Consumer medicine information

Calquence

Acalabrutinib

BRAND INFORMATION

Brand name

Calquence

Active ingredient

Acalabrutinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Calquence.

What is in this leaflet

This leaflet answers some common questions about CALQUENCE. It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CALQUENCE against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CALQUENCE is used for

CALQUENCE is an anticancer medicine used in adults to treat:

  • Mantle Cell Lymphoma (MCL), a type of blood cancer that affects the lymph nodes (lymph glands). It is used in patients who have had at least one other treatment for their cancer.
  • Chronic Lymphocytic Leukaemia (CLL)/Small Lymphocytic Lymphoma (SLL), a type of blood cancer that affects lymphocytes (a certain type of white blood cell) and the lymph nodes.

CALQUENCE contains the active ingredient acalabrutinib which belongs to a group of anti-cancer medicines called Bruton tyrosine kinase (BTK) inhibitors. BTK is a protein in the body that helps cancer cells to grow.

CALQUENCE works by blocking BTK which may help to reduce the number of cancer cells and may slow the spread of the cancer.

Ask your doctor, nurse or pharmacist if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

It is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children or adolescents under the age of 18 years.

Before you take CALQUENCE

When you must not take it

Do not take CALQUENCE if you have an allergy to any medicine containing acalabrutinib or other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Tell your doctor if you are pregnant or plan to become pregnant. You should not take CALQUENCE if you are pregnant and you should not get pregnant while you are taking CALQUENCE. CALQUENCE may harm your unborn baby.

Tell your doctor if you are breastfeeding or planning to breastfeed. You should not breastfeed during treatment with CALQUENCE. It is not known if CALQUENCE passes into your breast milk. Do not breast-feed during treatment with CALQUENCE and for at least 2 weeks after your final dose of CALQUENCE.

Do not take it after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor, nurse or pharmacist.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • any unusual bruising or bleeding, or you have any bleeding disorders
  • infections (bacterial, viral and/or fungal)
  • any liver problems
  • a liver infection (Hepatitis B), so that your doctor can look out for signs of reactivation of this infection, such as fever, chills, weakness, confusion, vomiting and jaundice (yellowing of the skin or eyeballs).
  • have or have had heart rhythm problems (such as atrial fibrillation)
  • any other medical conditions

Tell your doctor if you have recently undergone surgery or are planning any surgery or medical or dental procedures. Your doctor may ask you to stop taking CALQUENCE for up to 7 days before or after a medical, surgical or dental procedure as it may increase your risk of bleeding.

If you have not told your doctor, nurse or pharmacist about any of the above, tell them before you start taking CALQUENCE.

Taking other medicines

Tell your doctor, nurse or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

CALQUENCE may make you bleed more easily. This means you should tell your doctor if you take other medicines that increase your risk of bleeding. These include:

  • Medicines used to treat pain and inflammatory conditions (e.g. aspirin and non-steroidal anti-inflammatory [NSAIDS] such as ibuprofen)
  • Medicines used to prevent blood clots, such as antiplatelet therapy or blood thinners (e.g. aspirin, warfarin)

In addition, some medicines and CALQUENCE may interfere with each other. These include:

  • Medicines used to control heart rhythm disturbances (e.g. amiodarone, diltiazem, verapamil)
  • Antibiotics used to treat bacterial infections (e.g. clarithromycin, erythromycin, telithromycin, ciprofloxacin, rifampin)
  • Medicines to treat fungal infections (e.g. fluconazole, posaconazole, ketoconazole, itraconazole, voriconazole)
  • Medicines used to treat HIV infection (e.g. ritonavir, cobicistat, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, darunavir/ritonavir or fosamprenavir)
  • Medicines used to treat hepatitis C infection (e.g. telaprevir)
  • Medicines used to prevent seizures or to treat epilepsy (e.g. carbamazepine, phenytoin)
  • St. John's wort - a herbal medicine used to treat depression
  • Medicines used to reduce stomach acid, such as antacids (e.g. calcium carbonate), histamine-2 receptor blockers (e.g. ranitidine or famotidine) or certain medicines used to treat severe acid indigestion, such as proton pump inhibitors (e.g. omeprazole, esomeprazole)
  • Methotrexate, a medicine used to treat other cancers or to treat immune disorders such as rheumatoid arthritis or psoriasis.
  • Medicines used to control blood sugar in patients with diabetes (eg. metformin)

These medicines may be affected by CALQUENCE or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor, nurse and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take CALQUENCE

Follow all directions given to you by your doctor, nurse or pharmacist carefully. Check with your doctor, nurse or pharmacist if you are not sure The instructions may differ from the information contained in this leaflet.

How much to take

The usual dose is one 100 mg capsule twice a day. Doses should be taken about 12 hours apart.

How to take it

Swallow the capsule whole with water. Do not chew, dissolve, or open the capsules.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

You can check when you last took a capsule of CALQUENCE by looking at the sun and moon symbols on the blister pack. There is a sun (for the morning) and a moon (for the evening). This will tell you whether you have taken the dose.

You can take CALQUENCE with or without food.

It is important that you tell your doctor that you are taking any of the medicines mentioned in the 'Taking other medicines section', as you may need to:

  • avoid taking certain medicines including certain medicines used to treat fungal infections, or reduce stomach acid (proton pump inhibitors)
  • take your medicine at a different time to CALQUENCE including other medicines which reduce your stomach acid.
  • Temporarily increase or decrease your dose of CALQUENCE depending on which other medicine.

How long to take it

Continue taking your medicine for as long as your doctor tells you. Do not change your dose or stop taking it.

If you forget to take it

If you have missed a dose by less than 3 hours take the missed dose right away. Take the next dose at your usual time.

If you miss a dose by more than 3 hours, skip the missed dose. Take the next dose at your usual time

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor, nurse or pharmacist.

If you have trouble remembering to take your medicine, ask your nurse or pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much CALQUENCE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using CALQUENCE

Things you must do

If you are about to be started on any new medicine, remind your doctor, nurse and pharmacist that you are taking CALQUENCE.

Tell any other doctors, dentists, nurses and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

You should be careful to protect yourself from the sun. Like other cancer medicines, new cancers such as skin cancers have been known to occur in patients taking CALQUENCE.

If you are about to have any blood tests, tell your doctor and nurse that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked.

Things to be careful of

Be careful driving or operating machinery until you know how CALQUENCE affects you. CALQUENCE is unlikely to affect the ability to drive and use machines. However, if you feel dizzy, weak or tired while taking CALQUENCE, take special care when driving or using machines.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking CALQUENCE.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

  • Infection, signs include fever, chills, or flu-like symptoms
  • headache
  • nausea, vomiting
  • dizziness
  • stomach pain
  • diarrhoea
  • constipation
  • rash
  • bruising
  • bleeding, including nose bleeds
  • feeling very tired (fatigue)
  • muscle and bone pain
  • joint pain
  • new cancers, including skin cancer

The above list includes the more common side effects of your medicine.

Tell your doctor, nurse or pharmacists as soon as possible if you notice any of the following:

  • signs or symptoms of serious bleeding, such as blood in your stools or urine or bleeding that lasts for a long time or that you cannot control.
  • Signs or symptoms of an infection (fungal, viral or bacterial - eg pneumonia and aspergillosis) such as fevers, chills, body aches, cold or flu symptoms, feel tired or feel short of breath.
  • Signs and symptoms of heart problems (eg atrial fibrillation) such as chest discomfort, shortness of breath or heart palpitations/change in rhythm (racing, pounding or fluttering).

The above list includes serious side effects that may require medical attention.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Like other cancer medicines, new cancers such as skin cancers have been known to occur in patients taking CALQUENCE.

Some side effects can also be found when your doctor or nurse does regular blood tests. These include:

  • decreased number of white blood cells (neutropenia).
  • decreased number of red blood cells (anaemia).
  • decreased number of platelets which are cells that help your blood to clot (thrombocytopenia).
  • Condition called tumour lysis syndrome (TLS), when there are unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment. Signs of TLS are changes in kidney function, abnormal heartbeat, or seizures.

After using CALQUENCE

Storage

Keep your capsules in a cool dry place where the temperature stays below 30°C.

Do not store CALQUENCE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

CALQUENCE is a size 1 hard gelatin capsule with a yellow body and blue cap, marked in black ink with 'ACA 100 mg'.

CALQUENCE is supplied in a carton containing 7 blister strips, each containing 8 capsules (a total of 56 capsules in a carton).

Ingredients

CALQUENCE contains 100 mg of acalabrutinib as the active ingredient.

Other ingredients:

  • silicified microcrystalline cellulose
  • pregelatinised starch
  • magnesium stearate (E572)
  • sodium starch glycollate Type A
  • The capsule consists of gelatin, titanium dioxide (E171), iron oxide yellow (E172) and indigo carmine aluminium lake (E132) with black ink (shellac, iron oxide black (E172) and polypropylene glycol)

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes (include any that are appropriate).

Supplier

CALQUENCE is supplied in Australia by:

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared on 22 November 2019.

Australian Registration Number(s):

100 mg capsules - AUST R 321419

CALQUENCE is a registered trade mark of the AstraZeneca group of companies.

© AstraZeneca, 2019

Doc ID-004136617 v2

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Calquence

Active ingredient

Acalabrutinib

Schedule

S4

 

1 Name of Medicine

Acalabrutinib.

2 Qualitative and Quantitative Composition

Each capsule contains 100 mg acalabrutinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule, hard.
Size 1 hard gelatin capsule with a yellow body and blue cap, marked in black ink with 'ACA 100 mg'.

4 Clinical Particulars

4.1 Therapeutic Indications

Calquence is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.
This indication is approved via the provisional approval pathway, based on overall response rate. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.
Calquence is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).

4.2 Dose and Method of Administration

Treatment with Calquence should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Recommended dosage (18 years and above).

Mantle cell lymphoma (MCL).

The recommended dose of Calquence for the treatment of MCL is 100 mg (1 capsule) twice daily.

Chronic lymphocytic leukemia (CLL).

The recommended dose of Calquence for the treatment of CLL is 100 mg (1 capsule) twice daily, either as monotherapy or in combination with obinutuzumab. Administer Calquence prior to obinutuzumab when given on the same day. Refer to the obinutuzumab product information for recommended obinutuzumab dosing information (for details of the combination regimen, see Section 5.1 Pharmacodynamic Properties).
Doses should be separated by approximately 12 hours.
Treatment with Calquence should continue until disease progression or unacceptable toxicity.

Missed dose.

If a patient misses a dose of Calquence by more than 3 hours, instruct the patient to take the next dose at its regularly scheduled time. Extra capsules of Calquence should not be taken to make up for a missed dose.

Dose adjustments.

Adverse reactions.

Recommended dose modifications of Calquence for Grade 3 or greater adverse reactions are provided in Table 1.

Dose adjustments for use with CYP3A inhibitors or inducers, and gastric acid reducing medicines.

Recommended dose adjustments are described in Table 2 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special patient populations.

Renal impairment.

No dose adjustment is recommended in patients with mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics and safety of Calquence in patients with severe renal impairment (eGFR < 29 mL/min/1.73 m2) or end-stage renal disease have not been studied (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST). It is not recommended to administer Calquence in patients with severe hepatic impairment (Child-Pugh C or total bilirubin > 3 times ULN and any AST) (see Section 5.2 Pharmacokinetic Properties).

Severe cardiac disease.

Patients with severe cardiovascular disease were excluded from Calquence clinical studies.

Use in the elderly.

No dose adjustment is necessary based on age (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Calquence in children and adolescents aged less than 18 years have not been established.

Method of administration.

Calquence should be swallowed whole with water at approximately the same time each day. Calquence can be taken with or without food. The capsule should not be chewed, dissolved, or opened.

4.3 Contraindications

None.

4.4 Special Warnings and Precautions for Use

Haemorrhage.

Serious haemorrhagic events, including fatal events, have occurred in the combined safety database of 1040 patients with hematologic malignancies treated with Calquence monotherapy. Major haemorrhage (Grade 3 or higher bleeding events, serious, or any central nervous system events) occurred in 3.6% of patients, with fatalities occurring in 0.1% of patients. Overall, bleeding events including bruising and petechiae of any grade occurred in 46% of patients with haematological malignancies.
The mechanism for the bleeding events is not well understood. Use of antithrombotic agents concomitantly with Calquence may increase the risk of haemorrhage. In Calquence clinical trials, 3% of patients taking Calquence without antithrombotic agents experienced major haemorrhage. The addition of antithrombotic agents increased the percentage to 4.3%. Consider the risks and benefits of antithrombotic agents when co-administered with Calquence. Patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding Calquence for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infection.

Serious infections (bacterial, viral or fungal), including fatal events have occurred in the combined safety database of 1040 patients with haematologic malignancies treated with Calquence monotherapy. Consider prophylaxis in patients who are at increased risk for opportunistic infections.
Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation, aspergillosis, and progressive multifocal leukoencephalopathy (PML) have occurred. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Cytopenias.

In the combined safety database of 1040 patients with haematologic malignancies, patients treated with Calquence monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (21%), anaemia (10%) and thrombocytopenia (7%) based on laboratory measurements. Monitor complete blood counts as medically appropriate during treatment.

Second primary malignancies.

Second primary malignancies, including non-skin cancers, occurred in 12% of patients with haematologic malignancies treated with Calquence monotherapy in the combined safety database of 1040 patients. The most frequent second primary malignancy was skin cancer, which occurred in 7% of patients. Monitor patients for the appearance of skin cancers. Advise protection from sun exposure.

Atrial fibrillation and flutter.

In the combined safety database of 1040 patients with haematologic malignancies treated with Calquence monotherapy, Grade 3 atrial fibrillation and atrial flutter occurred in 1% of patients and Grade 1 or 2 in 3% of patients. Monitor for symptoms (e.g. palpitations, dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an ECG as appropriate.

Use in the elderly.

Of the 1040 patients in clinical trials of Calquence monotherapy, 41% were ≥ 65 years of age 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.

Paediatric use.

The safety and efficacy of Calquence in children and adolescents aged less than 18 years have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions with CYP3A inhibitors and inducers, or gastric acid reducing medicines.

The clinical impact and prevention or management of interactions with CYP3A inhibitors or inducers, or gastric acid reducing medicines are provided in Table 3 and Table 4 respectively. Also see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Effects of acalabrutinib and its active metabolite, ACP-5862, on CYP450 and UGT enzymes.

In vitro data indicate no relevant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A2 or UGT2B7 by acalabrutinib or ACP-5862 at therapeutic concentrations. Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.

Effects of acalabrutinib and its active metabolite, ACP-5862, on drug transport systems.

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g. methotrexate) by inhibition of intestinal BCRP.
ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g. metformin) by inhibition of MATE1.
In vitro, acalabrutinib and ACP-5862 are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1 and OATP1B3. ACP-5862 is not a substrate of OATP1B1 or OATP1B3. Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3 and MATE2-K at clinically relevant concentrations.

Effect of food on acalabrutinib.

In healthy subjects, administration of a single 75 mg dose of acalabrutinib with a high fat, high calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 73% and Tmax was delayed 1-2 hours.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 16-times, or in female rats at exposures 14-times the AUC observed in patients at the recommended dose of 100 mg twice daily.
(Category C)
Based on findings in animals, Calquence may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to pregnant rabbits during organogenesis resulted decreased fetal body weights and delayed skeletal ossification at maternal exposures (AUC) approximately 3.6 times exposures in patients at the recommended dose of 100 mg twice daily. This dose was maternotoxic. Dystocia was observed in a rat study (see below). Advise pregnant women of the potential risk to a fetus.
In a combined fertility and embryofetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting prior to mating through the period of organogenesis. No effects on embryofetal development or survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 16-times the AUC in patients at the recommended dose of 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.
In a rat reproductive study involving dosing animals from implantation throughout gestation, parturition and lactation, dystocia (prolonged/difficult labour) was observed at ≥ 100 mg/kg/day, yielding exposures > 3.5-times the clinical exposure at 100 mg twice daily. Dystocia was not observed in rats at 50 mg/kg/day, associated with exposures approximately equivalent to the clinical exposure at 100 mg twice daily.
 No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from Calquence, advise lactating women not to breastfeed while taking Calquence and for at least 2 weeks after the final dose.

4.7 Effects on Ability to Drive and Use Machines

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 observe caution when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Mantle cell lymphoma (MCL).

The safety data described in this section reflect exposure to Calquence (100 mg twice daily) in 124 patients with previously treated MCL in ACE-LY-004 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of treatment with Calquence was 16.6 (range 0.1 to 26.6) months. A total of 91 (73.4%) patients were treated with Calquence for ≥ 6 months and 74 (59.7%) patients were treated for ≥ 1 year.
The most common adverse reactions (≥ 20%) of any grade were anaemia, thrombocytopenia, headache, neutropenia, diarrhoea, fatigue, myalgia, and bruising. Grade 1 severity for the non-haematologic, most common events were as follows: headache (25%), diarrhoea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-haematological adverse reaction (reported in at least 2% of patients) was diarrhoea.
Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.
Table 5 and Table 6 present the frequency category of adverse reactions observed in patients with MCL treated with Calquence.
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

Chronic lymphocytic leukemia (CLL).

The safety data described below reflect exposure to Calquence (100 mg twice daily) in two randomized controlled clinical trials (ELEVATE-TN and ASCEND) in patients with CLL (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The most common adverse reactions (≥ 20%) of any grade were infection, neutropenia, anaemia, thrombocytopenia, headache, diarrhoea, musculoskeletal pain, bruising, and nausea. The most commonly reported Grade ≥ 3 adverse reactions were infection, neutropenia, and anaemia.

ELEVATE-TN (patients with previously untreated CLL).

The safety of Calquence plus obinutuzumab (Calquence+G), Calquence monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicentre, open-label, phase 3 study, in 526 patients with previously untreated CLL. Details of the study treatment are described, see Section 5.1 Pharmacodynamic Properties, Clinical trials.
In the Calquence+G arm, adverse events led to regimen discontinuation in 11% of patients and a dose reduction of Calquence in 8% of patients. In the Calquence monotherapy arm, adverse events led to discontinuation in 9% and dose reduction in 3% of patients. In the GClb arm, adverse events led to regimen discontinuation in 14% of patients and a dose reduction of chlorambucil in 28% of patients. There were no dose reductions for obinutuzumab.
The adverse reactions described in Table 7 and Table 8 reflect exposure to Calquence in the Calquence+G and Calquence monotherapy arms with a median duration of exposure of 27.7 months in patients with previously untreated CLL. The median duration of exposure in the GClb arm was 5.6 months.

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) was reported in 2% of patients treated with Calquence+G. No patients experienced TLS in the Calquence monotherapy arm.

Atrial fibrillation/atrial flutter.

Atrial fibrillation/atrial flutter was reported in patients treated with Calquence+G and Calquence monotherapy with an incidence of 3% and 4%, respectively, including 1% with ≥ Grade 3 atrial fibrillation/atrial flutter in the Calquence+G arm. No patients experienced ≥ Grade 3 atrial fibrillation/atrial flutter in the Calquence monotherapy arm.

Infusion related reaction.

Infusion related reaction was reported in 14% and 40% of patients in the Calquence+G and GClb arms, respectively.

ASCEND (patients with CLL who received at least one prior therapy).

The safety of Calquence versus investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab was evaluated in a randomised, multicentre, open-label, phase 3 study, in 307 patients with relapsed or refractory CLL. Details of the study treatment are described, see Section 5.1 Pharmacodynamic Properties, Clinical trials.
In the Calquence arm, adverse events led to discontinuation in 10% and dose reduction in 3% of patients. In patients receiving idelalisib plus rituximab, adverse events led to regimen discontinuation in 9% of patients and a dose reduction of idelalisib in 24%. In patients receiving bendamustine plus rituximab, adverse events led to regimen discontinuation in 9% of patients and a dose reduction of bendamustine in 14% of patients. There were no dose reductions of rituximab.
The adverse reactions described in Table 9 and Table 10 reflect exposure to Calquence with a median duration of 15.7 months, exposure to idelalisib with a median duration of 11.5 months, exposure to rituximab with a median duration of 5.5 months, and exposure to bendamustine and a median duration of 5.6 months in patients with relapsed or refractory CLL.

Tumour lysis syndrome.

TLS was reported in patients treated with Calquence and idelalisib plus rituximab with an incidence of 1% in both arms. The one patient experiencing TLS treated with Calquence had Grade 3 TLS and bulky disease.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific treatment for acalabrutinib overdose and symptoms of overdose have not been established. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Acalabrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumour growth in mouse xenograft models.

Pharmacodynamics.

In patients with B-cell malignancies dosed with 100 mg twice daily, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.

Cardiac electrophysiology.

The effect of acalabrutinib on the QTc interval was evaluated in a randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of a single dose of acalabrutinib that is the 4-fold maximum recommended single dose did not prolong the QTc interval to any clinically relevant extent (i.e. ≥ 10 ms).

Clinical trials.

Mantle cell lymphoma (MCL).

The safety and efficacy of Calquence in MCL were evaluated in an open-label, multi-centre, single-arm Phase 2 study (ACE-LY-004) of 124 previously treated patients. All patients received Calquence 100 mg orally twice daily until disease progression or unacceptable toxicity. The trial did not include patients who received prior treatment with BTK inhibitors. The primary endpoint was investigator-assessed overall response rate (ORR) per the Lugano classification for non-Hodgkin's lymphoma (NHL). Duration of Response (DoR) was an additional outcome measure. Efficacy results are presented in Table 11.
The median age was 68 (range 42 to 90) years, 79.8% were male and 74.2% were Caucasian. At baseline, 92.8% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1 to 5), including 17.7% with prior stem cell transplant. The most common prior regimens were CHOP-based (51.6%) and ARA-C (33.9%). At baseline, 37.1% of patients had at least one tumour with a longest diameter ≥ 5 cm, 72.6% had extra nodal involvement including 50.8% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 43.5% and high in 16.9% of patients. The median dose intensity was 98.5%.

Lymphocytosis.

Upon initiation of Calquence, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count (ALC) increased ≥ 50% from baseline and a post baseline assessment ≥ 5x109) in 31.5% of patients in ACE-LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.

Chronic lymphocytic leukemia (CLL).

Patients with previously untreated CLL.

The safety and efficacy of Calquence in previously untreated CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients received Calquence plus obinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older or between 18 and 65 years of age with coexisting medical conditions were included in ELEVATE-TN. The trial also allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
Patients were randomised in a 1:1:1 ratio into 3 arms to receive:
Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.
Calquence monotherapy: Calquence 100 mg was administered twice daily until disease progression or unacceptable toxicity.
Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days.
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). After confirmed disease progression, 45 patients randomised on the GClb arm crossed over to Calquence monotherapy. Table 12 summarizes the baseline demographics and disease characteristics of the study population.
The primary endpoint was progression-free survival (PFS) of Calquence+G arm versus GClb arm as assessed by an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS by IRC indicated a 90% statistically significant reduction in the risk of disease progression or death for previously untreated CLL patients in the Calquence+G arm compared to the GClb arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 37 deaths: 9 (5%) in the Calquence+G arm, 11 (6.1%) in the Calquence monotherapy arm, and 17 (9.6%) in the GClb arm. Efficacy results are presented in Table 13. The Kaplan-Meier curves for PFS are shown in Figure 1.
PFS results for Calquence with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HRs of Calquence with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.15 [95% CI (0.09, 0.25)], respectively.

Patients with CLL who received at least one prior therapy.

The safety and efficacy of Calquence in relapsed or refractory CLL were evaluated in a randomised, multi-centre, open-label phase 3 study (ASCEND) of 310 patients who received at least one prior therapy. Patients received Calquence monotherapy or investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab. The trial allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
Patients were randomised 1:1 to receive either:
Calquence 100 mg twice daily until disease progression or unacceptable toxicity; or
Investigator's choice: idelalisib 150 mg twice daily until disease progression or unacceptable toxicity in combination with ≤ 8 infusions of rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles.
Bendamustine 70 mg/m2 (Day 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles.
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥ 4). After confirmed disease progression, 35 patients randomised on investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab crossed over to Calquence. Table 14 summarizes the baseline demographics and disease characteristics of the study population.
The primary endpoint was PFS as assessed by IRC IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 16.1 months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the Calquence arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 33 deaths: 15 (9.7%) in the Calquence monotherapy arm and 18 (11.6%) in the investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab arm. Efficacy results are presented in Table 15. The Kaplan-Meier curve for PFS is shown in Figure 2.
PFS results for Calquence were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HR was 0.27 [95% CI (0.17, 0.44)].

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862 were studied in healthy subjects and patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose). Population PK modelling suggests that the PK of acalabrutinib and ACP-5862 does not differ significantly in patients with different B-cell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including MCL and CLL), the geometric mean steady state daily area under the plasma drug concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) of acalabrutinib were 1893 nanogram.h/mL and 466 nanogram/mL, respectively, and for ACP-5862 were 4091 nanogram.h/mL and 420 nanogram/mL, respectively.

Absorption.

The median time to peak plasma concentrations (Tmax) was 0.75 hours for Calquence, and 1.0 hour for ACP-5862. The absolute bioavailability of Calquence was 25%.

Distribution.

Reversible binding to human plasma protein was 97.5% for acalabrutinib and 98.6% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The mean steady-state volume of distribution (Vss) was approximately 34 L for acalabrutinib.

Metabolism.

In vitro, acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.
Acalabrutinib may inhibit intestinal BCRP substrates (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), while ACP-5862 may inhibit MATE1 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.

Excretion.

Following a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life (t½) of acalabrutinib was 0.9 (range: 0.6 to 2.8) hours. The median t½ of the active metabolite, ACP-5862, was 6.9 hours (range: 2.7 to 9.1) hours.
The mean apparent oral clearance (CL/F) was 70 L/hr for acalabrutinib and 13 L/hr for ACP-5862, with similar PK between patients and healthy subjects, based on population PK analysis.
Following administration of a single 100 mg radiolabelled [14C]-acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the faeces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and faeces.

Specific populations.

Age, race, and body weight.

Age (32 to 90 years), sex, race (Caucasian, African American), and body weight (40 to 149 kg) did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862, based on population PK analysis.

Renal impairment.

Acalabrutinib undergoes minimal renal elimination. Based on population PK analysis, no clinically relevant PK difference was observed in 543 patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR < 29 mL/min/1.73 m2, MDRD) or renal impairment requiring dialysis.

Hepatic impairment.

Acalabrutinib is metabolized in the liver. In hepatic impairment studies, compared to subjects with normal liver function (n=6), acalabrutinib exposure (AUC) was increased by 1.9-fold, 1.5-fold, and 5.3-fold in subjects with mild (n=6) (Child-Pugh A), moderate (n=6) (Child-Pugh B) and severe (n=8) (Child-Pugh C) hepatic impairment, respectively. Based on a population PK analysis, no clinically relevant PK difference was observed in subjects with mild (n=79) or moderate (n=6) hepatic impairment (total bilirubin between 1.5 to 3 times the upper limit of normal [ULN] and any AST) relative to subjects with normal (n=651) hepatic function (total bilirubin and AST within ULN).

Drug interaction studies.

Effect of CYP3A inhibitors on acalabrutinib.

Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.
Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax and AUC increased by 2- to almost 3-fold (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effect of CYP3A inducers on acalabrutinib.

Co-administration with a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gastric acid reducing medicines.

Acalabrutinib solubility decreases with increasing pH. Co-administration with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43% (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay.

Carcinogenicity.

Carcinogenicity studies have not been conducted with acalabrutinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Silicified microcrystalline cellulose, pregelatinised starch, magnesium stearate (E572), and sodium starch glycollate Type A.

Capsule.

Shell: gelatin, titanium dioxide (E171), iron oxide yellow (E172) and indigo carmine aluminium lake (E132); Ink: shellac, iron oxide black (E172) and propylene glycol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Polyamide-aluminium-polyvinylchloride/aluminium blisters. Cartons of 56 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

CAS 1420477-60-6.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes