martes, 21 de marzo de 2017

FDA Approves KISQALI® (ribociclib) in Combination with an Aromatase Inhibitor as Initial Endocrine-Based Therapy for the Treatment of Postmenopausal Women with Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer

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FDA Approves KISQALI® (ribociclib) in Combination with an Aromatase Inhibitor as Initial Endocrine-Based Therapy for the Treatment of Postmenopausal Women with Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer

On March 13, 2017, the U.S. Food and Drug Administration (FDA) approved KISQALI (ribociclib) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. The approved recommended dosage of KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally with or without food, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Coadminister KISQALI with letrozole 2.5 mg taken once daily throughout the 28-day cycle. Refer to the full prescribing information of letrozole. For dosing and administration with other aromatase inhibitors, refer to the applicable full prescribing information.
Avoid use of KISQALI in patients who already have or who are at significant risk of developing QTc prolongation. Avoid using KISQALI with drugs known to prolong QTc interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTc interval. If strong inhibitors cannot be avoided, reduce KISQALI dose to 400 mg. Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with KISQALI. Repeat ECGs at approximately Day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated. KISQALI may require dose interruption, reduction, or discontinuation for QTc interval prolongation.
Monitor patients for hepatobiliary toxicity and neutropenia before initiating therapy with KISQALI. Monitor every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. KISQALI may require dose interruption, reduction, or discontinuation.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA:  Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6.
Dose Proportionality:  Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (Cmax) and area under the time concentration curve (AUC)) across the dose range of 50 to 1200 mg (0.08 to 2 times the approved recommended dosage) following both single dose and repeated doses.
Accumulation:  Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
Absorption:  The time to reach Cmax (Tmax) following ribociclib administration was between 1 and 4 hours.
Distribution:  Plasma protein binding was 70% in vitro. The apparent volume of distribution at steady-state (Vss/F) was 1090 L.
Elimination:  The apparent oral clearance (CL/F) was 25.5 L/hr at steady state following 600 mg dosing in patients with advanced cancer. Half-life (based on accumulation ratio) is 32 hours (63% CV).
Metabolism:  Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Ribociclib was the major circulating drug-derived entity in plasma (44%).
Active Metabolites:  The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure,respectively. Clinical activity (pharmacological and safety) of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites. 
Excretion:  Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radiolabeled ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine. Unchanged drug accounted for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively.
Exposure-Safety:  A PK/PD analysis with ribociclib at doses from 50 to 1200 mg (0.08 to 2 times the approved recommended dosage) in patients with advanced cancer suggested a concentration-dependent increase in QTc interval. The estimated mean change from baseline in QTcF was 22.9 ms (90% CI: 21.6, 24.1) at the mean observed Cmax at steady-state following administration at the recommended 600 mg dose.
Drug Interaction Potential
Coadministration of a strong CYP3A4 inhibitor (ritonavir) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose (0.7 times approved recommended dosage). A significant reduction in LEQ803 exposure was also observed. Avoid concomitant use of strong CYP3A inhibitors and consider alternative concomitant medications with less potential for CYP3A inhibition. If coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily. Instruct patients to avoid pomegranates, pomegranate juice, and grapefruit, which are known to inhibit CYP3A enzymes and may increase ribociclib exposure.
Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma Cmax and AUCinf of ribociclib by 81% and 89%, respectively, following a single 600 mg ribociclib dose. The LEQ803 Cmaxincreased 1.7-fold and AUCinf decreased by 27%. Avoid concomitant use of strong CYP3A inducers and consider alternative concomitant medication with no or minimal potential to induce CYP3A.
Coadministration of a sensitive CYP3A4 substrate (midazolam) with multiple doses of KISQALI (400 mg, 0.7 times approved recommended dosage) increased the midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. KISQALI given at the clinically relevant dose of 600 mg is predicted to increase the midazolam Cmax and AUCinf by 2.4- and 5.2-fold, respectively. Caution is recommended when KISQALI is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index may need to be reduced as ribociclib can increase the exposure.
Coadministration of ribociclib with drugs that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not identified in a population PK analysis and was not predicted using physiologically based PK models.
Data from clinical trials in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and aromatase inhibitors including letrozole, anastrozole and exemestane.
Use in Specific Populations
Hepatic Impairment: The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (Child-Pugh Class B; geometric mean ratio [GMR]: 1.50 for Cmax; 1.32 for AUCinf) and severe (Child-Pugh Class C; GMR: 1.34 for Cmax; 1.29 for AUCinf) hepatic impairment. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C).
Renal Impairment: Mild to moderate (eGFR ≥ 30 mL/min/1.73m2) renal impairment had no effect on the exposure of ribociclib. The pharmacokinetics of ribociclib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) is unknown.
Age, body weight, gender, and race were not associated with a clinically meaningful effect on the pharmacokinetics of ribociclib.
Safety and Efficacy
The efficacy of KISQALI was established in a randomized, double-blind, placebo-controlled, multicenter clinical study (MONALEESA-2) of KISQALI plus letrozole versus placebo plus letrozole conducted in postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease. A total of 668 patients were randomized to receive either ribociclib plus letrozole (n=334) or placebo plus letrozole (n=334). A pre-planned interim efficacy analysis demonstrated an improvement in investigator-assessed progression-free survival (PFS) with hazard ratio of 0.556 (95% CI: 0.429, 0.720; p<0 .0001="" 14.7="" 31.1="" 37.1="" 43.2="" 46.6="" 52.7="" 58.9="" and="" are="" arm.="" arm="" been="" ci:="" data="" disease="" estimated="" had="" immature.="" in="" letrozole="" measurable="" median="" months="" not="" objective="" overall="" p="" patients="" pfs="" placebo-containing="" placebo="" plus="" rate="" reached="" response="" ribociclib-containing="" ribociclib="" survival="" the="" was="" with="">
The most common adverse reactions (reported at a frequency ≥ 20%) observed in patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common Grade 3/4 adverse reactions (reported at a frequency >2%) were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting.

Full prescribing information is available at  
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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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