KISQALI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KISQALI (KISQALI).
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Kisqali (ribociclib) selectively inhibits CDK4 and CDK6, which are involved in cell cycle progression. By inhibiting these kinases, it reduces retinoblastoma protein (Rb) phosphorylation, leading to cell cycle arrest in the G1 phase and reduced proliferation of cancer cells.
| Metabolism | Primarily metabolized by CYP3A4. Also metabolized by CYP3A5 and flavin-containing monooxygenase (FMO) to a minor extent. Ribociclib is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2C9, and CYP2D6. |
| Excretion | Primarily hepatic metabolism via CYP3A4, with 69% of dose eliminated in feces (as unchanged drug and metabolites) and 23% in urine (mostly as metabolites). Unchanged ribociclib accounts for <10% of excreted drug. |
| Half-life | Terminal half-life is approximately 32 hours (range 29-40 hours) after oral administration, supporting once-daily dosing. The long half-life allows for steady-state achievement within 8 days. |
| Protein binding | Approximately 90% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein (AAG). |
| Volume of Distribution | Mean apparent volume of distribution (Vd/F) is 900 L (oral), indicating extensive tissue distribution. The large Vd suggests significant extravascular binding and distribution into tissues. |
| Bioavailability | Absolute oral bioavailability is approximately 70% (range 60-80%). Administration with food increases exposure (Cmax by 50%, AUC by 20%), but it is taken without regard to food per labeling. |
| Onset of Action | Clinical effect (CDK4/6 inhibition) onset occurs within days, but maximal antiproliferative effect requires sustained exposure over weeks; measurable reduction in tumor cell proliferation observed after 1-2 weeks of continuous dosing. |
| Duration of Action | Pharmacodynamic effects persist for the dosing interval (24 hours) due to sustained drug levels; suppression of retinoblastoma protein phosphorylation lasts throughout the dosing period. Clinical duration of response is variable, typically measured in months, depending on tumor characteristics. |
600 mg orally once daily for 21 consecutive days followed by 7 days off treatment (28-day cycle), in combination with an aromatase inhibitor or fulvestrant.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl 30-89 mL/min). Not recommended for use in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease due to lack of data. |
| Liver impairment | Child-Pugh A: no dose adjustment. Child-Pugh B: reduce dose to 400 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No recommended dosing available. |
| Geriatric use | No specific dose adjustment required based on age. Monitor for adverse reactions due to reduced organ function (e.g., hepatic, renal, cardiac) and concurrent diseases or drug therapy. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KISQALI (KISQALI).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions (e.g., myelosuppression, infections), advise women not to breastfeed during treatment and for at least 3 weeks after last dose. M/P ratio unknown. |
| Teratogenic Risk | Pregnancy category X. Based on its mechanism of action (CDK4/6 inhibition) and animal studies, KISQALI (ribociclib) can cause fetal harm. There are no adequate human studies. If used during pregnancy or if patient becomes pregnant while taking the drug, apprise of potential hazard to the fetus. Embryotoxicity and teratogenicity observed in rats at exposures below clinical exposure. Avoid use in pregnant women. |
■ FDA Black Box Warning
Interstitial lung disease (ILD)/pneumonitis: Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with Kisqali. Monitor for pulmonary symptoms. Withhold, dose reduce, or permanently discontinue Kisqali based on severity.
| Serious Effects |
["Concomitant use with strong CYP3A4 inducers","History of serious hypersensitivity reaction to ribociclib or any component of the formulation"]
| Precautions | ["Interstitial lung disease/pneumonitis","Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)","QT interval prolongation: Monitor electrocardiograms (ECGs) and electrolytes before and during treatment; avoid use with drugs known to prolong QT interval and in patients with significant cardiac conditions","Hepatobiliary toxicity: Monitor liver function tests (LFTs) before and during treatment; dose adjustments required for elevations","Neutropenia: Monitor complete blood counts (CBCs) before and during treatment; dose modifications for severe neutropenia","Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential to use effective contraception"] |
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| Fetal Monitoring | Monitor complete blood count (CBC) before starting, every 2 weeks for first 2 cycles, then before each cycle. Monitor LFTs (ALT/AST) and serum creatinine before start, every 2 weeks for first 2 cycles, then before each cycle. Monitor ECG before start and at day 14 of cycle 1; repeat if indicated. Assess pregnancy status prior to initiation. During pregnancy, if accidental exposure occurs, perform fetal ultrasound and monitor for growth restriction. |
| Fertility Effects | Based on animal studies, ribociclib may impair fertility in females and males. In female rats, effects included increased embryonic resorptions, reduced corpora lutea, and prolonged estrous cycles. In male rats, reduced sperm motility and concentration were observed. Human fertility impact unknown; however, recommend fertility preservation counseling prior to treatment. |