preloder

Abemaciclib


Abemaciclib

is a drug for the
treatment
of advanced or

metastatic

breast cancers

.
Dosing
Adult dosing:
Important Note:
  • Before initiating

    therapy

    ; perform a CBC and ALT; AST and

    serum

    bilirubin


  • Breast cancer; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ; in combination with an

    aromatase inhibitor

    for initial endocrine therapy:

  • 150 mg
    orally twice daily in combination with an

    aromatase inhibitor

    until

    disease

    progression or unacceptable toxicity

  • Breast cancer; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ; in combination with fulvestrant for progression following endocrine

    therapy

    :

  • 150 mg
    orally twice daily in combination with fulvestrant 500 mg IM on day 1; 15; and 29 and once monthly thereafter until

    disease

    progression or unacceptable toxicity
    Premenopausal and perimenopausal women; administer goserelin for at least 4 weeks prior to and for the duration of
    treatment

  • Breast cancer; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ; monotherapy for progression following endocrine

    therapy

    and prior chemotherapy in the

    metastatic

    setting:

  • 200 mg orally twice daily continued until

    disease

    progression or unacceptable toxicity

  • Pediatric dosing:
    Important Note:
  • Before initiating

    therapy

    ; perform a CBC and ALT; AST and serum bilirubin

  • General Dosage Information:
  • Safety and effectiveness not established in pediatric patients

  • Indications
    FDA-Labeled Indications:
  • Breast cancer

    ; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ; in combination with an

    aromatase inhibitor

    for initial

    endocrine

    therapy

  • Breast cancer

    ; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ; in combination with fulvestrant for progression following

    endocrine

    therapy

  • Breast cancer

    ; Advanced or

    metastatic

    ; HER2-negative;

    hormone

    receptor-positive

    disease

    ;

    monotherapy

    for progression following

    endocrine

    therapy

    and prior

    chemotherapy

    in the

    metastatic

    setting
  • Mechanism of Action
  • Abemaciclib

    is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In

    estrogen receptor

    -positive (ER+)

    breast cancer

    cell

    lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb)

    cell cycle progression

    , and

    cell proliferation

    . In vitro, continuous exposure to

    abemaciclib

    inhibited Rb phosphorylation and blocked progression from G1 into S phase of the

    cell cycle

    , resulting in senescence and apoptosis. In

    breast cancer

    xenograft models,

    abemaciclib

    dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of

    tumor

    size.
  • Adverse Effect
    Common:
    Gastrointestinal:
  • Abdominal pain

    (29% to 39%)
  • Decrease in appetite

    (24% to 45%)
  • Diarrhea

    ; All Grades (81% to 90%)
  • Nausea

    (39% to 64%)
  • Vomiting

    (26% to 35%)

  • Hematologic:
  • Anemia

    ; All Grades (25% to 29%)
  • Leukopenia

    ; All Grades (17% to 28%)
  • Neutropenia

    ; All Grades (37% to 46%)

  • Immunologic:
  • Infectious

    disease

    (31% to 43%)

  • Neurologic:
  • Headache

    (20%)

  • Other:
  • Fatigue

    (40% to 65%)

  • Serious:
    Gastrointestinal:
  • Diarrhea

    Grade 3 (9% to 20%)

  • Hematologic:
  • Febrile neutropenia

    (Less than 1%)
  • Neutropenia

    ; Grade 3 or 4 (Grade 3: 19% to 24%, Grade 4: 2% to 5%)
  • Neutropenic sepsis

  • Venous thromboembolism

    (5%)

  • Hepatic:
  • Alanine aminotransferase (ALT)/ Glutamic pyruvic transaminase (SGPT) level raised (13% to 16%)
  • Aspartate aminotransferase (AST)/ Serum glutamic oxaloacetic transaminase (SGOT) level raised (12% to 15%)

  • Neurologic:
  • Cerebral infarction


  • Respiratory:
  • Pneumonitis


  • Contraindication
  • Specific contraindications have not been determined
  • Interaction
    Strong CYP3A Inhibitors:
  • Strong CYP3A4 inhibitors

    increased the exposure of

    abemaciclib

    plus its active

    metabolites

    to a clinically meaningful extent and may lead to increased toxicity.

  • Ketoconazole:


  • Avoid concomitant

    use

    of

    ketoconazole

    .

    Ketoconazole

    is predicted to increase the AUC of

    abemaciclib

    by up to 16-fold

  • Other Strong CYP3A Inhibitors:
  • In patients with recommended starting doses of 200 mg twice daily or
    150 mg
    twice daily, reduce the

    abemaciclib

    dose

    to 100mg twice daily with concomitant

    use

    of other

    strong CYP3A inhibitors

    . In patients who have had a

    dose

    reduction to 100mg twice daily due to
    adverse reactions
    , further reduce the

    abemaciclib

    dose

    to 50mg twice daily with concomitant

    use

    of other

    strong CYP3A inhibitors

    . If a patient taking

    abemaciclib

    discontinues a strong CYP3A inhibitor, increase the

    abemaciclib

    dose

    (after 3-5 half-lives of the inhibitor) to the

    dose

    that was used before starting the strong inhibitor. Patients should avoid grapefruit products

  • Strong CYP3A Inducers:
  • Co administration of

    abemaciclib

    with rifampin, a

    strong CYP3A inducer

    , decreased the

    plasma concentrations

    of

    abemaciclib

    plus its active

    metabolites

    and may lead to reduced activity. Avoid concomitant

    use

    of

    strong CYP3A inducers

    and consider alternative agents

  • Major:
  • Carbamazepine (theoretical)
  • Enzalutamide (theoretical)
  • Fosnetupitant (theoretical)
  • Fosphenytoin (theoretical)
  • Ketoconazole

    (theoretical)
  • Lumacaftor (theoretical)
  • Mitotane (theoretical)
  • Netupitant (theoretical)
  • Phenytoin (theoretical)
  • Rifampin (theoretical)
  • Phamacokinetics
    Absorption:
  • Time for Maximum plasma concentration (Tmax); oral: 8 hours
  • Bioavailability; oral: 45%
  • Effect of food: Maximum

    serum concentration

    (Cmax) increased by 26% and AUC increased by 9%

  • Distribution:
  • Plasma Protein binding: 96.3% to

    plasma proteins

    ,

    albumin

    , and alpha-1-acid

    glycoprotein

  • Volume of Distribution (Vd): 690.3L

  • Metabolism:
  • Hepatic: Extensive
  • N-desethyl

    abemaciclib

    (M2): Major; active
  • Hydroxy

    abemaciclib

    (M20): Major; active
  • Hydroxy-N-desethyl

    abemaciclib

    (M18): Major; active
  • Substrate of CYP3A4
  • Substrate and inhibitor of P-gp and BCRP
  • Inhibitor of OCT2; MATE1; and MATE2-K

  • Excretion:
  • Renal: 3%
  • Feces: 81% as

    metabolites


  • Elimination:
  • 18.3 hours

  • Precaution
    Gastrointestinal:
  • Diarrhea

    has been reported and may be associated with dehydration or infection. Consider

    antidiarrheal

    therapy

    and discontinue

    use

    for

    severe diarrhea

    or

    diarrhea

    resulting in hospitalization.
    Treatment
    may be resumed at lower

    dose

    upon resolution

  • Hematologic:
  • Fatal neutropenic sepsis has been reported

  • Neutropenia

    ; including

    febrile neutropenia

    ; has occurred; monitoring recommended and interruption; reduction; or delay of
    treatment
    may be required
  • Venous thromboembolic events

    ; including

    deep vein thrombosis

    ;

    pulmonary embolism

    ;

    cerebral venous sinus

    thrombosis

    ; subclavian and

    axillary vein thrombosis

    ; and

    inferior vena cava thrombosis

    ; have been reported; monitoring recommended

  • Hepatic:
  • Hepatotoxicity

    and increases in ALT have been reported; monitoring recommended and interruption; reduction; discontinuation; or delay of
    treatment
    may be required

  • Reproductive:
  • Drug may cause fetal harm;

    use

    of adequate contraception is required during
    treatment
    and for at least 3 weeks after final dose

  • Pregnancy Category
  • Fetal risk cannot be ruled out.
  • Breast Feeding
  • Infant risk cannot be ruled out.
  • Monitoring
  • Tumor response may indicate efficacy

  • CBC:
  • At baseline; every 2 weeks for the first
    2 months
    ; monthly for
    2 months
    ; and then as clinically indicated; including differential

  • Liver function tests:
  • At baseline; every 2 weeks for the first
    2 months
    ; monthly for
    2 months
    ; and then as clinically indicated

  • Pregnancy status:
  • In females of reproductive potential prior to initiating

    therapy

  • Signs and symptoms of

    thrombosis

    and

    pulmonary embolism


  • How to Take or Administration
    Oral:
  • Take without regard to meals, at approximately the same time daily.
  • Missed

    dose

    or

    vomiting

    : Take the next

    dose

    at its scheduled time
  • Swallow
    tablets
    whole; do not crush, chew, or split. Do not ingest any
    tablet
    that is broken, cracked, or not intact.
  • Dosage Form
    Oral Tablet:
  • 50 mg
  • 100 mg
  • 150 mg
  • 200 mg

  • Treatment
    Management of Mild to Moderate Toxicity:
  • Treatment
    is symptomatic and supportive. Treat persistent

    nausea

    and

    vomiting

    with

    antiemetics

    as needed. Correct any significant fluid and/or

    electrolyte abnormalities

    in patients with significant

    vomiting

    and/or diarrhea. Early management of

    diarrhea

    with

    antidiarrheal

    agents (i.e.; loperamide) should be considered. Monitor vital signs regularly. Consider administering colony stimulating factors (Filgrastim or Sargramostim) as these patients may be a risk to develop significant neutropenia

  • Management of Severe Toxicity:
  • Treatment
    is symptomatic and supportive. Monitor vital signs regularly. Administer colony stimulating factors (Filgrastim or Sargramostim) in patients that appear to be at risk for severe neutropenia. Bleeding and risk of infection may develop from this syndrome or hematologic toxicity. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia; anemia or hemorrhage

  • Toxicology
  • A specific toxic

    dose

    has not been established. At the time of this review; overdose was not reported.
  • Patient Counselling or Clinical Teaching
  • Tell patient to report loose stools and start antidiarrheal

    therapy

  • Advise patient to report fever or symptoms of infection
  • Recommend patient report symptoms of hepatotoxicity
  • Warn patient to report symptoms of thromboembolism
  • Instruct females of reproductive potential to avoid pregnancy and

    use

    effective contraception during

    therapy

    and for at least 3 weeks after last dose
  • Side effects may include

    nausea

    ;

    abdominal pain

    ;

    fatigue

    ;

    decreased appetite

    ;

    vomiting

    ;

    headache

    ; and

    alopecia

  • Tell patient to take
    tablet
    at the same time every day
  • Counsel patient to avoid grapefruit products during

    therapy













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