gen-name>
Larotrectinib
</gen-name>
<cas-num>
1223405-08-0
</cas-num>
<chem-name>
(3S)-
<ital>
N
</ital>
-{5-[(2
<ital>
R
</ital>
)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
sulfate
</chem-name>
<mol-form>
C
<sub>
21
</sub>
H
<sub>
22
</sub>
F
<sub>
2
</sub>
N
<sub>
6
</sub>
O
<sub>
2
</sub>
•H
<sub>
2
</sub>
O
<sub>
4
</sub>
S
</mol-form>
<inv-num>
LOXO-101
</inv-num>
</drug-name-info>
<class-alt>
Tropomyosin Kinase Inhibitor
</class-alt>
<class-alt>
TRK Inhibitor
</class-alt>
<class-alt>
Kinase Inhibitors
</class-alt>
<class-alt>
Receptor Tyrosine Kinase Inhibitors
</class-alt>
<class-alt>
Tyrosine Kinase Inhibitors
</class-alt>
</intro-info>
<brand-info>
<tn>
Vitrakvi
<sup>
®
</sup>
</tn>
</brand-info>
<intro-desc sect-id='id10000001' entity-id='42229-5'>
<head class='a-head'>
Introduction
</head>
<para>
Antineoplastic agent; a potent and selective inhibitor of tropomyosin receptor kinase (Trk) A, TrkB, and TrkC.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
</para>
</intro-desc>
<uses sect-id='uses' entity-id='34067-9'>
<head class='a-head'>
Uses
</head>
<sect sect-id='uses-1' entity-id='42229-5'>
<head class='b-head'>
Solid Tumors with Neurotrophic Receptor Tyrosine Kinase (
<ital>
NTRK
</ital>
) Gene Fusion
</head>
<para>
Treatment of solid tumors harboring an
<ital>
NTRK
</ital>
fusion (without a known acquired mutation for resistance) in patients who have metastatic disease or may
experience severe morbidity following surgical resection and whose disease progressed following prior
therapy or those who are not candidates for other treatment options
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
(designated an orphan drug by FDA for these cancers).
<ref-callout href='r3180645'>
5
</ref-callout>
</para>
<para>
Accelerated approval based on overall response rate and duration of response.
<ref-callout href='r3180641'>
1
</ref-callout>
Continued approval may be contingent on verification and description of clinical benefit in confirmatory
studies.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Confirmation of the presence of
<ital>
NTRK
</ital>
fusion is necessary prior to initiation of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
In clinical studies,
<ital>
NTRK
</ital>
fusion status of tumor specimens was determined by fluorescence in situ hybridization (FISH), reverse
transcription-polymerase chain reaction (RT-PCR), or next-generation sequencing (NGS).
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
</para>
</sect>
</uses>
<dosage-admin sect-id='dosage-admin' entity-id='34068-7'>
<head class='a-head'>
Dosage and Administration
</head>
<sect sect-id='gen-dosage' entity-id='34068-7'>
<head class='b-head'>
General
</head>
<para>
<list list-type='bullet'>
<item>
<para>
Confirm presence of
<ital>
NTRK
</ital>
fusion prior to initiation of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='uses-1'>
(See Solid Tumors with Neurotrophic Receptor Tyrosine Kinase [
<ital>
NTRK
</ital>
] Gene Fusion under Uses.)
</xref-internal>
</para>
</item>
</list>
</para>
<sect sect-id='rest-dist' entity-id='42229-5'>
<head class='c-head'>
Restricted Distribution
</head>
<para>
<list list-type='bullet'>
<item>
<para>
Obtain larotrectinib only through designated specialty pharmacies and distributors.
<ref-callout href='r3180648'>
8
</ref-callout>
</para>
</item>
<item>
<para>
Contact the manufacturer at 844-634-8725 or consult the Vitrakvi
<sup>
®
</sup>
website (
<a href='https://www.vitrakvi.com'>
[Web]
</a>
) for specific ordering and availability information.
<ref-callout href='r3180648'>
8
</ref-callout>
</para>
</item>
</list>
</para>
</sect>
</sect>
<admin sect-id='admin' entity-id='60562-6'>
<head class='b-head'>
Administration
</head>
<sect sect-id='admin-oral' entity-id='60562-6'>
<head class='c-head'>
Oral Administration
</head>
<sect sect-id='admin-oral-1' entity-id='42229-5'>
<head class='d-head'>
Capsules
</head>
<para>
Administer orally twice daily without regard to meals.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Swallow capsules whole with a full glass of water; do not chew or crush.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='admin-oral-2' entity-id='42229-5'>
<head class='d-head'>
Oral Solution
</head>
<para>
Administer orally twice daily without regard to meals.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Use an oral dosing syringe; follow the patient instructions provided by the manufacturer.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
</admin>
<dosage sect-id='dosage'>
<head class='b-head'>
Dosage
</head>
<para>
Available as larotrectinib sulfate; dosage expressed in terms of larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Oral solution and capsules may be interchanged at equal doses.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<sect sect-id='dosage-ped' entity-id='34081-0'>
<head class='c-head'>
Pediatric Patients
</head>
<sect sect-id='dosage-ped-1' entity-id='34068-7'>
<head class='d-head'>
Solid Tumors with
<ital>
NTRK
</ital>
Fusion
</head>
<sect sect-id='id10000002' entity-id='34068-7'>
<head class='e-head'>
Oral
</head>
<para>
Body surface area (BSA) <1 m
<sup>
2
</sup>
: 100 mg/m
<sup>
2
</sup>
twice daily.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
BSA ≥1 m
<sup>
2
</sup>
: 100 mg twice daily.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Continue therapy until disease progression or unacceptable toxicity occurs.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
If concomitant use with potent CYP3A4 inhibitors or inducers cannot be avoided, adjust dosage of
larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di'>
(See Interactions.)
</xref-internal>
</para>
</sect>
</sect>
<sect sect-id='dosage-ped-2' entity-id='34068-7'>
<head class='d-head'>
Dosage Modification for Toxicity
</head>
<para>
If grade 3 or 4 adverse reaction occurs, interrupt therapy for up to 4 weeks.
<ref-callout href='r3180641'>
1
</ref-callout>
If resolution or improvement to grade 1 or baseline observed within 4 weeks, resume drug at reduced
dosage (or discontinue) as described in Table 1.
<ref-callout href='r3180641'>
1
</ref-callout>
Permanently discontinue therapy if grade 3 or 4 adverse reaction does not improve within 4 weeks of
treatment interruption.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<table>
<head>
Table 1. Dosage Modifications for Larotrectinib Toxicity in Pediatric Patients.
<ref-callout href='r3180641'>
1
</ref-callout>
</head>
<tgroup cols='3'>
<colspec colnum='1' colname='col1' colwidth='*'/>
<colspec colnum='2' colname='col2' colwidth='*'/>
<colspec colnum='3' colname='col3' colwidth='*'/>
<thead>
<row valign='middle' rowsep='1'>
<entry colname='col1'>
<para>
Toxicity Occurrence
</para>
</entry>
<entry colname='col2'>
<para>
Pediatric Patients with BSA ≥1 m
<sup>
2
</sup>
(Starting Dosage = 100 mg twice daily)
</para>
</entry>
<entry colname='col3'>
<para>
Pediatric Patients with BSA <1 m
<sup>
2
</sup>
(Starting Dosage = 100 mg/m
<sup>
2
</sup>
twice daily)
</para>
</entry>
</row>
</thead>
<tbody>
<row>
<entry colname='col1'>
<para>
First
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 75 mg twice daily
</para>
</entry>
<entry colname='col3'>
<para>
Restart at 75 mg/m
<sup>
2
</sup>
twice daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Second
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 50 mg twice daily
</para>
</entry>
<entry colname='col3'>
<para>
Restart at 50 mg/m
<sup>
2
</sup>
twice daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Third
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 100 mg once daily
</para>
</entry>
<entry colname='col3'>
<para>
Restart at 25 mg/m
<sup>
2
</sup>
twice daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Fourth
</para>
</entry>
<entry colname='col2'>
<para>
Permanently discontinue drug
</para>
</entry>
<entry colname='col3'>
<para>
Permanently discontinue drug
</para>
</entry>
</row>
</tbody>
</tgroup>
</table>
</sect>
</sect>
<sect sect-id='dosage-adult' entity-id='34068-7'>
<head class='c-head'>
Adults
</head>
<sect sect-id='dosage-adult-1' entity-id='34068-7'>
<head class='d-head'>
Solid Tumors with
<ital>
NTRK
</ital>
Fusion
</head>
<sect sect-id='id10000003' entity-id='34068-7'>
<head class='e-head'>
Oral
</head>
<para>
100 mg twice daily.
<ref-callout href='r3180641'>
1
</ref-callout>
Continue therapy until disease progression or unacceptable toxicity occurs.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
If concomitant use with potent CYP3A4 inhibitors or inducers cannot be avoided, adjust dosage of
larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di'>
(See Interactions.)
</xref-internal>
</para>
</sect>
</sect>
<sect sect-id='dosage-adult-2' entity-id='34068-7'>
<head class='d-head'>
Dosage Modification for Toxicity
</head>
<para>
If grade 3 or 4 adverse reaction occurs, interrupt therapy for up to 4 weeks.
<ref-callout href='r3180641'>
1
</ref-callout>
If resolution or improvement to grade 1 or baseline observed within 4 weeks, resume drug at reduced
dosage (or discontinue) as described in Table 2.
<ref-callout href='r3180641'>
1
</ref-callout>
Permanently discontinue therapy if grade 3 or 4 adverse reaction does not improve within 4 weeks of
treatment interruption.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<sect sect-id='id10000004' entity-id='34068-7'>
<head class='e-head'>
Oral
</head>
<table table-id='tbl2'>
<head>
Table 2. Dosage Modifications for Larotrectinib Toxicity in Adults.
<ref-callout href='r3180641'>
1
</ref-callout>
</head>
<tgroup cols='2'>
<colspec colnum='1' colname='col1' colwidth='*'/>
<colspec colname='col2' colnum='2' colwidth='*'/>
<thead>
<row rowsep='1'>
<entry colname='col1'>
<para>
Toxicity Occurrence
</para>
</entry>
<entry colname='col2'>
<para>
Dosage Modification after Recovery from Toxicity (Starting Dosage = 100 mg twice daily)
</para>
</entry>
</row>
</thead>
<tbody>
<row>
<entry colname='col1'>
<para>
First
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 75 mg twice daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Second
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 50 mg twice daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Third
</para>
</entry>
<entry colname='col2'>
<para>
Restart at 100 mg once daily
</para>
</entry>
</row>
<row>
<entry colname='col1'>
<para>
Fourth
</para>
</entry>
<entry colname='col2'>
<para>
Permanently discontinue drug
</para>
</entry>
</row>
</tbody>
</tgroup>
</table>
</sect>
</sect>
</sect>
</dosage>
<sect sect-id='dosage-spec-pop' entity-id='43684-0'>
<head class='b-head'>
Special Populations
</head>
<sect sect-id='dosage-hepatic-imp' entity-id='42229-5'>
<head class='c-head'>
Hepatic Impairment
</head>
<para>
Moderate or severe hepatic impairment (Child-Pugh class B or C): Reduce initial dosage by 50% (e.g.,
dosage of 100 mg twice daily reduced to 50 mg twice daily; dosage of 100 mg/m
<sup>
2
</sup>
twice daily reduced to 50 mg/m
<sup>
2
</sup>
twice daily).
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-5'>
(See Hepatic Impairment under Cautions.)
</xref-internal>
</para>
<para>
Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='dosage-renal-imp' entity-id='42229-5'>
<head class='c-head'>
Renal Impairment
</head>
<para>
No dosage adjustment required.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-6'>
(See Renal Impairment under Cautions.)
</xref-internal>
</para>
</sect>
<sect sect-id='dosage-ger' entity-id='42229-5'>
<head class='c-head'>
Geriatric Patients
</head>
<para>
No specific dosage recommendations.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-4'>
(See Geriatric Use under Cautions.)
</xref-internal>
</para>
</sect>
</sect>
</dosage-admin>
<cauts sect-id='cauts' entity-id='42232-9'>
<head class='a-head'>
Cautions
</head>
<sect sect-id='contra' entity-id='34070-3'>
<head class='b-head'>
Contraindications
</head>
<para>
<list list-type='bullet'>
<item>
<para>
Manufacturer states none known.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
</list>
</para>
</sect>
<sect sect-id='warn-precaut' entity-id='43685-7'>
<head class='b-head'>
Warnings/Precautions
</head>
<sect sect-id='warn-precaut-1' entity-id='42229-5'>
<head class='c-head'>
Neurologic Effects
</head>
<para>
Adverse neurologic effects (i.e., delirium, dysarthria, dizziness, gait disturbances, paresthesia, memory
impairment, tremor) and grade 4 encephalopathy reported.
<ref-callout href='r3180641'>
1
</ref-callout>
Generally occurs within 3 months of initiation of therapy, but may occur as early as 1 day or as late as
2.2 years following initiation of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
If neurologic events occur, therapy interruption followed by dosage reduction or permanent discontinuance
of drug may be necessary.
<ref-callout href='r3180641'>
1
</ref-callout>
(
<xref-internal href='dosage-ped-2'>
See Dosage Modification for Toxicity under Dosage and Administration: Pediatric Patients
</xref-internal>
and
<xref-internal href='dosage-adult-2'>
Dosage and Administration: Adults,
</xref-internal>
and also
<xref-internal href='advice'>
see Advice to Patients
</xref-internal>
.)
</para>
</sect>
<sect sect-id='warn-precaut-2' entity-id='42229-5'>
<head class='c-head'>
Hepatotoxicity
</head>
<para>
ALT or AST elevations reported.
<ref-callout href='r3180641'>
1
</ref-callout>
Median time to occurrence 2 months (range: 1 month to 2.6 years).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Monitor liver function tests, including ALT and AST concentrations, every 2 weeks for the first month of
therapy and then monthly thereafter or more frequently as clinically indicated.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
If hepatotoxicity occurs, therapy interruption followed by dosage reduction or permanent discontinuance of
drug may be necessary.
<ref-callout href='r3180641'>
1
</ref-callout>
(
<xref-internal href='dosage-ped-2'>
See Dosage Modification for Toxicity under Dosage and Administration: Pediatric Patients
</xref-internal>
and
<xref-internal href='dosage-adult-2'>
Dosage and Administration: Adults
</xref-internal>
.)
</para>
</sect>
<sect sect-id='warn-precaut-3' entity-id='42229-5'>
<head class='c-head'>
Fetal/Neonatal Morbidity and Mortality
</head>
<para>
Based on its mechanism of action and animal findings, larotrectinib may cause fetal harm.
<ref-callout href='r3180641'>
1
</ref-callout>
Embryofetal toxicity and teratogenicity demonstrated in animals.
<ref-callout href='r3180641'>
1
</ref-callout>
Crosses placenta in animals.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Possible association between decreased Trk-mediated signaling and obesity, developmental delays, cognitive
impairment, insensitivity to pain, and anhidrosis based on data from individuals with congenital mutations
in the Trk pathway.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Perform pregnancy test prior to initiating larotrectinib therapy in women of reproductive potential.
<ref-callout href='r3180641'>
1
</ref-callout>
Avoid pregnancy during therapy and for ≥1 week after drug discontinuance.
<ref-callout href='r3180641'>
1
</ref-callout>
Advise women of reproductive potential and men who are partners of such women to use effective
contraception while receiving the drug and for ≥1 week after discontinuance of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-precaut-4' entity-id='42229-5'>
<head class='c-head'>
Impairment of Fertility
</head>
<para>
Results of animal studies suggest larotrectinib may impair female fertility.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-spec-pop' entity-id='43684-0'>
<head class='c-head'>
Specific Populations
</head>
<sect sect-id='warn-spec-pop-1' entity-id='42229-5'>
<head class='d-head'>
Pregnancy
</head>
<para>
May cause fetal harm.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-precaut-3'>
(See Fetal/Neonatal Morbidity and Mortality under Cautions.)
</xref-internal>
</para>
</sect>
<sect sect-id='warn-spec-pop-2'>
<head class='d-head'>
Lactation
</head>
<para>
Not known whether larotrectinib distributes into milk, affects milk production, or affects nursing
infants.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Women should not breast-feed during therapy and for 1 week following drug discontinuance.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-spec-pop-3'>
<head class='d-head'>
Pediatric Use
</head>
<para>
Safety and efficacy not established in pediatric patients <28 days of age.
<ref-callout href='r3180641'>
1
</ref-callout>
Efficacy of larotrectinib for solid tumors harboring
<ital>
NTRK
</ital>
fusion in pediatric patients is supported by 3 noncomparative studies that included 12 patients
≥28 days of age.
<ref-callout href='r3180641'>
1
</ref-callout>
Based on limited safety data in 44 pediatric patients receiving the drug, grade 3 or 4 weight gain or
neutropenia occurred more frequently in pediatric patients compared with adults.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
No differences in pharmacokinetics observed between pediatric patients and adults.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-spec-pop-4'>
<head class='d-head'>
Geriatric Use
</head>
<para>
In clinical trials evaluating larotrectinib, 22% of patients were ≥65 years of age and 5% were
≥75 years of age.
<ref-callout href='r3180641'>
1
</ref-callout>
Insufficient experience in patients ≥65 years of age to determine whether they respond
differently than younger patients.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-spec-pop-5'>
<head class='d-head'>
Hepatic Impairment
</head>
<para>
Systemic exposure increased in individuals with moderate or severe hepatic impairment (Child-Pugh class
B or C); dosage adjustment is necessary.
<ref-callout href='r3180641'>
1
</ref-callout>
(
<xref-internal href='absorp-6'>
See Special Populations under Pharmacokinetics
</xref-internal>
and also
<xref-internal href='dosage-hepatic-imp'>
see Hepatic Impairment under Dosage and Administration
</xref-internal>
.)
</para>
<para>
Systemic exposure not substantially altered in individuals with mild hepatic impairment (Child-Pugh
class A).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-spec-pop-6'>
<head class='d-head'>
Renal Impairment
</head>
<para>
Systemic exposure not substantially altered in individuals with end-stage renal disease requiring
dialysis.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='absorp-6'>
(See Special Populations under Pharmacokinetics.)
</xref-internal>
</para>
</sect>
</sect>
</sect>
<sect sect-id='com-adv-eff' entity-id='34084-4'>
<head class='b-head'>
Common Adverse Effects
</head>
<para>
Fatigue,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
nausea,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
dizziness,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
cough,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
vomiting,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
constipation,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
diarrhea,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
dyspnea,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
pyrexia,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
peripheral edema,
<ref-callout href='r3180641'>
1
</ref-callout>
weight gain,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
myalgia/arthralgia,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
headache,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
abdominal pain,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
decreased appetite,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
muscular weakness,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
back or extremity pain,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
hypertension,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
fall,
<ref-callout href='r3180641'>
1
</ref-callout>
nasal congestion,
<ref-callout href='r3180641'>
1
</ref-callout>
elevated ALT and/or AST concentrations,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
anemia,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
hypoalbuminemia,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
elevated alkaline phosphatase concentrations,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
neutropenia.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
</para>
</sect>
</cauts>
<di sect-id='di' entity-id='34073-7'>
<head class='a-head'>
Interactions
</head>
<para>
Metabolized principally by CYP3A4.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Inhibits CYP3A4 in vitro.
<ref-callout href='r3180647'>
7
</ref-callout>
Does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant
concentrations in vitro.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not organic anion
transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP)
1B1, and OATP1B3 in vitro.
<ref-callout href='r3180641'>
1
</ref-callout>
Does not inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, bile salt export pump (BSEP),
multidrug and toxin extrusion (MATE) transporter 1, and MATE2K at clinically relevant concentrations in vitro.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<sect sect-id='di-1' entity-id='42229-5'>
<head class='b-head'>
Drugs and Foods Affecting Hepatic Microsomal Enzymes
</head>
<para>
Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to
larotrectinib) and increased risk of toxicity.
<ref-callout href='r3180641'>
1
</ref-callout>
Avoid concomitant use.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use cannot be avoided, reduce larotrectinib dosage by 50% (e.g., dosage of 100 mg twice
daily reduced to 50 mg twice daily; dosage of 100 mg/m
<sup>
2
</sup>
twice daily reduced to 50 mg/m
<sup>
2
</sup>
twice daily).
<ref-callout href='r3180641'>
1
</ref-callout>
When concomitant use of the potent CYP3A4 inhibitor is discontinued, return larotrectinib dosage (after
3–5 elimination half-lives of the CYP3A4 inhibitor) to dosage used prior to initiation of the potent
CYP3A4 inhibitor.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di-specific'>
(See Specific Drugs and Foods under Interactions.)
</xref-internal>
</para>
<para>
Potent inducers of CYP3A4: Potential pharmacokinetic interaction (decreased systemic exposure to
larotrectinib) and reduced larotrectinib efficacy.
<ref-callout href='r3180641'>
1
</ref-callout>
Avoid concomitant use.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use cannot be avoided, double dosage of larotrectinib (e.g., dosage of 100 mg twice daily
increased to 200 mg twice daily; dosage of 100 mg/m
<sup>
2
</sup>
twice daily increased to 200 mg/m
<sup>
2
</sup>
twice daily).
<ref-callout href='r3180641'>
1
</ref-callout>
When concomitant use of the potent CYP3A4 inducer is discontinued, return larotrectinib dosage (after
3–5 elimination half-lives of the CYP3A4 inducer) to dosage used prior to initiation of the potent
CYP3A4 inducer.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di-specific'>
(See Specific Drugs and Foods under Interactions.)
</xref-internal>
</para>
</sect>
<sect sect-id='di-2' entity-id='42229-5'>
<head class='b-head'>
Drugs Metabolized by Hepatic Microsomal Enzymes
</head>
<para>
Substrates of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to CYP3A4
substrate) and increased adverse effects.
<ref-callout href='r3180641'>
1
</ref-callout>
Avoid concomitant use with sensitive CYP3A4 substrates.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use cannot be avoided, monitor for CYP3A4 substrate-related toxicity.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di-specific'>
(See Specific Drugs and Foods under Interactions.)
</xref-internal>
</para>
</sect>
<sect sect-id='di-specific' entity-id='42229-5'>
<head class='b-head'>
Specific Drugs and Foods
</head>
<table frame='topbot'>
<tgroup cols='3' colsep='0' rowsep='0'>
<colspec colnum='1' colname='col1' colwidth='*'/>
<colspec colnum='2' colname='col2' colwidth='*'/>
<colspec colnum='3' colname='col3' colwidth='*'/>
<thead>
<row valign='bottom' rowsep='1'>
<entry colname='col1'>
<para>
Drug or Food
</para>
</entry>
<entry colname='col2'>
<para>
Interaction
</para>
</entry>
<entry colname='col3'>
<para>
Comments
</para>
</entry>
</row>
</thead>
<tbody>
<row valign='top'>
<entry colname='col1'>
<para>
Grapefruit or grapefruit juice
</para>
</entry>
<entry colname='col2'>
<para>
Potential increased systemic exposure to larotrectinib and increased risk of toxicity
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
<entry colname='col3'>
<para>
Avoid concomitant use
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'>
<para>
Itraconazole
</para>
</entry>
<entry colname='col2'>
<para>
Increased peak plasma concentrations and AUC of larotrectinib by 2.8- and 4.3-fold, respectively
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
</entry>
<entry colname='col3'>
<para>
Avoid concomitant use;
<ref-callout href='r3180641'>
1
</ref-callout>
if concomitant use cannot be avoided, reduce larotrectinib dosage by 50%
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
When itraconazole is discontinued, return larotrectinib dosage (after 3–5 elimination
half-lives of itraconazole) to prior dosage
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'>
<para>
Midazolam
</para>
</entry>
<entry colname='col2'>
<para>
Potential increased peak plasma concentrations and AUC of midazolam (a CYP3A4 substrate) and
increased toxicity
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
<entry colname='col3'>
<para>
Avoid concomitant use;
<ref-callout href='r3180641'>
1
</ref-callout>
if concomitant use cannot be avoided, monitor for midazolam toxicity
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'>
<para>
Rifampin
</para>
</entry>
<entry colname='col2'>
<para>
Multiple-dose rifampin (potent CYP3A inducer) decreased peak plasma concentration and AUC of
larotrectinib by 71 and 81%, respectively
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Single-dose rifampin (P-gp inhibitor) increased peak plasma concentration and AUC of larotrectinib
by 1.8- and 1.7-fold
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
</entry>
<entry colname='col3'>
<para>
Avoid concomitant use;
<ref-callout href='r3180641'>
1
</ref-callout>
if concomitant use cannot be avoided, double dosage of larotrectinib
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
When rifampin is discontinued, return larotrectinib dosage (after 3–5 elimination half-lives
of rifampin) to prior dosage
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'>
<para>
St. John’s wort
<ital>
(Hypericum perforatum)
</ital>
</para>
</entry>
<entry colname='col2'>
<para>
Potential decreased peak plasma concentrations and AUC of larotrectinib and reduced efficacy
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
<entry colname='col3'>
<para>
Avoid concomitant use; if concomitant use cannot be avoided, double dosage of larotrectinib
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
When St. John's wort is discontinued, return larotrectinib dosage (after 3–5 elimination
half-lives of St. John's wort) to prior dosage
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</entry>
</row>
</tbody>
</tgroup>
</table>
</sect>
</di>
<pkin sect-id='pkin' entity-id='43682-4'>
<head class='a-head'>
Pharmacokinetics
</head>
<sect sect-id='absorp' entity-id='42229-5'>
<head class='b-head'>
Absorption
</head>
<sect sect-id='absorp-1' entity-id='42229-5'>
<head class='c-head'>
Bioavailability
</head>
<para>
Systemic exposure increases in a dose-proportional manner over a dose range of 100–400 mg and in a
slightly more than dose-proportional manner over a dose range of 600–900 mg.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Peak plasma concentrations achieved in approximately 1 hour following oral administration of larotrectinib
capsules.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Steady-state concentrations are achieved within 3 days.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Mean absolute oral bioavailability is 34% following oral administration of larotrectinib capsules.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
AUC of oral solution similar to that observed with larotrectinib capsules; however, peak plasma
concentrations are 36% higher following administration of the oral solution.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='absorp-4' entity-id='42229-5'>
<head class='c-head'>
Food
</head>
<para>
Administration with a high-fat meal decreased peak plasma concentrations by 35% and delayed time to peak
plasma concentrations by 2 hours, but did not substantially affect the extent of absorption.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
</sect>
<sect sect-id='absorp-6' entity-id='42229-5'>
<head class='c-head'>
Special Populations
</head>
<para>
Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased by 1.3- or 2-fold,
respectively; peak plasma concentrations similar to those in individuals with normal hepatic function.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Severe hepatic impairment (Child-Pugh class C): AUC and peak plasma concentrations increased by 3.2- and
1.5-fold, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
End-stage renal disease requiring dialysis: AUC and peak plasma concentrations increased by 1.5- and
1.3-fold, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Moderate or severe renal impairment (Cl
<sub>
cr
</sub>
≤60 mL/minute): Pharmacokinetics not studied.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Age (28 days to 82 years), sex, or body weight (3.8–179 kg) does not affect pharmacokinetics of
larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
<sect sect-id='dist' entity-id='42229-5'>
<head class='b-head'>
Distribution
</head>
<sect sect-id='dist-1' entity-id='42229-5'>
<head class='c-head'>
Extent
</head>
<para>
Crosses placenta in animals.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Not known whether larotrectinib is distributed into milk.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='dist-2' entity-id='42229-5'>
<head class='c-head'>
Plasma Protein Binding
</head>
<para>
70% (independent of larotrectinib concentration).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
<sect sect-id='elim' entity-id='42229-5'>
<head class='b-head'>
Elimination
</head>
<sect sect-id='elim-1' entity-id='42229-5'>
<head class='c-head'>
Metabolism
</head>
<para>
Principally metabolized by CYP3A4.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='elim-2' entity-id='42229-5'>
<head class='c-head'>
Elimination Route
</head>
<para>
Eliminated in feces (58% [5% as unchanged drug]) and urine (39% [20% as unchanged drug]).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='elim-3' entity-id='42229-5'>
<head class='c-head'>
Half-life
</head>
<para>
2.9 hours.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
</pkin>
<stab sect-id='stab' entity-id='42229-5'>
<head class='a-head'>
Stability
</head>
<sect sect-id='storage' entity-id='44425-7'>
<head class='b-head'>
Storage
</head>
<sect sect-id='storage-1' entity-id='42229-5'>
<head class='c-head'>
Oral
</head>
<sect sect-id='storage-1a' entity-id='42229-5'>
<head class='d-head'>
Capsules
</head>
<para>
20–25°C (may be exposed to 15–30°C).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='storage-1b' entity-id='42229-5'>
<head class='d-head'>
Solution
</head>
<para>
2–8°C.
<ref-callout href='r3180641'>
1
</ref-callout>
Do not freeze.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Opened bottles: 2–8°C.
<ref-callout href='r3180641'>
1
</ref-callout>
Discard after 90 days of first opening.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
</sect>
</stab>
<moa sect-id='actions' entity-id='43679-0'>
<head class='a-head'>
Actions
</head>
<para>
<list list-type='bullet'>
<item>
<para>
Potent and selective inhibitor of TrkA, TrkB, and TrkC.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
</para>
</item>
<item>
<para>
TrkA, TrkB, and TrkC are encoded by
<ital>
NTRK1
</ital>
,
<ital>
NTRK2
</ital>
, and
<ital>
NTRK3
</ital>
and are involved in the initiation of various cascades of intracellular signaling events (i.e.,
Ras/MAPK/ERK, PI3K/Akt, and PLCγ1/Pkc signal transduction pathways) that lead to cell
proliferation, differentiation, apoptosis, and regulation of processes critical to neuron survival in
the central and peripheral nervous systems.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
<ref-callout href='r3180646'>
6
</ref-callout>
<ref-callout href='r3180649'>
9
</ref-callout>
<ref-callout href='r31806410'>
10
</ref-callout>
<ref-callout href='r31806411'>
11
</ref-callout>
</para>
</item>
<item>
<para>
Chromosomal rearrangements of
<ital>
NTRK1
</ital>
,
<ital>
NTRK2
</ital>
, and
<ital>
NTRK3
</ital>
genes result in formation of a constitutively active chimeric Trk oncogenic fusion protein and
dysregulation of Trk signaling and subsequent tumorigenesis.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
<ref-callout href='r3180646'>
6
</ref-callout>
<ref-callout href='r3180649'>
9
</ref-callout>
<ref-callout href='r31806410'>
10
</ref-callout>
</para>
</item>
<item>
<para>
Inhibits wild-type TrkA, TrkB, and TrkC.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
</item>
<item>
<para>
Induces antitumor activity in cell lines with Trk expression from constitutive activation, deletion of a
protein regulatory domain, or overexpression of wild-type Trk.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
</item>
<item>
<para>
Inhibits tyrosine kinase nonreceptor 2 (TNK2).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Clinical resistance attributed to secondary point mutations of the NTRK kinase domain in 90% of cases.
<ref-callout href='r3180647'>
7
</ref-callout>
Demonstrates minimal activity in cell lines with point mutations in the TrkA kinase domain, including
the acquired resistance mutation G595R.
<ref-callout href='r3180641'>
1
</ref-callout>
Acquired resistance also identified in cells lines with G623R, G696A, and F617L point mutations in the
TrkC kinase domain.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
</list>
</para>
</moa>
<advice-patient sect-id='advice' entity-id='34076-0'>
<head class='a-head'>
Advice to Patients
</head>
<para>
<list list-type='bullet'>
<item>
<para>
Importance of instructing patients to read the manufacturer's patient information.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Importance of advising patients to take larotrectinib exactly as prescribed and to not alter the dosage
or discontinue therapy unless advised to do so by their clinician.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of advising patients to swallow larotrectinib capsules whole and to not chew or crush the
capsules.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Importance of advising patients to take a missed dose as soon as it is remembered unless the dose was
missed by more than 6 hours, in which case they should not take the missed dose.
<ref-callout href='r3180641'>
1
</ref-callout>
If a dose is vomited, importance of administering the next dose at the regularly scheduled time.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Risk of adverse neurologic effects.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of informing clinician if new or worsening manifestations of neurologic events (e.g.,
confusion; speech difficulties; dizziness; coordination difficulties; tingling, numbness, or burning
sensation in hands and feet) occur.
<ref-callout href='r3180641'>
1
</ref-callout>
Necessity of advising patients to avoid driving or operating hazardous machinery if they experience
neurologic events.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Risk of hepatotoxicity; importance of regular liver function test monitoring.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of immediately informing clinician if signs or symptoms of hepatotoxicity (e.g., loss of
appetite, nausea, vomiting, abdominal pain [especially right upper quadrant pain]) occur.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Risk of fetal harm.
<ref-callout href='r3180641'>
1
</ref-callout>
Necessity of advising women of reproductive potential to avoid pregnancy and to use effective
contraceptive methods while receiving larotrectinib and for ≥1 week following discontinuance of
therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of advising men who are partners of such women that they should use effective methods of
contraception while receiving the drug and for ≥1 week after the drug is discontinued.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of women informing their clinicians if they become pregnant during therapy or think they may
be pregnant.
<ref-callout href='r3180641'>
1
</ref-callout>
Advise men and women of reproductive potential of potential risk to the fetus.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Importance of advising women to avoid breast-feeding while receiving larotrectinib and for 1 week after
discontinuance of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Risk of impaired female fertility.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Importance of informing clinicians of existing or contemplated concomitant therapy, including
prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort [
<ital>
Hypericum perforatum
</ital>
], grapefruit, grapefruit juice), as well as any concomitant illnesses (e.g., hepatic impairment).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</item>
<item>
<para>
Importance of informing patients of other important precautionary information.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='cauts'>
(See Cautions.)
</xref-internal>
</para>
</item>
</list>
</para>
</advice-patient>
<preps sect-id='preps' entity-id='43678-2'>
<head class='a-head'>
Preparations
</head>
<para>
<ital>
Excipients in commercially available drug preparations may have clinically important effects in some
individuals; consult specific product labeling for details.
</ital>
</para>
<para>
<ital>
Please refer to the
<a href='https://www.ashp.org/Drug-Shortages'>
ASHP Drug Shortages Resource Center
</a>
for information on shortages of one or more of these preparations.
</ital>
</para>
<para>
Distribution of larotrectinib is restricted.
<ref-callout href='r3180648'>
8
</ref-callout>
<xref-internal href='rest-dist'>
(See Restricted Distribution under Dosage and Administration.)
</xref-internal>
</para>
<table frame='topbot'>
<head>
Larotrectinib Sulfate
</head>
<tgroup cols='5' colsep='0' rowsep='0' align='left'>
<colspec colnum='1' colname='col1' colwidth='*'/>
<colspec colnum='2' colname='col2' colwidth='*'/>
<colspec colnum='3' colname='col3' colwidth='*'/>
<colspec colnum='4' colname='col4' colwidth='*'/>
<colspec colnum='5' colname='col5' colwidth='*'/>
<thead>
<row rowsep='1' valign='bottom'>
<entry colname='col1'>
<para>
Routes
</para>
</entry>
<entry colname='col2'>
<para>
Dosage Forms
</para>
</entry>
<entry colname='col3'>
<para>
Strengths
</para>
</entry>
<entry colname='col4'>
<para>
Brand Names
</para>
</entry>
<entry colname='col5'>
<para>
Manufacturer
</para>
</entry>
</row>
</thead>
<tbody>
<row valign='top'>
<entry colname='col1'>
<para>
Oral
</para>
</entry>
<entry colname='col2'>
<para>
Capsules
</para>
</entry>
<entry colname='col3'>
<para>
25 mg (of larotrectinib)
</para>
</entry>
<entry colname='col4'>
<para>
<tn>
Vitrakvi
<sup>
®
</sup>
</tn>
</para>
</entry>
<entry colname='col5'>
<para>
<co-name>
Loxo Oncology
</co-name>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'/>
<entry colname='col2'/>
<entry colname='col3'>
<para>
100 mg (of larotrectinib)
</para>
</entry>
<entry colname='col4'>
<para>
<tn>
Vitrakvi
<sup>
®
</sup>
</tn>
</para>
</entry>
<entry colname='col5'>
<para>
<co-name>
Loxo Oncology
</co-name>
</para>
</entry>
</row>
<row valign='top'>
<entry colname='col1'/>
<entry colname='col2'>
<para>
Solution
</para>
</entry>
<entry colname='col3'>
<para>
20 mg (of larotrectinib) per mL
</para>
</entry>
<entry colname='col4'>
<para>
<tn>
Vitrakvi
<sup>
®
</sup>
</tn>
</para>
</entry>
<entry colname='col5'>
<para>
<co-name>
Loxo Oncology
</co-name>
</para>
</entry>
</row>
</tbody>
</tgroup>
</table>
</preps>
<copyright>
<para>
AHFS
<sup>
®
</sup>
DI Essentials™. © Copyright, 2004-2022, Selected Revisions September 30, 2019. American Society of
Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
</para>
</copyright>
<refs sect-id='refs' entity-id='34093-5'>
<head class='a-head'>
References
</head>
<cited-refs complete-list='complete'>
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Loxo Oncology. Vitrakvi
<sup>
®
</sup>
(larotrectinib) capsules and oral solution prescribing information. Stamford, CT: 2018 Dec.
</ref>
<ref ref-num='2' ref-id='r3180642'>
Drilon A, Laetsch TW, Kummar S et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and
Children.
<ital>
N Engl J Med
</ital>
. 2018; 378:731-9.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/29466156?dopt=AbstractPlus'>
[PubMed 29466156]
</a>
</ref>
<ref ref-num='3' ref-id='r3180643'>
Hong DS, Bauer TM, Lee JJ et al. Larotrectinib in adult patients with solid tumours: a multi-centre,
open-label, phase I dose-escalation study.
<ital>
Ann Oncol
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. 2019; 30:325-31.
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[PubMed 30624546]
</a>
</ref>
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Laetsch TW, DuBois SG, Mascarenhas L et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene
fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
<ital>
Lancet Oncol
</ital>
. 2018; 19:705-14.
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[PubMed 29606586]
</a>
</ref>
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Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Rockville, MD.
From FDA web site.
<a target='_base' href='http://www.accessdata.fda.gov/scripts/updlisting/oopd/index.cfm'>
[Web]
</a>
</ref>
<ref ref-num='6' ref-id='r3180646'>
Lange AM, Lo H. Inhibiting TRK Proteins in Clinical Cancer Therapy.
<ital>
Cancers
</ital>
. 2018; 10:1-15.
</ref>
<ref ref-num='7' ref-id='r3180647'>
Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210861Orig1s000
and 211710Orig1s000: Multi-discipline review. From FDA website.
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href='https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf'>
[Web]
</a>
</ref>
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Bayer. TRAKAssist. From Bayer for US Healthcare Professionals website. Accessed 2019 Jun 19.
<a target='_base' href='https://www.hcp.vitrakvi-us.com/access/'>
[Web]
</a>
</ref>
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Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy.
<ital>
Cancer Discov
</ital>
. 2015; 5:25-34.
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[PubMed 25527197]
</a>
</ref>
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Ricciuti B, Genova C, Crinò L et al. Antitumor activity of larotrectinib in tumors harboring
<ital>
NTRK
</ital>
gene fusions: a short review on the current evidence.
<ital>
Onco Targets Ther
</ital>
. 2019; 12:3171-3179.
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[PubMed 31118670]
</a>
</ref>
<ref ref-num='11' ref-id='r31806411'>
Amatu A, Sartore-Bianchi A, Siena S.
<ital>
NTRK
</ital>
gene fusions as novel targets of cancer therapy across multiple tumour types.
<ital>
ESMO Open
</ital>
. 2016; 1:e000023.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/27843590?dopt=AbstractPlus'>
[PubMed 27843590]
</a>
</ref>
<ref ref-num='12' ref-id='r31806412'>
Hsiao SJ, Zehir A, Sireci AN et al. Detection of Tumor NTRK Gene Fusions to Identify Patients Who May
Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy.
<ital>
J Mol Diagn
</ital>
. 2019; 21:553-571.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/31075511?dopt=AbstractPlus'>
[PubMed 31075511]
</a>
</ref>
</cited-refs>
</refs>
</ahfs-mono>
</ahfs>
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