Kisqali Femara Co-Pack (ribociclib succinate/letrozole)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Ribociclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.
Letrozole, an aromatase inhibitor, is an antineoplastic agent.
Ribociclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent. Several mechanisms contribute to the dysregulation of the cell cycle during the G1 into S phase, including amplification or overexpression of the cyclin D oncogene or the loss of intrinsic CDK inhibitors (i.e., p16, p15, p18, p19, p21, p27, p57) in breast cancer. Ribociclib specifically inhibits CDK4 and CDK6 and blocks the interaction of CDK4 and CDK6 with cyclin D, resulting in inhibition of phosphorylation of the tumor suppressor protein retinoblastoma and inhibition of progression of the cell cycle from the G1 into S phase.
In vitro, ribociclib has demonstrated decreased phosphorylation of retinoblastoma protein and reduced cellular proliferation of breast cancer cell lines by inhibiting the G1 into S phase of the cell cycle. In addition, ribociclib reduced tumor volume, which correlated with inhibition of retinoblastoma protein phosphorylation, in xenograft models of human cancer. The combination of ribociclib and an antiestrogen agent (e.g., letrozole, fulvestrant) also has demonstrated increased inhibition of tumor growth compared with either drug alone in patient-derived estrogen receptor-positive breast tumor xenografts.
AUC and peak plasma concentrations of ribociclib are more than dose proportional over the dose range of 50-1200 mg. Peak plasma concentrations of ribociclib are achieved about 1-4 hours following oral administration of the drug. Following repeated doses of ribociclib 600 mg once daily, steady-state concentrations of the drug were achieved in 8 days and the mean accumulation ratio for the drug was 2.5.
Oral administration of ribociclib with a high-fat, high-calorie meal (approximately 800-1000 calories with fat accounting for approximately 50% of the caloric content) did not affect the rate or extent of absorption of the drug. Ribociclib is approximately 70% bound to plasma proteins. Ribociclib is metabolized mainly in the liver via oxidation by cytochrome P-450 (CYP) isoenzyme 3A4.
Clinical activity from the main circulating metabolites (CCI284, LEQ803, and a secondary glucuronide) is negligible, and these metabolites account for 18-22% of total plasma concentrations of the drug. Following oral administration of a single radiolabeled dose of ribociclib, 69% of the radioactivity was recovered in feces and 23% was recovered in urine. The mean plasma elimination half-life of the drug is 29.7-54.7 hours.
Population pharmacokinetic analysis indicated that age, gender, race, and body weight do not have clinically important effects on the exposure of ribociclib.
Letrozole, a benzyltriazole derivative, is a selective, nonsteroidal aromatase inhibitor. Letrozole differs structurally from aminoglutethimide but shares the pharmacologic activity of competitive aromatase inhibition; although both drugs are selective nonsteroidal inhibitors, letrozole is more potent and selective on a molar basis. Competitive aromatase inhibitors also have been referred to as type II inhibitors of the enzyme.
Like anastrozole, letrozole is a triazole derivative. The N-4 nitrogen of the triazole ring, which coordinates with the heme iron atom of the aromatase enzyme complex, is thought to be responsible for the high affinity of the drug for the estrogen synthetase enzyme.
The growth of some breast cancers is stimulated or maintained by estrogens; in these cancers, decreasing estrogen levels or inhibiting estrogen effects can lead to decreased tumor mass or delayed cancer progression. In postmenopausal women, estrogens are primarily produced through the action of aromatase enzymes, which convert adrenal androgens (e.g., androstenedione, testosterone) to estrone and estradiol. Letrozole selectively inhibits synthesis of estrogens via inhibition of the aromatase enzyme; it does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.
Suppression of plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline, with maximal suppression achieved within 2-3 days, has been observed in postmenopausal women with advanced breast cancer receiving daily letrozole doses of 0.1-5 mg. Suppression was dose-related, and letrozole doses equal to or exceeding 0.5 mg resulted in suppression to estrone and estrone sulfate concentrations below the lower limit of detection in many cases. Suppression of serum estrogen concentrations was maintained throughout treatment in all patients receiving daily letrozole doses equal to or exceeding 0.5 mg.
Letrozole is rapidly and completely absorbed from the GI tract following oral administration. Steady-state plasma concentrations of the drug are reached in 2-6 weeks in patients receiving letrozole 2.5 mg daily. Letrozole exhibits slightly nonlinear pharmacokinetics with repeated administration of 2.5 mg daily, with steady-state plasma concentrations 1.5-2 times higher than predicted based on plasma concentrations measured after a single dose.
However, continuous accumulation of letrozole does not occur, and steady-state concentrations are maintained over extended periods of daily drug administration. Food does not affect the oral absorption of the drug.
Letrozole is weakly bound to plasma proteins. It has a terminal elimination half-life of about 2 days. The primary elimination pathway of letrozole consists of slow metabolism in the liver to a pharmacologically inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) followed by renal excretion of the glucuronide conjugate of this metabolite.
Formation of the carbinol metabolite is mediated by cytochrome P-450 (CYP) isoenzymes 3A4 and 2A6, and formation of the ketone analog of the carbinol metabolite is mediated by isoenzyme 2A6.
Following oral administration of radiolabeled letrozole, 90% of the administered dose was excreted in the urine. Of the radiolabeled drug recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% consisted of 2 unidentified metabolites, and 6% was unchanged drug.
Age-related differences in pharmacokinetics over the range of 35 years of age to greater than 80 years of age have not been observed in patients receiving letrozole in clinical trials. Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole have not been evaluated.
Generic name: ribociclib succinate/letrozole
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Kisqali Femara Co-Pack:
- Hormone Receptor (HR)-Positive, Her2-Negative Advanced Breast Cancer
- Hormone Receptor (HR)-Positive, Her2-Negative Early-Stage Breast Cancer
Also known as: Hormone Receptor (HR)-Positive, Her2-Negative Metastatic Breast Cancer, Hormone Receptor(+), Her2(-) Early Breast Cancer, Hr+, Her2- Early Breast Ca, Hr-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer, Hr-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Metastatic Breast Cancer.
Dosing
Dosage of ribociclib succinate is expressed in terms of ribociclib.
Dosage interruption and/or reduction, or discontinuance of ribociclib therapy, may be necessary based on severity of adverse reactions. Dosage adjustment of ribociclib is recommended based on individual safety and tolerability.
Early breast cancer: If dosage reduction from 400 mg once daily is necessary, the dosage should be reduced to 200 mg once daily. If the toxicity recurs at a dosage of 200 mg once daily, ribociclib therapy should be discontinued.
Advanced or metastatic breast cancer: If dosage reduction from 600 mg once daily is necessary, the dosage should be reduced to 400 mg once daily. If the toxicity recurs at a dosage of 400 mg once daily, the dosage should be reduced to 200 mg once daily. If the toxicity recurs at a dosage of 200 mg once daily, ribociclib therapy should be discontinued.
Concomitant use of ribociclib with drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided, and selection of an alternative drug with less CYP3A inhibition potential is recommended. If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of ribociclib to 200 mg once daily in patients with early breast cancer and 400 mg once daily in patients with advanced or metastatic breast cancer. When concomitant use of the strong CYP3A inhibitor is discontinued, the ribociclib dosage should be returned (after at least 5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong CYP3A inhibitor.
Ribociclib is administered orally without regard to food at approximately the same time each day, preferably in the morning. The tablets should be swallowed intact and should not be broken, chewed, crushed, or split.
If a dose of ribociclib is missed or vomited, patients should not take an extra dose. The next dose should be taken at the regularly scheduled time.
Store ribociclib tablets at 20oC to 25oC for up to 2 months.
Ribociclib is commercially available as a single entity (Kisqali(R)) and also available copackaged with letrozole (Kisqali(R) Femara(R) Co-Pack). Clinicians should consult the respective manufacturers' labeling for information on dosage and administration (including dosage adjustments), adverse effects, and contraindications of other antineoplastic agents used in combination regimens.
Letrozole is administered orally. Food does not affect the absorption of letrozole, and the drug may be administered without regard to meals.
Commercially available letrozole tablets should be stored at a controlled room temperature of 20-25degreesC (excursions permitted between 15-30degreesC).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Ribociclib is metabolized mainly in the liver via oxidation by cytochrome P-450 (CYP) isoenzyme 3A4. In vitro studies indicate that ribociclib is a reversible inhibitor of CYP isoenzymes 1A2, 2E1, and 3A4/5 at clinically relevant concentrations; the drug demonstrates time-dependent inhibition of CYP3A4/5. In vitro studies indicate that ribociclib does not inhibit CYP isoenzymes 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 at clinically relevant concentrations. In vitro, ribociclib does not exhibit time-dependent inhibition of CYP isoenzymes 1A2, 2C9, and 2D6 or induce CYP isoenzymes 1A2, 2B6, 2C9, and 3A4 at clinically relevant concentrations.
In vitro studies indicate that ribociclib may inhibit breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, multidrug and toxic compound extrusion protein (MATE) 1, and bile salt export pump (BSEP), but has a low potential for inhibition of P-glycoprotein (P-gp), MATE2K, OCT1, organic anion transport protein (OATP) 1B1, and OATP1B3 at clinically relevant concentrations. In vitro, the drug is not a substrate for OCT1, OATP1B1, or OATP1B3.
Letrozole is a substrate of cytochrome P-450 (CYP) 3A4 and CYP2A6. Letrozole has been shown to inhibit CYP2A6 and CYP2C19 in human liver microsomes, but the clinical significance of this is not known.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*None.
*Pregnancy.
*Known hypersensitivity to letrozole or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 20% or more of patients receiving ribociclib for early breast cancer include decreased lymphocytes, leukocytes, neutrophils, and hemoglobin, increased ALT and AST, infections, increased creatinine, decreased platelets, headache, nausea, and fatigue.
Adverse effects reported in 20% or more of patients receiving ribociclib for advanced or metastatic breast cancer include decreased leukocytes, neutrophils, hemoglobin, and lymphocytes, increased ALT, AST, and gamma glutamyl transferase, infections, nausea, increased creatinine, fatigue, decreased platelets, diarrhea, vomiting, headache, constipation, alopecia, rash, cough, back pain, and decreased serum glucose.
The most common adverse effects (occurring in greater than 20% of patients) are hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of ribociclib have not been established in pediatric patients.
The manufacturer states that safety and efficacy of letrozole in pediatric patientshave not been established.
Adverse effects on bone (bone maturation, BMD) and neuroendocrine and reproductive development disorders of the hypothalamic-pituitary axis were reported following administration of letrozole 0.003-0.3 mg/kg daily in young rats (exposures less than that expected at the recommended human adult dosage) for 12 weeks beginning on postnatal day 7.
Ribociclib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) There are no available human data informing the drug-associated risk.
Confirmation of pregnancy status prior to initiation of ribociclib therapy is recommended.
Letrozole is contraindicated in women who are pregnant since the drug can cause fetal toxicity when administered to pregnant women. The manufacturer states that a pregnancy test should be performed prior to initiation of letrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug. If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential hazard to the fetus.
Spontaneous abortion and congenital birth defects have been reported during postmarketing experience when the drug was used in pregnant women; however, postmarketing reports on letrozole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. In animal reproduction studies, letrozole administered to pregnant rats and rabbits during organogenesis was associated with increased pregnancy loss (increased postimplantation loss, increased resorption, and decreased number of live fetuses) and teratogenicity (skeletal and renal malformations) at dosages approximately 0.1 times the maximum recommended human dosage on a mg/m2 basis.
Ribociclib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans. Because of the potential for serious adverse reactions to ribociclib in nursing infants, women should be advised to discontinue breastfeeding during and for at least 3 weeks after discontinuance of ribociclib therapy. The effects of the drug or its metabolites on nursing infants or on milk production are unknown.
It is not known whether letrozole is distributed into human milk or if the drug has any effects on nursing infants or on milk production. Because many drugs are distributed into milk and because impaired reproductive performance has been observed in male offspring of lactating rats and letrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during letrozole therapy and for at least 3 weeks after discontinuance of the drug.
There are currently no specific dosage recommendations for geriatric patients.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In the NATALEE study, 16% of patients were 65 years of age and older and 2.4% of patients were 75 years of age and older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults with early breast cancer.
In the MONALEESA-2 or MONALEESA-3 study, 45 or 47%, respectively, of patients were 65 years of age or older and 11 or 14%, respectively, were 75 years of age or older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults with advanced or metastatic breast cancer.
In the clinical trial evaluating letrozole as initial adjuvant therapy for early-stage breast cancer, 36% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Adverse effects generally occurred more frequently in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.
In the clinical trial evaluating letrozole as extended adjuvant therapy for early-stage breast cancer, 41% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.
In clinical trials evaluating letrozole as first-line or second-line therapy for advanced or metastatic breast cancer, about one-third of patients were 70 years of age or older (median age: 64-65 years). Among patients receiving letrozole as first-line therapy in a clinical trial, higher response rate and longer time to tumor progression were observed in geriatric patients (70 years or older) compared with younger patients.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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