HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`CALQUENCE safely and effectively. See full prescribing information for
`CALQUENCE.
`
`CALQUENCE® (acalabrutinib) capsules, for oral use
`Initial U.S. Approval: 2017
`
` --------------------------- INDICATIONS AND USAGE --------------------------
`CALQUENCE is a kinase inhibitor indicated for the treatment of adult
`patients with mantle cell lymphoma (MCL) who have received at least one
`prior therapy. (1)
`
`This indication is approved under accelerated approval based on overall
`response rate. Continued approval for this indication may be contingent upon
`verification and description of clinical benefit in confirmatory trials. (1, 14)
`
` ---------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`Recommended dose is 100 mg orally approximately every twelve hours;
`swallow whole with water and with or without food. (2.1)
`Advise patients not to break, open, or chew capsules. (2.1)
`Manage toxicities using treatment interruption, dose reduction, or
`discontinuation. (2.2)
`
`
`
`
` --------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Capsules: 100 mg. (3)
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
`Hemorrhage: Monitor for bleeding and manage appropriately. (5.1)
`
`Infections: Monitor patients for signs and symptoms of infection and
`treat as needed. (5.2)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Dose Modifications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hemorrhage
`5.2 Infection
`5.3 Cytopenias
`5.4 Second Primary Malignancies
`5.5 Atrial Fibrillation and Flutter
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`
`Cytopenias: Monitor complete blood counts monthly during treatment.
`(5.3)
`Second Primary Malignancies: Other malignancies have occurred in
`patients, including skin cancers and other carcinomas. Advise patients to
`use sun protection. (5.4)
`Atrial Fibrillation and Flutter: Monitor for atrial fibrillation and atrial
`flutter and manage as appropriate. (5.5)
`
` ------------------------------ ADVERSE REACTIONS -----------------------------
`Most common adverse reactions (reported in ≥ 20% of patients) were: anemia,
`thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and
`bruising. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
` ------------------------------ DRUG INTERACTIONS -----------------------------
`
`CYP3A Inhibitors: Avoid co-administration with strong CYP3A
`inhibitors. Dose adjustments may be recommended. (2.2, 7, 12.3)
`CYP3A Inducers: Avoid co-administration with strong CYP3A
`inducers. Dose adjustments may be recommended. (2.2, 7, 12.3)
`Gastric Acid Reducing Agents: Avoid co-administration with proton
`pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and
`antacids. (2.2, 7, 12.3)
`
`
`
` ----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Lactation: Advise women not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 10/2017
`
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`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 (14)]. Continued approval for this indication may be contingent upon verification and description
`of clinical benefit in confirmatory trials.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`The recommended dose of CALQUENCE is 100 mg taken orally approximately every twelve hours until
`disease progression or unacceptable toxicity.
`
`Advise patients to swallow capsule whole with water. Advise patients not to open, break or chew the
`capsules. CALQUENCE may be taken with or without food. If a dose of CALQUENCE is missed by
`more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time.
`Extra capsules of CALQUENCE should not be taken to make up for a missed dose.
`
`2.2 Dose Modifications
`
`Adverse Reactions
`
`Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are
`provided in Table 1.
`
`Table 1: Recommended Dose Modifications for Adverse Reactions
`
`Event
`
`Grade 3 or greater non-
`hematologic toxicities,
`
`Grade 3 thrombocytopenia
`with bleeding,
`
`Grade 4 thrombocytopenia
`or
`
`Third
`
`Grade 4 neutropenia lasting
`longer than 7 days
`
`Adverse
`Reaction
`Occurrence
`
`Dose Modification
`(Starting dose = 100 mg twice daily)
`
`Interrupt CALQUENCE.
`
`First and Second
`
`Once toxicity has resolved to Grade 1 or
`baseline level, CALQUENCE therapy may be
`resumed at 100 mg twice daily.
`
`Interrupt CALQUENCE.
`
`Once toxicity has resolved to Grade 1 or
`baseline level, CALQUENCE therapy may be
`resumed at 100 mg daily.
`
`Fourth
`
`Discontinue CALQUENCE.
`
`Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
`CTCAE) version 4.03.
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`Dose Modifications for Use with CYP3A Inhibitors or Inducers
`
`Recommended dose modifications are described below [see Drug Interactions (7)].
`
`CYP3A
`
`Co-administered Drug
`
`Recommended CALQUENCE use
`
`Strong CYP3A inhibitor
`
`Inhibition
`
`If these inhibitors will be used short-term (such as anti-
`infectives for up to seven days), interrupt CALQUENCE.
`
`Avoid concomitant use.
`
`Moderate CYP3A inhibitor
`
`100 mg once daily.
`
`Induction
`
`Strong CYP3A inducer
`
`Avoid concomitant use.
`
`If these inducers cannot be avoided, increase
`CALQUENCE dose to 200 mg twice daily.
`
`Concomitant Use with Gastric Acid Reducing Agents
`
`Proton Pump Inhibitors: Avoid concomitant use [see Drug Interactions (7)].
`
`H2-Receptor Antagonists: Take CALQUENCE 2 hours before taking a H2-receptor antagonist [see Drug
`Interactions (7)].
`
`Antacids: Separate dosing by at least 2 hours [see Drug Interactions (7)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`100 mg capsules.
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hemorrhage
`
`Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612
`patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher
`bleeding events, including gastrointestinal, intracranial, and epistaxis have been reported in 2% of
`patients. Overall, bleeding events including bruising and petechiae of any grade occurred in
`approximately 50% of patients with hematological malignancies.
`
`The mechanism for the bleeding events is not well understood. CALQUENCE may further increase the
`risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and 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.
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`5.2 Infection
`
`Serious infections (bacterial, viral or fungal), including fatal events and opportunistic infections have
`occurred in the combined safety database of 612 patients with hematologic 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 4
`infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive
`multifocal leukoencephalopathy (PML) have occurred. Monitor patients for signs and symptoms of
`infection and treat as medically appropriate.
`
`5.3 Cytopenias
`
`In the combined safety database of 612 patients with hematologic malignancies, patients treated with
`CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia
`(11%) and thrombocytopenia (8%) based on laboratory measurements. In the CALQUENCE clinical
`Trial LY-004, patients’ complete blood counts were assessed monthly during treatment.
`
`5.4 Second Primary Malignancies
`
`Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with
`hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of
`612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients.
`Advise protection from sun exposure.
`
`5.5 Atrial Fibrillation and Flutter
`
`In the combined safety database of 612 patients with hematologic malignancies treated with
`CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients,
`and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`
` Hemorrhage [see Warnings and Precautions (5.1)]
`
`Infection [see Warnings and Precautions (5.2)]
` Cytopenias [see Warnings and Precautions (5.3)]
` Second Primary Malignancies [see Warnings and Precautions (5.4)]
` Atrial Fibrillation and Flutter [see Warnings and Precautions (5.5)]
`
`6.1 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.
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`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 (14)]. 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 (%)
`
`1.6
`
`3.2
`0.8
`1.6
`-
`1.6
`
`0.8
`
`0.8
`
`-
`0.8
`
`0.8
`
`Nervous system disorders
`Headache
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Abdominal pain
`Constipation
`Vomiting
`General Disorders
`Fatigue
`Musculoskeletal and connective tissue disorders
`Myalgia
`Skin & subcutaneous tissue disorders
`Bruising†
`Rash†
`Vascular disorders
`Hemorrhage/Hematoma†
`Respiratory, thoracic & mediastinal disorders
`-
`6
`Epistaxis
`*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’
`
`
`39
`
`31
`19
`15
`15
`13
`
`28
`
`21
`
`21
`18
`
`8
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`Table 3: Hematologic Adverse Reactions Reported* in ≥ 20% of Patients with MCL in Trial
`LY-004
`
`Hematologic
`Adverse Reactions
`
`Grade ≥ 3 (%)
`All Grades (%)
`10
`46
`Hemoglobin decreased
`12
`44
`Platelets decreased
`15
`36
`Neutrophils decreased
`*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03;
`based on laboratory measurements and adverse reactions.
`
`CALQUENCE 100 mg twice daily
`N=124
`
`Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
`
`7 DRUG INTERACTIONS
`
`Strong CYP3A Inhibitors
` Co-administration of CALQUENCE with a strong CYP3A inhibitor (itraconazole)
`increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].
`
`Clinical
`Impact
`
`Prevention or
`Management
`
`
`Increased acalabrutinib concentrations may result in increased toxicity.
` Avoid co-administration of strong CYP3A inhibitors with CALQUENCE.
` Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see
`Dosage and Administration (2.2)].
`
`Moderate CYP3A Inhibitors
` Co-administration of CALQUENCE with a moderate CYP3A inhibitor may
`Clinical
`Impact
`increase acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].
`
`Prevention or
`Management
`
`
`Increased acalabrutinib concentrations may result in increased toxicity.
` When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce
`acalabrutinib dose to 100 mg once daily.
`
`Strong CYP3A Inducers
` Co-administration of CALQUENCE with a strong CYP3A inducer (rifampin)
`Clinical
`Impact
`decreased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3)].
` Decreased acalabrutinib concentrations may reduce CALQUENCE activity.
` Avoid co-administration of strong CYP3A inducers with CALQUENCE.
`
`If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to
`200 mg twice daily.
`
`Prevention or
`Management
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`Gastric Acid Reducing Agents
` Co-administration of CALQUENCE with a proton pump inhibitor, H2-receptor
`antagonist, or antacid may decrease acalabrutinib plasma concentrations [see
`Clinical Pharmacology (12.3)].
` Decreased acalabrutinib concentrations may reduce CALQUENCE activity.
`
`If treatment with a gastric acid reducing agent is required, consider using a H2-
`receptor antagonist (e.g., ranitidine or famotidine) or an antacid (e.g., calcium
`carbonate).
`
`Clinical
`Impact
`
`Antacids
`
`Separate dosing by at least 2 hours [see Dosage and
`Administration (2.2)].
`
`Prevention or
`Management
`
`H2-receptor
`antagonists
`
`Take CALQUENCE 2 hours before taking the H2-receptor
`antagonist [see Dosage and Administration (2.2)].
`
`Proton pump
`inhibitors
`
`Avoid co-administration. Due to the long-lasting effect of proton
`pump inhibitors, separation of doses may not eliminate the
`interaction with CALQUENCE.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`
`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 in
`reduced fetal growth at maternal exposures (AUC) approximately 4 times exposures in patients at the
`recommended dose of 100 mg twice daily (see Data). Advise pregnant women of the potential risk to a
`fetus.
`
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2-4% and 15-20%, respectively.
`
`Data
`
`Animal Data
`
`In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered
`orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No
`effects on embryo-fetal development and 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 an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally
`at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of
`acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in
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`decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant
`rabbits was approximately 4-times the AUC in patients at 100 mg twice daily.
`
`8.2 Lactation
`
`Risk Summary
`
`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.
`
`8.4 Pediatric Use
`
`The safety and efficacy of CALQUENCE in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`Eighty (64.5%) of the 124 MCL patients in clinical trials of CALQUENCE were 65 years of age or older,
`and 32 patients (25.8%) were 75 years of age or older. No clinically relevant differences in safety or
`efficacy were observed between patients ≥ 65 years and younger.
`
`11 DESCRIPTION
`
`CALQUENCE (acalabrutinib) is an inhibitor of Bruton tyrosine kinase (BTK). The molecular formula for
`acalabrutinib is C26H23N7O2, and the molecular weight is 465.51. The chemical name is 4-{8-amino-3-
`[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide.
`
`The chemical structure of acalabrutinib is shown below:
`
`
`
`Acalabrutinib is a white to yellow powder with pH-dependent solubility. It is freely soluble in water at pH
`values below 3 and practically insoluble at pH values above 6.
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`CALQUENCE capsules for oral administration contains 100 mg acalabrutinib and the following inactive
`ingredients: silicified microcrystalline cellulose, partially pregelatinized starch, magnesium stearate, and
`sodium starch glycolate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, FD&C
`Blue 2 and is imprinted with edible black ink.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 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 BTK-
`mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell
`proliferation and survival.
`
`12.2 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).
`
`12.3 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.
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`Distribution
`
`Reversible binding of acalabrutinib to human plasma protein was 97.5%. The in vitro mean blood-to-
`plasma 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
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`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 (7)].
`
`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 (7)].
`
`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 (7)].
`
`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.
`
`Reference ID: 4174611
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`Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by
`inhibition of intestinal BCRP.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenicity studies have not been conducted with acalabrutinib.
`
`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.
`
`In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 18-
`times, or in female rats at exposures 16-times the AUC observed in patients at the recommended dose of
`100 mg twice daily.
`
`14 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.
`
`Reference ID: 4174611
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`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]
` Complete Response (CR) (%) [95% CI]
` Partial Response (PR) (%) [95% CI]
`Duration of Response (DoR)
` Median DoR in months [range]
`*Per 2014 Lugano Classification.
`CI= Confidence Interval; NR=Not Reached; + indicates censored observations
`
`81 [73, 87]
`40 [31, 49]
`41 [32, 50]
`
`NR [1+ to 20+]
`
`80 [72, 87]
`40 [31, 49]
`40 [32, 50]
`
`NR [0+ to 20+]
`
`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.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`How Supplied
`
`Pack Size
`
`Contents
`
`NDC Number
`
`Bottle containing 60 capsules
`
`60-count bottle
`
`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].
`
`17 PATIENT COUNSELING INFORMATION
`
`Advise the patient to read the FDA-approved patient labeling (Patient Information).
`
`Hemorrhage
`
`Inform patients to report signs or symptoms of severe bleeding. Inform patients that CALQUENCE may
`need to be interrupted for major surgeries [see Warnings and Precautions (5.1)].
`
`Reference ID: 4174611
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`Infections
`
`Inform patients to report signs or symptoms suggestive of infection [see Warnings and Precautions
`(5.2)].
`
`Cytopenias
`
`Inform patients that they will need periodic blood tests to check blood counts during treatment with
`CALQUENCE [see Warnings and Precautions (5.3)].
`
`Second Primary Malignancies
`
`Inform patients that other malignancies have been reported in patients who have been treated with
`CALQUENCE, including skin cancer. Advise patients to use sun protection [see Warnings and
`Precautions (5.4)].
`
`Atrial Fibrillation and Flutter
`
`Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of
`breath, and chest discomfort [see Warnings and Precautions (5.5)].
`
`Dosing Instructions
`
`Instruct patients to take CALQUENCE orally twice daily, about 12 hours apart. CALQUENCE may be
`taken with or without food. Advise patients that CALQUENCE capsules should be swallowed whole with
`a glass of water, without being opened, broken, or chewed [see Dosage and Administration (2.1)].
`
`Missed Dose
`
`Advise patients that if they miss a dose of CALQUENCE, they may still take it up to 3 hours after the
`time they would normally take it. If more than 3 hours have elapsed, they should be instructed to skip that
`dose and take their next dose of CALQUENCE at the usual time. Warn patients they should not take extra
`capsules to make up for