KISQALI FEMARA CO-PACK (COPACKAGED)

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KISQALI FEMARA CO-PACK (COPACKAGED) (KISQALI FEMARA CO-PACK (COPACKAGED)).

How it works

Kisqali (ribociclib) is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, which blocks retinoblastoma protein phosphorylation, leading to G1 cell cycle arrest and reduced proliferation of breast cancer cells. Femara (letrozole) is a nonsteroidal aromatase inhibitor, inhibiting estrogen synthesis by blocking the conversion of androgens to estrogens. The co-pack provides combination therapy for HR+/HER2- breast cancer.

What the body does with it

Metabolism	Ribociclib: Primarily metabolized by CYP3A4. Letrozole: Metabolized by CYP3A4 and CYP2A6 to a pharmacologically inactive carbinol metabolite.
Excretion	Ribociclib: 69% fecal (unchanged and metabolites), 23% renal (12% unchanged). Letrozole: ~90% renal as inactive metabolite, <5% unchanged.
Half-life	Ribociclib: 29.6–57.3 hours (mean ~48 h), supporting once-daily dosing. Letrozole: 48–60 hours, steady-state reached in 2–6 weeks.
Protein binding	Ribociclib: ~70% bound to human plasma proteins (primarily albumin). Letrozole: 60–65% bound to albumin.
Volume of Distribution	Ribociclib: 35.9 L/kg (large, indicating extensive tissue distribution). Letrozole: 1.9 L/kg (moderate distribution into tissues).
Bioavailability	Ribociclib: Not determined; absorbed rapidly with Tmax 1–4 h. Letrozole: 100% oral bioavailability, well absorbed.
Onset of Action	Ribociclib: Cell cycle arrest within 24–48 hours in sensitive tumors. Letrozole: Estradiol suppression begins 24–72 hours post-dose, maximal suppression by 14 days.
Duration of Action	Ribociclib: Inhibits CDK4/6 for duration of dosing; effect wanes over 5–6 halflives after cessation. Letrozole: Estradiol suppression persists for 1–3 weeks after discontinuation.

Classification & Brands

Dosing & administration

KISQALI (ribociclib) 600 mg orally once daily for 21 consecutive days followed by 7 days off treatment in a 28-day cycle, in combination with FEMARA (letrozole) 2.5 mg orally once daily continuously.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) and in patients on hemodialysis due to lack of data.
Liver impairment	Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce ribociclib dose to 400 mg once daily. Child-Pugh C: Not recommended. Letrozole: No dose adjustment for mild to moderate hepatic impairment; insufficient data in severe impairment.
Pediatric use	Safety and efficacy not established in pediatric patients. No recommended dose.
Geriatric use	No specific dose adjustment required for elderly patients. Clinical studies included patients aged ≥65 years; no overall differences in safety or efficacy observed.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KISQALI FEMARA CO-PACK (COPACKAGED) (KISQALI FEMARA CO-PACK (COPACKAGED)).

Breastfeeding

Not recommended during treatment and for at least 3 weeks after last dose; ribociclib and letrozole are excreted in human milk; M/P ratio for ribociclib is 1.5; letrozole M/P ratio not established; potential for serious adverse reactions in breastfed infant.

Teratogenic Risk

First trimester: Known teratogen; animal studies show embryo-fetal mortality and malformations at clinically relevant exposures; avoid use. Second/third trimester: Risk of fetal harm; use only if maternal benefit justifies risk. Male-mediated: Potential risk via seminal fluid; men with female partners of reproductive potential should use effective contraception during treatment and for 3 weeks after last dose.

Warnings & precautions

■ FDA Black Box Warning

No FDA boxed warning for ribociclib or letrozole.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to ribociclib or letrozole.","Pre-menopausal women unless receiving LHRH agonist (for letrozole).","Concurrent use of strong CYP3A4 inducers (for ribociclib)."]

Clinical Precautions

Precautions

["Hepatotoxicity: Elevations in transaminases and bilirubin; monitor LFTs regularly.","QT prolongation: Risk of arrhythmias; monitor ECG and electrolytes.","Neutropenia: Can cause severe neutropenia; monitor CBCs regularly.","Interstitial lung disease/pneumonitis: Monitor for pulmonary symptoms.","Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception.","Severe cutaneous adverse reactions: Such as Stevens-Johnson syndrome.","Pancreatitis: Monitor for symptoms.","Bone health: Letrozole may cause osteoporosis; monitor bone mineral density."]

Clinical Tips & Counseling

Drug interactions

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KISQALI FEMARA CO-PACK (COPACKAGED)

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KISQALI FEMARA CO-PACK (COPACKAGED) (KISQALI FEMARA CO-PACK (COPACKAGED)).

How it works

What the body does with it

Metabolism	Ribociclib: Primarily metabolized by CYP3A4. Letrozole: Metabolized by CYP3A4 and CYP2A6 to a pharmacologically inactive carbinol metabolite.
Excretion	Ribociclib: 69% fecal (unchanged and metabolites), 23% renal (12% unchanged). Letrozole: ~90% renal as inactive metabolite, <5% unchanged.
Half-life	Ribociclib: 29.6–57.3 hours (mean ~48 h), supporting once-daily dosing. Letrozole: 48–60 hours, steady-state reached in 2–6 weeks.
Protein binding	Ribociclib: ~70% bound to human plasma proteins (primarily albumin). Letrozole: 60–65% bound to albumin.
Volume of Distribution	Ribociclib: 35.9 L/kg (large, indicating extensive tissue distribution). Letrozole: 1.9 L/kg (moderate distribution into tissues).
Bioavailability	Ribociclib: Not determined; absorbed rapidly with Tmax 1–4 h. Letrozole: 100% oral bioavailability, well absorbed.
Onset of Action	Ribociclib: Cell cycle arrest within 24–48 hours in sensitive tumors. Letrozole: Estradiol suppression begins 24–72 hours post-dose, maximal suppression by 14 days.
Duration of Action	Ribociclib: Inhibits CDK4/6 for duration of dosing; effect wanes over 5–6 halflives after cessation. Letrozole: Estradiol suppression persists for 1–3 weeks after discontinuation.

Classification & Brands

Dosing & administration

KISQALI (ribociclib) 600 mg orally once daily for 21 consecutive days followed by 7 days off treatment in a 28-day cycle, in combination with FEMARA (letrozole) 2.5 mg orally once daily continuously.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) and in patients on hemodialysis due to lack of data.
Liver impairment	Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce ribociclib dose to 400 mg once daily. Child-Pugh C: Not recommended. Letrozole: No dose adjustment for mild to moderate hepatic impairment; insufficient data in severe impairment.
Pediatric use	Safety and efficacy not established in pediatric patients. No recommended dose.
Geriatric use	No specific dose adjustment required for elderly patients. Clinical studies included patients aged ≥65 years; no overall differences in safety or efficacy observed.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KISQALI FEMARA CO-PACK (COPACKAGED) (KISQALI FEMARA CO-PACK (COPACKAGED)).

Breastfeeding

Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

No FDA boxed warning for ribociclib or letrozole.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to ribociclib or letrozole.","Pre-menopausal women unless receiving LHRH agonist (for letrozole).","Concurrent use of strong CYP3A4 inducers (for ribociclib)."]