VITRAKVI LAROTRECTINIB 25 mg Capsule, 60-count
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Kinase Inhibitor class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Larotrectinib is used to treat a certain type of solid tumors in adults, children, and infants 4 weeks of age and older that have spread to other parts of the body or cannot be treated successfully with surgery. This medication is used only if there are no other treatments available and the tumors have worsened after receiving other treatments. Larotrectinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that tells the cancer cells to multiply. This may help slow the growth of tumors.
Read the full MedlinePlus article ↗- Vitrakvi isn't tied to one specific cancer type — it targets a specific genetic change called an NTRK gene fusion that can show up in many different solid tumors, in both adults an...
- What kind of cancer is Vitrakvi actually used for?
- Good news — you can take Vitrakvi with or without food, whichever is more convenient or comfortable for you. A high-fat meal can slightly change how quickly the drug is absorbed, b...
- Can I take Vitrakvi with food, or does it have to be on an empty stomach?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Larotrectinib — tap one for details:
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💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 2G86QN327L
Gelatin is a protein derived from animal collagen, commonly used in medicines as a gelling agent and capsule material. It helps create soft or hard capsule shells that hold and release medication, and can also thicken liquid formulations.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
2 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $237.20 | $14,232.13 / 60 capsules |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Vitrakvi 25 mg 50419-0390-01 | Bayer | 60 capsules | — | — | FDA listed | — |
| Vitrakvi 25 mgthis 71777-0390-01 | Loxo | 60 capsules | — | — | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 10047097 ↗ | Method of use | U-2474 | Oct 21, 2029 |
| US 9447104 ↗ | Method of use | U-2470 | Oct 21, 2029 |
| US 8865698 ↗ | Method of use | U-2469 | Oct 21, 2029 |
| US 10005783 ↗ | Method of use | U-2472 | Oct 21, 2029 |
| US 9782414 ↗ | Method of use | U-2475 | Nov 16, 2035 |
| US 10005783 ↗ | Method of use | U-2472 | Oct 21, 2029 |
| US 10047097 ↗ | Method of use | U-2474 | Oct 21, 2029 |
| US 9676783 ↗ | Method of use | U-2469 | Oct 21, 2029 |
| US 10285993 ↗ | Method of use | U-2470 | Nov 16, 2035 |
| US 11974998 ↗ | Method of use | U-4124 | May 16, 2037 |
| US 11974998 ↗ | Method of use | U-4124 | May 16, 2037 |
| US 11337967 ↗ | Method of use | U-4123 | May 16, 2037 |
| US 11337967 ↗ | Method of use | U-4123 | May 16, 2037 |
| US 10813936 ↗ | Method of use | U-2987 | Nov 16, 2035 |
| US 10813936 ↗ | Method of use | U-2987 | Nov 16, 2035 |
| US 8865698 ↗ | Method of use | U-2469 | Oct 21, 2029 |
| US 9782414 ↗ | Method of use | U-2475 | Nov 16, 2035 |
| US 9447104 ↗ | Method of use | U-2470 | Oct 21, 2029 |
| US 10285993 ↗ | Method of use | U-2470 | Nov 16, 2035 |
| US 9676783 ↗ | Method of use | U-2469 | Oct 21, 2029 |
| US 10774085 ↗ | Method of use | U-2470 | Oct 21, 2029 |
| US 10774085 ↗ | Method of use | U-2470 | Oct 21, 2029 |
| US 8513263 ↗ | Drug substance | — | Dec 23, 2029 |
| US 8513263 ↗ | Drug substance | — | Dec 23, 2029 |
| US 10799505 ↗ | Drug substance | — | Aug 15, 2036 |
| US 10172861 ↗ | Drug substance | — | Nov 16, 2035 |
| US 10799505 ↗ | Drug substance | — | Aug 15, 2036 |
| US 9127013 ↗ | Drug substance | — | Oct 21, 2029 |
| US 9127013 ↗ | Drug substance | — | Oct 21, 2029 |
| US 10172861 ↗ | Drug substance | — | Nov 16, 2035 |
Is there a generic version of VITRAKVI 25 MG CAPSULE?
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Where does this data come from?
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 71777-0390-01 You're viewing this | 60 CAPSULE in 1 BOTTLE (71777-390-01) | 2018-11-26 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
Questions about this listing
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14 )] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials ( 1 , 14 ).
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion ( 2.1 , 14 ). • Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least
1.0Meter-Squared: 100 mg orally twice daily ( 2.2 ) • Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than
1.0Meter-Squared: 100 mg/m 2 orally twice daily ( 2.2 )
2.1Patient Selection Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of NTRK gene fusion is not currently available.
2.2Recommended Dosage Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least
1.0Meter-Squared The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity. Recommended Dosage in Pediatric Patients with Body Surface Area Less Than
1.0Meter-Squared The recommended dosage of VITRAKVI is 100 mg/m 2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity.
2.3Dosage Modifications for Adverse Reactions For Grade 3 or 4 adverse reactions: • Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks. • Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks. The recommended dosage modifications for VITRAKVI for adverse reactions are provided in Table 1 .
Table 1 Recommended Dosage Modifications for VITRAKVI for Adverse Reactions Dosage Modification Adult and Pediatric Patients with Body Surface Area of at Least 1.0 m 2 Pediatric Patients with Body Surface Area Less Than 1.0 m 2 First 75 mg orally twice daily 75 mg/m 2 orally twice daily Second 50 mg orally twice daily 50 mg/m 2 orally twice daily Third 100 mg orally once daily 25 mg/m 2 orally twice daily Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications.
2.4Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .
2.5Dosage Modifications for Coadministration with Strong CYP3A4 Inducers Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the VITRAKVI dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the VITRAKVI dose taken prior to initiating the CYP3A4 inducer [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .
2.6Dosage Modifications for Patients with Hepatic Impairment Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] .
2.7Administration VITRAKVI capsule or oral solution may be used interchangeably. Do not make up a missed dose within 6 hours of the next scheduled dose. If vomiting occurs after taking a dose of VITRAKVI, take the next dose at the scheduled time.
Capsules Swallow capsules whole with water. Do not chew or crush the capsules. Oral Solution • Store the glass bottle of VITRAKVI oral solution in the refrigerator.
Discard any unused VITRAKVI oral solution remaining after 90 days of first opening the bottle. • Prior to preparing an oral dose for administration, refer to the Instructions for Use.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Capsules • 25 mg: white opaque hard gelatin capsule, size 2, with blue printing of "LOXO" and "LARO 25 mg" on body of capsules. 25 mg larotrectinib is equivalent to 30.7 mg larotrectinib sulfate. • 100 mg: white opaque hard gelatin capsule, size 0, with blue printing of "LOXO" and "LARO 100 mg" on body of capsule. 100 mg larotrectinib is equivalent to 123 mg larotrectinib sulfate.
Oral Solution • 20 mg/mL: clear yellow to orange solution. 20 mg/mL larotrectinib is equivalent to 24.6 mg/mL larotrectinib sulfate. • Capsules: 25 mg, 100 mg ( 3 ) • Oral Solution: 20 mg/mL ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS None. None. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Neurotoxicity: Advise patients and caretakers of the risk of neurologic adverse reactions. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity.
( 2.3 , 5.1 ) • Hepatotoxicity: Monitor liver tests including ALT and AST every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.6 , 5.2 ) • Embryo-Fetal Toxicity: Can cause fetal harm.
Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.3 , 8.3 )
5.1Neurotoxicity Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively [see Adverse Reactions ( 6.1 )] . The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%).
Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%). Advise patients and caretakers of these risks with VITRAKVI.
Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration ( 2.3 )] .
5.2Hepatotoxicity Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients [see Adverse Reactions ( 6.1 )] . One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years).
The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.
Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration ( 2.3 )] .
5.3Embryo-Fetal Toxicity Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus.
Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI [see Use in Specific Populations ( 8.1 , 8.3 )] .
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Neurotoxicity [see Warnings and Precautions ( 5.1 )] • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥ 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 176 patients, including 70 (40%) patients exposed for greater than 6 months and 35 (20%) patients exposed for greater than 1 year. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 70)], one pediatric dose-finding trial [SCOUT (n = 43)], and one single arm trial [NAVIGATE (n = 63)].
All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 176 patients, the median age was 51 years (range: 28 days to 82 years); 25% were 18 years or younger; 52% were male; and 72% were White, 11% were Hispanic/Latino, 8% were Black, and 3% were Asian. The most common tumors in order of decreasing frequency were soft tissue sarcoma (16%), salivary gland (11%), lung (10%), thyroid (9%), colon (8%), infantile fibrosarcoma (8%), primary central nervous system (CNS) (7%), or melanoma (5%).
NTRK gene fusions were present in 60% of VITRAKVI-treated patients. Most adults (80%) received VITRAKVI 100 mg orally twice daily and 68% of pediatrics (18 years or younger) received VITRAKVI 100 mg/m 2 twice daily up to a maximum dose of 100 mg twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics [see Pediatric Use ( 8.4 )] .
The most common adverse reactions (≥ 20%) in order of decreasing frequency were fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough, increased ALT, constipation, and diarrhea. The most common serious adverse reactions (≥ 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting. Grade 3 or 4 adverse reactions occurred in 51% of patients; adverse reactions leading to dose interruption or reduction occurred in 37% of patients and 13% permanently discontinued VITRAKVI for adverse reactions.
The most common adverse reactions (1-2% each) that resulted in discontinuation of VITRAKVI were brain edema, intestinal perforation, pericardial effusion, pleural effusion, small intestinal obstruction, dehydration, fatigue, increased ALT, increased AST, enterocutaneous fistula, increased amylase, increased lipase, muscular weakness, abdominal pain, asthenia, decreased appetite, dyspnea, hyponatremia, jaundice, syncope, vomiting, acute myeloid leukemia, and nausea. The most common adverse reactions (≥ 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%).
Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 5% of patients are summarized in Table 2 and Table 3 , respectively. Table 2 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction VITRAKVI N = 176 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03.
(%) Grade 3-4 One Grade 4 adverse reaction of pyrexia. (%)…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS • Strong CYP3A4 Inhibitors: Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration cannot be avoided, reduce the VITRAKVI dose. ( 2.4 , 7.1 ) • Strong CYP3A4 Inducers: Avoid coadministration of strong CYP3A4 inducers with VITRAKVI.
If coadministration cannot be avoided, increase the VITRAKVI dose. ( 2.5 , 7.1 ) • Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with VITRAKVI. ( 7.2 )
7.1Effects of Other Drugs on VITRAKVI Strong CYP3A4 Inhibitors Coadministration of VITRAKVI with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration ( 2.4 )] .
Strong CYP3A4 Inducers Coadministration of VITRAKVI with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of VITRAKVI [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with strong CYP3A4 inducers, including St. John’s wort.
If coadministration of strong CYP3A4 inducers cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration ( 2.5 )] .
7.2Effects of VITRAKVI on Other Drugs Sensitive CYP3A4 Substrates Coadministration of VITRAKVI with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of VITRAKVI with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. ( 8.2 ) • Hepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. ( 2.6 , 8.7 )
8.1Pregnancy Risk Summary Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data ) .
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily].
In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily).
8.2Lactation Risk Summary There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose.
8.3Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI [see Use in Specific Populations ( 8.1 )] . Contraception VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Females Advise female patients of reproductive potential to use effective contraception during treatment with VITRAKVI and for at least 1 week after the final dose.
Males Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the final dose. Infertility Females Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, VITRAKVI may reduce fertility [See Nonclinical Toxicology ( 13.1 )] .
8.4Pediatric Use The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 days and older [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )] . The efficacy of VITRAKVI was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies ( 14 )] . The safety of VITRAKVI was evaluated in 44 pediatric patients who received VITRAKVI.
Of these 44 patients, 27% were 1 month to < 2 years (n = 12), 43% were 2 years to < 12 years (n = 19), and 30% were 12 years to < 18 years (n = 13);…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data ) .
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily].
In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily).
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 days and older [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )] . The efficacy of VITRAKVI was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies ( 14 )] . The safety of VITRAKVI was evaluated in 44 pediatric patients who received VITRAKVI.
Of these 44 patients, 27% were 1 month to < 2 years (n = 12), 43% were 2 years to < 12 years (n = 19), and 30% were 12 years to < 18 years (n = 13); 43% had metastatic disease and 57% had locally advanced disease; and 91% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were infantile fibrosarcoma (32%), soft tissue sarcoma (25%), primary CNS tumors (20%), and thyroid cancer (9%). The median duration of exposure was 5.4 months (range: 9 days to 1.9 years).
Due to the small number of pediatric and adult patients, the single arm design of clinical studies of VITRAKVI, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to VITRAKVI are related to patient age or other factors. Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (at least a 5% increase in per-patient incidence) in pediatric patients compared to adult patients were increased weight (11% vs.
2%) and neutropenia (20% vs. 2%). One of the 44 pediatric patients discontinued VITRAKVI due to an adverse reaction (Grade 3 increased ALT).
The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults [see Clinical Pharmacology ( 12.3 )]. Juvenile Animal Toxicity Data Larotrectinib was administered in a juvenile toxicity study in rats at twice daily doses of 0.2, 2 and 7.5 mg/kg from postnatal day (PND) 7 to 27 and at twice daily doses of 0.6, 6 and 22.5mg/kg between PND 28 and 70. The dosing period was equivalent to human pediatric populations from newborn to adulthood.
The doses of 2/6 mg/kg twice daily [approximately 0.7 times the human exposure (AUC) at the clinical dose of 100 mg twice daily] and 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily) resulted in mortality between PND 9 to 99; a definitive cause of death was not identified in the majority of cases. The main findings were transient central nervous system-related signs including head flick, tremor, and circling in both sexes. An increase in the number of errors in a maze swim test occurred in females at exposures of approximately 4 times the human exposure (AUC) at the clinical dose of 100 mg twice daily.
Decreased growth and delays in sexual development occurred in the mid- and high-dose groups. Mating was normal in treated animals, but a reduction in pregnancy rate occurred at the high-dose of 7.5/22.5 mg/kg twice daily (approximately 4 times the human exposure at the clinical dose of 100 mg twice daily).
🧓 Geriatric Use ▾
8.5Geriatric Use Of 176 patients in the overall safety population who received VITRAKVI, 22% of patients were ≥ 65 years of age and 5% of patients were ≥ 75 years of age. Clinical studies of VITRAKVI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration.
TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 . Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.
Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.
12.2Pharmacodynamics Cardiac Electrophysiology At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.
12.3Pharmacokinetics The pharmacokinetics of larotrectinib were studied in healthy subjects and adult and pediatric patients with locally advanced or metastatic solid tumors. In healthy subjects who received a single dose of VITRAKVI capsules, systemic exposure (C max and AUC) of larotrectinib was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twice daily in Study LOXO-TRK-14001, peak plasma levels (C max ) of larotrectinib were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days.
Mean steady-state larotrectinib [coefficient of variation (CV%)] for C max was 788 (81%) ng/mL and AUC 0-24hr was 4351 (97%) ng*h/mL. Absorption The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules and the C max was 36% higher with the oral solution.
Effect of Food The AUC of larotrectinib was similar and the C max was reduced by 35% after oral administration of a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the C max and AUC in the fasted state. Distribution The mean (CV%) volume of distribution (V ss ) of larotrectinib is 48 (38%) L following intravenous administration of larotrectinib in healthy subjects. Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations.
The blood-to-plasma concentration ratio is 0.9. Elimination The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of VITRAKVI in healthy subjects. Metabolism Larotrectinib is metabolized predominantly by CYP3A4.
Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma. Excretion Following oral administration of a single [ 14 C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine. Specific Populations Age (range: 28 days to 82 years), sex…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration.
TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 . Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.
Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Capsules 25 mg: Hard gelatin opaque white capsule size #2 with blue printing of "LOXO" and "LARO 25 mg" on the body of the capsule. • 60 count bottle NDC# 71777-390-01 100 mg: Hard gelatin opaque white capsule size #0 with blue printing of "LOXO" and "LARO 100 mg" on the body of the capsule. • 60 count bottle NDC# 71777-391-01 Store capsules at room temperature 20°C to 25°C (68°F to 77°F); temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].
Oral Solution 20 mg/mL: Clear yellow to orange solution. • 100 mL bottle NDC# 71777-392-01 Refrigerate oral solution at 2°C to 8°C (36°F to 46°F). Do not freeze.
📋 Description ▾
11 DESCRIPTION Larotrectinib is a kinase inhibitor. VITRAKVI (larotrectinib) capsules and oral solution are formulated using larotrectinib sulfate. The molecular formula for larotrectinib sulfate is C 21 H 24 F 2 N 6 O 6 S and the molecular weight is 526.51 g/mol for the sulfate salt and 428.44 g/mol for the free base.
The chemical name is (3 S )- N -{5-[(2 R )-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate. Larotrectinib sulfate has the following chemical structure: Larotrectinib sulfate is an off-white to pinkish yellow solid that is not hygroscopic. The aqueous solubility of larotrectinib at 37°C is pH dependent (very soluble at pH 1.0 and freely soluble at pH 6.8, according to USP descriptive terms of solubility).
VITRAKVI (larotrectinib) capsules and oral solution are for oral use. Each capsule contains 25 mg or 100 mg larotrectinib (30.7 mg and 123 mg larotrectinib sulfate, respectively) in a hard gelatin capsule. The capsule is composed of gelatin, titanium dioxide, and edible ink.
The oral solution contains 20 mg/mL larotrectinib (24.6 mg/mL larotrectinib sulfate) and the following inactive ingredients: purified water, hydroxypropyl betadex, sucrose, glycerin, sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol and flavoring. Preserved with methylparaben and potassium sorbate. image of the chemical structure of VITRAKVI
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Neurotoxicity Advise patients to notify their healthcare provider if they experience new or worsening neurotoxicity. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions [see Warnings and Precautions ( 5.1 )] .
Hepatotoxicity Advise patients that they will need to undergo laboratory tests to monitor liver function [see Warnings and Precautions ( 5.2 )] . Embryo-Fetal Toxicity Advise males and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during the treatment with VITRAKVI and for at least 1 week after the final dose [see Use in Specific Populations ( 8.3 )] .
Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for at least 1 week after the final dose [see Use in Specific Populations ( 8.3 )] . Lactation Advise women not to breastfeed during treatment with VITRAKVI and for 1 week following the final dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that VITRAKVI may impair fertility [See Nonclinical Toxicology ( 13.1 )] .
Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking VITRAKVI [see Drug Interactions ( 7.1 , 7.2 )] .
Manufactured for: Loxo Oncology, Inc. Stamford, CT 06901