CALQUENCE

To date, acalabrutinib has been used in trials studying the treatment of B-All, myelofibrosis, ovarian cancer, multiple myeloma, and Hodgkin lymphoma, among others.

As of October the FDA approved Astra Zeneca's Oral administered Calquence (acalabrutinib, capsules).

Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and in adult patients with Mantle cell lymphoma (MCL) who have already received at least one prior therapy.

In August 2022, the FDA approved a new tablet formulation of Calquence, enabling the co-administration of this drug with proton pump inhibitors (PPIs). 7, 8 Unlike Calquence capsules, the co-administration of Calquence tablets and PPIs does not have an effect in the pharmacokinetics of acalabrutinib. 6, 7 Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK.

Nevertheless, acalabrutinib was approved under the FDA's accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint.

Continued approval for acalabrutinib's currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials.

Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations.

It also received Orphan

Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib 5.

Acalabrutinib is indicated for

The treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy.

The treatment of adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

In combination with rituximab and bendamustine for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).

Acalabrutinib is a Bruton Tyrosine

Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells.

It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection.

The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours.

The mean steady-state volume of distribution is approximately 34 L.

Acalabrutinib is mainly metabolized by

CYP3A enzymes.

ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib.

ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK.

Hover over products below to view reaction partners Acalabrutinib Acalabrutinib M27 Metabolite (ACP-5862) Acalabrutinib M2 Metabolite Acalabrutinib M3 Metabolite Acalabrutinib M16 Metabolite Acalabrutinib M2 Metabolite Acalabrutinib M23 Metabolite (ACP-5134) Acalabrutinib M24 Metabolite Acalabrutinib M45 Metabolite Acalabrutinib M5 Metabolite (ACP-5530) Acalabrutinib M7 Metabolite (ACP-5531) Acalabrutinib M10 Metabolite (ACP-5461) Acalabrutinib M25 Metabolite Acalabrutinib M37 Metabolite Acalabrutinib M14 Metabolite (ACP-5825).

After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine.

An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite.

After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6-2.8) hours.

The half-life of the active metabolite, ACP-5862, is about 6.9 hours.

Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis.

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Data regarding the toxicity of acalabrutinib is not readily available.

• Recommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food.

• Advise patients not to chew, crush, dissolve, or cut tablets.

• Manage toxicities using treatment interruption, dose reduction, or discontinuation.

• Avoid CALQUENCE in patients with severe hepatic impairment. 2.1 Recommended Dosage CALQUENCE Administration Instructions Advise patients to swallow tablet whole with water.

Advise patients not to chew, crush, dissolve, or cut the tablets.

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 tablets of

CALQUENCE should not be taken to make up for a missed dose.

CALQUENCE as Monotherapy For patients with

MCL, CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

CALQUENCE in Combination with Bendamustine and Rituximab For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

Start CALQUENCE on Day of

Cycle 1 (each cycle is 28 days) and administer until disease progression or unacceptable toxicity.

Administer bendamustine 90 mg/m on Days and 2 and rituximab 375 mg/m on Day of Cycle and continue for a total of 6 cycles.

Patients achieving a response (PR or CR) after the first 6 cycles may receive maintenance rituximab on Day of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.

For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

Start CALQUENCE at

Cycle 1 (each cycle is 28 days).

Start obinutuzumab at

Cycle for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing.

Administer CALQUENCE prior to obinutuzumab when given on the same day. CALQUENCE in Combination with Venetoclax For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity or completion of 14 cycles of treatment.

Start venetoclax at

Cycle for total of 12 cycles.

Start venetoclax at 20 mg daily for first week of treatment and increase weekly as per dosing schedule for 5-week ramp up (up to 400 mg daily) as described in the venetoclax USPI.

Refer to the venetoclax

USPI for additional details. 2.2 Recommended Dosage for Drug Interactions Dosage Modifications for Use with CYP3A Inhibitors or Inducers These are described in Table 1.

Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers CYP3A Co-administered Drug Recommended CALQUENCE use Inhibition Strong CYP3A inhibitor Avoid co-administration.

If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE.

After discontinuation of strong

CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.

CYP3A inhibitor Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily.

CYP3A inducer Avoid co-administration.

If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours. 2.3 Dosage Modifications for Adverse Reactions Recommended dosage modifications are provided in Table and 4.

Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab Event Adverse Reaction Occurrence Dosage Modification (Starting dose = 100 mg approximately every 12 hours) Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days First and Second Interrupt CALQUENCE.

Once toxicity has resolved to

Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours.

Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily.

Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR Adverse Reaction Severity a Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours) Neutropenia b Absolute neutrophil count less than 0.5 x 10 9 /L for greater than 7 days Interrupt CALQUENCE.

Grade ≤ 2, resume CALQUENCE at starting dosage.

Upon 2nd or 3rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 4th occurrence.

For bendamustine b

Interrupt bendamustine.

Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m 2.d,e Thrombocytopenia f Platelet count to 50 x 10 9 /L with clinically significant bleeding or platelet count less than 25 x 10 9 /L Interrupt CALQUENCE.

Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage.

If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Consider discontinuing CALQUENCE at 3rd occurrence.

For bendamustinef

Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2.e Non-hematologic adverse reactions Grade 3 or higher Interrupt CALQUENCE.

If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 3rd occurrence of Grade 4 toxicity.

Grade 3 toxicity, consider the risks and benefits of continuing CALQUENCE.

For bendamustine

Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2.e a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b For neutropenia with ANC less than 1 x 10 9 /L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m 2 may be appropriate in certain circumstances. c Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. d Consider use of myeloid growth factors before bendamustine dosage reduction. e Consider discontinuing bendamustine if additional dosage reduction is required. f For thrombocytopenia, a platelet count below 50 x 10 9 /L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding.

Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with Venetoclax Adverse Reactiona Adverse Reaction Occurrence Dose Modification Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days First occurrence Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE and/or venetoclax at same dose.

Second occurrence Interrupt

CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE at same dose and venetoclax at one lower dose levelc.

Subsequent occurrence Withhold

CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1 or baseline.b,d Grade 3 or 4 thrombocytopenia and/or bleedingf First occurrence Interrupt CALQUENCE and/or venetoclax.

When bleeding resolves and thrombocytopenia is

Grade ≤ 1 or baseline without transfusion support for 5 consecutive days, restart CALQUENCE and/or venetoclax at same dose.

CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline.

CALQUENCE at same dose and/or restart venetoclax at one lower dose level.e Subsequent occurrences of severe thrombocytopenia Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline.

CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c,d,e Grade 3 or 4 tumour lysis syndrome (TLS) First and subsequent episodes If a subject experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax and acalabrutinib dose should be withheld.

If resolved within 24–48 hours of last dose, treatment can be resumed at the same dose.

For events of clinical

TLS or blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at one lower dose level.c When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis.

Grade 3 other non-hematologic eventsg First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1.

CALQUENCE and/or venetoclax at same dose.

CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1d.

Grade 4 other non-hematologic eventsg First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1.

CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c, e Second occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1d. a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Growth factor may be used at physician discretion. c See venetoclax USPI for dose level reductions details. d Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax. e CALQUENCE dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. f Platelets may be used at physician discretion. g Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤ 1 according to the NCI CTCAE definitions.

In such cases, if a subject is clinically stable, resumption of CALQUENCE may be possible based on clinical judgement of the treating physician.

Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

Number 60-count bottle Bottle containing 60 tablets with a child-resistant closure 100 mg, orange, oval, biconvex tablet, with debossment ‘ACA100’ on one side and plain on the reverse 0310-3512-60 Storage Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) .

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia 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 animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours.

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 to 4% and to 20%, respectively.

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.

AUC at 200 mg/kg/day in pregnant rats was approximately 9 times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours.

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 decreased fetal body weights and delayed skeletal ossification.

AUC at 100 mg/kg/day in pregnant rabbits was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours.

In a pre.

• and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2 times the AUC in patients at 100 mg approximately every 12 hours.

Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5 times the AUC in patients at 100 mg approximately every 12 hours.

The safety and efficacy of

CALQUENCE in pediatric patients have not been established.

Of the 1,758 CALQUENCE-treated patients with B-cell malignancies (excluding previously untreated MCL) in clinical trials, 1,074 (61%) were 65 years of age or older, and 341 (19%) were 75 years of age or older.

Among patients 65 years of age or older, 73% had Grade 3 or higher adverse reactions and 55% had serious adverse reactions.

Among patients younger than age 65, 58% had Grade 3 or higher adverse reactions and 35% had serious adverse reactions.

No clinically relevant differences in efficacy were observed between patients ≥ 65 years and younger.

Of patients that received CALQUENCE in combination with venetoclax in AMPLIFY, 33% (97/291) were ≥ 65 years of age, and 4.5% (13/291) were ≥ 75 years of age.

In patients 65 years of age or older and younger than age 65, the fatal adverse reactions were 5% and 2.6% respectively.

No clinically relevant differences in efficacy were observed between patients ≥ 65 years of age and younger adults.

Of the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were to 74 years of age and 83 (28%) were 75 years of age and older.

No clinically relevant differences in safety or efficacy were observed between patients ages to 74 years and those who were 75 years of age and older.