CALQUENCE Film-coated tablet Ref.[51594] Active ingredients: Acalabrutinib

Haemorrhage

Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcome, have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with obinutuzumab. These events have occurred in patients both with and without thrombocytopenia. Overall, the bleeding events were less severe events including bruising and petechiae (see section 4.8).

The mechanism for the bleeding events is not well understood.

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 Calquence.

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

Infections

Serious infections (bacterial, viral or fungal), including fatal events have occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with obinutuzumab. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred (see section 4.8).

Viral reactivation

Cases of hepatitis B reactivation have been reported in patients receiving Calquence. Hepatitis B virus (HBV) status should be established before initiating treatment with Calquence. If patients have positive hepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of Calquence within the context of a prior or concomitant immunosuppressive therapy. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, then appropriate diagnostic evaluations should be undertaken and treatment with Calquence should be suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be considered.

Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Cytopenias

Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia, occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor complete blood counts as medically indicated (see section 4.8).

Second primary malignancies

Second primary malignancies, including skin and non-skin cancers, occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Skin cancers were commonly reported. Monitor patients for the appearance of skin cancers and advise protection from sun exposure (see section 4.8).

Atrial fibrillation

Atrial fibrillation/flutter occurred in patients with haematologic malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor for symptoms (e.g., palpitations, dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an ECG as medically indicated (see sections 4.5 and 4.2). In patients who develop atrial fibrillation on therapy with Calquence, a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk for thromboembolic disease, tightly controlled treatment with anticoagulants and alternative treatment options to Calquence should be considered.

Other medicinal products

Co-administration of strong CYP3A inhibitors with Calquence may lead to increased acalabrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3A inducers may lead to decreased acalabrutinib exposure and consequently a risk for lack of efficacy. Concomitant use with strong CYP3A inhibitors should be avoided. If these inhibitors will be used shortterm (such as anti-infectives for up to seven days), treatment with Calquence should be interrupted. Patients should be closely monitored for signs of toxicity if a moderate CYP3A inhibitor is used (see sections 4.2 and 4.5). Concomitant use with strong CYP3A4 inducers should be avoided due to risk for lack of efficacy.

Calquence contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Acalabrutinib and its active metabolite are primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4), and both substances are substrates for P-gp and breast cancer resistance protein (BCRP).

Active substances that may increase acalabrutinib plasma concentrations

CYP3A/P-gp inhibitors

Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib C_max and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively.

Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gp inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (see section 4.2).

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 (see Section 4.2).

Active substances that may decrease acalabrutinib plasma concentrations

CYP3A inducers

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.

Gastric acid reducing medicinal products

No clinically significant differences in acalabrutinib pharmacokinetics were observed when a 100 mg acalabrutinib tablet was used concomitantly with a proton pump inhibitor (rabeprazole 20 mg twice daily for 3 days). Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H₂-receptor antagonists, antacids), unlike aclabrutinib capsules which show impaired uptake when given with acid reducing agents

Active substances whose plasma concentrations may be altered by Calquence

CYP3A substrates

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).

Effect of acalabrutinib on CYP1A2 substrates

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

Effects of acalabrutinib and its active metabolite, ACP-5862, on medicinal product transport systems

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP (see section 5.2). 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.

ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see section 5.2). 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 Calquence.

Women of childbearing potential

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

Pregnancy

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 (see section 5.3).

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

Breast-feeding 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 Calquence and for 2 days after receiving the last dose.

Fertility

There are no data on the effect of Calquence on human fertility. In a non-clinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed (see section 5.3).

Calquence 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 Calquence 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 Calquence 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 Calquence as treatment for haematological malignancies. The median duration of Calquence 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 3. 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 4. 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 Calquence 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 Calquence 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 Calquence 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 Calquence 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.