DRUG INTERACTIONS- summary

CYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended.

CYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended.

Gastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs).

Stagger dosing with H2-receptor antagonists and antacids.

U.S. FDA APPROVED  DRUGS DURING 2017

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.

 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.

 DOSAGE AND ADMINISTRATION-

 Recommended dose is 100 mg orally approximately every twelve hours; swallow whole with water and with or without food.

 Advise patients not to break, open, or chew capsules.                                                    Manage toxicities using treatment interruption, dose reduction, or discontinuation. 

 DOSAGE FORMS AND STRENGTHS-                                                                   Capsules: 100 mg.

 CONTRAINDICATIONS-

 None.

 WARNINGS AND PRECAUTIONS-

Hemorrhage: Monitor for bleeding and manage appropriately.

 Infections: Monitor patients for signs and symptoms of infection and treat as needed. 

 ADVERSE REACTIONS-

 Most common adverse reactions (reported in = 20% of patients) were: anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising.

 CONTRAINDICATIONS-

 None.

 WARNINGS AND PRECAUTIONS-

Hemorrhage: Monitor for bleeding and manage appropriately.

 Infections: Monitor patients for signs and symptoms of infection and treat as needed. 

Cytopenias: Monitor complete blood counts monthly during treatment.

 Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers and other carcinomas. Advise patients to use sun protection.

Atrial Fibrillation and Flutter: Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

DOSAGE AND ADMINISTRATION-

 Recommended dose is 100 mg orally approximately every twelve hours; swallow whole with water and with or without food.

 Advise patients not to break, open, or chew capsules.                                                    Manage toxicities using treatment interruption, dose reduction, or discontinuation. 

 DOSAGE FORMS AND STRENGTHS-                                                                   Capsules: 100 mg.

 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.

Infections-                                                                                                                    Inform patients to report signs or symptoms suggestive of infection

Cytopenias-                                                                                                                         Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE

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

Atrial Fibrillation and Flutter-                                                                                         Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort

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..

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 the dose that they missed

 Drug Interactions-                                                                                                              Advise patients to inform their healthcare providers of all concomitant medications, including over-thecounter medications, vitamins and herbal products

Lactation-                                                                                                                      Advise women not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose

.

Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 Under license of Acerta Pharma B.V. CALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2017

CLINICAL PHARMACOLOGY-

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 BTKmediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.

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, 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).

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. Reference ID: 4174611 10

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 Reference ID: 4174611 11 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 

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

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

 USE IN SPECIFIC POPULATIONS-

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.

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.

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.

3. Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established.

4. 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.