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<ahfs-mono unit-id='a318064' cpyrt-date='20181217' cx-date='20190930' mono-type='overview'>
<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 Sulfate
</print-title>
<full-title>
Larotrectinib Sulfate
</full-title>
<short-title>
Larotrectinib
</short-title>
<drug-name-info>
<gen-name>
Larotrectinib Sulfate
</gen-name>
<cas-num>
1223405-08-0
</cas-num>
<chem-name>
(3
<ital>
S
</ital>
)-
<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>
<intro-desc sect-id='id10000001' entity-id='42229-5'>
<head class='a-head'>
Introduction
</head>
<para>
Larotrectinib, a potent and selective inhibitor of tropomyosin receptor kinase (Trk) A, TrkB, and TrkC, is an
antineoplastic agent.
<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 Gene Fusion
</head>
<para>
Larotrectinib sulfate is used for the treatment of solid tumors harboring a neurotrophic receptor tyrosine
kinase (
<ital>
NTRK
</ital>
) gene 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>
The presence of
<ital>
NTRK
</ital>
fusion should be confirmed prior to initiation of therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
An FDA-approved diagnostic test for detection of
<ital>
NTRK
</ital>
fusion is not currently available; however, in clinical studies, presence of
<ital>
NTRK
</ital>
fusion 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>
Larotrectinib has been designated an orphan drug by FDA for the treatment of these cancers.
<ref-callout href='r3180645'>
5
</ref-callout>
The accelerated approval of larotrectinib for this indication is based on overall response rate and
duration of response.
<ref-callout href='r3180641'>
1
</ref-callout>
Continued approval for this indication may be contingent on verification and description of clinical
benefit of larotrectinib in confirmatory studies.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
The incidence of solid tumors harboring activating
<ital>
NTRK
</ital>
fusions has not been fully characterized; however, 1500–5000 cases are estimated per year in the US.
<ref-callout href='r3180647'>
7
</ref-callout>
Although a relatively small subset (less than 1%) of patients with common solid tumors (e.g., lung, colon,
or prostate cancer) harbor
<ital>
NTRK
</ital>
fusions, such fusions have been frequently reported in certain rare cancers (i.e., 91–100% of mammary
analogue secretory carcinomas, secretory breast carcinomas, or infantile fibrosarcomas; 61% of congenital
mesoblastic nephromas; 12–15% of papillary thyroid cancers).
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
<ref-callout href='r31806412'>
12
</ref-callout>
</para>
<para>
The current indication for larotrectinib in the treatment of solid tumors harboring
<ital>
NTRK
</ital>
fusion is based principally on data from 3 open-label noncomparative studies (LOXO-TRK-14001, SCOUT, and
NAVIGATE) evaluating larotrectinib in patients with unresectable or metastatic solid tumors harboring
<ital>
NTRK
</ital>
fusion.
<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>
The primary efficacy population consisted of the initial 55 adult and pediatric patients enrolled in the
LOXO-TRK-14001, SCOUT, and NAVIGATE studies with solid tumors harboring an
<ital>
NTRK
</ital>
fusion.
<ref-callout href='r3180641'>
1
</ref-callout>
Patients were eligible for these studies if they experienced disease progression following prior systemic
therapy, if available, or if severe morbidity following surgical resection for locally advanced disease was
expected.
<ref-callout href='r3180641'>
1
</ref-callout>
In these studies, adult patients received larotrectinib 100 mg orally twice daily and pediatric patients
(18 years of age or younger) received larotrectinib 100 mg/m
<sup>
2
</sup>
(maximum dose of 100 mg) orally twice daily.
<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>
Therapy was continued until the occurrence of unacceptable toxicity or disease progression.
<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>
The primary efficacy end points were overall response rate and duration of response (as evaluated by a
blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST).
<ref-callout href='r3180641'>
1
</ref-callout>
In the primary efficacy population, the median age of patients was 45 years (range: 4 months to 76 years);
78% of patients were 18 years of age or older, 22% were younger than 18 years of age, 93% had an Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1, 67% were white, 7% were Hispanic or Latino,
4% were Asian, and 4% were black.
<ref-callout href='r3180641'>
1
</ref-callout>
Most patients (82%) had metastatic disease and 18% had unresectable locally advanced disease.
<ref-callout href='r3180641'>
1
</ref-callout>
The majority (98%) of patients in the primary efficacy population had received prior surgery, radiation
therapy, or systemic therapy for their disease; 82% of these patients had received a median of 2 prior
systemic therapies and 35% had received at least 3 prior systemic therapies.
<ref-callout href='r3180641'>
1
</ref-callout>
The most common cancers in the primary efficacy population were salivary gland tumors (22%), soft tissue
sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
At the time of data analysis, the overall response rate in the primary efficacy population was 75%; complete
response was achieved in 22% of patients.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
The median duration of response had not been reached at the time of the analysis; however, 73, 63, or 39%
of patients had durable responses of 6, 9, or 12 months or longer, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180642'>
2
</ref-callout>
The overall response rate in patients with infantile fibrosarcoma, thyroid carcinoma, gastrointestinal
stromal tumor (GIST), soft tissue sarcoma, salivary gland cancer, lung cancer, melanoma, or colon cancer was
100, 100, 100, 91, 83, 75, 50, or 25%, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
Stable disease was reported in patients with cholangiocarcinoma, appendix cancer, or pancreatic cancer
while progressive disease was reported in one patient with breast cancer.
<ref-callout href='r3180641'>
1
</ref-callout>
The most common
<ital>
NTRK
</ital>
fusion was
<ital>
ETV6-NTRK3
</ital>
;
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
<ref-callout href='r3180644'>
4
</ref-callout>
however,
<ital>
NTRK
</ital>
fusions were inferred in 3 patients with infantile fibrosarcoma with documented
<ital>
ETV6
</ital>
translocation as detected by FISH.
<ref-callout href='r3180641'>
1
</ref-callout>
The overall response rate in patients with tumors harboring inferred
<ital>
ETV6-NTRK3
</ital>
,
<ital>
IRF2BP2-NTRK1
</ital>
,
<ital>
SQSTM1-NTRK1
</ital>
, documented
<ital>
ETV6-NTRK3
</ital>
,
<ital>
TPM3-NTRK1
</ital>
, or
<ital>
LMNA-NTRK1
</ital>
fusion was 100, 100, 100, 84, 56, or 40%, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
Although
<ital>
PDE4DIP-NTRK1
</ital>
,
<ital>
PPL-NTRK1
</ital>
,
<ital>
STRN-NTRK2
</ital>
,
<ital>
TPM4-NTRK3
</ital>
,
<ital>
TPR-NTRK1
</ital>
, and
<ital>
TRIM63-NTRK1
</ital>
fusions were detected in one patient each, patients with tumors harboring these
<ital>
NTRK
</ital>
fusions achieved complete or partial responses.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</uses>
<dosage-admin sect-id='dosage-admin' entity-id='34068-7'>
<head class='a-head'>
Dosage and Administration
</head>
<admin sect-id='gen-dosage-ov' entity-id='42229-5'>
<head class='b-head'>
General
</head>
<para>
Presence of a neurotrophic receptor tyrosine kinase (
<ital>
NTRK
</ital>
) gene fusion must be confirmed prior to initiation of therapy with larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='uses-1'>
(See Uses: Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion.)
</xref-internal>
</para>
<sect sect-id='rest-dist' entity-id='42229-5'>
<head class='c-head'>
Restricted Distribution
</head>
<para>
Larotrectinib sulfate can only be obtained through designated specialty pharmacies and distributors.
<ref-callout href='r3180648'>
8
</ref-callout>
Clinicians may contact the manufacturer (Bayer) 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>
</sect>
</admin>
<admin sect-id='admin' entity-id='60562-6'>
<head class='b-head'>
Administration
</head>
<para>
Larotrectinib is administered orally (as capsules or oral solution) twice daily without regard to meals.
<ref-callout href='r3180641'>
1
</ref-callout>
The capsules should be swallowed whole with water; they should
<ital>
not
</ital>
be chewed or crushed.
<ref-callout href='r3180641'>
1
</ref-callout>
The oral solution should be administered using an oral dosing syringe according to the manufacturer's
directions.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Larotrectinib capsules should be stored at room temperature of 20–25°C, but may be exposed to
15–30°C.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Larotrectinib oral solution should be stored in a refrigerator at 2–8°C; the oral solution should
not be frozen.
<ref-callout href='r3180641'>
1
</ref-callout>
Unused portions of larotrectinib oral solution should be discarded after 90 days of opening the bottle.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</admin>
<dosage sect-id='dosage' entity-id='34068-7'>
<head class='b-head'>
Dosage
</head>
<para>
Dosage of larotrectinib sulfate is expressed in terms of larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
The oral solution and capsules may be interchanged at equal doses.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<sect sect-id='dosage-1' entity-id='34068-7'>
<head class='c-head'>
Solid Tumors with Neurotrophic Receptor Tyrosine Kinase Gene Fusion
</head>
<para>
For the treatment of solid tumors harboring
<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, the recommended dosage of
larotrectinib in
<ital>
adult and pediatric patients with a body surface area (BSA) of at least 1 m
<sup>
2
</sup>
</ital>
is 100 mg twice daily.
<ref-callout href='r3180641'>
1
</ref-callout>
In
<ital>
pediatric patients with a BSA less than 1 m
<sup>
2
</sup>
</ital>
, the recommended dosage of larotrectinib is 100 mg/m
<sup>
2
</sup>
twice daily.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Larotrectinib therapy should be continued until disease progression or unacceptable toxicity occurs.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='dosage-2' entity-id='34068-7'>
<head class='c-head'>
Dosage Modification for Toxicity
</head>
<para>
If a grade 3 or 4 adverse reaction occurs, larotrectinib therapy should be withheld.
<ref-callout href='r3180641'>
1
</ref-callout>
If the grade 3 or 4 adverse reaction resolves to grade 1 or baseline within 4 weeks of withholding
larotrectinib, the drug should be resumed at a reduced dosage (or discontinued) as described in Table 1.
<ref-callout href='r3180641'>
1
</ref-callout>
If the grade 3 or 4 adverse reaction does not resolve within 4 weeks of withholding larotrectinib, the
drug should be permanently discontinued.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<table table-id='tbl1'>
<head>
Table 1. Dosage Modifications for Larotrectinib Toxicity.
<ref-callout href='r3180641'>
1
</ref-callout>
</head>
<tgroup cols='3'>
<colspec colnum='1' colname='col1' colwidth='*'/>
<colspec colname='col2' colnum='2' colwidth='*'/>
<colspec colname='col3' colnum='3' colwidth='*'/>
<thead>
<row>
<entry colname='col1'/>
<entry namest='col2' nameend='col3' align='center' rowsep='1' colname='col2'>
<para>
Dosage Modification after Recovery from Toxicity
</para>
</entry>
</row>
</thead>
<tbody>
<row rowsep='1'>
<entry colname='col1'>
<para>
Toxicity Occurrence
</para>
</entry>
<entry colname='col2'>
<para>
Adult and Pediatric Patients with BSA of 1 m
<sup>
2
</sup>
or More
</para>
<para>
(Starting Dosage = 100 mg twice daily)
</para>
</entry>
<entry colname='col3'>
<para>
Pediatric Patients with BSA Less than 1 m
<sup>
2
</sup>
</para>
<para>
(Starting Dosage = 100 mg/m
<sup>
2
</sup>
twice daily)
</para>
</entry>
</row>
<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 larotrectinib
</para>
</entry>
<entry colname='col3'>
<para>
Permanently discontinue larotrectinib
</para>
</entry>
</row>
</tbody>
</tgroup>
</table>
</sect>
<sect sect-id='dosage-3' entity-id='34068-7'>
<head class='c-head'>
Concomitant Use with CYP3A4 Inhibitors or Inducers
</head>
<para>
Concomitant use of larotrectinib with
<ital>
potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4
</ital>
should be avoided; however, if such concomitant use cannot be avoided, the manufacturer recommends
reducing the dosage of larotrectinib 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, the larotrectinib dosage should be
returned (after at least 3–5 elimination half-lives of the CYP3A4 inhibitor) to the dosage used
prior to initiation of the potent CYP3A4 inhibitor.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di-1a'>
(See Inhibitors of CYP3A4 under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal
Enzymes.)
</xref-internal>
</para>
<para>
Concomitant use of larotrectinib with
<ital>
potent inducers of CYP3A4
</ital>
should be avoided; however, if such concomitant use cannot be avoided, the manufacturer recommends
doubling the 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, the larotrectinib dosage should be
returned (after at least 3–5 elimination half-lives of the CYP3A4 inducer) to the dosage used prior
to initiation of the potent CYP3A4 inducer.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='di-1b'>
(See Inducers of CYP3A4 under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)
</xref-internal>
</para>
</sect>
</dosage>
<sect sect-id='spec-pop-ov' entity-id='42229-5'>
<head class='b-head'>
Special Populations
</head>
<para>
For patients with moderate or severe hepatic impairment (Child-Pugh class B or C), the manufacturer
recommends reducing the initial dosage of larotrectinib 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>
No initial dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-5'>
(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
</xref-internal>
</para>
<para>
The manufacturer states that no adjustment to the dosage of larotrectinib is necessary in patients with
renal impairment.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-6'>
(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
</xref-internal>
</para>
<para>
The manufacturer makes no specific dosage recommendations for geriatric patients.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-spec-pop-4'>
(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
</xref-internal>
</para>
</sect>
</dosage-admin>
<cauts sect-id='cauts' entity-id='42232-9'>
<head class='a-head'>
Cautions
</head>
<sect sect-id='contraindic' entity-id='34070-3'>
<head class='b-head'>
Contraindications
</head>
<para>
The manufacturer states that there are no known contraindications to the use of larotrectinib sulfate.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='warn-precaut-ov' 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>
Larotrectinib can cause a variety of adverse neurologic effects including delirium, dysarthria, dizziness,
gait disturbance, paresthesia, memory impairment, and tremor.
<ref-callout href='r3180641'>
1
</ref-callout>
In the principal efficacy studies of larotrectinib in patients with unresectable or metastatic solid
tumors, neurologic events occurred in 53% of 176 patients receiving the drug and were grade 3 or 4 in 6 or
0.6%, respectively, of patients.
<ref-callout href='r3180641'>
1
</ref-callout>
Most patients (65%) experienced neurologic events within 3 months of initiation of larotrectinib therapy;
however, neurologic events have occurred as early as 1 day or as late as 2.2 years following initiation of
the drug.
<ref-callout href='r3180641'>
1
</ref-callout>
Grade 4 encephalopathy also was reported in 1 of 176 patients (0.6%) receiving larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
Temporary interruption or dosage reduction of larotrectinib was necessary because of dizziness, gait
disturbance, delirium, memory impairment, or tremor in 3, 1, 1, 1, or 1%, respectively, of patients
receiving the drug.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
</para>
<para>
Temporary interruption of larotrectinib therapy followed by dosage reduction or permanent discontinuance
of therapy may be necessary in patients experiencing neurologic events during therapy with the drug, and
such patients should be advised not to drive or operate machinery.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='dosage-2'>
(See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)
</xref-internal>
</para>
</sect>
<sect sect-id='warn-precaut-2' entity-id='42229-5'>
<head class='c-head'>
Hepatotoxicity
</head>
<para>
Elevations in aminotransferase (ALT and/or AST) concentrations have been reported in patients receiving
larotrectinib.
<ref-callout href='r3180641'>
1
</ref-callout>
In the principal efficacy studies of larotrectinib in patients with unresectable or metastatic solid
tumors, elevations in serum concentrations of ALT or AST occurred in 45% of 176 patients receiving the
drug and were grade 3 or 4 in 6 or 0.6%, respectively, of patients.
<ref-callout href='r3180641'>
1
</ref-callout>
The median time to occurrence of elevated ALT or AST concentration was 2 months (range: 1 month to 2.6
years).
<ref-callout href='r3180641'>
1
</ref-callout>
Temporary interruption or dosage reduction of larotrectinib was necessary because of elevated AST or ALT
concentrations in 4 or 6%, respectively, of patients receiving the drug.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
Therapy was discontinued because of elevations in ALT or AST concentrations in 2% of patients receiving
the drug.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Liver function tests, including ALT and AST concentrations, should be monitored 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>
Temporary interruption of larotrectinib therapy followed by dosage reduction or permanent discontinuance
of therapy may be necessary if hepatotoxicity occurs.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='dosage-2'>
(See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)
</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>
Larotrectinib may cause fetal harm in humans based on its mechanism of action and animal findings;
embryofetal toxicity and teratogenicity have been demonstrated in animals.
<ref-callout href='r3180641'>
1
</ref-callout>
There are no available data regarding use of larotrectinib in pregnant women.
<ref-callout href='r3180641'>
1
</ref-callout>
Larotrectinib has been shown to cross the placenta in animals.
<ref-callout href='r3180641'>
1
</ref-callout>
In animal reproduction studies, fetal anasarca and omphalocele were observed in rats and rabbits
receiving larotrectinib at exposure levels approximately 11 and 0.7 times the human exposure,
respectively, at the recommended dosage.
<ref-callout href='r3180641'>
1
</ref-callout>
Literature reports in individuals with congenital mutations in the tropomyosin receptor kinase (Trk)
pathway suggest an association between decreased Trk-mediated signaling and obesity, developmental delays,
cognitive impairment, insensitivity to pain, and anhidrosis.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Pregnancy should be avoided during larotrectinib therapy.
<ref-callout href='r3180641'>
1
</ref-callout>
The manufacturer recommends confirmation of pregnancy status prior to initiation of larotrectinib in
women of reproductive potential and states that such women should be advised to use effective
contraceptive methods while receiving larotrectinib and for at least 1 week after discontinuance of the
drug.
<ref-callout href='r3180641'>
1
</ref-callout>
In addition, men with such female partners should use effective methods of contraception while receiving
larotrectinib and for at least 1 week after discontinuance of the drug.
<ref-callout href='r3180641'>
1
</ref-callout>
Patients should be apprised of the potential hazard to the fetus if larotrectinib is used during
pregnancy.
<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>
Based on animal studies, larotrectinib may impair female fertility.
<ref-callout href='r3180641'>
1
</ref-callout>
The effect of the drug on fertility in humans is not known.
<ref-callout href='r3180641'>
1
</ref-callout>
In a repeat-dose toxicity study, decreased uterine weight, uterine atrophy, decreased corpora lutea, and
increased incidence of anestrus were observed in female rats receiving larotrectinib at exposure levels
approximately 10–45 times the human exposure at the recommended dosage.
<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>
Larotrectinib may cause fetal harm if administered to pregnant women based on its mechanism of action
and animal findings.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='warn-precaut-3'>
(See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
</xref-internal>
</para>
</sect>
<sect sect-id='warn-spec-pop-2'>
<head class='d-head'>
Lactation
</head>
<para>
It is not known whether larotrectinib or its metabolites are distributed into human milk.
<ref-callout href='r3180641'>
1
</ref-callout>
Because of the potential for serious adverse reactions to larotrectinib in breast-fed infants, women
should be advised not to breast-feed while receiving the drug and for 1 week after the last dose.
<ref-callout href='r3180641'>
1
</ref-callout>
The effects of the drug on breast-fed infants or on the production of milk are unknown.
<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 of larotrectinib have not been established in pediatric patients younger than 28
days.
<ref-callout href='r3180641'>
1
</ref-callout>
Efficacy of larotrectinib in pediatric patients with solid tumors harboring a neurotrophic receptor
tyrosine kinase (
<ital>
NTRK
</ital>
) gene fusion has been established in 3 noncomparative studies that included 12 pediatric patients 28
days of age or older.
<ref-callout href='r3180641'>
1
</ref-callout>
Based on limited safety data in 44 pediatric patients receiving larotrectinib, some grade 3 or 4
adverse effects and laboratory abnormalities (i.e., weight gain, neutropenia) occurred more frequently
in pediatric patients compared with adults; however, because the studies were uncontrolled, it is
unclear whether this effect was related to larotrectinib or to other confounding factors (e.g.,
differences in susceptibility to infection).
<ref-callout href='r3180641'>
1
</ref-callout>
No differences in pharmacokinetics were 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 in patients with unresectable or metastatic solid tumors,
22% of patients receiving larotrectinib were 65 years of age or older, while 5% were 75 years of age or
older.
<ref-callout href='r3180641'>
1
</ref-callout>
There is insufficient experience in patients 65 years of age or older to determine whether geriatric
patients 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>
Following administration of a single 100-mg dose of larotrectinib, the area under the plasma
concentration-time curve (AUC) in individuals with mild, moderate, or severe hepatic impairment
(Child-Pugh class A, B, or C) was increased by 1.3-, 2-, or 3.2-fold, respectively, compared with
individuals with normal hepatic function; peak plasma concentrations were increased by 1.5-fold in
individuals with severe hepatic impairment compared with individuals with normal hepatic function.
<ref-callout href='r3180641'>
1
</ref-callout>
Initial dosage adjustment is required in patients with moderate or severe hepatic impairment.
<ref-callout href='r3180641'>
1
</ref-callout>
<xref-internal href='spec-pop-ov'>
(See Dosage and Administration: Special Populations.)
</xref-internal>
</para>
</sect>
<sect sect-id='warn-spec-pop-6'>
<head class='d-head'>
Renal Impairment
</head>
<para>
Following administration of a single 100-mg dose of larotrectinib to individuals with end-stage renal
disease requiring dialysis, AUC and peak plasma concentrations were increased by 1.5- and 1.3-fold,
respectively, compared with individuals with normal renal function (creatinine clearance of 90 mL/minute
or greater).
<ref-callout href='r3180641'>
1
</ref-callout>
Larotrectinib has not been studied in patients with moderate or severe renal impairment (creatinine
clearance of 60 mL/minute or less).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
</sect>
<sect sect-id='com-adv-eff' entity-id='34084-4'>
<head class='b-head'>
Common Adverse Effects
</head>
<para>
Adverse effects reported in at least 10% of patients receiving larotrectinib include 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>
and nasal congestion.
<ref-callout href='r3180641'>
1
</ref-callout>
Laboratory abnormalities reported in at least 5% of patients receiving larotrectinib include elevated
concentrations of aminotransferases (i.e., ALT, AST),
<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 concentrations of alkaline phosphatase,
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180643'>
3
</ref-callout>
and 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'>
Drug Interactions
</head>
<para>
Larotrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
In vitro studies indicate that larotrectinib is an inhibitor of CYP3A4.
<ref-callout href='r3180647'>
7
</ref-callout>
In vitro, larotrectinib does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at
clinically relevant concentrations.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
In vitro, larotrectinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer
resistance protein (BCRP), but is not a substrate for organic anion transporter (OAT) 1, OAT3, organic cation
transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, or OATP1B3.
<ref-callout href='r3180641'>
1
</ref-callout>
In vitro studies indicate that larotrectinib 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.
<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>
<sect sect-id='di-1a' entity-id='42229-5'>
<head class='c-head'>
Inhibitors of CYP3A4
</head>
<para>
Concomitant use of larotrectinib with potent inhibitors of CYP3A4 may increase systemic exposure to
larotrectinib and possible toxicity.
<ref-callout href='r3180641'>
1
</ref-callout>
When the potent CYP3A inhibitor itraconazole (200 mg once daily for 7 days) was administered
concomitantly with larotrectinib (single 100-mg dose), peak plasma concentration and area under the plasma
concentration-time curve (AUC) of larotrectinib were increased by 2.8- and 4.3-fold, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
The potential for moderate or weak CYP3A inhibitors to alter larotrectinib pharmacokinetics has not been
established.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Concomitant use of larotrectinib with potent inhibitors of CYP3A4 (e.g., itraconazole, grapefruit juice)
should be avoided.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, the manufacturer recommends reducing
the dosage of larotrectinib 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, the larotrectinib dosage should be
returned (after at least 3–5 elimination half-lives of the CYP3A4 inhibitor) to the dosage used
prior to initiation of the potent CYP3A4 inhibitor.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
<sect sect-id='di-1b' entity-id='42229-5'>
<head class='c-head'>
Inducers of CYP3A4
</head>
<para>
Concomitant use of larotrectinib with potent inducers of CYP3A4 may decrease systemic exposure to
larotrectinib and reduce larotrectinib efficacy.
<ref-callout href='r3180641'>
1
</ref-callout>
When the potent CYP3A inducer rifampin (600 mg once daily for 11 days) was administered concomitantly
with larotrectinib (single 100-mg dose), peak plasma concentration and AUC of larotrectinib were decreased
by 71 and 81%, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
The potential for moderate or weak CYP3A inducers to alter larotrectinib pharmacokinetics has not been
established.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Concomitant use of larotrectinib with potent inducers of CYP3A4 (e.g., rifampin, St. John's wort [
<ital>
Hypericum perforatum
</ital>
]) should be avoided.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use of a potent CYP3A4 inducer cannot be avoided, the manufacturer recommends doubling the
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, the larotrectinib dosage should be
returned (after at least 3–5 elimination half-lives of the CYP3A4 inducer) to the dosage used prior
to initiation of the potent CYP3A4 inducer.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
<sect sect-id='di-2' entity-id='42229-5'>
<head class='b-head'>
Drugs Metabolized by Hepatic Microsomal Enzymes
</head>
<sect sect-id='di-2a' entity-id='42229-5'>
<head class='c-head'>
Substrates of CYP3A4
</head>
<para>
Larotrectinib may increase systemic exposure and risk of adverse effects of other drugs metabolized by
CYP3A4.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
When the sensitive CYP3A4 substrate midazolam (single 2-mg dose) was administered concomitantly with
larotrectinib (100 mg twice daily for 10 days) in healthy individuals, peak plasma concentration and AUC
of midazolam were both increased by 1.7-fold; peak plasma concentration and AUC of the major metabolite of
midazolam (1-hydroxymidazolam) were both increased by 1.4-fold.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
Concomitant use with sensitive substrates of CYP3A4 (e.g., midazolam) should be avoided.
<ref-callout href='r3180641'>
1
</ref-callout>
If concomitant use of a sensitive CYP3A4 substrate cannot be avoided, the patient should be monitored for
CYP3A4 substrate-related toxicity.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</sect>
</sect>
<sect sect-id='di-3' entity-id='42229-5'>
<head class='b-head'>
Drugs Affecting the P-glycoprotein Transport System
</head>
<para>
When the P-gp inhibitor rifampin (single 600-mg dose) was administered concomitantly with larotrectinib
(single 100-mg dose) in healthy individuals, peak plasma concentration and AUC of larotrectinib were
increased by 1.8- and 1.7-fold, respectively.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
<xref-internal href='di-1'>
(See Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)
</xref-internal>
</para>
</sect>
</di>
<desc sect-id='desc' entity-id='34089-3'>
<head class='a-head'>
Description
</head>
<para>
Larotrectinib, a potent and selective inhibitor of tropomyosin receptor kinase (Trk) A, TrkB, and TrkC, is an
antineoplastic agent.
<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>
The Trk family of tyrosine kinases (encoded by the neurotrophic receptor tyrosine kinase genes
<ital>
NTRK1
</ital>
,
<ital>
NTRK2
</ital>
, and
<ital>
NTRK3
</ital>
) 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), which leads 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>
Chromosomal rearrangements of the
<ital>
NTRK1
</ital>
,
<ital>
NTRK2
</ital>
, and
<ital>
NTRK3
</ital>
genes result in fusions with an unrelated gene.
<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>
These
<ital>
NTRK
</ital>
gene fusions encode a constitutively active chimeric Trk oncogenic fusion protein resulting in 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>
In vitro biochemical assays have shown that larotrectinib inhibits the activity of wild-type TrkA, TrkB, and
TrkC.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
In vitro and in vivo, larotrectinib has demonstrated 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>
Larotrectinib also has demonstrated inhibition of tyrosine kinase nonreceptor 2 (TNK2).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Clinical resistance to larotrectinib has been attributed to secondary point mutations of the NTRK kinase
domain in 90% of cases.
<ref-callout href='r3180647'>
7
</ref-callout>
Larotrectinib has shown 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 to larotrectinib also has been identified in cell lines with G623R, G696A, or F617L point
mutations in the TrkC kinase domain.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
Following oral administration of larotrectinib capsules, systemic exposure to larotrectinib increases in a
dose-proportional manner over a dose range of 100–400 mg and increases in a slightly more than
dose-proportional manner over a dose range of 600–900 mg.
<ref-callout href='r3180641'>
1
</ref-callout>
Following oral administration of larotrectinib capsules at a dosage of 100 mg twice daily, peak plasma
concentrations of the drug were achieved in approximately 1 hour and steady-state concentrations were achieved
within 3 days.
<ref-callout href='r3180641'>
1
</ref-callout>
The mean absolute oral bioavailability of larotrectinib capsules was 34%.
<ref-callout href='r3180641'>
1
</ref-callout>
The area under the plasma-concentration time curve (AUC) for larotrectinib oral solution was similar to the
AUC for larotrectinib capsules; peak plasma concentrations were 36% higher for larotrectinib oral solution
compared with larotrectinib capsules.
<ref-callout href='r3180641'>
1
</ref-callout>
Administration of larotrectinib capsules (single 100-mg dose) with a high-fat meal decreased peak plasma
concentrations by 35% and delayed the time to peak plasma concentrations by 2 hours compared with
administration in the fasted state, but did not substantially affect the extent of absorption.
<ref-callout href='r3180641'>
1
</ref-callout>
<ref-callout href='r3180647'>
7
</ref-callout>
Larotrectinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.
<ref-callout href='r3180641'>
1
</ref-callout>
Larotrectinib is 70% bound to plasma proteins, and binding is independent of larotrectinib concentration.
<ref-callout href='r3180641'>
1
</ref-callout>
Following oral administration of a single 100-mg radiolabeled dose of larotrectinib, 58% of the dose was
recovered in feces (5% as unchanged drug) and 39% was recovered in urine (20% as unchanged drug).
<ref-callout href='r3180641'>
1
</ref-callout>
The terminal half-life of larotrectinib is 2.9 hours.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<para>
The pharmacokinetics of larotrectinib do not appear to be affected by age (range of 28 days to 82 years), sex,
or body weight (range of 3.8–179 kg).
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
</desc>
<advice-patient sect-id='advice-patient' entity-id='34076-0'>
<head class='a-head'>
Advice to Patients
</head>
<para>
Importance of instructing patients to read the manufacturer's patient information.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<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>
<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>
<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>
<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>
<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 at least 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 at least 1 week after the drug is discontinued.
<ref-callout href='r3180641'>
1
</ref-callout>
Importance of women informing 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>
<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>
<para>
Risk of impaired female fertility.
<ref-callout href='r3180641'>
1
</ref-callout>
</para>
<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>
<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>
</advice-patient>
<gs-ref entity-id='42229-5'>
<head class='a-head'>
Additional Information
</head>
<para>
Overview
<sup>
®
</sup>
<xref-external href='a300005.xml'>
(see Users Guide)
</xref-external>
. For additional information on this drug until a more detailed monograph is developed and published, the
manufacturer’s labeling should be consulted. It is
<ital>
essential
</ital>
that the manufacturer’s labeling be consulted for more detailed information on usual cautions,
precautions, contraindications, potential drug interactions, laboratory test interferences, and acute
toxicity. For further information on the handling of antineoplastic agents,
<xref-external href='a390010.xml'>
see the ASHP Guidelines on Handling Hazardous Drugs
</xref-external>
at
<a href='https://www.ahfsdruginformation.com'>
[Web]
</a>
.
</para>
</gs-ref>
<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>
Larotrectinib sulfate can only be obtained through designated specialty pharmacies and distributors.
<ref-callout href='r3180648'>
8
</ref-callout>
<xref-internal href='rest-dist'>
(See Restricted Distribution under Dosage and Administration: General.)
</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>
Drug Information. © Copyright, 1959-2022, 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'>
<ref ref-num='1' ref-id='r3180641'>
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
</ital>
. 2019; 30:325-31.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/30624546?dopt=AbstractPlus'>
[PubMed 30624546]
</a>
</ref>
<ref ref-num='4' ref-id='r3180644'>
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.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/29606586?dopt=AbstractPlus'>
[PubMed 29606586]
</a>
</ref>
<ref ref-num='5' ref-id='r3180645'>
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.
<a target='_base'
href='https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf'>
[Web]
</a>
</ref>
<ref ref-num='8' ref-id='r3180648'>
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>
<ref ref-num='9' ref-id='r3180649'>
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.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/25527197?dopt=AbstractPlus'>
[PubMed 25527197]
</a>
</ref>
<ref ref-num='10' ref-id='r31806410'>
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.
<a target='_base' href='http://www.ncbi.nlm.nih.gov/pubmed/31118670?dopt=AbstractPlus'>
[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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