DRUG INTERACTIONS

 

 CYP3A4 Inhibitors: Avoid concomitant use of KISQALI with strong CYP3A inhibitors.

 If strong inhibitors cannot be avoided, reduce KISQALI dose. 

 

CYP3A4 Inducers: Avoid concomitant use of KISQALI with strong CYP3A inducers. 

 

CYP3A substrates: The dose of sensitive CYP3A substrates with narrow therapeutic

 indices may need to be reduced when given concurrently with KISQALI. 

 

 Drugs known to prolong QT interval: Avoid concomitant use of drugs known to

prolong QT interval such as anti-arrhythmic medicines. 

 

BRIEF SUMMARY

 

RIBOCICIB- (Mar 20170

 

Indn-      To treat postmenopausal womenwith a type of advanced  breast cancer

 

Comp-        Tablets: 200 mg  I tablets are taken orally with or without food in combination with letrozole. 

 Recommended starting dose: 600 mg orally (three 200 mg tablets) taken

 once daily with or without food for 21 consecutive days followed by 7 days off

 treatment. 

 

ADR-          Most common adverse reactions (incidence . 20%) are neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache 

and back pain. 

 

CI-      None.

WARNINGS-

 

 QT interval prolongation: 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. 

 

Pat Infn

 

 

 

 

 

============================================================

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  6

  

Name of the  Drug-         KISQUALI

 

Active Ingredient-           Ribociclib                                                                                                                                                                                                                Pharmacological Classification- 

 

                       To treat postmenopausal womenwith a type of advanced

                       breast cancer                       

                                                                                                                           

Date of Approval-          03-13-2017

 

 (Ref- FDA approved List 2017)                                                                                                                                                                                                                     HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use KISQALI 

safely and effectively. See full prescribing information for KISQALI.

 

KISQALIR (ribociclib) tablets, for oral use

Initial U.S. Approval: 2017

 

                                                                                                                                               INDICATIONS AND USAGE

 

KISQALI is a kinase inhibitor indicated 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. 

 

                              

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS

 

Most common adverse reactions (incidence . 20%) are neutropenia, nausea, 

fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache 

and back pain. 

CONTRAINDICATIONS

None.

 

 

WARNINGS AND PRECAUTIONS

 

 QT interval prolongation: 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. 

 

 Hepatobiliary toxicity: Increases in serum transaminase levels have been observed. 

 Perform Liver Function Tests (LFTs) before initiating treatment with KISQALI. 

 

  Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each

  subsequent 4 cycles, and as clinically indicated. 

 

  Neutropenia: Perform Complete Blood Count (CBC) before initiating therapy with 

  KISQALI. 

  Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 

  4 cycles, and as clinically indicated. 

 

 Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk 

 to a fetus and to use effective contraception during therapy. 

 

INDICATIONS AND USAGE

 

KISQALI is a kinase inhibitor indicated 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. 

 

DOSAGE AND ADMINISTRATION

 

 KISQALI tablets are taken orally with or without food in combination with letrozole. 

 Recommended starting dose: 600 mg orally (three 200 mg tablets) taken

 once daily with or without food for 21 consecutive days followed by 7 days off

 treatment. 

 

Dose interruption, reduction, and/or discontinuation may be required based on

 individual safety and tolerability. 

 

DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg 

 

PATIENT COUNSELING INFORMATION

 

Advise the patient to read the FDA-approved patient labeling (Patient Information).

 

QT Prolongation

Inform patients of the signs and symptoms of QT prolongation. Advise patients 

to contact their healthcare provider immediately for signs or symptoms of 

QT prolongation .

 

Hepatobiliary Toxicity

Inform patients of the signs and symptoms of hepatobiliary toxicity. Advise patients 

to contact their healthcare provider immediately for signs or symptoms of hepatobiliary

 toxicity 

 

Neutropenia

Advise patients of the possibility of developing neutropenia and to immediately 

contact their healthcare provider should they develop a fever, particularly in association 

with any suggestion of infection 

 

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use

effective contraception during KISQALI therapy and for at least 3 weeks after

the last dose. Advise females to contact their healthcare provider if they 

become pregnant, or if pregnancy is suspected, during treatment with KISQALI 

 

Lactation

Advise lactating women not to breastfeed during treatment with KISQALI and for 

at least 3 weeks after the last dose .

 

Drug Interactions

Inform patients to avoid pomegranate or pomegranate juice, and grapefruit or grapefruit 

juice while taking KISQALI 

 

 Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs 

known to prolong the QT interval 

 

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

 

CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 

Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases 

are activated upon binding to Dcyclins and play a crucial role in signaling pathways 

 which lead to cell cycle progression and cellular proliferation.

 

The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation

 of the retinoblastoma protein (pRb).In vitro, ribociclib decreased pRb phosphorylation

 leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation 

 in breast cancer cell lines.

 

 In vivo, treatment with single agent ribociclib in a rat  xenograft model with human tumo

 cells led to decreased tumor volumes, which correlated with inhibition of pRb 

phosphorylation. In studies using patient-derived  estrogen receptor positive breast

 cancer xenograft models, combination of ribociclib  and antiestrogen (e.g. letrozole)

 resulted in increased tumor growth inhibition compared to each drug alone.

 

2. Pharmacodynamics

 Cardiac Electrophysiology

 Serial, triplicate ECGs were collected following a single dose and at steady-state

  to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer.

 A pharmacokinetic-pharmacodynamic analysis included a total of 267 patients treated

  with ribociclib at doses ranging from 50 to 1200 mg, including 193 patients treated with 

 ribociclib 600 mg. The analysis suggested that ribociclib causes

 concentration-dependent increases in the 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.

 

3. Pharmacokinetics

 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 mg to 1200 mg following both single dose and

 repeated doses.

 

 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.

 

Food Effect: 

Compared to the fasted state, oral administration of a single 600 mg dose of 

KISQALI film-coated tablet with a high-fat, high-calorie meal  (approximately 800 to

1000 calories with ~50% calories from fat, ~35% calories  from carbohydrates, 

and ~15% calories from protein) had no effect on the rate and extent of absorption

 of ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12).

 

Distribution

Binding of ribociclib to human plasma proteins in vitro was approximately 70% and 

independent of concentration (10 to 10,000 ng/mL). 

Ribociclib was equally distributed between red blood cells and plasma with a mean 

in vivo blood-toplasma ratio of 1.04. The apparent volume of distribution at

steady-state (Vss/F) was 1090 L based on population PK analysis.

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

 Risk Summary

 Based on findings from animal studies and the mechanism of action, KISQALI can

 cause fetal harm when administered to a pregnant woman .

 

There are no available human data informing the drug-associated risk.

 In animal reproduction studies, administration of ribociclib to pregnant animals

 during organogenesis resulted in increased incidences of postimplantation loss

 and reduced fetal weights in rats and increased incidences of fetal abnormalities 

 in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, 

 at the highest recommended dose of 600 mg/day based on AUC. 

Advise pregnant women of the potential risk to a fetus.

 

The background risk of major birth defects and miscarriage for the indicated population

 is unknown. However, the background risk of major birth defects is 2-4% and o

 miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population.

 

 Animal Data

 In embryo-fetal development studies in rats and rabbits, pregnant animals received

 oral doses of ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, 

 during the period of organogenesis.

 

 In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced 

 fetal weights accompanied by skeletal changes related to the lower fetal weights. 

 There were no significant effects on embryo-fetal viability or fetal morphology at

  50 or 300 mg/kg/day.

 

In rabbits at doses . 30 mg/kg/day, there were adverse effects on embryo-fetal

 development including increased incidences of fetal abnormalities

 (malformations and external, visceral and skeletal variants) and fetal growth

(lower fetal weights).

 

 These findings included reduced/small lung lobes, additional vessel on the 

descending aorta, additional vessel on the aortic arch  small eyes, diaphragmatic

hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory

 lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae,

and reduced number of phalanges in the pollex. 

 

There was no evidence of increased incidence of embryo-fetal mortality. 

There was no maternal toxicity observed at 30 mg/kg/day.

 

At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic 

exposures (AUC) were approximately 0.6 and 1.5 times, respectively, 

the exposure in patients at the highest recommended dose of 600 mg/day.

 

2. Lactation

 Risk Summary

 It is not known if ribociclib is present in human milk. There are no data on the effects

 of ribociclib on the breastfed infant or on milk production. 

  Ribociclib and its metabolites readily passed into the milk of lactating rats.

 

  Because of the potential for serious adverse reactions in breastfed infants 

 from KISQALI, advise lactating women not to breastfeed while taking

  KISQALI and for at least 3 weeks after the last dose.

 

3. Females and Males of Reproductive Potential

Pregnancy Testing

 Based on animal studies, KISQALI can cause fetal harm when administere

 to a pregnant woman.Females of reproductive potential should have a pregnancy

 test prior to starting treatment with KISQALI.

 

 Contraception

 Females

 Based on animal studies, KISQALI can cause fetal harm when administered

  to a pregnant woman. Advise females of reproductive potential to use effective 

 contraception (methods that result in less than 1% pregnancy rates) during 

treatment with KISQALI and for at least 3 weeks after the last dose.

 

Infertility

Males

Based on animal studies, KISQALI may impair fertility in males of reproductive 

potential 

 

4. Pediatric Use

The safety and efficacy of KISQALI in pediatric patients has not been established.

 

5. Geriatric Use

 Of 334 patients who received KISQALI in Study 1, 150 patients (45%) wer

 65 years of age and 35 patients (11%) were .75 years of age. 

  No overall differences in safety or effectiveness of KISQALI were observed 

 between these patients and younger patients.

 

6. Hepatic Impairment

 No dose adjustment is necessary in patients with mild hepatic impairment

 (Child-Pugh A). 

 A reduced starting dose of 400 mg is recommended in patients with moderate 

 (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) 

 

 Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic 

 impairment had no effect on the exposure of ribociclib. 

 The mean exposure for ribociclib was increased less than 2-fold in patients with 

 moderate (geometric mean ratio [GMR]: 1.50 for Cmax; 1.32 for AUCinf) and 

  severe (GMR: 1.34 for Cmax; 1.29 for AUCinf) hepatic impairment .

 

 OVERDOSAGE

 There are no known cases of overdose with KISQALI. General symptomatic and 

 supportive measures should be initiated in all cases of overdose where necessary.