DRUG INTERACTIONS

1. Effects 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 .

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 

2.Strong CYP3A4 Inducers

Coadministration of VITRAKVI with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of VITRAKVI.

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.

 3.Effects 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 

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.

BRIEF SUMMARY

LAROTRECTINB- (Nov 2018)

Indn-     To treat patients whose cancers have a specific genetic  feature (biomarker)

Comp-      • Capsules: 25 mg, 100 mg • Oral Solution: 20 mg/mL                                       • Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared: 100 mg orally twice daily 

ADR-     The most common adverse reactions (= 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. 

CI-    None. 

WARNINGS-

 • 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.

 • 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

Pat Infm-

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 

Hepatotoxicity                                                                                                           Advise patients that they will need to undergo laboratory tests to monitor liver function

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  53

ADVERSE REACTIONS

 The most common adverse reactions (= 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. 

CONTRAINDICATIONS                                                                                             None. 

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.

 • 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. 

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. 

 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 

Hepatotoxicity                                                                                                           Advise patients that they will need to undergo laboratory tests to monitor liver function 

Embryo-Fetal Toxicity                                                                                              Advise males and females of reproductive potential of the potential risk to a fetus 

Use in Specific Populations                                                                                     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 

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 

Lactation                                                                                                                    Advise women not to breastfeed during treatment with VITRAKVI and for 1 week following the final dose 

Infertility                                                                                                                     Advise females of reproductive potential that VITRAKVI may impair fertility 

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 

Manufactured for: Loxo Oncology, Inc. Stamford, CT 06901 Reference ID: 4354324

 CLINICAL PHARMACOLOGY

1 Mechanism 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 IC50 values between 5-11 nM.

2 Pharmacodynamics -                                                                                            Cardiac Electrophysiology                                                                                              At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTc intervals to any clinically relevant extent.

3 Pharmacokinetics                                                                                                       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 (Cmax 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 (Cmax) 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 Cmax was 788 (81%)ng/mL and AUC0-24hr 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 Cmax was 36% higher with the oral solution.

Effect of Food

The AUC of larotrectinib was similar and the Cmax 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 Cmax and AUC in the fasted state. 

Distribution

The mean (CV%) volume of distribution (Vss) 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 [ 14C] 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.

Elimination

Following oral administration of a single [ 14C] 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, and body weight (range: 3.8 kg to 179 kg) had no clinically meaningful effect on the pharmacokinetics of larotrectinib.

Pediatric Patients In pediatric patients, the larotrectinib geometric mean (%CV) AUC0-24hr by age subgroup was: 3348 (66%) ng*h/mL in patients 1 month to < 2 years (n = 9), 4135 (36%) ng*h/mL in patients 2 to < 12 years (n = 15), and 3108 (69%) ng*h/mL and in patients 12 to < 18 years (n = 9).

Patients with Renal Impairment

Following oral administration of a single 100 mg dose of VITRAKVI capsules in subjects with end-stage renal disease (e.g., subjects who required dialysis), the AUC0-INF of larotrectinib increased 1.5-fold and Cmax increased 1.3-fold as compared to that in subjects with normal renal function (creatinine clearance = 90 mL/min as estimated by Cockcroft-Gault).

The pharmacokinetics of VITRAKVI in patients with moderate to severe renal impairment (creatinine clearance = 60 mL/min) have not been studied.

Patients with Hepatic Impairment

Following oral administration of a single 100 mg dose of VITRAKVI capsules, the AUC0-INF of larotrectinib increased 1.3-fold in subjects with mild hepatic impairment (Child-Pugh A), 2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) as compared to that in subjects with normal hepatic function.

The Cmax was similar in subjects with mild and moderate hepatic impairment and the Cmax of larotrectinib increased 1.5-fold in subjects with severe hepatic impairment as compared to that in subjects with normal hepatic function 

Drug Interaction Studies Clinical Studies

Effect of Strong CYP3A Inhibitors: Coadministration of a single 100 mg dose of VITRAKVI capsules with a strong CYP3A inhibitor (itraconazole) increased the AUC0-INF of larotrectinib by 4.3-fold and the Cmax by 2.8-fold as compared to VITRAKVI administered alone 

The effects of CYP3A moderate and weak inhibitors on the pharmacokinetics of larotrectinib have not been studied.

Effect of Strong CYP3A Inducers:

Coadministration of a single 100 mg dose of VITRAKVI capsules with a strong CYP3A inducer (rifampin) decreased the AUC0-INF of larotrectinib by 81% and of Cmax by 71% as compared to VITRAKVI administered alone [see Dosage and Administration (2.5), Drug Interactions (7.1)].

The effects of CYP3A weak and moderate inducers on the pharmacokinetics of larotrectinib have not been studied.

Effect of Strong P-glycoprotein (P-gp) Inhibitors:

Coadministration of a single 100 mg dose of VITRAKVI capsules with a P-gp inhibitor (rifampin) increased the AUC0-INF of larotrectinib by 1.7-fold and the Cmax by 1.8-fold as compared to VITRAKVI administered alone.

Effect of Larotrectinib on CYP3A4 Substrates:

Coadministration of VITRAKVI capsules 100 mg twice daily with a sensitive CYP3A4 substrate (midazolam) increased both the AUC0-INF and Cmax of midazolam by 1.7-fold as compared to midazolam administered alone.

The AUC0-INF and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold as compared to when midazolam was administered alone 

In Vitro Studies Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP. Larotrectinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.

Effect of Larotrectinib on Transporters: Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinically relevant concentrations.

Effect of Larotrectinib on CYP Substrates: Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 , 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 

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.

2. Lactation 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.

3. Females and Males of Reproductive Potential Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI 

Contraception                                                                                                        VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman 

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  Female                                                                                                         Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, VITRAKVI may reduce fertility.

4 Pediatric 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.

The pharmacokinetics of VITRAKVI in the pediatric population were similar to those seen in adults 

5 Geriatric 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.

6 Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe  (Child-Pugh C) hepatic impairment

Reduce VITRAKVI dose as recommended 

7 Renal Impairment

No dose adjustment is recommended for patients with renal impairment of any severity