Kryxana

Ribociclib.

Film coated, light greyish violet, round, curved with beveled edges, debossed with "RIC" on one side and "NVR" on the other side.
Tablet: 200 mg ribociclib (equivalent to 254.40 mg ribociclib succinate).
KRYXANA (ribociclib) is a kinase inhibitor.
The chemical name of ribociclib succinate is: Butanedioic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1/1).
Ribociclib succinate is a light yellow to yellowish brown crystalline powder. The molecular formula for ribociclib succinate is C₂₃H₃₀N₈O·C₄H₆O₄ and the molecular weight is 552.64 g/mol (Free base: 434.55 g/mol).
KRYXANA film-coated tablets are supplied for oral use and contain 200 mg of ribociclib free base (equivalent to 254.40 mg ribociclib succinate).
Excipients/Inactive Ingredients: The tablets also contain colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline cellulose. The film-coating contains iron oxide black, iron oxide red, lecithin (soya), polyvinyl alcohol (partially hydrolysed), talc, titanium dioxide, and xanthan gum as inactive ingredients.

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 are downstream of 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, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. 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) therapies 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.
Pharmacodynamics: The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KRYXANA have not been fully characterized in patients.
Cardiac Electrophysiology: A concentration-QT analysis of the data in patients with breast cancer treated with KRYXANA at doses ranging from 50 to 1200 mg (0.083 to 2 times of the approved recommended high dose) suggested that ribociclib causes concentration-dependent increases in QTcF interval [see QT Interval Prolongation and Increased QT Prolongation with Concomitant Use of Tamoxifen under Precautions].
In patients with advanced or metastatic breast cancer the estimated mean QTcF interval change from baseline for the KRYXANA 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 mean steady-state C_max [see QT Interval Prolongation and Increased QT Prolongation with Concomitant Use of Tamoxifen under Precautions].
Clinical Studies: MONALEESA-2: KRYXANA in Combination with Letrozole: Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: MONALEESA-2 (NCT01958021) was a randomized (1:1), double-blind, placebo-controlled, multicenter clinical study of KRYXANA plus letrozole vs. placebo plus letrozole conducted in postmenopausal women (N=668) with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease.
Participants were randomized to receive either KRYXANA plus letrozole or placebo plus letrozole, 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 KRYXANA 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.
The median age was 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 are summarized in Table 1, Figure 1 and Figure 2. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. Consistent results were observed across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. (See Table 1, Figures 1 and 2.)

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MONALEESA-7: KRYXANA in Combination with a Non-Steroidal Aromatase Inhibitor with or without Goserelin: Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: MONALEESA-7 (NCT02278120) was a randomized (1:1), double-blind, placebo-controlled study of KRYXANA plus either a NSAI or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women (N=672) with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease.
Participants were randomized to receive KRYXANA plus NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin, 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 KRYXANA 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.
The median age was 44 years (range, 25 to 58). Patients were primarily White (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 KRYXANA or placebo with NSAI plus goserelin are summarized in Table 2, Figure 3, and Figure 4. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. (See Table 2, Figures 3 and 4.)

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MONALEESA-3: KRYXANA in Combination with Fulvestrant: 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 (NCT06129786) was a randomized (2:1) double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of postmenopausal women (N=726) with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
Participants were randomized to receive KRYXANA 600 mg and fulvestrant or placebo and fulvestrant, 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 KRYXANA 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.
The median age was 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 White (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. Patients enrolled in this study were treated in the first- or second-line setting, and 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 3, Figure 5 and Figure 6. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. (See Table 3, Figures 5 and 6.)

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COMPLEEMENT-1: KRYXANA in combination with Letrozole with or without Goserelin or Leuprolide: Men with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: COMPLEEMENT-1 (NCT 02941926) was an open-label, multicenter clinical study of ribociclib in combination with letrozole and goserelin or leuprolide for the treatment of adults with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease.
The study included 39 male patients who received KRYXANA 600 mg orally once daily for 21 consecutive days followed by 7 days off; and letrozole 2.5 mg orally once daily for 28 days; and goserelin 3.6 mg as injectable subcutaneous implant or leuprolide 7.5 mg as intramuscular injection administered on Day 1 of each 28-day cycle. Patients were treated until disease progression or unacceptable toxicity occurred.
Male patients enrolled in this study had a median age of 62 years (range, 33 to 80). Of these patients, 39% were 65 years and older, including 10% aged 75 years and older. The male patients enrolled were White (72%), Asian (8%), and Black (3%), with 17% unknown. Nearly all male patients (97%) had an ECOG performance status of 0 or 1. The majority of male patients (97%) had 4 or less metastatic sites, which were primarily bone and visceral (69% each). Table 4 summarizes the efficacy results in male patients from COMPLEEMENT-1. (See Table 4.)

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Pharmacokinetics: Ribociclib exhibited over-proportional increases in exposure (C_max and AUC) across the dose range of 50 mg to 1200 mg (0.083 to 2 times of the approved recommended high dose) following both single dose and repeated doses of KRYXANA.
Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a mean accumulation ratio of 2.5 (range, 0.97 to 6.4), and mean (coefficient of variation (CV%)) steady-state ribociclib C_max was 1820 (62%) ng/mL and AUC was 23800 (66%) ng*h/mL.
Absorption: The T_max following ribociclib administration was between 1 and 4 hours. The mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8%.
Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of KRYXANA 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 clinically meaningful differences in ribociclib C_max or AUC_inf.
Distribution: Ribociclib protein binding in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). The mean in vivo blood-to-plasma ratio was 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L.
Metabolism: 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. 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 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 represented approximately 14% and 4% of the administered dose in feces and urine, respectively.
Elimination: The mean plasma effective half-life (CV%) was 32.0 hours (63%) and the mean apparent oral clearance (CL/F) was 25.5 L/hr (66%) at steady-state following 600 mg dose of KRYXANA in patients with advanced cancer.
The mean apparent plasma terminal half-life of ribociclib ranged from 29.7 to 54.7 hours and mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy adults.
Following a single oral dose of radio-labeled ribociclib in healthy adults, 92% of the total administered radioactive dose was recovered within 22 days; 69% in feces and 23% in urine.
Specific Populations: Patients with Hepatic Impairment: Compared to adults with normal hepatic function, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of ribociclib; while in adults with moderate (Child-Pugh class B) hepatic impairment, the mean ratio was 1.44 for C_max and 1.28 for AUC_inf; and in adults with severe (Child-Pugh class C) hepatic impairment, the mean ratio was 1.32 for C_max and 1.29 for AUC_inf.
Patients with Renal Impairment: In adults with severe renal impairment and ESRD, ribociclib AUC_inf increased 2.4-fold and 3.8-fold, and C_max increased 2.1-fold and 2.7-fold relative to the exposure in adults with normal renal function.
Mild or moderate renal impairment had no effect on the exposure of ribociclib. A sub-group analysis of data from studies following oral administration of KRYXANA in patients with advanced cancer who have mild to moderate renal impairment, AUC and C_max were comparable to those in patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure.
Effect of Age, Weight, Gender, and Race: No clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib were identified.
Drug Interaction Studies: Clinical Studies and Model-Informed Approaches: Drugs That Affect Ribociclib Plasma Concentrations: CYP3A Inhibitors: Following a single 400 mg dose of KRYXANA with ritonavir (a strong CYP3A inhibitor), ritonavir (100 mg twice a day for 14 days) increased ribociclib C_max and AUC_inf by 1.7-fold and 3.2-fold, respectively, compared to ribociclib alone. C_max and AUC for LEQ803 (a prominent metabolite of ribociclib, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase ribociclib steady-state C_max and AUC by 1.1-fold and 1.2-fold, respectively, following KRYXANA 400 mg once daily, and 1.1-fold and 1.1-fold, respectively, following KRYXANA 600 mg once daily.
CYP3A Inducers: Following a single 600 mg dose of KRYXANA with rifampicin (a strong CYP3A4 inducer) at 600 mg daily for 14 days, ribociclib C_max decreased by 81% and AUCinf decreased by 89%, while LEQ803 C_max increased 1.7-fold and AUCinf decreased by 27% compared to ribociclib alone. A moderate CYP3A inducer (efavirenz) is predicted to decrease ribociclib steady-state C_max by 55% and AUC by 74%, following KRYXANA 400 mg once daily, and by 52% and 71%, respectively, following KRYXANA 600 mg once daily.
Drugs That are Affected by KRYXANA: CYP3A4 and CYP1A2 Substrates: In a cocktail study with midazolam (sensitive CYP3A4 substrate) multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam C_max by 2.1-fold and increased AUC_inf by 3.8-fold compared to midazolam alone. Administration of KRYXANA 600 mg once daily is predicted to increase midazolam C_max and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg ribociclib on caffeine (sensitive CYP1A2 substrate) was minimal, with C_max decreased by 10% and AUC_inf increased by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at KRYXANA 600 mg once daily dose.
Gastric pH-Elevating Agents: Coadministration of ribociclib with drugs that elevate the gastric pH is not predicted to alter ribociclib absorption.
Letrozole: Data from a clinical trial in patients with breast cancer 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: KRYXANA is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen C_max 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 KRYXANA 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 KRYXANA has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. KRYXANA 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 OCT1 in vitro.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 2-year carcinogenicity study with oral administration of ribociclib daily in cycles of 3 weeks on/1 week off, ribociclib was not carcinogenic at doses up to 50 mg/kg in male rats and 600 mg/kg in female rats. Systemic exposure in male and female rats were 1.3 and 1.8 times, respectively, the human exposure at the highest recommended dose of 600 mg/day based on AUC.
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.
Animal Toxicology and/or Pharmacology: 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 C_max).

KRYXANA is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine-based therapy in pre/perimenopausal or postmenopausal women or in men; or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men.

Dosing and Administration: The recommended dose of KRYXANA 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. KRYXANA can be taken with or without food [see Pharmacology: Pharmacokinetics under Actions].
When given with KRYXANA, refer to the Full Prescribing Information for the recommended dose of endocrine therapy.
Pre/perimenopausal women, or men, treated with the combination KRYXANA plus an aromatase inhibitor should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
Men treated with the combination of KRYXANA plus fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
Patients should take their dose of KRYXANA 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. KRYXANA 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: Dose Modifications for Adverse Reactions: The recommended dose modifications for adverse reactions are listed in Table 5. (See Table 5.)

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Tables 6, 7, 8, 9, 10, and 11 summarize recommendations for dose interruption, reduction, or discontinuation of KRYXANA in the management of specific adverse reactions. Dose modification of KRYXANA is recommended based on individual safety and tolerability. (See Tables 6, 7, 8, 9, 10 and 11.)

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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.
Dose Modification for Use with Strong CYP3A Inhibitors: Avoid concomitant use of KRYXANA with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition [see Drugs That May Increase Ribociclib Plasma Concentrations under Interactions].
If a strong CYP3A inhibitor must be coadministered, reduce the KRYXANA dose to 400 mg once daily. If the strong inhibitor is discontinued, change the KRYXANA 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 [see Drugs That May Increase Ribociclib Plasma Concentrations under Interactions and Pharmacology: Pharmacokinetics under Actions].
Dose Modification for Hepatic Impairment: The recommended starting dose is 400 mg KRYXANA once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics under Actions].
Review the Full Prescribing Information for the co-administered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.
Dose Modification for Severe Renal Impairment: The recommended starting dose is 200 mg KRYXANA once daily for patients with severe renal impairment [see Renal Impairment under Precautions and Pharmacology: Pharmacokinetics under Actions].

There is limited experience with reported cases of overdose with KRYXANA in humans. General symptomatic and supportive measures should be initiated in all cases of overdose where necessary.

Hypersensitivity to the active substance or to peanut, soya or any of the excipients.

Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KRYXANA and other CDK4/6 inhibitors.
Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.6% of KRYXANA-treated patients had ILD/pneumonitis (any Grade, 0.4% had Grade 3-4, and 0.1% had a fatal outcome). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [see Postmarketing Experience under Adverse Reactions].
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt KRYXANA immediately and evaluate the patient. Permanently discontinue KRYXANA in patients with severe ILD/pneumonitis or any recurrent symptomatic ILD/pneumonitis [see Dose Modifications under Dosage & Administration].
Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with KRYXANA [see Postmarketing Experience under Adverse Reactions].
If signs or symptoms of severe cutaneous reactions occur, interrupt KRYXANA until the etiology of the reaction has been determined [see Dose Modifications under Dosage & Administration]. Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management.
If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KRYXANA. Do not reintroduce KRYXANA in patients who have experienced SCARs or other life threatening cutaneous reactions during KRYXANA treatment.
QT Interval Prolongation: KRYXANA has been shown to prolong the QT interval in a concentration-dependent manner [see Pharmacology: Pharmacodynamics under Actions].
Avoid KRYXANA in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with: congenital long QT syndrome; uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities; taking drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.
Based on the observed QT prolongation during treatment, KRYXANA may require dose interruption, reduction or discontinuation as described in Table 8 [see Dose Modifications under Dosage & Administration and Drugs That Prolong the QT Interval under Interactions].
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, and MONALEESA-7) who received 600 mg KRYXANA plus NSAI or fulvestrant, 15 out of 1054 patients (1.4%) had a >500 ms post-baseline QTcF value and 61 out of 1054 patients (6%) had a >60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KRYXANA. There were no reported cases of Torsades de Pointes.
In MONALEESA-2, in the KRYXANA 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 [see Adverse Reactions].
Perform ECG in all patients prior to starting KRYXANA. Initiate treatment with KRYXANA 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 KRYXANA at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KRYXANA [see Dose Modifications under Dosage & Administration].
Increased QT Prolongation With Concomitant Use of Tamoxifen: Avoid use of tamoxifen with KRYXANA. 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 (NSAIs) 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 KRYXANA and tamoxifen combination and in 18/245 (7%) of patients receiving KRYXANA plus an NSAI [see Pharmacology: Pharmacodynamics under Actions].
Hepatotoxicity: In patients with advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KRYXANA.
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7 and MONALEESA-3) treated with KRYXANA Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥3 ALT/AST elevation, the median time-to-onset was 92 days for the KRYXANA plus aromatase inhibitor or fulvestrant treatment arms. The median time to resolution to Grade ≤2 was 21 days in the KRYXANA plus aromatase inhibitor or fulvestrant treatment arms. 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 (Hy's Law) occurred in 6 (1%) patients and all patients recovered after discontinuation of KRYXANA.
Perform liver function tests (LFTs) in all patietns before initiating KRYXANA. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated [see Dose Modifications under Dosage & Administration].
Based on the severity of the transaminase elevations, KRYXANA may require dose interruption, reduction, or discontinuation as described in Table 9 (Dose Modification and Management for Hepatobiliary Toxicity) [see Dose Modifications under Dosage & Administration].
Neutropenia: KRYXANA causes concentration-dependent neutropenia.
In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7, and MONALEESA-3) who received KRYXANA plus NSAI or fulvestrant, 75% had neutropenia, 62% had Grade 3 or 4 decrease in neutrophil count (based on laboratory findings), and 1.7% had febrile neutropenia. The median time to Grade ≥2 neutropenia was 17 days. The median time to resolution of Grade ≥3 neutropenia to Grade <3 was 12 days. Treatment discontinuation due to neutropenia was required in 1% of patients.
Perform a complete blood count (CBC) in all patients before initiating KRYXANA. 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, KRYXANA may require dose interruption, reduction or discontinuation as described in Table 10 [see Dose Modifications under Dosage & Administration].
Embryo-Fetal Toxicity: Based on findings from animal studies and the mechanism of action, KRYXANA 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 KRYXANA and for at least 3 weeks after the last dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions].
Hepatic Impairment: No dose adjustment is necessary in patients with breast cancer who have mild hepatic impairment (Child-Pugh class A) [see Pharmacology: Pharmacokinetics under Actions]. A reduced starting dose of 400 mg is recommended in patients with advanced or metastatic breast cancer who have moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Dose Modifications under Dosage & Administration].
Renal Impairment: No dose adjustment is necessary in patients with breast cancer who have mild to moderate (30 mL/min to 89 mL/min/1.73 m² ≤estimated glomerular filtration rate (eGFR)) renal impairment. A reduced starting dose of 200 mg is recommended in patients with breast cancer who have severe renal impairment [see Dose Modifications under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and efficacy of KRYXANA in pediatric patients has not been established.
Use in the Elderly: Of 334 patients with advanced or metastatic breast cancer who received KRYXANA in MONALEESA-2, 150 patients (45%) were ≥65 years of age and 35 patients (11%) were ≥75 years of age. Of 484 patients with advanced or metastatic breast cancer who received KRYXANA in MONALEESA-3, 226 patients (47%) were ≥65 years of age and 65 patients (14%) were ≥75 years of age. Of 248 patients with advanced or metastatic breast cancer who received KRYXANA in MONALEESA-7, no patients were ≥65 years of age. No overall differences in safety or effectiveness of KRYXANA were observed between older and younger adults with advanced or metastatic breast cancer.

Pregnancy: Risk Summary: Based on findings from animal studies and the mechanism of action, KRYXANA can cause fetal harm when administered to a pregnant woman [see Pharmacology: Mechanism of Action under Actions].
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 post implantation 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 as follows). 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 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 13^th 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.
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 KRYXANA, advise lactating women not to breastfeed while taking KRYXANA 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.
Females and Males of Reproductive Potential: Based on animal studies and mechanism of action, KRYXANA can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned].
Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to starting treatment with KRYXANA.
Contraception: Females: Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with KRYXANA and for at least 3 weeks after the last dose.
Infertility: Males: Based on animal studies, KRYXANA may impair fertility in males of reproductive potential [see Pharmacology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].

The following adverse reactions are discussed in greater detail in other sections of the monograph: Interstitial Lung Disease/Pneumonitis [see Interstitial Lung Disease/Pneumonitis under Precautions]; Severe Cutaneous Adverse Reactions [see Severe Cutaneous Adverse Reactions under Precautions]; QT Interval Prolongation [see QT Interval Prolongation and Increased QT Prolongation With Concomitant Use of Tamoxifen under Precautions]; Hepatotoxicity [see Hepatotoxicity under Precautions]; Neutropenia [see Neutropenia under Precautions].
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.
The pooled safety population described in the Precautions reflects exposure to KRYXANA in 1065 patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), of whom 76% were exposed for 6 months or longer, and 62% were exposed for greater than one year. The most common (≥20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%), creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%), vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash (24%), back pain (24%), and glucose serum decreased (20%).
MONALEESA-2: KRYXANA in Combination with Letrozole: Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: The safety of KRYXANA was evaluated in MONALEESA-2, a clinical trial of 668 postmenopausal women receiving KRYXANA plus letrozole or placebo plus letrozole [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure to KRYXANA plus letrozole was 13 months with 58% of patients exposed for ≥12 months.
Serious adverse reactions occurred in 21% of patients who received KRYXANA plus letrozole. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus letrozole included abdominal pain (1.5%), vomiting (1.5%), constipation (1.2%), nausea (1.2%), anemia (1.2%), febrile neutropenia (1.2%), dyspnea (1.2%), and alanine aminotransferase increased (1.2%).
Fatal adverse reactions occurred in 1.8% of patients who received KRYXANA. Fatal adverse reactions in ≥0.1% of patients receiving KRYXANA included acute respiratory failure (0.6%), acute myocardial infarction, sudden death (with Grade 3 hypokalemia and Grade 2 QT prolongation), unknown cause, and pneumonia (0.3% each). Permanent discontinuation of both KRYXANA and letrozole due to an adverse reaction occurred in 7% of patients. Permanent discontinuation of KRYXANA alone occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and letrozole in ≥2% of patients were alanine aminotransferase increased (5%), aspartate aminotransferase increased (3%), and vomiting (2%).
Dosage interruptions of both KRYXANA and letrozole due to an adverse reaction occurred in 71% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (39%), neutrophils decreased (12%), vomiting (6%), nausea (5%), alanine aminotransferase increased (5%), and leukocytes decreased (5%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 45% of patients receiving KRYXANA plus letrozole. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (24%), neutrophils decreased (8%), and alanine aminotransferase increased (3%).
Antiemetics and antidiarrheal medications were used to manage symptoms as clinically indicated.
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutrophils decreased, leukocytes decreased, hemoglobin decreased, nausea, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhea, alopecia, vomiting, platelets decreased, constipation, headache, and back pain.
Table 12 summarizes the adverse reactions in MONALEESA-2. (See Table 12.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-2 receiving KRYXANA plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%). Table 13 summarizes the laboratory abnormalities in MONALEESA-2. (See Table 13.)

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MONALEESA-7: KRYXANA in Combination with a Non-Steroidal Aromatase Inhibitor: Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: The safety of KRYXANA was evaluated in MONALEESA-7, a clinical trial of 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KRYXANA plus a NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure in the KRYXANA plus a NSAI arm was 15.2 months with 66% of patients exposed for ≥12 months. The safety data reported as follows are based on 495 pre/perimenopausal patients receiving KRYXANA plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
Serious adverse reactions occurred in 17% of patients who received KRYXANA plus NSAI plus goserelin. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus NSAI plus goserelin included drug-induced liver injury (1.6%), abdominal pain (1.2%), dyspnea (1.2%), febrile neutropenia (1.2%), and back pain (1.2%).
Permanent discontinuation of both KRYXANA and NSAI due to an adverse reaction occurred in 3% of patients. Permanent discontinuation of KRYXANA alone occurred in 3% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and NSAI in ≥2% of patients were alanine aminotransferase increased (2%), and aspartate aminotransferase increased (2%).
Dosage interruptions of KRYXANA plus NSAI plus goserelin due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (41%), neutrophils decreased (26%), and leukocytes decreased (6%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 33% of patients receiving KRYXANA plus NSAI plus goserelin. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (17%), neutrophils decreased (5%), and alanine aminotransferase increased (2%).
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, infections, arthralgia, alanine aminotransferase increased, nausea, platelets decreased, and alopecia.
Table 14 summarizes the adverse reactions in MONALEESA-7. (See Table 14.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-7 receiving KRYXANA plus NSAI included thrombocytopenia (9%), dry skin (9%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%). (See Table 15.)

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MONALEESA-3: KRYXANA in Combination with Fulvestrant: 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 of KRYXANA was evaluated in MONALEESA-3, a clinical trial of 724 postmenopausal women receiving KRYXANA plus fulvestrant or placebo plus fulvestrant. [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure to KRYXANA plus fulvestrant was 15.8 months with 58% of patients exposed for ≥12 months.
Serious adverse reactions occurred in 29% of patients who received KRYXANA plus fulvestrant. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus fulvestrant included pneumonia (1.9%), nausea (1.4%), vomiting (1.4%), anemia (1.2%), dyspnea (1.2%), neutropenia (1.2%). One case (0.2%) of fatal adverse reaction (pneumonia) occurred in patients who received KRYXANA plus fulvestrant.
Fatal adverse reactions occurred in 1.2% of patients who received KRYXANA. Fatal adverse reactions in ≥0.1% of patients receiving KRYXANA included cardiac failure, ventricular arrhythmia, pneumonia, acute respiratory distress, pulmonary embolism, and hemorrhagic shock (0.2% each). Permanent discontinuation of both KRYXANA and fulvestrant due to an adverse reaction occurred in 8% of patients. Permanent discontinuation of KRYXANA alone occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and fulvestrant in ≥2% of patients were alanine aminotransferase increased (5%), and aspartate aminotransferase increased (3%).
Dosage interruptions of KRYXANA plus fulvestrant due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (40%), neutrophils decreased (13%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), and leukocytes decreased (5%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 32% of patients receiving KRYXANA plus fulvestrant. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (15%), and neutrophils decreased (3%).
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, lymphocytes decreased, creatinine increased, hemoglobin decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, infections, platelets decreased, diarrhea, vomiting, constipation, glucose serum decreased, cough, rash, and pruritus.
Table 16 summarizes the adverse reactions in MONALEESA-3. (See Table 16.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-3 receiving KRYXANA plus fulvestrant included 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%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%). (See Table 17.)

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COMPLEEMENT-1: KRYXANA in Combination with Letrozole and Goserelin or Leuprolide: Men with HR-positive, HER2-negative Advanced Breast Cancer for Initial Endocrine-Based Therapy: The safety of KRYXANA in combination with letrozole was evaluated in men (n=39) in an open-label, multicenter clinical trial for the treatment of adult patients with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease (COMPLEEMENT-1) [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
The median duration of exposure to KRYXANA was 20.8 months (range, 0.5 to 30.6 months).
Other adverse reactions occurring in men treated with KRYXANA plus letrozole and goserelin or leuprolide were similar to those occurring in women treated with KRYXANA plus endocrine therapy.
Postmarketing Experience: The following adverse events have been reported during post-approval use of KRYXANA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Respiratory disorders: Interstitial lung disease/pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia, and systemic symptoms (DRESS).

Drugs That May Increase Ribociclib Plasma Concentrations: CYP3A4 Inhibitors: Coadministration of strong CYP3A inhibitors increases ribociclib exposure [see Pharmacology: Pharmacokinetics under Actions]. Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation [see QT Interval Prolongation under Precautions]. Avoid concomitant use of strong CYP3A inhibitors with KRYXANA and consider alternative concomitant medications with less potential for CYP3A inhibition.
In patients with advanced or metastatic breast cancer, if coadministration of KRYXANA with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KRYXANA to 400 mg once daily [see Dose Modifications under Dosage & Administration].
Drugs That May Decrease Ribociclib Plasma Concentrations: CYP3A4 Inducers: Coadministration of strong CYP3A4 inducers decreases the plasma exposure of ribociclib [see Pharmacology: Pharmacokinetics under Actions]. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A.
Effect of KRYXANA on Other Drugs: CYP3A Substrates: Coadministration of sensitive CYP3A4 substrates with multiple doses of KRYXANA increases the substrate exposure [see Pharmacology: Pharmacokinetics under Actions]. For CYP3A substrates where minimal increases in the concentration may increase CYP3A substrate adverse reactions, monitor for increased adverse reactions of the CYP3A substrate during treatment with KRYXANA. The dose of the sensitive CYP3A substrate may need to be reduced as KRYXANA can increase its exposure.
Drugs That Prolong the QT Interval: Avoid coadministration of KRYXANA with products with a known potential to prolong QT interval, such as antiarrhythmic drugs and other drugs that are known to prolong the QT interval. If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated [see QT Interval Prolongation under Precautions and Pharmacology: Pharmacodynamics under Actions].

Do not store above 30°C.

Targeted Cancer Therapy

L01EF02 - ribociclib ; Belongs to the class of cyclin-dependent kinase (CDK) inhibitors. Used in the treatment of cancer.

B