Vorasidenib

In vitro, vorasidenib is an inhibitor of breast cancer resistance protein (BCRP). Caution should be exercised when administering vorasidenib with BCRP substrates (including, but not limited to, rosuvastatin).

Cytochrome P450 (CYP) substrates with narrow therapeutic index

Co-administration of vorasidenib with CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 substrates with narrow therapeutic index (including, but not limited to, amitriptyline, alfentanil, carbamazepine, ciclosporin, dosulepin, everolimus, fentanyl, fosphenytoin, ifosfamide, imipramine, phenobarbital, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tamoxifen, trimipramine, valproic acid, and warfarin) may decrease the plasma concentrations of these medicinal products. Concomitant use of substrates of these enzymes with narrow therapeutic index should be avoided in patients taking vorasidenib.

Sensitive substrates of CYP enzymes without narrow therapeutic index

Co-administration of vorasidenib with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 without narrow therapeutic index (including, but not limited to, bupropion, buspirone, celecoxib, darunavir, ibrutinib, midazolam, repaglinide, saquinavir, tipranavir, and triazolam) may decrease the plasma concentrations of these medicinal products. Consider alternative therapies that are not sensitive substrates of these enzymes during treatment with vorasidenib.

Co-administration of vorasidenib with moderate CYP1A2 inducers (phenytoin and rifampicin) may decrease vorasidenib plasma concentration. Consider alternative therapies that are not moderate CYP1A2 inducers during treatment with vorasidenib.

Co-administration of vorasidenib with strong CYP1A2 inhibitors (fluvoxamine and ciprofloxacin) may increase vorasidenib plasma concentration. Concomitant use of strong CYP1A2 inhibitors should be avoided and consider alternative therapies that are not strong inhibitors of CYP1A2 during treatment with vorasidenib.

In an in vivo drug-drug interaction study, co-administration of 20 mg vorasidenib with a strong CYP1A2 inhibitor (500 mg ciprofloxacin twice daily for 14 days) increased vorasidenib maximum plasma concentration (C_max) by 29% and area under the plasma time-concentration curve (AUC) by 153%.

The pharmacokinetics of vorasidenib and metabolite AGI-69460 have not been studied in patients with eGFR ≤40 mL/min/1.73 m² or renal impairment requiring dialysis. Vorasidenib should not be used in patients with eGFR ≤40 mL/min/1.73 m² or who require dialysis.

The pharmacokinetics of vorasidenib and AGI-69460 have not been studied in patients with severe hepatic impairment (Child-Pugh class C). Vorasidenib should be used with caution in patients with severe hepatic impairment and this patient population should be closely monitored.

Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended during treatment and for at least 2 months after the last dose.

There are no human data on the effect of vorasidenib on fertility. Findings on reproductive organs were observed during repeat-dose toxicity studies in female and male animals. The clinical relevance of these effects is unknown. Male and female patients who are planning to conceive a child should be advised to seek reproductive counselling, and men should seek advice on cryo-preservation of sperm prior to treatment.

There are no or limited amount of data from the use of vorasidenib in pregnant women. Studies in animals have shown embryo-foetal development toxicity.

Vorasidenib should not be used during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential or male patients with female partners of childbearing potential should be advised on the potential risk to a foetus.

It is unknown whether vorasidenib and its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment and for at least 2 months after the last dose.

Women of childbearing potential / Contraception

Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with vorasidenib.

Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for at least 2 months after the last dose. Since the effect of vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.

Fertility

There are no human data on the effect of vorasidenib on fertility. Findings on reproductive organs were observed during repeat-dose toxicity studies in female and male animals. The clinical relevance of these effects is unknown. Male and female patients who are planning to conceive a child should be advised to seek reproductive counselling, and men should seek advice on cryo-preservation of sperm prior to treatment.

Vorasidenib has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The most common adverse reactions, including laboratory abnormalities, were ALT increased (59.3%), AST increased (45.5%), GGT increased (37.7%), fatigue (36.5%) and diarrhoea (24.6%).

The most common grade ≥3 adverse reactions were ALT increased (9.6%), AST increased (4.2%) and GGT increased (3.0%).

Serious adverse reactions of ALT increased occurred in 0.6% of patients who received vorasidenib.

Permanent discontinuation of vorasidenib due to grade ≥3 ALT increased was reported in 3.0% of patients.

Dose interruptions due to an adverse reaction occurred in 18.6% of patients treated with vorasidenib. The most common adverse reactions requiring dose interruption were ALT increased (14.4%) and AST increased (6.0%).

Dose reductions of vorasidenib due to an adverse reaction occurred in 9.6% of patients. The most common adverse reaction requiring dose reduction was ALT increased (7.8%).

Tabulated list of adverse reactions

Adverse reactions reported in patients treated with vorasidenib are listed below in the table by MedDRA system organ class and by frequency.

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions reported in patients treated with vorasidenib in the INDIGO trial (Study AG881-C-004) (N=167):

^a Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown.

Description of selected adverse reactions

Hepatobiliary disorders

In Study AG881-C-004, of the 167 patients treated with vorasidenib, 18.6% experienced elevations in ALT >3 times the ULN and 8.4% experienced elevations in AST >3 times the ULN. Among these patients, 1.2% had concurrent elevations in ALT or AST >3 times the ULN and total bilirubin >2 times the ULN. Liver enzyme and bilirubin increases were transient and improved or resolved with dose modification or permanent discontinuation of treatment. Hepatic failure and hepatic necrosis were observed in one patient treated with vorasidenib and autoimmune hepatitis was observed in one patient treated with vorasidenib.