Ribociclib

Usage

Ribociclib is prescribed for the treatment of hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer. Specifically, it is used:

• In combination with an aromatase inhibitor for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
• In combination with fulvestrant for women with HR-positive, HER2-negative advanced or metastatic breast cancer who have received prior endocrine therapy.
• In combination with an aromatase inhibitor as adjuvant treatment of pre/perimenopausal women with HR-positive, HER2-negative early breast cancer at high risk of recurrence who have received no prior systemic therapy for their early breast cancer.

Pharmacological Classification: Ribociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor.

Mechanism of Action: Ribociclib works by inhibiting CDK4 and CDK6, which are enzymes involved in cell cycle regulation. By blocking these enzymes, ribociclib prevents cancer cells from progressing through the cell cycle and proliferating. This primarily affects the G1 phase of the cell cycle.

Alternate Names

International/Regional Variations: The generic name ribociclib is generally consistent internationally.

Brand Names: Kisqali®

How It Works

Pharmacodynamics: Ribociclib exerts its anti-cancer effects by inhibiting CDK4 and CDK6. This leads to cell cycle arrest in the G1 phase and suppression of tumor growth.

Pharmacokinetics:

• Absorption: Ribociclib is absorbed orally with a median time to reach peak plasma concentration of 1-4 hours. Food does not significantly affect absorption.
• Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by other CYP enzymes.
• Elimination: Ribociclib is eliminated primarily through hepatic metabolism, with a small amount excreted unchanged in the urine and feces. The elimination half-life is approximately 30 hours.

Mode of Action (Cellular/Molecular): Ribociclib directly binds to and inhibits CDK4 and CDK6, preventing the phosphorylation of retinoblastoma protein (Rb). This leads to cell cycle arrest in the G1 phase and inhibits tumor cell proliferation.

Receptor Binding/Enzyme Inhibition: Ribociclib acts as a selective reversible inhibitor of CDK4 and CDK6.

Elimination Pathways: Predominantly hepatic metabolism via CYP3A4, with subsequent biliary and fecal excretion. Minimal renal excretion.

Dosage

Standard Dosage

Adults:

• Advanced or Metastatic Breast Cancer: 600 mg orally once daily for 21 consecutive days, followed by a 7-day break (one cycle). This 28-day cycle is repeated as long as the patient is tolerating the medication and benefiting from treatment.

• Early Breast Cancer: 400 mg orally once daily for 21 consecutive days, followed by a 7-day break (one cycle). This 28-day cycle is repeated for two years in conjunction with hormone therapy.

Children: Ribociclib is not indicated for use in pediatric patients.

Special Cases:

• Elderly Patients: No specific dose adjustments are recommended based on age alone. However, close monitoring for adverse events is recommended.

• Patients with Renal Impairment: For patients with severe renal impairment (creatinine clearance <30 mL/min), the recommended starting dose is 400 mg once daily.

• Patients with Hepatic Dysfunction: For patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 400 mg once daily. Ribociclib is not recommended for patients with severe hepatic impairment (Child-Pugh C).

• Patients with Comorbid Conditions: Dosage adjustments may be necessary depending on the specific comorbid condition. For example, patients with QT prolongation may require closer monitoring or dose reductions.

Clinical Use Cases

Ribociclib is specifically indicated for breast cancer as described in the “Usage” section. It is not indicated for use in the scenarios listed below:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations

Dosage Adjustments

Dose reductions or interruptions may be necessary based on individual patient tolerance and adverse events. The most common reasons for dose modifications include neutropenia, hepatotoxicity, and QT prolongation.

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, fatigue, leukopenia, neutropenia, elevated liver enzymes, alopecia, headache, back pain, abdominal pain, rash.

Rare but Serious Side Effects:

Hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, severe cutaneous reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), and infections.

Long-Term Effects: Long-term effects are still being investigated.

Adverse Drug Reactions (ADR): Severe cutaneous reactions, hepatotoxicity, interstitial lung disease, and QT prolongation are serious ADRs that require immediate intervention. Neutropenia requires close monitoring and potential dose adjustments.

Contraindications

• Hypersensitivity to ribociclib or any of its components.
• Severe hepatic impairment (Child-Pugh C).
• Co-administration with strong CYP3A4 inducers.

Drug Interactions

• CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, grapefruit juice) can significantly increase ribociclib plasma concentrations, increasing the risk of side effects.
• CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) can decrease ribociclib plasma concentrations, reducing its efficacy.
• Drugs that Prolong the QT Interval: Concurrent use with drugs that prolong the QT interval (e.g., certain antiarrhythmics, antipsychotics, antibiotics) should be avoided or carefully monitored.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Ribociclib is contraindicated during pregnancy. It can cause fetal harm. Effective contraception should be used during treatment and for at least 3 weeks after the last dose.

• Breastfeeding: Ribociclib should not be used during breastfeeding. It is unknown if ribociclib passes into breast milk. Breastfeeding should be discontinued during treatment and for at least 3 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: CDK4/6 inhibitor, blocks cell cycle progression in G1 phase.
• Side Effects: Common: Nausea, fatigue, neutropenia, elevated liver enzymes. Serious: Hepatotoxicity, interstitial lung disease, QT prolongation.
• Contraindications: Hypersensitivity, severe hepatic impairment, co-administration with strong CYP3A4 inducers, pregnancy.
• Drug Interactions: CYP3A4 inhibitors/inducers, QT-prolonging drugs.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy and breastfeeding.
• Dosage: Advanced/Metastatic: 600 mg daily x 21 days, followed by 7 days off. Early breast cancer: 400 mg daily x 21 days, followed by 7 days off.
• Monitoring Parameters: Complete blood counts (CBCs), liver function tests (LFTs), ECG (for QT interval).

Popular Combinations

• Ribociclib + Letrozole
• Ribociclib + Anastrozole
• Ribociclib + Fulvestrant

Precautions

• General Precautions: Monitor for hepatotoxicity, neutropenia, QT prolongation. Assess baseline liver function and cardiac function (ECG).
• Specific Populations: Contraindicated in pregnancy and breastfeeding. Caution in patients with renal or hepatic impairment.
• Lifestyle Considerations: Avoid grapefruit and grapefruit juice. Alcohol in moderation does not appear to have a clinically significant interaction.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ribociclib?

A: The recommended dosage for advanced or metastatic breast cancer is 600 mg orally once daily for 21 days followed by 7 days off treatment. For early breast cancer, the dose is 400 mg orally once daily for 21 days followed by 7 days off treatment.

Q2: What are the most common side effects of Ribociclib?

A: The most common side effects include neutropenia, nausea, fatigue, leukopenia, elevated liver enzymes, alopecia, headache, back pain, abdominal pain, and rash.

Q3: How does Ribociclib interact with other medications?

A: Ribociclib interacts with strong CYP3A4 inhibitors and inducers, as well as QT prolonging drugs. Co-administration should be avoided or carefully managed.

Q4: Can Ribociclib be used during pregnancy or breastfeeding?

A: No, Ribociclib is contraindicated during pregnancy and breastfeeding due to the potential for fetal harm.

Q5: What monitoring parameters are important for patients taking Ribociclib?

A: Monitor complete blood counts (CBCs), liver function tests (LFTs), and ECGs (for QT interval) regularly.

Q6: What are the signs of serious adverse reactions to Ribociclib?

A: Signs of serious adverse reactions include jaundice, dark urine, right upper quadrant pain (hepatotoxicity), new or worsening cough, shortness of breath (interstitial lung disease), palpitations, dizziness, syncope (QT prolongation), and severe skin reactions.

Q7: How should the dose of Ribociclib be adjusted for patients with renal or hepatic impairment?

A: For patients with severe renal impairment or moderate hepatic impairment, the starting dose should be reduced to 400 mg once daily. Ribociclib is not recommended for patients with severe hepatic impairment.

Q8: What is the mechanism of action of Ribociclib?

A: Ribociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). This leads to G1 cell cycle arrest and inhibition of tumor cell proliferation.

Q9: Is there a specific time of day to take Ribociclib?

A: It is recommended to take Ribociclib at approximately the same time each day, preferably in the morning.