Acalabrutinib

Mantle cell lymphoma (previously treated): Treatment of mantle cell lymphoma (MCL) in patients who have received at least 1 prior therapy.

Mild to moderate impairment (Child-Pugh classes A and B): There are no dosage adjustments provided in the manufacturer's labeling; however, no pharmacokinetic differences have been observed in patients with mild to moderate hepatic impairment versus patients with normal hepatic function.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Note: Due to the potential bleeding risk, consider benefit-risk of interrupting treatment for 3 to 7 days prior to and after surgery.

Hematologic toxicities: Grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting longer than 7 days:

First and second occurrence: Interrupt treatment; may resume at 100 mg twice daily after toxicity resolves to grade 1 or baseline.

Third occurrence: Interrupt treatment; may resume at 100 mg once daily after toxicity resolves to grade 1 or baseline.

Fourth occurrence: Discontinue acalabrutinib.

Nonhematologic toxicities: Grade 3 or higher toxicity:

First and second occurrence: Interrupt treatment; may resume at 100 mg twice daily after toxicity resolves to grade 1 or baseline.

Third occurrence: Interrupt treatment; may resume at 100 mg once daily after toxicity resolves to grade 1 or baseline.

Fourth occurrence: Discontinue acalabrutinib.

Administer doses with or without food, approximately 12 hours apart. Swallow capsule whole with water; do not open, break, or chew capsules. Avoid concomitant use with proton pump inhibitors; administer acalabrutinib 2 hours prior to H2-receptor antagonists; separate acalabrutinib from antacids by at least 2 hours.

Concerns related to adverse effects:

• Bone marrow suppression: Grade 3 or 4 cytopenias including neutropenia, anemia, and thrombocytopenia have occurred in patients with hematologic malignancies treated with acalabrutinib (as a single agent). In studies, CBC was monitored monthly.

• Cardiovascular adverse effects: Atrial fibrillation and atrial flutter (any grade) occurred in a small percentage of patients with hematologic malignancies treated with acalabrutinib (as a single agent); grade 3 events were reported. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

• GI toxicity: Diarrhea, nausea, and vomiting may commonly occur, although generally mild.

• Hemorrhage: Serious hemorrhagic events (some fatal) have been reported in patients with hematologic malignancies who received acalabrutinib. Overall, bleeding events, including bruising and petechiae (any grade), occurred in approximately half of patients with hematological malignancies who received acalabrutinib. Grade 3 or higher bleeding events (including GI, intracranial, and epistaxis) have been reported rarely. While the mechanism for bleeding events is not well understood, acalabrutinib may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies; monitor these patients for signs of bleeding. Depending upon the type of surgery and the risk of bleeding, consider the benefit-risk of withholding acalabrutinib treatment for 3 to 7 days before and after surgery.

• Infection: Serious bacterial, viral, or fungal infections (including fatal events and opportunistic infections) have occurred in patients with hematologic malignancies treated with acalabrutinib (as a single agent). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Grade 3 or higher infections occurred in about one-fifth of these patients; pneumonia was the most frequent grade 3 or 4 infection. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have also occurred. Monitor for signs and symptoms of infection and manage as medically appropriate.

• Secondary malignancies: Second primary malignancies, including non-skin carcinomas, have occurred in about one-tenth of patients with hematologic malignancies treated with acalabrutinib (as a single agent); the most frequent second primary malignancy was skin cancer. Advise patients to utilize protection from sun exposure.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Drugs that affect gastric pH: Avoid concomitant use with proton pump inhibitors; administer acalabrutinib 2 hours prior to H2-receptor antagonists; separate acalabrutinib from antacids by at least 2 hours.

Take the missed dose as soon as you remember. If you are more than 3 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• unusual bleeding (nose, mouth, vagina, or rectum), or any bleeding that will not stop;

• signs of bleeding inside your body--dizziness, weakness, confusion, problems with speech, prolonged headache, black or bloody stools, pink or brown urine, or coughing up blood or vomit that looks like coffee grounds;

• heart rhythm problems--chest pain, shortness of breath, pounding heartbeats or fluttering in your chest, feeling light-headed;

• low red blood cells (anemia)--pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet;

• signs of infection--fever, chills, tiredness, flu-like symptoms, cough with mucus, chest pain, trouble breathing; or

• signs of a serious brain infection--any change in your mental state, decreased vision, weakness on one side of your body, or problems with walking (may start gradually and get worse quickly).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• bruising;

• headache;

• muscle pain;

• diarrhea; or

• feeling tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Feeling tired or weak.
• Muscle pain.
• Loose stools (diarrhea).
• Upset stomach or throwing up.
• Belly pain.
• Hard stools (constipation).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

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In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For acalabrutinib, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to acalabrutinib or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of acalabrutinib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of acalabrutinib in the elderly.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking acalabrutinib, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using acalabrutinib with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Aprepitant
• Atazanavir
• Boceprevir
• Calcium Carbonate
• Carbamazepine
• Cimetidine
• Ciprofloxacin
• Clarithromycin
• Cobicistat
• Conivaptan
• Crizotinib
• Cyclosporine
• Dexlansoprazole
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Diltiazem
• Dronedarone
• Enzalutamide
• Erythromycin
• Esomeprazole
• Famotidine
• Fluconazole
• Fluvoxamine
• Fosphenytoin
• Idelalisib
• Imatinib
• Indinavir
• Itraconazole
• Ketoconazole
• Lansoprazole
• Letermovir
• Lopinavir
• Lumacaftor
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Mitotane
• Nefazodone
• Nelfinavir
• Nilotinib
• Nizatidine
• Omeprazole
• Pantoprazole
• Phenytoin
• Posaconazole
• Rabeprazole
• Ranitidine
• Rifampin
• Ritonavir
• Saquinavir
• Sodium Bicarbonate
• St John's Wort
• Telaprevir
• Telithromycin
• Verapamil
• Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using acalabrutinib with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use acalabrutinib, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of acalabrutinib. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems or
• Heart rhythm problems (eg, atrial fibrillation, atrial flutter)—Use with caution. May make these conditions worse.

• Infection (eg, hepatitis B)—May decrease your body's ability to fight an infection.