Acalabrutinib - Usage, Dosage, Side Effects, Drug Warnings, and Precautions

Overview:

Aclabrutinib is commercially called Calquence. The drug was approved by the FDA (Food and Drug Administration) in 2017. Acalabrutinib is a member of the imidazopyridines class and is a second-generation bruton tyrosine kinase (BTK) inhibitor for treating mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It can inhibit bruton tyrosine kinase's activity and stop the activation of the BCR (B-cell antigen receptor) signaling pathway, thus preventing the growth of malignant B cells. It is more selective and potent than Ibrutinib and is expected to have fewer side effects. The food and drug administration (FDA) approved the drug for its overall response rate in treating severe conditions. They further granted priority review and breakthrough therapy designations to this drug. However, it is associated with an elevation in serum enzymes and causes reactivation of hepatitis B, which can sometimes be fatal. Furthermore, many studies across different countries are conducted to understand better and expand the pharmaceutical use of the drug, Acalabrutinib.

How Does Acalabrutinib Work?

Acalabrutinib is a bruton kinase inhibitor that blocks the action of abnormal proteins that stimulate cancer cells to multiply, thereby preventing the spread of the cancer cells.

Uses:

Acalabrutinib is indicated for

1. It is prescribed for individuals with prior therapy for mantle cell lymphoma.

2. It is also prescribed for adult individuals with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

Dosage:

• Acalabrutinib as Monotherapy: Acalabrutinib can be administered 100 mg orally every 12 hours by individuals with mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic leukemia until the progression of the disease.

• Aclabrutinib in Combination with Obinutuzumab: The administration of Acalabrutinib and Obinutuzumab combination is done under two cycles. The first cycle involves the administration of Acalabrutinib 100 mg orally every 12 hours. The number of days in each cycle is 28. The second cycle is started with Obinutuzumab for a period covering six cycles.

• The patients are advised to swallow the capsule with water and not to break it open.

• The drug can be taken with or without food.

• Patients are advised not to take extra capsules to make up for a missed dose.

• If a dose of Acalabrutinib is missed for more than three hours, the dose can be skipped, and the next dose is taken at the right time.

Warnings:

• Opportunistic Infections: Patients with hematologic malignancies are prone to opportunistic infections. The common opportunistic infections are hepatitis B virus reactivation, Epstein Barr virus reactivation, cytomegalovirus, fungal pneumonia, and progressive multifocal leukoencephalopathy. The individuals with increased risk are considered for prophylaxis.

• Hemorrhage: Patients with hematologic malignancies are at risk for excessive bleeding when treated with Acalabrutinib. The administration of antithrombotic agents with Acalabrutinib increases the risk of bleeding. Hence they have to be considered before co-administration of those drugs.

• Cytopenias: Patients with hematologic malignancies, when treated with Acalabrutinib, showed cytopenias which include anemia, neutropenia, lymphopenia, and thrombocytopenia. The blood count of such patients has to be monitored regularly.

• Secondary Primary Malignancies: About 12 % of individuals exposed to Acalabrutinib were diagnosed with skin cancer in a clinical trial.

• Atrial Fibrillation and Flutter: The risk of atrial fibrillation and flutter is increased in patients with hypertension, arrhythmias, acute infections, and other cardiac risk factors when administered Acalabrutinib.

For Patients:-

What Do You Need to Know About Lymphoma?

Lymphoma is a cancer of the germ-fighting system of the body, the lymphatic system. The system includes lymph glands, the thymus, the spleen, and bone marrow. The main types are Hodgkin’s and non-Hodgkin’s lymphoma. The treatment modalities involve chemotherapy, immunotherapy, radiation therapy, bone marrow transplant, or a combination.

What Do You Need to Know About Chronic Lymphocytic Leukemia?

Chronic lymphocytic leukemia is cancer involving the blood and the bone marrow. Each term defines the condition. The word ‘chronic’ indicates the slow progression of leukemia. The term ‘lymphocytic’ denotes lymphocytic cells affected by leukemia. The condition can be diagnosed using blood tests, bone marrow biopsy, aspiration, computed tomography, and positron emission tomography.

Learn More About Acalabrutinib:-

Before Starting Acalabrutinib: Before taking any medication, in this case, Acalabrutinib, it is good to understand its risks and benefits and discuss it with your doctor to gain knowledge. This is very important as different people have different medical conditions, and there may be serious reactions if the person is allergic to them.

When and How Often to Take Acalabrutinib?

Acalabrutinib should be taken twice daily at a dosage of 100 milligrams. The dosage may vary at times which the doctor will decide. And the duration of drug intake depends on its progressive effects over the condition and until you can cope with its side effects.

How Effective Is Acalabrutinib?

In a study assessing the long-term benefits of Acalabrutinib observed in relapsed or refractory chronic lymphocytic leukemia over the standard of care, the response rate was around 83 %, with side effects in 37 % of the individuals.

Things to Inform Your Doctor Before They Prescribe You Acalabrutinib:

Inform the doctor of the following before they can prescribe you Acalabrutinib.

• If you had recent surgery or are planning to have surgery. Acalabrutinib is generally stopped for any planned surgical procedures.

• If you have bleeding problems.

• If you have or had any recent infection.

• If you have or had liver diseases such as hepatitis B infection.

• If you have or had problems with heart rhythm.

• If you are allergic to any substance or medication.

• If you are pregnant or planning to become pregnant.

• If you breastfeed or plan to breastfeed.

• If you are currently under medications or vitamin or herbal supplements.

Starting Acalabrutinib:-

How to Take Acalabrutinib?

• Acalabrutinib has to be taken as advised by the healthcare professional.

• Do not change the dose or discontinue the drug without your doctor’s consent.

• The reduction or elevation in dosage will be mentioned by your doctor as and when required.

• Acalabrutinib 100 mg is advised to be taken twice daily.

• The drug can be taken with or without food.

• Do not open the capsule. Instead, swallow it with a glass of water.

• If you are under H-2 receptor blockers (acid-reducing medicines), take Acalabrutinib two hours prior.

• If you are under an antacid, take Acalabrutinib two hours after taking the antacid.

Things to Do After You Start Taking Acalabrutinib:

You have to schedule regular appointments with your doctor to monitor the improvement of the condition and to check for adverse reactions. Report to the doctor immediately if you have bleeding, black stools, blood in urine and stools, swelling, pain, red spots in the skin, nosebleeds, or vaginal bleeding. Check with your doctor even if you experience weight loss, night sweats, headache, blurred vision, ulcers in the mouth, and runny nose. These may be the signs of any infection. And it is better to perform blood tests at regular intervals to monitor the condition and check for adverse effects.

Look Out for Side Effects:

The drug may cause the following side effects, which you must carefully note and report to the doctor to get checked immediately.

• Bleeding gums.

• Coughing up blood.

• Difficulty in breathing.

• Dizziness.

• Breathing.

• Pain, redness, and swelling.

• Nosebleeds.

• Paralysis.

• Black stools.

• Black urine.

• Constipation.

• Diarrhea.

• Nausea.

• Vomiting.

• Stomach pain.

• Joint pain.

• Rashes.

Dietary Alterations:

Interaction of Acalabrutinib with grapefruit juice can increase the serum concentration of Acalabrutinib. St.John’s Wort, a herb used to suppress anxiety, reduces the serum concentration of Acalabrutinib. Hence the doctor has to be consulted before taking the medication.

What Should Be Done When You Miss a Dose?

If the duration of missing the dose exceeds three hours, it is better to skip the missed dose, take the next dose at the right time, and follow the upcoming schedule regularly. Avoid taking extra doses to compensate for the missed dose.

What Should Be Done to Treat Acalabrutinib Overdose?

There is no specific treatment to treat Acalabrutinib overdose. The best way to approach the situation is to monitor the patient for signs and symptoms of adverse effects and manage the symptoms.

How to Store Acalabrutinib?

Acalabrutinib should be stored in the original, closed container at room temperature. Avoid placing it in heat, moisture, and direct sunlight. Keep it away from children. Better to discard the old and outdated medicines.

How to Handle Acalabrutinib?

If a caregiver gets you the medicine, they should wear gloves before taking it out of the container or direct the medicine directly into your hands. They should wash their hands before and after handling the medicine.

How to Dispose of Acalabrutinib?

The medicine should be disposed of so that it does not reach children and pets. The drug should not be flushed in the toilet as well. Instead, a medicine take-back program can be used as the best approach to dispose of unused medicines. A medicine take-back program can be recommended to your community by contacting the pharmacist or the local recycling center. The FDA has mentioned the take-back program for the safe disposal of medicines.

Avoid Self-Medication:

The medicine should be taken for a condition for which it was not prescribed. And do not suggest the medicine to others who have similar symptoms you have. Instead, get consent from your doctor before taking or suggesting the medication to avoid serious complications.

Staying On Acalabrutinib:-

Tips to Stay On Track:

• Stay in contact with your doctor.

• Report to your doctor if you feel unwell after taking medicine.

• Take only the prescribed amount of medicine.

• Do not overtake the medicine if you miss a dose.

• Scheduling an appointment with your doctor at regular intervals can help you stay on track with the dosage of medicines.

For Doctors:-

Indication:

Acalabrutinib is indicated in patients suffering from mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic leukemia.

Pharmacology:

Mechanism of Action:

Acalabrutinib is a bruton tyrosine kinase inhibitor. Bruton tyrosine kinase is a signaling factor of the B cell antigen receptor and cytosine kinase receptor. These signaling molecules activate the B cell proliferation, chemotaxis, and adhesion. The drug with its active metabolite forms a covalent bond with cysteine residues in the bruton tyrosine kinase, inhibiting its enzymatic activity.

Pharmacodynamics:

When 100 mg Acalabrutinib is administered to patients with B cell malignancies every 12 hours, the inhibition of bruton tyrosine kinase was evident.

Cardiac Electrophysiology: The QTc interval is the measurement recorded in the electrocardiogram to assess the electrical activity of the heart. A randomized trial was carried out to evaluate the effect of Acalabrutinib on the QTc interval, which showed that a single dose of Acalabrutinib did not prolong the QTc interval to any relevant extent.

Chemical Taxonomy:

Ingredients:

Active Ingredient:

The only active ingredient present in Calquence is Acalabrutinib.

Inactive Ingredients:

The inactive ingredients present in Calquence are;

• Silicified microcrystalline cellulose.

• Partially pregelatinized starch.

• Magnesium stearate.

• Sodium starch glycolate.

The capsule shell contains titanium dioxide, gelatin, and yellow iron oxide, and is imprinted with edible ink.

Absorption:

• The mean bioavailability of Acalabrutinib was 25 % with a median time to peak plasma concentrations of 0.9 hours.

• The administration of 75 mg Acalabrutinib with high-fat and high-calorie meals did not affect the AUC (area under the curve which reflects the actual exposure of the body to the drug after administration) when compared with dosing under fasted conditions.

Distribution:

• Acalabrutinib has a reverse binding efficiency to plasma protein of 97.5 %.

• The mean blood to plasma ratio of Acalabrutinib is 0.8.

• The mean steady-state volume of distribution of Acalabrutinib is 52 %.

Metabolism:

Acalabrutinib is metabolized by CYP3A (cytochrome P450, family 3, subfamily A) enzymes and by glutathione conjugation and amide hydrolysis.

Elimination:

• The mean terminal elimination half-life of Acalabrutinib is 59 % (one hour).

• The mean oral clearance for Acalabrutinib is 35 % (71 L per hour)

Toxicity:

Acalabrutinib was not found to be carcinogenic, mutagenic, or clastogenic. The mutagenicity was tested in an in vivo bacterial reverse mutation assay and clastogenicity in an in vitro human lymphocyte chromosomal aberration assay. The drug had no effects on fertility in male and female rats when administered at a recommended dose of 100 mg twice daily.

Warning and Precaution:

• Serious and Opportunistic Infections: Individuals with hematologic malignancies are more prone to opportunistic infections if they take Acalabrutinib. In clinical trials, patients with respiratory tract infections, when administered Acalabrutinib were affected by grade 3 infections which may include bacterial, fungal, and viral infections. The infections occurred even in the absence of neutropenia. The other opportunistic infections occurring in recipients of Acalabrutinib are fungal pneumonia, Epstein Barr virus, cytomegalovirus, and hepatitis B virus reactivation. The patients at increased risk should be monitored for signs and symptoms, and prophylactic medicines should be administered.

• Hemorrhage: The administration of Acalabrutinib was found to cause hemorrhage in patients with hematologic malignancies. In clinical trials with 1029 patients, 3 % of the patients were found to have higher bleeding of central nervous system bleeding, and 0.1 % of patients had fatal bleeding. Other grades of bleeding occurred in 22 % of the patients. The intake of Acalabrutinib with antithrombotic agents was also found to cause hemorrhage. In clinical trials, bleeding was evident in 2.7 % of patients taking Acalabrutinib without antithrombotic agents and 3.6 % of patients with antithrombotic agents. Therefore, the co-administration of Acalabrutinib with an antithrombotic agent has to be considered to reduce the risk of bleeding. Acalabrutinib can be stopped for three to seven days before and after the surgery depending on the risk of bleeding.

• Cytopenias: Cytopenia is the reduction in all the cells of blood which include neutropenia, anemia, thrombocytopenia, and lymphopenia. The condition can occur in individuals with hematologic malignancies who take Acalabrutinib. In a clinical trial, 12 % of the patients treated with Acalabrutinib were found to show neutropenia. The blood counts of such susceptible patients have to be monitored regularly, and the dose has to be modified accordingly.

• Secondary Primary Malignancies: In clinical trials, 12 % of patients among 1029 were found to develop skin cancer and other tumors when exposed to Acalabrutinib. The patients have to be monitored regularly for skin cancer and to be protected from direct sun exposure.

• Atrial Fibrillation and Flutter: Atrial fibrillation can occur on the administration of Acalabrutinib if the patients have hypertension, acute infection, cardiac risk factors, and previous arrhythmia. Those patients have to be monitored for symptoms of arrhythmia such as syncope, dyspnoea, dizziness, palpitation, etc.

Dosage and Forms:

• Acalabrutinib is an orally administered drug.

• It is available in capsules.

• Recommended dosage is 100 mg every 12 hours.

Administration of the Drug:

• Acalabrutinib should be taken twice daily.

• The dose of the drug recommended is 100 mg orally.

• The drug can be taken with or without food.

• The capsule should be taken as a whole with water and should not be broken or chewed.

• The dose should be taken regularly and not skipped.

• If missed, overdose should be avoided.

Considerations for Administration:

• Patients with hematologic malignancies have to be monitored regularly for any risk of bleeding, opportunistic infections, etc.

• The blood counts of the individuals with cardiac risk factors are essential to be monitored as the uptake of Acalabrutinib can lead to cytopenia or atrial fibrillation.

• Administration with gastric acid reducing agents should also be considered as they may reduce the effect of the drug.

Contraindications:

Acalabrutinib is contraindicated in patients who have,

• Hypersensitivity to the ingredients in the drug.

• Have a history of prolonged QT intervals.

• History of arrhythmias.

• In patients with severe renal disorders.

• In patients with severe hepatic impairment.

• It is contraindicated in pregnant women.

• It is also contraindicated in feeding mothers.

Clinical Studies for Acalabrutinib:

• A clinical trial of 1029 patients was conducted. A group of 820 patients has been treated with Calquence monotherapy in six trials, and 209 patients have been treated with Calquence with Obinutuzumab in two trials. 88 % of the patients received treatment for six months, and 79 % of them received it for at least one year. The adverse reactions such as neutropenia, anemia, thrombocytopenia, headache, upper respiratory infection, diarrhea, and musculoskeletal pain occurred in 30 % of the patients. The safe dose of Acalabrutinib 100 mg every 12 hours in 124 patients previously treated for mantle cell lymphoma was described, and the dose was reduced and discontinued in 1.6% and 6.5 %, respectively. And the safety data of administration of Acalarbrutinib 100 mg every 12 hours with or without Obinutuzumab for chronic lymphocytic leukemia was described from two randomized controlled trials.

• The efficacy of Acalabrutinib was studied through an open-label, phase 2 study in 124 subjects with mantle cell lymphoma who had received at least one therapy. The age group of the subjects was 42 to 90 years. The drug was administered 100 mg orally every 12 hours until the disease progressed or the drug turned toxic. The dose intensity was found to be 98.5 %, and the major efficacy was the overall response rate with a follow-up of 15.2 months.

• The efficacy of Acalabrutinib for chronic lymphocytic leukemia was studied through a randomized, multicenter, open-label, three-arm elevate-in trial. The three arms include Calquence monotherapy, Calquence and Obinutuzumab, and Calquence and Chlorambucil. The study was carried out on 535 untreated subjects. The overall cervical was not reached in any of the three arms after a median follow-up for 29 months.

Drug Interactions:

• Strong CYP3A Inhibitors: The administration of Acalabrutinib with CYP3A inhibitors can cause increased plasma concentration of Acalabrutinib and may result in toxicity. If the inhibitor is used for the short term, Acalabrutinib administration can be interrupted.

• Moderate CYP3A Inhibitors: Co-administration of Acalabrutinib with a moderate CYP3A inhibitor can increase the plasma concentration of Acalabrutinib. So Acalabrutinib dose has to be reduced to 100 mg once daily.

• Strong CYP3A Inducers: The administration of Acalabrutinib with CYP3A inducers can cause decreased plasma concentration of Acalabrutinib and reduce its activity. In this case, the dose of Acalabrutinib has to be increased to 200 mg twice daily.

• Gastric Acid Reducing Agents: The administration of Acalabrutinib with proton pump inhibitor, H 2-receptor antagonist, and antacid can reduce the plasma concentration of Acalabrutinib. In the case of administering antacids and H 2 receptor agonists with Acalabrutinib, the dose has to be separated by two hours. The proton pump inhibitors have long-lasting effects. Hence the separation of doses will not help.

Other Specifications:-

Acalabrutinib in Pregnant Women:

The use of Acalabrutinib in pregnant women has not been studied extensively and does not have much data. However, the study in pregnant rats showed the risk to the fetus due to the administration of Acalabrutinib. Reduced fetal growth and difficult labor were evident in those rats. Hence the drug is contraindicated in pregnant women unless there is a need to treat any clinical condition.

Acalabrutinib in Lactating Women:

The excretion of Acalabrutinib in mother’s milk is unknown. The study on rats showed that Acalabrutinib was found in the milk of breastfeeding rats. Hence the women under Acalabrutinib are advised not to breastfeed or allowed to breastfeed two days after the last dose.

Acalabrutinib in Pediatric Patients:

Drug administration in pediatric patients for safety and efficacy has not been established.

Acalabrutinib in Geriatric Patients:

There are no dose adjustments required in geriatric patients. The dose can be the same as any other young patient.

Acalabrutinib in Renal Impairment Patients:

The use of Acalabrutinib in mild to moderate renal patients has been studied in clinical trials. And no dose adjustment is necessary. Hydration should be maintained, and serum creatinine levels should be monitored. Severe renal patients or patients undergoing dialysis have not been administered Acalabrutinib. The drug can be administered in renal patients only if the benefits outweigh the risks.

Acalabrutinib in Hepatic Impairment Patients:

The dose of Acalabrutinib need not be altered in patients with mild to moderate hepatic impairment. However, patients with severe hepatic impairment have not been prescribed the drug, and moderate hepatic patients are regularly monitored for signs of toxicity.