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Ribociclib

Ribociclib

Indications, Uses, Dosage, Drugs Interactions, Side effects
Ribociclib
Medicine Type :
Allopathy
Prescription Type:
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Pharmacological Class:
CDK inhibitors (Cyclin-Dependent Kinase),
Therapy Class:
Antineoplastic agent,
Approved Countries
India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Ribociclib is an antineoplastic agent belonging to the pharmacological class of CDK (Cyclin-Dependent Kinase) inhibitors.

The FDA approves Ribociclib for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early, advanced or metastatic breast cancer.

Ribociclib exhibits a 65.8% bioavailability and reaches peak plasma levels quickly, in 1-4 hours and distributes evenly across red blood cells and plasma, binding to plasma proteins to a degree of around 70%. Metabolism in Phase I and II conjugates is produced via hepatic metabolism, primarily by CYP3A4. Predominantly excreted (69%), with a minor renal route (23%).

The most common side effects of ribociclib include decreased white blood cell count, nausea, fatigue, diarrhoea, hair loss, vomiting, constipation, headache, and back pain.

Ribociclib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Ribociclib is an antineoplastic agent belonging to the pharmacological class of CDK (Cyclin-Dependent Kinase) inhibitors.

Under certain tissue types, inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may offer protection against neoplastic processes. For example, research on knockout mice has shown that CDK4 is unnecessary for normal mammary tissue development. Still, it is essential for the formation of mammary tumours produced by Ras, indicating a possible therapeutic window for a less harmful course of therapy. Many preclinical models have demonstrated the dose-dependent anticancer efficacy of ribociclib, which has been described as a highly selective CDK4/6 inhibitor. It stopped tumour cells at the G1 checkpoint, preventing them from multiplying and so inhibiting the development of the tumour cells.

Ribociclib reaches peak plasma time within 1-4 hours after administration.

Ribociclib reaches peak plasma concentration within 1-4 hours after administration.

Ribociclib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without meals.

Metastatic breast cancer
In treatment of Metastatic breast cancer: Whether used alone or in combination with other drugs or treatment modalities like chemotherapy, ribociclib is an essential component of breast cancer treatment. It is utilized when the malignancy has spread, and prior therapies have not progressed significantly. In hormone receptor-positive and HER2-negative breast cancer, the mechanism of action is blocking the advancement of the cell cycle. Breast lumps, nipple discharge, and changes in breast texture or form are among the signs of breast cancer that are lessened by ribociclib. The drug is beneficial in fighting cancer since it prevents cancer cells from growing and increasing.

Ribociclib is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:

  • An aromatase inhibitor (such as letrozole) is the initial endocrine-based treatment for men, women, or premenopausal patients.
  • With fulvestrant as the initial endocrine-based therapy or, in the case of postmenopausal women or males, as the disease progresses.

Orally: Administer Ribociclib tablets orally daily once a day with water. Unless advised by a healthcare professional, tablets should not be crushed, chewed, or broken. Ribociclib and letrozole are best taken at the same time daily, preferably in the morning, with the option to take them with or without food. Broken or damaged tablets should not be ingested. If a dose is missed or vomited, no additional dose should be taken on that day, and the next dose should be taken at the regular scheduled time.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 200 mg

Ribociclib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Breast Cancer

For 21 days, administer 600 mg once a day, preferably in the morning. After seven days off, the medication is stopped to complete a 28-day cycle. Continue until the disease worsens or the toxicity becomes unacceptable. A luteinizing hormone-releasing hormone (LHRH) agonist should also be administered to premenopausal and perimenopausal women. Depending on each person's safety or tolerability, a dose decrease, stoppage, or withdrawal may be necessary.

Avoid consuming grapefruit or its juice while taking Ribociclib to avoid possible issues with drug metabolism. To control weight, eat a balanced diet and get regular exercise. Avoid drinking and smoking. Include leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, cabbage, beans, herbs, and spices. Avoid processed meats, fast food, fried foods, refined carbohydrates, and added sugar.

The dietary restriction should be individualized as per patient requirements.

  • Hypersensitivity to Ribociclib or any of its excipients.
  • Pregnancy and lactation.
  • Patients should be closely monitored for pulmonary symptoms indicating interstitial lung disease (ILD) or pneumonia. When a patient's respiratory symptoms become worse or new, interrupt them and evaluate them to rule out ILD or pneumonia. In situations when ILD/pneumonitis is severe or recurring, permanently stop using Ribociclib.
  • Interval Prolongation: Before starting ribociclib, perform electrocardiograms (ECGs) and electrolyte monitoring. ECGs should be repeated as necessary during the first cycle and at the start of the second. For six cycles, or as directed by a physician, check electrolytes at the beginning of each cycle. Do not use ribociclib with potent CYP3A inhibitors or medications that extend the QT interval.
  • Increased QT Prolongation: When Tamoxifen is Used Concurrently: Ribociclib should not be used with tamoxifen.
  • Liver Function Tests (LFTs) should be monitored before starting Ribociclib due to Hepatobiliary Toxicity. For the first two cycles, LFTs were monitored every two weeks, at the beginning of each of the subsequent four cycles, and as directed by a physician.
  • Before starting Ribociclib treatment for neutropenia, get a complete blood count (CBC). For the first two cycles, check the CBC every two weeks, then at the start of each of the subsequent four cycles, and as directed by a physician.
  • Ribociclib may be hazardous to developing fetus. Inform patients of the possible danger to an unborn child and advise safe contraception while they are receiving treatment.

Alcohol Warning

It is unsafe to consume Ribociclib with alcohol.

Breast Feeding Warning

It is not recommended for use during breastfeeding.

Pregnancy Warning

It is not recommended for use during pregnancy.

Food Warning

Avoid grapefruit, have a balanced diet, hydrate, and quit smoking.
The adverse reactions related to Ribociclib can be categorized as:
  • Common Adverse Effects: Neutropenia, leukopenia, infections, fatigue, nausea, headache, and diarrhoea.
  • Less Common Adverse Effects: QT interval prolongation, hepatobiliary toxicity (increased transaminase levels), and hematologic abnormalities.
  • Rare Adverse Effects: Interstitial lung disease/pneumonitis, QT prolongation with tamoxifen use, and embryo-fetal toxicity.
Postmarketing Reports
Disorders of the respiratory system: pneumonia and interstitial lung disease (ILD)
Disorders of the Skin and Subcutaneous Tissue: Toxic Epidermal Necrolysis (TEN), Drug-Induced Hypersensitivity Syndrome (DiHS)/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS),
The clinically relevant drug interactions of Ribociclib are briefly summarized here.
  • Drug-Drug Interactions: Tamoxifen, antiarrhythmics (amiodarone, disopyramide, quinidine, sotalol), and other recognized QT-prolonging drugs (such as ciprofloxacin, methadone, moxifloxacin, azithromycin, haloperidol, bepridil, pimozide) increase the risk of QT interval prolongation. Potent CYP3A4 inhibitors (e.g., clarithromycin, telithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nefazodone, nelfinavir, telaprevir, verapamil) may raise the plasma concentration of ribociclib. It might reduce the effectiveness and plasma concentration of CYP3A4 inducers (phenytoin, rifampicin, carbamazepine, etc.). May increase the levels of CYP3A4 substrates in the serum (e.g., tacrolimus, ergotamine, dihydroergotamine, alfuzosin, cisapride, quetiapine, simvastatin, alfentanil, fentanyl, ciclosporin, midazolam).
  • Food Interaction: It could increase systemic exposure to ribociclib when grapefruits or grapefruit juice are consumed. This may cause St. John's wort to have a lower serum concentration.
The common side effects of ribociclib include:
Stomach upset
Diarrhoea
Nausea
Reduced number of white blood cells
Vomiting
Tiredness
Constipation
Hair loss
Fatigue
Back pain
Weakness
Dizziness/light-headedness
Headache
Cough
Loss of appetite
Painful and frequent urination
Fever
  • Pregnancy
FDA Pregnancy Category X: Avoid using while pregnant. The risks are more significant than the possible benefits. There are safer options available.
There is no human data available to inform us about the risks linked with drugs.
Based on results from research on animals and the mode of action, when given to a pregnant woman, it can damage the fetus.
Administration during organogenesis increased frequencies of embryonic malformations in rabbits and rats at doses 0.6 or 1.5 times the human exposure and decreased fetal weights and postimplantation loss in rats, according to animal reproduction studies.
Infertility: May reduce male fertility based on research on animals.
Contraception
Before beginning therapy, fertile women should undergo a pregnancy test.
Women: Advise women who are fertile to use effective contraception (methods with <1% pregnancy rate) both throughout treatment and for a minimum of three weeks following the final dosage.
  • Nursing Mothers
The presence of Ribociclib in human milk is unknown. No information is available regarding the effects of Ribociclib on the breastfed newborn or on milk production. Lactating rats' milk easily absorbed Ribociclib and its metabolites. It is advised that nursing mothers refrain from breastfeeding while taking Ribociclib and for at least three weeks following the final dosage due to the possibility of significant adverse effects in breastfed newborns.
Animal Data
Breastfeeding rats given a single 50 mg/kg dosage had 3.56 times the amount of ribociclib exposure in their milk compared to their mothers' plasma.
  • Pediatric Use
The safety and effectiveness of Ribociclib in pediatric patients have not been established.
Dose Adjustment in Kidney Impairment Patients:
Moderate to mild (CrCl ≥30 mL/min): No dosage modification is required.
Severe (CrCl 15–30 mL/min): Reduce the initial dosage to 200 mg daily.
Dose Adjustment in Hepatic Impairment Patients:
Mild (Child-Pugh A): There is no need to adjust the dosage.
Reduce the initial dose to 400 mg/day for moderate-to-severe (Child-Pugh B or C) conditions.
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Ribociclib.
Signs and Symptoms
Overconsumption of Ribociclib could lead to nausea, vomiting, thrombocytopenia, neutropenia, and possible QTc prolongation.
Management
There is no specific antidote for Ribociclib, and treatment should focus on managing adverse reactions. When an overdose occurs, stop the Ribociclib immediately and start treating the patient with supportive and symptomatic care.
Pharmacodynamic
Electrophysiology of the Heart
In patients with advanced cancer, serial, triplicate ECGs were obtained at steady-state and after a single dosage to assess the impact of ribociclib on the QTcF interval. A pharmacokinetic-pharmacodynamic investigation comprised 997 participants who received 50–1200 mg of ribociclib. According to the investigation, ribociclib increases the QTcF interval in a concentration-dependent manner. When KISQALI 600 mg was combined with aromatase inhibitors or fulvestrant, the estimated mean change from baseline in QTcF was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and 34.7 ms (90% CI: 31.6, 37.8) when combined with tamoxifen at the geometric mean Cmax at steady-state.
Pharmacokinetics
  • Absorption: With a mean absolute bioavailability of 65.8%, ribociclib reaches maximal plasma concentration (Cmax) in 1 to 4 hours of administration. There is no impact of a high-fat meal on absorption.
  • Distribution: Ribociclib binds to human plasma proteins (~70%) independently of concentration. It equally distributes between red blood cells and plasma, with an apparent volume of distribution at steady-state (Vss/F) of 1090 L.
  • Metabolism: Phase II conjugations and oxidation are involved in hepatic metabolism, mainly carried out by CYP3A4. Exposure is influenced by the metabolites M13, M4, and M1. However, the parent drug is primarily responsible for therapeutic action.
  • Elimination: The apparent oral clearance (CL/F) of Ribociclib is 25.5 L/hr, and its plasma effective half-life is 32.0 hours. Feces account for 69% of elimination, with kidneys contributing 23%. The medication is extensively metabolized; 17% of the substance remains unaltered in faeces and 12% in urine.
  • Parati MC, Pedersini R, Perego G, Reduzzi R, Savio T, Cabiddu M, Borgonovo K, Ghilardi M, Luciani A, Petrelli F. Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. Breast Cancer (Dove Med Press). 2022 Apr 12;14:101-111. doi: 10.2147/BCTT.S341857. PMID: 35440873; PMCID: PMC9013420.
  • De Laurentiis M, Caputo R, Mazza M, Mansutti M, Masetti R, Ballatore Z, Torrisi R, Michelotti A, Zambelli A, Ferro A, Generali D, Vici P, Coltelli L, Fabi A, Marchetti P, Ballestrero A, Spazzapan S, Frassoldati A, Sarobba MG, Grasso D, Zamagni C. Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. Target Oncol. 2022 Nov;17(6):615-625. doi: 10.1007/s11523-022-00913-x. Epub 2022 Sep 24. PMID: 36152144; PMCID: PMC9684264.
  • Decker T, Lüdtke-Heckenkamp K, Melnichuk L, Hirmas N, Lübbe K, Zahn MO, Schmidt M, Denkert C, Lorenz R, Müller V, Zahm DM, Mundhenke C, Bauer S, Thill M, Seropian P, Filmann N, Loibl S. Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA). Breast. 2023 Dec;72:103575. doi: 10.1016/j.breast.2023.08.007. Epub 2023 Sep 1. PMID: 37690320; PMCID: PMC10507224.
  • Burris HA 3rd. Ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Expert Rev Anticancer Ther. 2018 Mar;18(3):201-213. doi: 10.1080/14737140.2018.1435275. Epub 2018 Feb 19. PMID: 29457921.
  • US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Kisqali® (ribociclib)
  • https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf
  • https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209092s004lbl.pdf
  • https://www.ncbi.nlm.nih.gov/books/NBK548818/
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Chumbeni
Dr. Chumbeni E Lotha has completed her Bachelor of Pharmacy from RIPANS, Mizoram and Doctor of Pharmacy from SGRRU,Dehradun. She can be reached at editorial@medicaldialogues.in
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Dr JUHI SINGLA
Dr JUHI SINGLA has completed her MBBS from Era’s Lucknow Medical college and done MD pharmacology from SGT UNIVERSITY Gurgaon. She can be contacted at editorial@medicaldialogues.in. Contact no. 011-43720751
Published on: 30 Jan 2024 11:31 AM
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