Consumer medicine information

Calquence Tablets

Acalabrutinib

BRAND INFORMATION

Brand name

Calquence Tablets

Active ingredient

Acalabrutinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Calquence Tablets.

SUMMARY CMI

CALQUENCE® Tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using CALQUENCE tablets?

CALQUENCE tablets contain the active ingredient acalabrutinib maleate monohydrate. CALQUENCE tablets are used to treat Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukaemia (CLL)/Small Lymphocytic Lymphoma (SLL).

For more information, see Section 1. Why am I using CALQUENCE tablets? in the full CMI.

2. What should I know before I use CALQUENCE tablets?

Do not use if you have ever had an allergic reaction to CALQUENCE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use CALQUENCE tablets? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CALQUENCE tablets and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use CALQUENCE tablets?

  • The usual dose is one 100 mg tablet twice a day. Doses should be taken about 12 hours apart.
  • Swallow the tablet whole with water. Do not chew, crush, dissolve, or divide the tablets.

More instructions can be found in Section 4. How do I use CALQUENCE tablets? in the full CMI.

5. What should I know while using CALQUENCE?

Things you should do
  • Remind any doctor, dentist, nurse, surgeon or pharmacist you visit that you are using CALQUENCE tablets.
  • You should be careful to protect yourself from the sun.
Things you should not do
  • Do not stop using this medicine or change the dose without checking with your doctor.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take it after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.
Driving or using machines
  • Be careful driving or operating machinery until you know how CALQUENCE tablets affects you.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.
  • Do not store CALQUENCE tablets or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car.

For more information, see Section 5. What should I know while using CALQUENCE tablets? in the full CMI.

6. Are there any side effects?

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. Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you: fever, chills, headache, nausea, vomiting, dizziness, stomach pain, diarrhoea, constipation, rash, bruising, bleeding, fatigue, muscle and bone pain, joint pain, new cancers. Tell your doctor, nurse or pharmacist as soon as possible if you notice any of the following: signs or symptoms of serious bleeding, infection or heart problems.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

CALQUENCE® Tablets

Active ingredient(s): acalabrutinib maleate monohydrate

This medicine has provisional registration in Australia for (CALQUENCE is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy). The decision to provisionally register this new use of the medicine has been made on the basis of promising results from preliminary studies. More evidence is required to be submitted when available to substantiate the benefit of the medicine for this use.

Consumer Medicine Information (CMI)

This leaflet provides important information about using CALQUENCE tablets. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using CALQUENCE tablets.

Where to find information in this leaflet:

1. Why am I using CALQUENCE tablets?
2. What should I know before I use CALQUENCE tablets?
3. What if I am taking other medicines?
4. How do I use CALQUENCE tablets?
5. What should I know while using CALQUENCE tablets?
6. Are there any side effects?
7. Product details

1. Why am I using CALQUENCE?

CALQUENCE tablets contain the active ingredient acalabrutinib maleate monohydrate.

CALQUENCE 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.

CALQUENCE tablets are used 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.

2. What should I know before I use CALQUENCE?

Do not use CALQUENCE tablets if:

  • you are pregnant or intend to become pregnant
  • you are breastfeeding
  • you are allergic to acalabrutinib, or any of the 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.

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

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes
  • have any other medical conditions such as:
    - 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
  • take any medicines for any other condition
  • have recently undergone surgery or are planning any surgery or medical or dental procedures.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

You should not take CALQUENCE tablets if you are pregnant and you should not get pregnant while you are taking CALQUENCE tablets.

CALQUENCE tablets may harm your unborn baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed during treatment with CALQUENCE tablets.

It is not known if CALQUENCE tablets pass into your breast milk. Do not breast-feed during treatment with CALQUENCE tablets and for at least 2 weeks after your final dose of CALQUENCE tablets.

3. What if I am taking other medicines?

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

Some medicines may interfere with CALQUENCE tablets and affect how it works.

  • 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
  • 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)

CALQUENCE tablets 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).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect CALQUENCE tablets.

4. How do I use CALQUENCE tablets?

Your doctor has prescribed CALQUENCE film-coated tablets for you. Please note CALQUENCE is also available as a 100 mg capsule and should not be interchanged with CALQUENCE film-coated tablets.

How much to take

  • The usual dose is one 100 mg tablet twice a day.

Follow the instructions provided and use CALQUENCE tablets until your doctor tells you to stop. Check with your doctor, nurse or pharmacist if you are not sure.

The instructions may differ from the information contained in this leaflet.

When to take CALQUENCE tablets

  • CALQUENCE tablets should be taken about 12 hours apart.
  • 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 tablet of CALQUENCE tablets 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.

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
  • take your medicine at a different time to CALQUENCE tablets
  • Temporarily decrease your dose of CALQUENCE depending on which other medicine.

How to take / use CALQUENCE tablets

  • Swallow the tablet whole with water. Do not chew, dissolve, divide, or crush the tablets.
  • You can take CALQUENCE with or without food.

If you forget to use CALQUENCE tablets

CALQUENCE tablets should be used regularly at the same time each day.

If you miss a dose by more than 3 hours, skip the dose you missed and take your next dose when you are meant to.

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

If you take too much CALQUENCE tablets

If you think that you have used too much CALQUENCE tablets, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using CALQUENCE tablets?

Things you should do

  • You should be careful to protect yourself from the sun.
  • If you are about to be started on any new medicine, remind your doctor, nurse and pharmacist that you are taking CALQUENCE tablets.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • 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.

Call your doctor straight away if you:

  • become pregnant while taking this medicine,

Remind any doctor, nurse, dentist or pharmacist you visit that you are using CALQUENCE tablets.

Things you should not do

  • Do not stop using this medicine or change the dose without checking with your doctor.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • 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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CALQUENCE tablets affects you.

CALQUENCE may cause dizziness, weakness or tiredness in some people.

Food and drink

  • You can take CALQUENCE tablets with or without food.

Looking after your medicine

Store it in a cool dry place where the temperature stays below 30°C. Keep CALQUENCE tablets away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • 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)
  • high blood pressure
  • muscle and bone pain
  • joint pain
  • new cancers, including skin cancer
The above list includes the more common side effects of your medicine.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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

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.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What CALQUENCE tablets contain

Active ingredient
(main ingredient)		acalabrutinib maleate monohydrate
Other ingredients
(inactive ingredients)		mannitol
microcrystalline cellulose
hyprolose
sodium stearylfumarate
hypromellose
copovidone
titanium dioxide
macrogol 3350
medium chain triglycerides
iron oxide yellow
iron oxide red

Do not take this medicine if you are allergic to any of these ingredients.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

What CALQUENCE looks like

The CALQUENCE 100 mg film-coated tablet is an orange, 7.5 x 13 mm, oval, biconvex tablet, debossed with ‘ACA 100’ on one side and plain on the reverse (Aust R 377410).

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

Who distributes CALQUENCE tablets

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113

Telephone:- 1800 805 342

This leaflet was prepared in August 2024.

CALQUENCE is a registered trademark of the AstraZeneca group of companies.

© AstraZeneca 2024

VV-RIM-04944888 v 3.0

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Calquence Tablets

Active ingredient

Acalabrutinib

Schedule

S4

 

1 Name of Medicine

Acalabrutinib maleate monohydrate.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains acalabrutinib maleate monohydrate equivalent to 100 mg of acalabrutinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The Calquence 100 mg film-coated tablet is an orange, 7.5 x 13 mm, oval, biconvex tablet, debossed with 'ACA 100' on one side and plain on the reverse.

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 tablet) twice daily.

Chronic lymphocytic leukemia (CLL).

The recommended dose of Calquence for the treatment of CLL is 100 mg (1 tablet) 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 tablets 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.

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 tablet should not be chewed, crushed, dissolved, or divided.

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.

The clinical impact and prevention or management of interactions with CYP3A inhibitors or inducers are provided in Table 3. 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 100 mg dose of acalabrutinib tablet 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 54% and Tmax was delayed 1-2 hours.

Gastric acid reducing medications.

Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids).

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. Clinical trials with acalabrutinib were studied with the acalabrutinib capsule formulation.

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 4 and Table 5 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 in 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 6 and Table 7 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 randomized, multicentre, open-label, Phase 3 study, in 307 patients with relapsed or refractory CLL. Details of the study treatment are described in 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 8 and Table 9 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.

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of Calquence. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular disorders.

Hypertension.

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.

Clinical trials with acalabrutinib were studied with the acalabrutinib capsule formulation.
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 10.
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 ≥ 5 x 109) 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 11 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 12. 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 13 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 14. 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.
Calquence tablets and Calquence capsules have been demonstrated to be bioequivalent. Geometric mean PK exposures (Cmax and AUClast or AUCinf) of acalabrutinib and ACP-5862 were similar (< 4% difference) between the tablet and capsule, with the 90% confidence intervals for geometric mean ratios within the pre-defined bioequivalence margin of 80% and 125%.

Absorption.

The median (min-max) time to peak plasma concentrations (Tmax) was 0.5 (0.2, 3.0) hours for acalabrutinib, and 0.75 (0.5, 4.0) hours for ACP-5862, following administration of acalabrutinib tablet. The absolute bioavailability of Calquence was 25% following oral administration of acalabrutinib capsule.

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 tablet, the median terminal elimination half-life (t1/2) of acalabrutinib was 1.3 (range: 0.8 to 9.0) hours. The median t1/2 of the active metabolite, ACP-5862, was 7.3 hours (range: 2.5 to 10.1) 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.

Co-administration of acalabrutinib tablet with a proton pump inhibitor (20 mg rabeprazole, twice daily for 3 days) increased AUC by 17% (up to 31% increase, based on upper limit of 90% confidence interval) and decreased Cmax by 24% (up to 45% decrease, based on lower limit of 90% confidence interval), with a delay in Tmax (up to 1 hour, approximately).

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

Tablet core.

Mannitol, microcrystalline cellulose, hyprolose, and sodium stearylfumarate.

Tablet coating.

Hypromellose, copovidone, titanium dioxide, macrogol 3350, medium chain triglycerides, iron oxide yellow, iron oxide red.

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 tablets.

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

Acalabrutinib maleate monohydrate is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6.

Chemical structure.

The chemical name is 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate (1:1:1).
Molecular formula: C26H23N7O2.C4H4O4.H2O.
Molecular weight: 599.59.

CAS number.

CAS 2641500-53-8.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes