Vitrakvi Special Precautions

Hepatic/Biliary/Pancreatic: Among the 279 patients who received VITRAKVI, treatment-emergent adverse events (TEAEs) of alanine transaminase (ALT) increased and aspartate transaminase (AST) increased of any grade were reported in 28% and 25% of patients, respectively. The maximum grades elevations were Grade 4 ALT increased in 2 patients (1%), Grade 4 AST increased in 1 patient (< 1%), Grade 3 ALT increased in 7 patients (3%) and Grade 3 AST increased in 6 patients (2%) (see Clinical Trial Adverse Reactions: Additional Information in Selected Adverse Reactions: Transaminase Elevations under Adverse Reactions). The median time to onset of ALT increased was 1.8 months (range: 0 days to 21.3 months). The median time to onset of AST increased was 1.5 months (range: 0 days to 21.3 months). Transaminase elevations led to dose modification and permanent discontinuation of VITRAKVI in 3% and 2% of patients, respectively.
Monitor for liver function including ALT and AST assessments. VITRAKVI can cause transaminase elevations. Consider baseline assessment of liver function, including transaminase levels, before the first dose and monthly for the first 3 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase elevations. Withhold or permanently discontinue VITRAKVI based on the severity and persistence of the transaminase elevation. If withheld, modify the VITRAKVI dosage when resumed (see Recommended Dose and Dosage Adjustment: Dose Modifications under Dosage & Administration). Patients with Grade 2 transaminase elevations should be followed with serial laboratory evaluations every one to two weeks after the observation of Grade 2 toxicity to establish whether a dose interruption or reduction is required. In patients with ≥ Grade 3 events in whom VITRAKVI has been withheld, regular reevaluation at least weekly is recommended.
Neurologic/Psychiatric: Among the 279 patients who received VITRAKVI, neurologic/psychiatric TEAEs of any grade occurred in 63% of patients, including Grade 3 and Grade 4 adverse events in 11% and < 2% of patients, respectively. Grade 4 encephalopathy, brain edema, seizure and cerebrovascular accident were reported in one patient each. Grade 3 events included delirium (1%), dizziness (1%), mental status change (1%), gait disturbance (1%), paresthesia (1%), and syncope (1%). The majority (80%) of neurologic adverse events occurred within the first three months of treatment (range: 0 days to 35.5 months). Dose modification (interruption, increase or reduction) based on neurologic toxicity of all grades occurred in 11% of patients, most commonly for dizziness (2%) (see Clinical Trial Adverse Reactions: Additional Information in Selected Adverse Reactions: Neurologic/Psychiatric events under Adverse Reactions).
Withholding, reducing, or permanently discontinuing VITRAKVI dosing should be considered, depending on the severity and persistence of these symptoms.
Sexual Health: Reproduction: Based on the mechanism of action and non-clinical data, there may be a risk of fetal harm when administering larotrectinib to a pregnant woman. Females of childbearing potential should have a pregnancy test prior to starting treatment with VITRAKVI.
Advise female patients of reproductive potential to use highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.
For males of reproductive potential with a non-pregnant female partner of child-bearing potential, advise use of highly effective contraception during treatment with VITRAKVI and for at least one month after the final dose.
Fertility: There are no clinical data on the effect of VITRAKVI on fertility. Non-clinical fertility studies with larotrectinib have not been conducted; however, changes to the female reproductive organs in rats were observed in a repeated-dose toxicity study. Lower fertility was noted in juvenile rats at high dose (see Pharmacology: Toxicology: Non-Clinical Toxicology under Actions).
Excipients with known effects (oral solution only): Each ml of VITRAKVI oral solution contains 2 mg of sodium benzoate. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
Driving and Operating Machinery: Neurologic adverse events and fatigue have very commonly been reported in patients receiving VITRAKVI and may influence the patient's ability to drive and use machines. Caution patients and caretakers about driving and operating potentially hazardous machinery, until they are reasonably certain VITRAKVI therapy does not affect them adversely (see Neurologic/Psychiatric as previously mentioned).
Use in Pregnancy: See Pregnant Women under Use in Pregnancy & Lactation.
Use in Lactation: See Breast-feeding under Use in Pregnancy & Lactation.
Use in Children: Among the 279 patients who received VITRAKVI, 92 (33%) were pediatric. Of these 92 patients, 36% were < 2 years (n=33), 41% were 2 years to < 12 years (n=38), and 23% were 12 years to < 18 years (n=21). The median duration of exposure was 7.4 months (range: 0.36 to 38.6 months). Treatment-emergent adverse events of Grade 3 or 4 severity occurring more frequently in pediatric patients compared to adult patients included increased weight (2% versus 0%) and neutropenia (9% versus 0%). Two pediatric patients discontinued VITRAKVI due to an adverse reaction Grade 3 ALT increased and neutrophil count decreased (see Clinical Trial Adverse Reactions: Clinical Trial Adverse Reactions (Pediatrics) under Adverse Reactions).
Based on a population pharmacokinetic analysis, in pediatric patients from 1 to 3 months of age, the drug exposure was 3-fold higher than in adults when using recommended doses. The clinical relevance is unknown (see Pharmacology: Pharmacokinetics under Actions).
Use in the Elderly: Among the 279 patients who received VITRAKVI, 54 (19%) patients were ≥ 65 years of age and 13 (5%) 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 (see Clinical Trial Adverse Reactions: Clinical Trial Adverse Reactions (Geriatrics) under Adverse Reactions).