Acalabrutinib Capsules

Name: Acalabrutinib Capsules

Indications

CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

How supplied

Dosage Forms And Strengths

100 mg capsules.

Storage And Handling

Pack Size Contents NDC Number
60-count bottle Bottle containing 60 capsules 100 mg, hard gelatin capsules with yellow body and blue cap, marked in black ink with ‘ACA 100 mg’ 0310-0512-60

Storage

Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, Under license of Acerta Pharma B.V. Revised: Oct 2017

Side effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Infection [see WARNINGS AND PRECAUTIONS]
  • Cytopenias [see WARNINGS AND PRECAUTIONS]
  • Second Primary Malignancies [see WARNINGS AND PRECAUTIONS]
  • Atrial Fibrillation and Flutter [see WARNINGS AND PRECAUTIONS]

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.

The safety data described in this section reflect exposure to CALQUENCE (100 mg twice daily) in 124 patients with previously treated MCL in Trial LY-004 [see Clinical Studies]. 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 anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 1 severity for the non-hematologic, most common events were as follows: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea.

Dose reductions or discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Tables 2 and 3 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.

Table 2: Non-Hematologic Adverse Reactions* in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004

Body System Adverse Reactions CALQUENCE 100 mg twice daily
N=124
All Grades (%) Grade ≥ 3 (%)
Nervous system disorders
Headache 39 1.6
Gastrointestinal disorders
Diarrhea 31 3.2
Nausea 19 0.8
Abdominal pain 15 1.6
Constipation 15 -
Vomiting 13 1.6
General Disorders
Fatigue 28 0.8
Musculoskeletal and connective tissue disorders
Myalgia 21 0.8
Skin & subcutaneous tissue disorders
Bruising† 21 -
Rash† 18 0.8
Vascular disorders
Hemorrhage/Hematoma† 8 0.8
Respiratory, thoracic & mediastinal disorders
Epistaxis 6 -
*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
†Bruising: Includes all preferred terms (PTs) containing 'bruise,' 'contusion,' 'petechiae,' or 'ecchymosis' Rash: Includes all PTs containing 'rash'
Hemorrhage/hematoma: Includes all PTs containing 'hemorrhage' or 'hematoma'

Table 3: Hematologic Adverse Reactions Reported* in ≥ 20% of Patients with MCL in Trial LY-004

Hematologic Adverse Reactions CALQUENCE 100 mg twice daily
N=124
All Grades (%) Grade ≥ 3 (%)
Hemoglobin decreased 46 10
Platelets decreased 44 12
Neutrophils decreased 36 15
*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03; based on laboratory measurements and adverse reactions.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

Clinical pharmacology

Mechanism Of Action

Acalabrutinib is a small-molecule inhibitor of 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 signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTKmediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.

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, doubledummy, 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).

Pharmacokinetics

The pharmacokinetics (PK) of acalabrutinib was studied in healthy subjects and patients with B-cell malignancies. Acalabrutinib exhibits almost linear PK across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose) and exhibits dose-proportionality. The daily area under the plasma drug concentration over time curve (AUC) was 1111 ng•h/mL and maximum plasma concentration (Cmax) of acalabrutinib was 323 ng/mL.

Absorption

The geometric mean absolute bioavailability of acalabrutinib was 25%. Median time to peak acalabrutinib plasma concentrations (Tmax) was 0.75 hours.

Effect Of Food

In healthy subjects, administration of a single 75 mg dose of acalabrutinib (0.75 times the approved recommended single dose) 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.

Distribution

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

Elimination

Following a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life (t1/2) of acalabrutinib was 0.9 (range: 0.6 to 2.8) hours. The t1/2 of the active metabolite, ACP-5862, was 6.9 hours.

Acalabrutinib mean apparent oral clearance (CL/F) was 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis.

Metabolism

Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. ACP-5862 was identified as the major active 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.

Excretion

Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 1% of the dose excreted as unchanged acalabrutinib.

Specific Populations

Age, Race, And Body Weight

Age (42 to 90 years), sex, race (Caucasian, African American), and body weight did not have clinically meaningful effects on the PK of acalabrutinib, 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 368 patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m², 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/1.73m², MDRD) or renal impairment requiring dialysis.

Hepatic Impairment

Acalabrutinib is metabolized in the liver. In a hepatic impairment study, compared to subjects with normal liver function (n=6), acalabrutinib exposure (AUC) was increased by less than two-fold in subjects with mild (n=6) (Child-Pugh A) and moderate (n=6) (Child-Pugh B) hepatic impairment, respectively. Based on a population PK analysis, no clinically relevant PK difference was observed in subjects with mild (n=41) or moderate (n=3) 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=527) hepatic function (total bilirubin and AST within ULN). Acalabrutinib PK has not been evaluated in patients with severe hepatic impairment (Child-Pugh C or total bilirubin between 3 and 10 times ULN and any AST).

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 DRUG 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 DRUG INTERACTIONS].

Gastric Acid Reducing Agents

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 DRUG INTERACTIONS].

In Vitro Studies

Metabolic Pathways

Acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, and CYP2D6. The active metabolite (ACP-5862) is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6 and CYP3A4/5.

Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; the active metabolite (ACP-5862) weakly induces CYP3A4.

Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.

Drug Transporter Systems

Acalabrutinib is a substrate of P-glycoprotein (P-gp) and BCRP. Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3.

Acalabrutinib does not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3 at clinically relevant concentrations.

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

Clinical Studies

The efficacy of CALQUENCE was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy.

The median age was 68 (range 42 to 90) years, 80% were male, and 74% were Caucasian. At baseline, 93% 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 18% with prior stem cell transplant. Patients who received prior treatment with BTK inhibitors were excluded. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). At baseline, 37% of patients had at least one tumor with a longest diameter ≥ 5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients.

CALQUENCE was administered orally at 100 mg twice daily until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. Tumor response was assessed according to the Lugano Classification for Non-Hodgkin's lymphoma (NHL). The major efficacy outcome of Trial LY-004 was overall response rate (ORR) and the median follow-up was 15.2 months.

Table 4: Efficacy Results in Patients with MCL in Trial LY-004

  Investigator Assessed
N=124
Independent Review Committee (IRC) Assessed
N=124
Overall Response Rate (ORR)*
Overall Response Rate (%) [95% CI] 81 [73, 87] 80 [72, 87]
Complete Response (CR) (%) [95% CI] 40 [31, 49] 40 [31, 49]
Partial Response (PR) (%) [95% CI] 41 [32, 50] 40 [32, 50]
Duration of Response (DoR)
Median DoR in months [range] NR [1+ to 20+] NR [0+ to 20+]
*Per 2014 Lugano Classification.
CI= Confidence Interval; NR=Not Reached; + indicates censored observations

The median time to best response was 1.9 months.

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 Trial LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.

Patient information

CALQUENCE®
(KAL-kwens)
(acalabrutinib) Capsules

What is CALQUENCE?

CALQUENCE is a prescription medicine used to treat adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.

It is not known if CALQUENCE is safe and effective in children.

What should I tell my healthcare provider before taking CALQUENCE?

Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you:

  • have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.
  • have bleeding problems.
  • have or had heart rhythm problems.
  • have an infection.
  • have or had hepatitis B virus (HBV) infection.
  • are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if CALQUENCE passes into your breast milk. Do not breastfeed during treatment with CALQUENCE and for 2 weeks after your final dose of CALQUENCE.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Taking CALQUENCE with certain other medications may affect how CALQUENCE works and can cause side effects. Especially tell your healthcare provider if you take a blood thinner medicine.

How should I take CALQUENCE?

  • Take CALQUENCE exactly as your healthcare provider tells you to take it.
  • Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.
  • Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.
  • Take CALQUENCE 2 times a day (about 12 hours apart).
  • Take CALQUENCE with or without food.
  • Swallow CALQUENCE capsules whole with a glass of water. Do not open, break, or chew capsules.
  • If you need to take an antacid medicine, take it either 2 hours before or 2 hours after you take CALQUENCE.
  • If you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE 2 hours before the acid reducer medicine.
  • If you miss a dose of CALQUENCE, take it as soon as you remember. If it is more than 3 hours past your usual dosing time, skip the missed dose and take your next dose of CALQUENCE at your regularly scheduled time. Do not take an extra dose to make up for a missed dose.

What are the possible side effects of CALQUENCE?

CALQUENCE may cause serious side effects, including:

  • Bleeding problems (hemorrhage) may happen during treatment with CALQUENCE, and can be serious. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:
    • blood in your stools or black stools (looks like tar)
    • pink or brown urine
    • unexpected bleeding, or bleeding that is severe or you cannot control
    • vomit blood or vomit that looks like coffee grounds
    • cough up blood or blood clots
    • dizziness
    • weakness
    • confusion
    • changes in your speech
    • headache that lasts a long time
  • Infections can happen during treatment with CALQUENCE. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, or flu-like symptoms.
  • Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with CALQUENCE, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.
  • Second primary cancers. New cancers have happened in people during treatment with CALQUENCE, including cancers of the skin. Use sun protection when you are outside in sunlight.
  • Heart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with CALQUENCE. Tell your healthcare provider if you have any of the following signs or symptoms:
    • your heartbeat is fast or irregular
    • feel lightheaded or dizzy
    • pass out (faint)
    • shortness of breath
    • chest discomfort

The most common side effects of CALQUENCE include:

  • headache
  • diarrhea
  • tiredness
  • muscle aches
  • bruising

These are not all the possible side effects of CALQUENCE.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.

How should I store CALQUENCE?

  • Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).

Keep CALQUENCE and all medicines out of the reach of children.

General information about the safe and effective use of CALQUENCE.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CALQUENCE for a condition for which it was not prescribed. Do not give CALQUENCE to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about CALQUENCE that is written for health professionals.

What are the ingredients in CALQUENCE?

Active ingredient: acalabrutinib

Inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate.

Capsule shell contains: gelatin, titanium dioxide, yellow iron oxide, FD&C Blue 2, and black ink.

This Patient Information has been approved by the U.S. Food and Drug Administration.

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