Ribociclib

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# Overview
Ribociclib is a kinase inhibitor that is FDA approved for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy when given in combination with an aromatase inhibitor; or of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy when given in combination with fulvestrant.   Common adverse reactions include neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Ribociclib is indicated in combination with:
- an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or
- fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.
- The recommended dose of Ribociclib is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food.
- When given with Ribociclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with Ribociclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
- Pre/perimenopausal women treated with the combination Ribociclib plus an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
- Patients should take their dose of Ribociclib at approximately the same time each day, preferably in the morning.
- If the patient vomits after taking the dose, or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Ribociclib tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
Dose Modifications for Adverse Reactions
- The recommended dose modifications for adverse reactions are listed in Table 1.
- Tables 2, 3, 4 and 5 summarize recommendations for dose interruption, reduction, or discontinuation of Ribociclib in the management of specific adverse reactions. Dose modification of Ribociclib is recommended based on individual safety and tolerability.
- Refer to the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information.
- Avoid concomitant use of Ribociclib with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition. If a strong CYP3A inhibitor must be coadministered, reduce the Ribociclib dose to 400 mg once daily. If the strong inhibitor is discontinued, change the Ribociclib dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.
- No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose is 400 mg Ribociclib once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C).
- Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.
- No dose adjustment is necessary in patients with mild or moderate renal impairment. The recommended starting dose is 200 mg Ribociclib once daily for patients with severe renal impairment.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ribociclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 4.
- Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of Ribociclib plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had a > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.
- These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
- In MONALEESA-2, on the Ribociclib plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.
- Assess ECG prior to initiation of treatment. Initiate treatment with Ribociclib only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.
- Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting Ribociclib therapy.
- Avoid the use of Ribociclib in patients who already have or who are at significant risk of developing QT prolongation, including patients with:
- long QT syndrome.
- uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias.
- electrolyte abnormalities.
- Avoid using Ribociclib with drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.
- Ribociclib is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAI) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the Ribociclib and tamoxifen combination and in 18/245 (7%) of patients receiving Ribociclib plus an NSAI.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in ALT (10% vs. 2%) and AST (7% vs. 2%) were reported in the Ribociclib and placebo arms, respectively.
- Among the patients who had Grade  3 ALT/AST elevation, the median time-to-onset was 85 days for the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade  2 was 22 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 (1%) patients and all patients recovered after discontinuation of Ribociclib. No cases occurred in MONALEESA-7.
- Perform LFTs before initiating therapy with Ribociclib. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the transaminase elevations, Ribociclib may require dose interruption, reduction, or discontinuation as described in Table 3 (Dose Modification and Management for Hepatobiliary Toxicity). Recommendations for patients who have elevated AST/ALT Grade  3 at baseline have not been established.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%), and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade  2 neutropenia was 16 days. The median time to resolution of Grade  3 (to normalization or Grade < 3) was 12 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.
- Perform CBC before initiating therapy with Ribociclib. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the neutropenia, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 2.
- Based on findings from animal studies and the mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of Ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with Ribociclib and for at least 3 weeks after the last dose.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- The safety data reported below are based on MONALEESA-2, a clinical study of 668 postmenopausal women receiving Ribociclib plus letrozole or placebo plus letrozole. The median duration of exposure to Ribociclib plus letrozole was 13 months with 58% of patients exposed for  12 months.
- Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving Ribociclib plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving Ribociclib plus letrozole, 7% were reported to have permanently discontinued both Ribociclib and letrozole and 7% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrhea medications were used to manage symptoms as clinically indicated.
- On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of Ribociclib plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on Ribociclib plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
- The most common ARs (reported at a frequency  20% on the Ribociclib arm and  2% higher than placebo) were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
- The most common Grade 3/4 ARs (reported at a frequency  5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia.
- In MONALEESA-2, syncope occurred in 9 patients (3%) in the Ribociclib plus letrozole arm vs. 3 (1%) in placebo plus letrozole arm.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 6 and Table 7, respectively.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either Ribociclib plus a non-steroidal aromatase inhibitor (NSAI) or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the Ribociclib arm was 15.2 months with 66% of patients exposed for  12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving Ribociclib plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
- Dose reductions due to ARs occurred in 33% of patients receiving Ribociclib plus NSAI plus goserelin, and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving Ribociclib plus NSAI, 3% were reported to have permanently discontinued both Ribociclib and NSAI and 3% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on Ribociclib in patients receiving Ribociclib plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%).
- The most common ARs (reported at a frequency  20% on the Ribociclib arm and  2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency  5%) were neutropenia, leukopenia, and abnormal liver function tests. See Table 8 below.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 8 and Table 9, respectively.
- Additional adverse reactions in MONALEESA-7 for patients receiving Ribociclib plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%) and syncope (0.4%).
- Postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- The safety data reported below are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving Ribociclib plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to Ribociclib plus fulvestrant was 15.8 months with 58% of patients exposed for  12 months.
- Dose reductions due to ARs occurred in 32% of patients receiving Ribociclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving Ribociclib plus fulvestrant, 8% were reported to have permanently discontinued both Ribociclib and fulvestrant and 9% were reported to have discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).
- The most common ARs (reported at a frequency  20% on the Ribociclib arm and 2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency  5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 10.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 10 and Table 11, respectively.
- Additional adverse reactions in MONALEESA-3 for patients receiving Ribociclib plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).

## Postmarketing Experience
There is limited information regarding Ribociclib Postmarketing Experience in the drug label.

# Drug Interactions
- Drugs That May Increase Ribociclib Plasma Concentrations
- Drugs That May Decrease Ribociclib Plasma Concentrations
- Effect of Ribociclib on Other Drugs
- Drugs That Prolong the QT Interval
CYP3A4 Inhibitors
- Coadministration of a strong CYP3A4 inhibitor (ritonavir) increased Ribociclib exposure in healthy subjects by 3.2-fold . Avoid concomitant use of strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole) and consider alternative concomitant medications with less potential for CYP3A inhibition.
- If coadministration of Ribociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Ribociclib to 400 mg once daily.
- Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to Ribociclib.
CYP3A4 Inducers
- Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of Ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A (e.g., phenytoin, rifampin, carbamazepine and St Johns Wort (Hypericum perforatum)).
CYP3A Substrates with Narrow Therapeutic Index
- Coadministration of midazolam (a sensitive CYP3A4 substrate) with multiple doses of Ribociclib (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone. Ribociclib given at the clinically relevant dose of 600 mg is predicted to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when Ribociclib is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as Ribociclib can increase their exposure.
- Avoid coadministration of Ribociclib with medicinal products with a known potential to prolong QT such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron).

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- Based on findings from animal studies and the mechanism of action, Ribociclib 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 (see Data). 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 of miscarriage is 15%-20% of clinically recognized pregnancies in the U.S. general population.
Data (Animal)
- 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribociclib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ribociclib during labor and delivery.

### Nursing Mothers
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 Ribociclib, advise lactating women not to breastfeed while taking Ribociclib and for at least 3 weeks after the last dose.
Data
- In lactating rats administered a single dose of 50 mg/kg, exposure to Ribociclib was 3.56-fold higher in milk compared to maternal plasma.

### Pediatric Use
- The safety and efficacy of Ribociclib in pediatric patients has not been established.

### Geriatic Use
- Of 334 patients who received Ribociclib in MONALEESA-2, 150 patients (45%) were  65 years of age and 35 patients (11%) were  75 years of age. Of 484 patients who received Ribociclib in MONALEESA-3, 226 patients (47%) were  65 years of age and 65 patients (14%) were  75 years of age. No overall differences in safety or effectiveness of Ribociclib were observed between these patients and younger patients.

### Gender
There is no FDA guidance on the use of Ribociclib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ribociclib with respect to specific racial populations.

### Renal Impairment
- Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73m2  estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2) or moderate (30 mL/min/1.73m2  eGFR < 60 mL/min/1.73m2) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), a starting dose of 200 mg is recommended. Ribociclib has not been studied in breast cancer patients with severe renal impairment.

### 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 : 1.44 for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment.

### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with Ribociclib.
Contraception
Females
- Based on animal studies, Ribociclib 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 Ribociclib and for at least 3 weeks after the last dose.
Infertility
- Based on animal studies, Ribociclib may impair fertility in males of reproductive potential.

### Immunocompromised Patients
There is no FDA guidance one the use of Ribociclib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- If patient vomits or misses a dose, do not give an additional dose that day.
- Give with or without food.
- Give at the same time as the aromatase inhibitor, preferably in the morning.
- Swallow tablets whole, do not chew, crush, or split. Do not ingest any tablet that is broken, cracked, or not in tact.

### Monitoring
- Tumor response may indicate efficacy.
- CBC, including differential: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Liver function tests: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Pregnancy test: Prior to initiation of treatment in females with reproductive potential.
- Serum electrolytes, including potassium, calcium, phosphorus, and magnesium: Prior to therapy initiation, the start of the the first 6 cycles and as clinically indicated.
- ECG: Prior to therapy initiation, at day 14 of the first cycle, at the start of the second cycle, and as clinically indicated.

# IV Compatibility
There is limited information regarding the compatibility of Ribociclib and IV administrations.

# Overdosage
There is limited information regarding Ribociclib overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins 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 tumor 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. Additionally, the combination of Ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.

## Structure

## Pharmacodynamics
Cardiac Electrophysiology
- Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of Ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with Ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that Ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for Ribociclib 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean Cmax at steady-state.

## 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 Ribociclib 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-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis.
Metabolism
- In vitro and in vivo studies indicated Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled Ribociclib to humans, the primary metabolic pathways for Ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of Ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). 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. Clinical activity (pharmacological and safety) of Ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites.
- Ribociclib was extensively metabolized with unchanged drug accounting 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. Numerous other metabolites were detected in both feces and urine in minor amounts ( 3% of the administered dose).
Elimination
- The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t 12) of Ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of Ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
- 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 radio-labeled 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.
Specific Populations
Patients with Hepatic Impairment
- Based on a pharmacokinetic trial in patients with hepatic impairment, mild (Child-Pugh class A) 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 (Child-Pugh class B; geometric mean ratio : 1.44 for Cmax; 1.28 for AUCinf) and severe (Child-Pugh class C; GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of Ribociclib, further supporting the findings from the dedicated hepatic impairment study.
Patients with Renal Impairment
- Mild (60 mL/min/1.73m2  eGFR < 90 mL/min/1.73m2) and moderate (30 mL/min/1.73m2  eGFR < 60 mL/min/1.73m2) renal impairment had no effect on the exposure of Ribociclib based on a population PK analysis.
- The effect of renal impairment on the pharmacokinetics of Ribociclib was assessed in a renal impairment study in non-cancer subjects with normal renal function (eGFR  90 mL/min/1.73 m2), severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), and End Stage Renal Disease (ESRD; eGFR < 15 mL/min/1.73 m2). In subjects with severe renal impairment, AUCinf increased by 1.96 fold, and Cmax increased by 1.51 fold compared to subjects with normal renal function.
Effect of Age, Weight, Gender, and Race
- Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of Ribociclib.
Drug Interaction Studies
Drugs That Affect Ribociclib Plasma Concentrations
- CYP3A Inhibitors: A drug interaction trial in healthy subjects was conducted with ritonavir (a strong CYP3A inhibitor). Compared to Ribociclib alone, ritonavir (100 mg twice a day for 14 days) increased Ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg Ribociclib dose. Cmax and AUC for LEQ803 (a prominent metabolite of LEE011, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase Ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively.
- CYP3A Inducers: A drug interaction trial in healthy subjects was conducted with rifampicin (a strong CYP3A4 inducer). Compared to Ribociclib alone, rifampicin (600 mg daily for 14 days) decreased Ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single 600 mg Ribociclib dose. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. A moderate CYP3A inducer (efavirenz) is predicted to decrease Ribociclib Cmax and AUC by 37% and 60%, respectively.
Drugs that are Affected by Ribociclib
- CYP3A4 and CYP1A2 Substrates: A drug interaction trial in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of Ribociclib (400 mg once daily for 8 days) increased midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. Administration of Ribociclib at 600 mg once daily is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg Ribociclib on caffeine was minimal, with Cmax decreased by 10% and AUCinf increased slightly by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at 600 mg Ribociclib once daily dose.
- Gastric pH-elevating Agents: 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 physiology based PK models.
- Letrozole: Data from a clinical trial in patients with breast cancer and population PK analysis indicated no drug interaction between Ribociclib and letrozole following coadministration of the drugs.
- Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and anastrozole following coadministration of the drugs.
- Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and exemestane following coadministration of the drugs.
- Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on Ribociclib exposure following coadministration of the drugs.
- Tamoxifen: Ribociclib is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen Cmax and AUC increased approximately 2-fold following coadministration of 600 mg Ribociclib.
In vitro Studies
- Effect of Ribociclib on CYP Enzymes: In vitro, Ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that Ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 at clinically relevant concentrations.
- Effect of Ribociclib on Transporters: In vitro evaluations indicated that Ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations.
- Effect of Transporters on Ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of Ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT-1 in vitro.

## Nonclinical Toxicology
- Carcinogenesis studies have not been conducted with Ribociclib.
- Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.
- In a fertility and early embryonic development study, female rats received oral doses of Ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC).
- A fertility study in male rats has not been performed with Ribociclib. In repeat-dose toxicity studies with oral administration of Ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses  75 mg/kg in rats and  1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.
- In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax).

# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-2 was a randomized, double-blind, placebo-controlled, multicenter clinical study of Ribociclib plus letrozole vs. 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), stratified according to the presence of liver and/or lung metastases. Letrozole 2.5 mg was given orally once daily for 28 days, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-2 had a median age of 62 years (range 23 to 91) and 45% of patients were older than 65. The majority of patients were White (82%), and all patients had an ECOG performance status of 0 or 1. A total of 47% of patients had received chemotherapy and 51% had received antihormonal therapy in the neoadjuvant or adjuvant setting. Thirty-four percent (34%) of patients had de novo metastatic disease, 21% had bone only disease, and 59% had visceral disease.
- The efficacy results from MONALEESA-2 are summarized in Table 12 and Figure 1. The results shown are from a pre-planned interim efficacy analysis of PFS. Results were consistent across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. At the time of the PFS analysis, 6.5% of patients had died, and overall survival data were immature.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was a randomized, double-blind, placebo-controlled study of Ribociclib plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease.
- A total of 672 patients were randomized to receive Ribociclib plus NSAI or tamoxifen plus goserelin (n = 335) or placebo plus NSAI or tamoxifen plus goserelin (n = 337), stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partner (tamoxifen and goserelin vs. NSAI and goserelin). NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg were given orally once daily on a continuous daily schedule, goserelin was administered as a sub-cutaneous injection on Day 1 of each 28 day cycle, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-7 had a median age of 44 years (range 25 to 58) and were primarily Caucasian (58%), Asian (29%), or Black (3%). Nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant vs. 18% in the neoadjuvant setting and 40% had received endocrine therapy in the adjuvant vs. 0.7% in the neoadjuvant setting prior to study entry. Forty percent (40%) of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, and endocrine combination partner.
- The efficacy results from a pre-specified subgroup analysis of 495 patients who had received Ribociclib or placebo with NSAI plus goserelin are summarized in Table 13 and Figure 2. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. Overall survival data were immature with 13% deaths.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- MONALEESA-3 was a randomized double-blind, placebo-controlled study of Ribociclib in combination with fulvestrant for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
- A total of 726 patients were randomized in a 2:1 ratio to receive Ribociclib 600 mg and fulvestrant (n = 484) or placebo and fulvestrant (n = 242), stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either Ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in this study had a median age of 63 years (range 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily Caucasian (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
- The efficacy results from MONALEESA-3 are summarized in Table 14 and Figure 3. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. At the time of the PFS analysis, 17% of patients had died, and overall survival data were immature.

# How Supplied
- Each film-coated tablet contains 200 mg of Ribociclib free base.
- Light greyish violet, round, curved with beveled edge, debossed with RIC on one side and NVR on the other side; available in:
- Blister pack (21 tablets)  each blister pack contains 21 tablets (200 mg per tablet) (600 mg daily dose). Outer container - 3 Blister packs per outer container          NDC 0078-0874-63
- Blister pack (14 tablets)  each blister pack contains 14 tablets (200 mg per tablet) (400 mg daily dose). Outer container - 3 Blisters packs per outer container          NDC 0078-0867-42
- Blister pack (21 tablets)  each blister pack contains 21 tablets (200 mg per tablet) (200 mg daily dose). Outer container  1 Blister pack per outer container          NDC 0078-0860-01

## Storage
- Store at 20C to 25C (68F to 77F). Store in the original package.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling 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 Ribociclib 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 Ribociclib.
Lactation
- Advise lactating women not to breastfeed during treatment with Ribociclib and for at least 3 weeks after the last dose.
Drug Interactions
- Inform patients to avoid grapefruit or grapefruit juice while taking Ribociclib.
- Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs known to prolong the QT interval.
Dosing
- Instruct patients to take the doses of Ribociclib at approximately the same time every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that Ribociclib may be taken with or without food.

# Precautions with Alcohol
Alcohol-Ribociclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Kisqali

# Look-Alike Drug Names
There is limited information regarding Ribociclib Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price