Bacrelba 20 mg & 40 mg Tablets

BACRELBA is indicated for the treatment of adult patients with:

• Newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in chronic phase (CP).
• Ph+ CML in CP harbouring the T315I mutation.

Posology

Treatment with BACRELBA should be initiated by a medical practitioner experienced in the use of anticancer therapies.

General target population

Ph+ CML-CP

The recommended total daily dose of BACRELBA is 80 mg. BACRELBA can be taken orally either as 80 mg once daily at approximately the same time each day, or as 40 mg twice daily at approximately 12-hour intervals. Patients changing from 40 mg twice daily to 80 mg once daily should start taking BACRELBA once daily approximately 12 hours after the last twice-daily dose, and then continue at 80 mg once daily. Patients changing from 80 mg once daily to 40 mg twice daily should start taking BACRELBA twice daily approximately 24 hours after the last once-daily dose and then continue at 40 mg twice daily at approximately 12-hour intervals. Any change in the dosage regimen is at the prescriberu2019s discretion, as necessary for the management of the patient.

Ph+ CML-CP harbouring the T315I mutation

The recommended dose of BACRELBA is 200 mg taken orally twice daily at approximately 12-hour intervals.

Treatment with BACRELBA should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

Missed dose

Once-daily dosage regimen: If a BACRELBA dose is missed by more than approximately 12 hours, it should be skipped and the next dose should be taken as scheduled. Twice-daily dosage regimens: If a BACRELBA dose is missed by more than approximately 6 hours, it should be skipped and the next dose should be taken as scheduled.

Dose modifications

Ph+ CML-CP

For the management of adverse drug reactions, BACRELBA dose can be reduced based on individual safety and tolerability, as described in Table 1. If adverse drug reactions are effectively managed, BACRELBA may be resumed as described in Table 1. BACRELBA should be permanently discontinued in patients unable to tolerate a total daily dose of 40 mg.

Ph+ CML-CP harbouring the T315I mutation

For the management of adverse drug reactions, BACRELBA dose can be reduced based on individual safety and tolerability, as described in Table 1. If adverse drug reactions are effectively managed, BACRELBA may be resumed as described in Table 1. BACRELBA should be permanently discontinued in patients unable to tolerate a dose of 160 mg twice daily.

BACRELBA is contraindicated in patients with hypersensitivity to asciminib or to any of the excipients listed in section 6.1.

Myelosuppression

Thrombocytopenia, neutropenia and anaemia occurred in patients receiving BACRELBA. Severe (NCI CTCAE grade 3 or 4) thrombocytopenia and neutropenia were reported during treatment with BACRELBA (see section 4.8). Myelosuppression was generally reversible and managed by temporarily withholding BACRELBA. Complete blood counts should be performed every two weeks for the first 3 months of treatment and monthly thereafter, or as clinically indicated. Patients should be monitored for signs and symptoms of myelosuppression. Based on the severity of thrombocytopenia and/or neutropenia, the BACRELBA dose should be reduced, temporarily withheld or permanently discontinued as described in Table 2 (see section 4.2).

Pancreatic toxicity

Pancreatitis and asymptomatic elevation of serum lipase and amylase, including severe reactions occurred in patients receiving BACRELBA (see section 4.8). Serum lipase and amylase levels should be assessed monthly during treatment with BACRELBA, or as clinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity. More frequent monitoring should be performed in patients with a history of pancreatitis. If serum lipase and amylase elevation are accompanied by abdominal symptoms, treatment should be temporarily withheld and appropriate diagnostic tests should be considered to exclude pancreatitis (see section 4.2).

QT prolongation

Electrocardiogram QT prolongation occurred in patients receiving BACRELBA (see section 4.8). It is recommended that an electrocardiogram is performed prior to the start of treatment with BACRELBA and monitored during treatment as clinically indicated. Hypokalaemia and hypomagnesaemia should be corrected prior to BACRELBA administration and monitored during treatment as clinically indicated. Caution should be exercised when administering BACRELBA at a total daily dose of 80 mg concomitantly with medicines known to cause torsades de pointes. Co-administration of BACRELBA at 200 mg twice daily concomitantly with medicines known to cause torsades de pointes should be avoided (see section 4.5 and 5).

Hypertension

Hypertension, including severe hypertension, occurred in patients receiving asciminib (see section 4.8). Hypertension should be monitored and managed using standard antihypertensive therapy during treatment with BACRELBA as clinically indicated.

Hypersensitivity

Hypersensitivity events occurred in 169 of 556 (30.4 %) patients receiving BACRELBA. with u2265 grade 3 events reported in 8 (1.4 %) patients. Patients should be monitored for signs and symptoms of hypersensitivity and appropriate treatment should be initiated as clinically indicated.

Hepatitis B reactivation

Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus following administration of other BCR-ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection before the start of treatment with BACRELBA. HBV carriers who require treatment with BACRELBA should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Embryo-foetal toxicity

Based on findings from animal studies, BACRELBA can cause foetal harm when administered to a pregnant woman. Pregnant women and females of reproductive potential should be advised of the potential risk to a foetus if BACRELBA is used during pregnancy or if the patient becomes pregnant while taking BACRELBA. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with BACRELBA. Sexually active females of reproductive potential should use effective contraception during treatment with BACRELBA and for at least 3 days after the last dose (see section 4.6).

Medicines that may increase asciminib plasma concentrations

Strong CYP3A4 inhibitors

Physiologically-based pharmacokinetic (PBPK) models predict that co-administration of BACRELBA at 200 mg twice daily with a strong CYP3A4 inhibitor (clarithromycin) would increase asciminib AUC tau and C max by 77 % and 49 %, respectively. Caution should be exercised during concomitant administration of BACRELBA 200 mg twice daily with strong CYP3A4 inhibitors including but not limited to clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Dose adjustment of BACRELBA is not required.

Medicines that may decrease asciminib plasma concentrations

Strong CYP3A4 inducers

Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUC inf by 14.9 %, while increasing asciminib C max by 9 % in healthy subjects receiving a single BACRELBA dose of 40 mg. PBPK models predict that co-administration of asciminib at 80 mg once daily with rifampicin would decrease asciminib AUC tau and C max by 52 % and 23 %, respectively, while co-administration of asciminib at 200 mg twice daily with rifampicin would decrease asciminib AUC tau and C max by 63 % and 47 %, respectively. Caution should be exercised during concomitant administration of BACRELBA at all recommended doses with strong CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin or St. Johnu2019s wort (Hypericum perforatum). Dose adjustment of BACRELBA is not required.

Medicines that may have their plasma concentrations altered by asciminib

CYP3A4 substrates with narrow therapeutic index

Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased midazolam AUC inf and C max by 28 % and 11 %, respectively, in healthy subjects receiving BACRELBA 40 mg twice daily. PBPK models predict that co-administration of asciminib at 80 mg once daily would increase midazolam AUC inf and C max by 24 % and 17 %, respectively, while co-administration of asciminib at 200 mg twice daily would increase midazolam AUC inf and C max by 88 % and 58 %, respectively. Caution should be exercised during concomitant administration of BACRELBA at all recommended doses with CYP3A4 substrates known to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substrates fentanyl, alfentanil, dihydroergotamine, or ergotamine (see section 5). Dose adjustment of BACRELBA is not required.

CYP2C9 substrates

Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUC inf and C max by 41 % and 8 %, respectively, in healthy subjects receiving BACRELBA 40 mg twice daily. PBPK models predict that co-administration of asciminib at 80 mg once daily would increase S-warfarin AUC inf and C max by 52 % and 4 %, respectively, while co-administration of asciminib at 200 mg twice-daily would increase S-warfarin AUC inf and C max by 314 % and 7 %, respectively. Caution should be exercised during concomitant administration of BACRELBA at 80 mg total daily dose with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (see section 5). Dose adjustment of BACRELBA is not required. Concomitant administration of BACRELBA at 200 mg twice daily with CYP2C9 sensitive substrates and CYP2C9 substrates known to have a narrow therapeutic index should be avoided and alternative medications should be considered (see section 5). If co-administration cannot be avoided, the CYP2C9 substrates dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of international normalized ratio (INR) monitoring should be increased as the anti-coagulant effect of warfarin may be enhanced.

Substrates of OATP1B, of BCRP or of both transporters

PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with an OATP1B substrate (pravastatin) would increase pravastatin C max by 43 % and 63 % and AUCinf by 37 % and 51 %, respectively, while co-administration of asciminib at 200 mg twice daily would increase pravastatin Cmax and AUCinf by 141 % and 137 %, respectively. PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with an OATP1B, CYP3A4 and P-gp substrate (atorvastatin) would increase atorvastatin Cmax by 97 % and 143 % and AUCinf by 81 % and 122%, respectively, while co-administration of asciminib at 200 mg twice daily would increase atorvastatin Cmax and AUCinf by 300 % and 326 %, respectively. PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a BCRP substrate (sulfasalazine) would increase sulfasalazine Cmax by 334 % and 342 % and AUCinf by 333 % and 340 %, respectively, while co-administration of asciminib at 200 mg twice daily would increase sulfasalazine Cmax and AUCinf by 353 % and 359 %, respectively. PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a BCRP and OATP1B substrate (rosuvastatin) would increase rosuvastatin Cmax by 453 % and 530 % and AUCinf by 190 % and 202 %, respectively, while co-administration of asciminib at 200 mg twice daily would increase rosuvastatin Cmax and AUCinf by 732 % and by 311 %, respectively. Caution should be exercised during concomitant administration of BACRELBA at all recommended doses with substrates of OATP1B, BCRP or both transporters, including, but not limited to sulfasalazine, methotrexate, pravastatin, atorvastatin, pitavastatin, rosuvastatin and simvastatin. Refer to OATP1B and BCRP substratesu2019 dose reductions, as recommended in their prescribing information. Concomitant administration of BACRELBA at all recommended doses with rosuvastatin should be avoided and alternative statins should be considered. If co-administration cannot be avoided, rosuvastatin dose should be reduced, as recommended in its prescribing information (see section 5.2).

P-gp substrates

Co-administration of BACRELBA with a medicine that is a substrate of P-gp may result in a clinically relevant increase in the plasma concentration of P-gp substrates, where minimal concentration changes may lead to serious toxicities (e.g. P-gp substrates with narrow therapeutic index such as digoxin).

QT prolongation

Caution should be exercised during concomitant administration of BACRELBA at 80 mg total daily dose and medicines known to cause torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide (see section 5). Concomitant administration of BACRELBA at 200 mg twice-daily dose and medicines known to cause torsades de pointes should be avoided (see section 5).

Drug-food interactions

The bioavailability of asciminib decreases on consumption of food (see sections 4.2 and 5).

Women of childbearing potential / contraception

The pregnancy status of women of childbearing potential should be verified prior to starting treatment with asciminib. Women of childbearing potential should be advised to use effective contraception during treatment with asciminib and for at least 3 days after stopping treatment and to avoid becoming pregnant while receiving asciminib.

Pregnancy

There are no or limited amount of data from the use of asciminib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). BACRELBA can cause foetal harm when administered to a pregnant woman. Asciminib is not recommended for use during pregnancy, or in women of childbearing potential not using contraception. The patient should be advised of a potential risk to the foetus if asciminib is used during pregnancy or if the patient becomes pregnant while taking asciminib.

Breastfeeding

It is not known if asciminib is transferred into human milk after administration of BACRELBA. There are no data on the effects of asciminib on the breastfed child or on milk production. Because of the potential for serious adverse drug reactions in the breastfed child, breast-feeding is not recommended during treatment with BACRELBA and for at least 3 days after the last dose.

Fertility

There are no data on the effect of asciminib on human fertility. In rat fertility studies, asciminib did not affect reproductive function in male and female rats (see section 5.3).

Patients experiencing dizziness, visual impairment or other undesirable effects with a potential impact on the ability to safely drive or use machines should refrain from these activities as long as these undesirable effects persist. (See section 4.8).

Summary of safety profile

The overall safety profile of BACRELBA has been evaluated in 556 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases receiving asciminib as monotherapy. It is based on the safety pool of the pivotal phase III study J12301 (ASC4FIRST) (N = 200 newly diagnosed Ph+ CML-CP patients), the pivotal phase III study A2301 (ASCEMBL) (N = 156 Ph+ CML-CP patients previously treated with two or more TKIs) and the phase I study X2101, including patients with:

• Ph+ CML-CP (N = 115),
• Ph+ CML-CP harbouring the T315I mutation (N = 70),
• Ph+ CML-AP (N = 15).

The safety pool (N = 556) includes patients receiving BACRELBA at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily. In the pooled dataset, the median duration of exposure to BACRELBA was 83.29 weeks (range: 0.1 to 439 weeks), with 79.3 % of patients exposed for at least 48 weeks and 42.4 % of patients exposed for at least 96 weeks, respectively.

The most common adverse drug reactions of any grade (incidence u2265 20 %) in patients receiving BACRELBA were musculoskeletal pain (32.9 %), thrombocytopenia (28.1 %), fatigue (25 %), upper respiratory tract infections (23.7 %), headache (21.8 %), neutropenia (21.6 %), and diarrhoea (22.5 %). The most common adverse drug reactions of u2265 grade 3 (incidence u2265 5 %) in patients receiving BACRELBA were thrombocytopenia (16.5 %), neutropenia (13.7 %), increased pancreatic enzymes (9.4 %) and hypertension (8.6 %). Serious adverse drug reactions occurred in 9.5 % of patients receiving BACRELBA. The most frequent serious adverse drug reactions (incidence u2265 1 %) were pleural effusion (1.6 %), lower respiratory tract infections (1.4 %), thrombocytopenia (1.3 %), pancreatitis (1.1 %) and pyrexia (1.1 %).

Tabulated summary of adverse reactions

Adverse drug reactions from clinical studies (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); very rare (< 1/10,000).

There is limited experience of BACRELBA overdose. In clinical studies, BACRELBA has been administered at doses up to 280 mg twice daily with no evidence of increased toxicity. General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.