Abemaciclib

INDICATION

 Abemaciclib, Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive. Human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

  Abemaciclib Indicated as mono-therapy for the treatment of adult patients with HR-positive, HER2-negative advanced. Or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Doses

Adult dosage

Tablet

    50mg

    100mg

    150mg200mg

Early Breast Cancer

Adult dosage

    150 mg orally twice a day PLUS tamoxifen or an aromatase inhibitor (see Prescribing Information)

    Continue for 2 years, or until disease recurrence or unacceptable toxicity

Advanced or Metastatic Breast Cancer

Adult dosage

    Mono-therapy

        200 mg orally twice a day

        Continue until disease progression or unacceptable toxicity

    Combination therapy with an aromatase inhibitor

        150 mg orally twice a day PLUS an aromatase inhibitor (see Prescribing Information)

    Combination therapy with fulvestrant

        150 mg orally twice a day PLUS

        Fulvestrant 500 mg Intramuscular on Days 1, 15, and 29, and then once monthly thereafter

Dosage Modifications

Adult dosage

    Dosage modifications for adverse effects

    Combined with fulvestrant, tamoxifen, or an aromatase inhibitor

    Starting dose: 150 mg twice a day

    First dose reduction: 100 mg twice a day

    Second dose reduction: 50 mg twice a day

    Discontinue if unable to tolerate 50 mg twice a day

Mono-therapy

    Starting dose: 200 mg twice a day

    First dose reduction: 150 mg twice a day

    Second dose reduction: 100 mg twice a day

    Third dose reduction: 50 mg twice a day

    Discontinue if unable to tolerate 50 mg twice a day

Administration

 Abemaciclib, May be taken with or without food.

Instruct patient to take dose at approximately the same time each day.

Contraindications

 Abemaciclib, Hypersensitivity to any of the ingredient of this product.

Side effects:

Common side effects of Abemaciclib include:

 Diarrhea, low white blood cell count (neutropenia, leukopenia), nausea, abdominal pain. Infections, fatigue, anemia, decreased appetite, vomiting, headache, low blood platelet count (thrombocytopenia), sores.

And inflammation inside the mouth, swelling of extremities, fever, cough, hair loss, itching, rash. Changes in taste, dizziness, alanine aminotransferase increased, aspartate aminotransferase increased, and weight loss.

Serious side effects of Abemaciclib include:

• Severe or ongoing diarrhea; pain or burning while urinating;
• liver problems–right-sided upper stomach pain, loss of appetite, easy bruising or bleeding, feeling very tired;
• low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or shortness of breath;
• signs of inflammation in the lungs–new or worsening cough, painful or difficult breathing, wheezing, feeling short of breath even while resting; or
• signs of a blood clot–pain or swelling in an arm or leg, chest pain, fast heartbeats, feeling short of breath.

Rare side effects of Abemaciclib include:

None

This is not a complete list of side effects. And other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Precaution & Warnings

• May cause fetal harm; advise women of reproductive potential to use effective contraception (see Pregnancy)
• Interstitial lung disease
• Severe, life-threatening, or fatal ILD and/or pneumonitis can occur; additionally cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported; monitor for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea
• Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD/pneumonitis; permanently discontinue therapy in all patients with Grade 3 or 4 ILD or pneumonitis

Venous thromboembolism

• In any case clinical trials, venous thromboembolic events (VTE) were reported in patients treated with abemaciclib plus an aromatase inhibitor (5%) and in patients treated with abemaciclib plus fulvestrant (5%)
• VTE (.g, deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, pelvic venous thrombosis, subclavian and axillary vein thrombosis, inferior vena cava thrombosis) reported in patients receiving abemaciclib and fulvestrant
• Therapy has not been studied in patients with early breast cancer with a history of venous thromboembolism
• Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat them as medically appropriate
• Dose interruption is recommended for early breast cancer patients with any grade venous thromboembolic event and advanced or metastatic breast cancer patients with a Grade 3 or 4 venous thromboembolic event
• Hepatotoxicity
• Increased transaminases were observed in clinical trials
• In patients who had a grade above 3 ALT elevation, the median time-to-onset was 57 days; whereas, a grade below 3 was 14 days
• In patients who had a grade above 3 AST elevation, the median time-to-onset was 185 days; whereas, a grade below 3 was 13 days
• Monitor liver function tests (LFTs) before the start of therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated; dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation

Neutropenia

• Neutropenia was observed in clinical trials; in patients with a grade above 3 neutropenia, the median time time-to-onset was 29 days and the median duration was 15 days
• Febrile neutropenia was reported in below 1% of patients exposed to abemaciclib in the MONARCH studies; 2 deaths due to neutropenic sepsis were observed in MONARCH 2
• Monitor complete blood counts before starting therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated; dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia; inform patients to promptly report any episodes of fever to their healthcare provider

Diarrhea

• Diarrhea incidence was reported to be greatest during the first month of dosing
• Diarrhea occurred in 81% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 90% of patients receiving abemaciclib alone in MONARCH 1
• Episodes of diarrhea have been associated with dehydration and infection; diarrhea incidence was greatest during the first month of dosing
• Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify the healthcare provider for further instructions and appropriate follow up; for Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue treatment until toxicity resolves to below Grade 1, and then resume treatment at next lower dose

Drug interaction overview

• Abemaciclib is metabolized to several metabolites primarily by CYP3A4
• 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 coadministration
• Other strong CYP3A inhibitors: Decrease recommended starting dose (see Dosage Modifications)
• Strong CYP3A inducers: Avoid coadministration

Pregnancy and Lactation

• There are no available human data are informing the drug-associated risk
• Based on findings from animal studies and the mechanism of action, can cause fetal harm when administered to a pregnant woman; advise pregnant women of the potential risk to a fetus
• In animal data, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose
• Verify pregnancy status in females of reproductive potential before initiating treatment
• Advise females of reproductive potential to use effective contraception during treatment and for at least 3 weeks after the last dose
• Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential

    Lactation

• Unknown if distributed in human breast milk
• Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed while taking abemaciclib and for at least 3 weeks after the last dose

Therapeutic class

 Antineoplastics CDK Inhibitors.

Drug mode of action

    Regulation of cell cycle is crucial in maintaining proper cell growth. Dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and also tumor formation in various cancers.

G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway.

as well as activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins. Which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb 1,2.

RB

Rb is a tumor suppressant protein that inhibits proliferation through binding to. And suppressing the activity of the E2F family of transcription factors 1.

However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes. Required for passage through the restriction point 1.

This leads to increased expression of downstream signalling molecules. Also activity of protein kinases that promote the cell cycle progression and initiation of DNA replication.

Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes. Involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing 1.

Inhibits

    Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency. Inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation. And its activity is specific for Rb-proficient cells 1. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6 2.

Drug Interaction

If your medical doctor is using this medicine to treat your pain. Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Abemaciclib has severe interactions with no other drugs
• Abemaciclib has serious interactions with at least 42 other drugs.
• Abemaciclib has moderate interactions with at least 44 other drugs.
• Abemaciclib has minor interactions with no other drugs

This information does not contain all possible interactions or adverse effects.

Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

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