Acalabrutinib

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP. To minimise the potential for an interaction in the Gastrointestinal (GI) tract, oral narrow therapeutic range BCRP substrates such as methotrexate should be taken at least 6 hours before or after acalabrutinib.

The active metabolite of acalabrutinib, ACP-5862, may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1. Patients taking concomitant medicinal products with disposition dependent upon MATE1 (e.g., metformin) should be monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving acalabrutinib.

In vitro studies indicate that acalabrutinib induces CYP1A2. Co-administration of acalabrutinib with CYP1A2 substrates (e.g., theophylline, caffeine) may decrease their exposure.

Based on in vitro data, it cannot be excluded that acalabrutinib is an inhibitor of CYP3A4 at the intestinal level and may increase the exposure of CYP3A4 substrates sensitive to gut CYP3A metabolism. Caution should be exercised if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeutic range administered orally (e.g., cyclosporine, ergotamine, pimozide).

Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mg isavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib C_max and AUC by 1.4-fold to 2-fold while the active metabolite ACP-5862 C_max and AUC was decreased by 0.65-fold to 0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions.

Co-administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreased acalabrutinib C_max and AUC by 68% and 77% in healthy subjects (N=24), respectively.

Concomitant use with strong inducers of CYP3A activity (e.g., phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant treatment with St. John’s wort, which may unpredictably decrease acalabrutinib plasma concentrations, should be avoided.

Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Use caution with antithrombotic agents and consider additional monitoring for signs of bleeding when concomitant use is medically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantly with acalabrutinib.

Consider the benefit-risk of withholding acalabrutinib for at least 3 days pre- and post-surgery.

There are no or limited amount of data from the use of acalabrutinib in pregnant women. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy. Dystocia (difficult or prolonged labour) was observed in the rat and administration to pregnant rabbits was associated with reduced foetal growth.

Acalabrutinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib.

It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed child or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the breast-fed child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with acalabrutinib and for 2 days after receiving the last dose.

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving acalabrutinib.

Fertility

There are no data on the effect of acalabrutinib on human fertility. In a non-clinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed.

Acalabrutinib has no or negligible influence on the ability to drive and use machines. However, during treatment with acalabrutinib, fatigue and dizziness have been reported and patients who experience these symptoms should be advised not to drive or use machines until symptoms abate.

Summary of the safety profile

Of the 1040 patients treated with acalabrutinib monotherapy, the most common (≥20%) adverse drug reactions (ADRs) of any grade reported in patients were infection (66.7%), headache (37.8%), diarrhoea (36.7%), bruising (34.1%), musculoskeletal pain (33.1%), nausea (21.7%), fatigue (21.3%), cough (21%) and rash (20.3%). The most commonly reported (≥5%) Grade ≥ 3 adverse drug reactions were infection (17.6%), leukopenia (14.3%), neutropenia (14.2%), and anaemia (7.8%).

Of the 223 patients treated with acalabrutinib combination therapy, the most common (≥20%) ADRs of any grade reported in patients were infection (74%), musculoskeletal pain (44.8%), diarrhoea (43.9%), headache (43%), leukopenia (31.8%), neutropenia (31.8%), cough (30.5%), fatigue (30.5%), arthralgia (26.9%), nausea (26.9%), dizziness (23.8%), and constipation (20.2%). The most commonly reported (≥5%) Grade ≥ 3 adverse drug reactions were leukopenia (30%), neutropenia (30%), infection (21.5%), thrombocytopenia (9%) and anaemia (5.8%).

Tabulated list of adverse reactions

The following adverse drug reactions (ADRs) have been identified in clinical studies with patients receiving acalabrutinib as treatment for haematological malignancies. The median duration of acalabrutinib treatment across the pooled dataset was 26.2 months.

Adverse drug reactions are listed according to system organ class (SOC) in MedDRA. Within each system organ class, the adverse drug reactions are sorted by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is 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.

Table 1. Adverse drug reactions* of patients with haematological malignancies treated with acalabrutinib monotherapy (n=1040):

^* Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
^† Includes multiple ADR term.
^± One case of drug-induced Tumour Lysis Syndrome was observed in acalabrutinib arm in the ASCEND Study.
^§ Represents the incidence of laboratory findings, not of reported adverse events.
^¶ Presented as CTCAE grade values.

Table 2. Adverse drug reactions* of patients with haematological malignancies treated with acalabrutinib combination therapy (n=223):

^* Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
^† Includes multiple ADR term.
^± One case of drug-induced Tumour Lysis Syndrome was observed in the acalabrutinib arm in the ASCEND Study.
^§ Represents the incidence of laboratory findings, not of reported adverse events.
^¶ Presented as CTCAE grade values.

Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 1,040 patients treated with acalabrutinib monotherapy, discontinuation due to adverse reactions were reported in 9.3% of the patients. These main adverse reactions included pneumonia, thrombocytopenia and diarrhoea. Dose reductions due to adverse reactions were reported in 4.2% of patients. These main adverse reactions included hepatitis B reactivation, sepsis, and diarrhoea.

Of the 223 patients treated with acalabrutinib combination, discontinuation due to adverse reactions were reported in 10.8% of the patients. These main adverse reactions included pneumonia, thrombocytopenia and diarrhoea. Dose reductions due to adverse reactions were reported in 6.7% of patients. These main adverse reactions included neutropenia, diarrhoea and vomiting.

Elderly

Of the 1,040 patients in clinical studies of acalabrutinib monotherapy, 41% were greater than 65 years and less than 75 years of age and 22% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger.

Of the 223 patients in clinical studies of acalabrutinib in combination of obinutuzumab therapy, 47% were greater than 65 years and less than 75 years of age and 26% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients and ≥65 years and younger.