Ribociclib 200 mg Film-coated tablets

For the use of only Registered Medical Practitioners or a Hospital or a Laboratory. Ribociclib 200 mg Film-coated tablets Kryxana ® Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE42 DESCRIPTION AND COMPOSITION Pharmaceutical form(s) Film-coated tablet 200 mg Light greyish violet, unscored, round, curved with beveled edges, debossed with “RIC” on one side and “NVR” on the other side. Active substance Each film-coated tablet contains ribociclib succinate, equivalent to 200 mg ribocilib. Excipients Tablet core: Microcrystalline cellulose; low-substituted hydroxypropylcellulose; crospovidone (Type A); colloidal silicon dioxide; magnesium stearate. Coating material: Polyvinyl alcohol (partially hydrolysed); titanium dioxide (E171); iron oxide black (E172); iron oxide red (E172); talc: lecithin (soy) (E322); xanthan gum. INDICATIONS Ribociclib is a kinase inhibitor 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 DOSAGE AND ADMINISTRATION Treatment with Ribociclib should be initiated by a physician experienced in the use of anticancer therapies. Dosage regimen General target population The recommended dose of Ribociclib is 600 mg (3 x 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 (see section INTERACTIONS). For dosing and administration with the aromatase inhibitor, refer to the applicable full prescribing information. Patients should take their dose of Ribociclib and the aromatase inhibitor at approximately the same time each day, preferably in the morning. Treatment of pre or peri-menopausal women with Ribociclib co-administration should include an LHRH agonist according to local clinical practice standards. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 1 of 25Dose modifications Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction, or discontinuation of Ribociclib. If dose reduction is required, the recommended dose reduction guidelines for adverse drug reactions (ADRs) are listed in Table 1. Table 1 Recommended Dose Modification Guidelines for Adverse Drug Reactions Ribociclib Dose Number of Tablets Starting dose 600 mg/day 3 × 200 mg tablets First dose reduction 400 mg/day 2 × 200 mg tablets Second dose reduction 200 mg/day* 1 × 200 mg tablet *If further dose reduction below 200 mg/day is required, discontinue the treatment. Tables 2, 3, 4 and 5 summarize recommendations for dose interruption, reduction, or discontinuation of Ribociclib in the management of specific ADRs. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (see sections WARNINGS AND PRECAUTIONS, ADVERSE DRUG REACTIONS). Table 2 Dose Modification and Management for Neutropenia Neutropenia Grade 1 or 2 Grade 3 Grade 3 febrile* Grade 4 neutropenia (ANC 1,000/mm3 – (ANC 500 - (ANC <500/mm3) <LLN) <1,000/mm3) No dose adjustment Interrupt Ribociclib Interrupt Ribociclib Interrupt Ribociclib is required. until recovery to until recovery of until recovery to Grade ≤2. neutropenia to Grade ≤2. Grade ≤2. Resume Resume Ribociclib Resume Ribociclib Ribociclib at the at the same dose at the next lower next lower dose level. dose level. level. If toxicity recurs at Grade 3, interrupt Ribociclib dose until recovery to Grade ≤2, then resume Ribociclib at the next lower dose level. Perform Complete Blood Counts (CBC) before initiating treatment with Ribociclib. After initiating treatment with Ribociclib, monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. *Grade 3 neutropenia with a single episode of fever >38.3ᵒC (or) above 38ᵒC for more than one hour and/or concurrent infection Grading according to CTCAE Version 4.03 CTCAE=Common Terminology Criteria for Adverse Events. Table 3 Dose Modification and Management for Hepatobiliary toxicity AST and/or ALT Grade 1 Grade 2 Grade 3 Grade 4 elevations from (>ULN – 3 x (>3 to 5 x ULN) (>5 to 20 x ULN) (>20 x ULN) baseline*, without ULN) India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 2 of 25increase in total No dose Baseline at <Grade 2: Interrupt Ribociclib Discontinue bilirubin above 2 x adjustment is until recovery to Ribociclib ULN Interrupt Ribociclib until required. ≤baseline Grade, then recovery to ≤baseline resume at next lower Grade, then resume dose level. Ribociclib at same dose level. If Grade 2 recurs, If Grade 3 recurs, resume Ribociclib at discontinue Ribociclib. next lower dose level. ------------------------------ Baseline at Grade 2: No dose interruption. Combined If patients develop ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN elevations in AST irrespective of baseline Grade, discontinue Ribociclib. and/or ALT together with total bilirubin increase, in the absence of cholestasis Perform Liver Function Tests (LFTs) before initiating treatment with Ribociclib. After initiating treatment with Ribociclib, monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. If Grade ≥2 abnormalities are observed, more frequent monitoring is recommended. *Baseline = prior to treatment initiation. Grading according to CTCAE Version 4.03 CTCAE=Common Terminology Criteria for Adverse Events. Table 4 Dose Modification and Management for QT prolongation ECGs with QTcF 1. Interrupt the Ribociclib dose >480 msec 2. If QTcF prolongation resolves to <481 msec, resume Ribociclib at the next lower dose level; 3. If QTcF ≥481 msec recurs, interrupt the Ribociclib dose until QTcF resolves to <481 msec; and then resume Ribociclib at next lower dose level ECGs with QTcF If QTcF greater than 500 msec: Interrupt Ribociclib until QTcF reaches <481 msec >500 msec then resume Ribociclib at next lower dose level. If QTcF interval prolongation is greater than 500 msec or shows a greater than 60 msec change from baseline in combination with Torsade de Pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently discontinue Ribociclib. Assess ECG prior to initiation of treatment. After initiating treatment with Ribociclib, repeat ECG at approximately day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended. Table 5 Dose Modification and Management for Other Toxicities* Other toxicities Grade 1 or 2 Grade 3 Grade 4 No dose adjustment is Interrupt Ribociclib dose Discontinue Ribociclib. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 3 of 25Other toxicities Grade 1 or 2 Grade 3 Grade 4 required. Initiate until recovery to Grade appropriate medical ≤1, then resume therapy and monitor as Ribociclib at the same clinically indicated. dose level. If Grade 3 recurs, resume Ribociclib at the next lower dose level. *excluding neutropenia, hepatobiliary toxicity, and QT interval prolongation. Grading according to CTCAE Version 4.03. CTCAE=Common Terminology Criteria for Adverse Events. Refer to the full prescribing information for the co-administered aromatase inhibitor or LHRH agonist for dose modification guidelines in the event of toxicity and other relevant safety information. Dose modification for use of Ribociclib with strong CYP3A inhibitors Concomitant use of Ribociclib should be avoided with strong CYP3A inhibitors and an alternative concomitant medication should be considered with low potential for CYP3A inhibition. If a strong CYP3A inhibitor must be co-administered, the Ribociclib dose should be reduced to 200 mg once daily. If the strong inhibitor is discontinued, the Ribociclib dose should be changed (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 sections WARNINGS AND PRECAUTIONS, INTERACTIONS AND CLINICAL PHARMACOLOGY). Special populations Renal impairment Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild or moderate renal impairment (see section CLINICAL PHARMACOLOGY). Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment, a starting dose of 200 mg is recommended. Ribociclib has not been studied in breast cancer patients with severe renal impairment(see section CLINICAL PHARMACOLOGY). Hepatic impairment Based on a hepatic impairment study in healthy subjects and non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A dose adjustment is required in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child- Pugh class C) and the starting dose of 400 mg is recommended. Ribociclib has not been studied in breast cancer patients with moderate and severe hepatic impairment (see section CLINICAL PHARMACOLOGY). Review the full prescribing information for the aromatase inhibitor, or the LHRH agonist for dose modifications related to hepatic impairment. Pediatric patients There are limited data in pediatric patients and the safety and efficacy of Ribociclib in this population has not been established. Geriatric patients (65 years of age or older) No dose adjustment is required in patients over 65 years of age (see section CLINICAL PHARMACOLOGY). Method of administration Ribociclib should be taken orally once daily at the same time every day, preferably in the morning, with or without food. If the patient vomits after taking the dose or misses a dose, an additional dose should not 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). Tablets that are broken, cracked, or India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 4 of 25otherwise not intact should not be ingested. CONTRAINDICATIONS Ribociclib is contraindicated in patients with hypersensitivity to the active substance, or to any of the excipients. WARNINGS AND PRECAUTIONS Neutropenia In the 3 phase III clincial studies (MONALEESA-2 (A2301), MONALEESA-7 (E2301-NSAI) and MONALEESA-3 (F2301)), neutropenia was the most frequently reported adverse drug reaction (73.7%) and a Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 58.4% of patients receiving Ribociclib plus any combination in the phase III clinical studies. Among the patients who had Grade 2, 3 or 4 neutropenia in the phase III clinical studies, the median time to Grade 2, 3 or 4 neutropenia was 16 days. The median time to resolution of Grade ≥3 (to normalization or Grade <3) was 12 days in the Ribociclib plus any combination treatment group. Severity of neutropenia is concentration dependent. Febrile neutropenia was reported in 1.4% of patients exposed to Ribociclib in the phase III clinical studies. Physicians should inform patients to promptly report any fever (see section ADVERSE DRUG REACTIONS). A complete blood count (CBC) should be performed before initiating therapy with Ribociclib. CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles then as clinically indicated. Based on the severity of the neutropenia, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 2 Dose Modification and Management for Neutropenia (see section DOSAGE AND ADMINISTRATION). In patients who develop Grade 1 or 2 neutropenia, no Ribociclib dose adjustment is required. In patients who develop Grade 3 neutropenia without fever, the Ribociclib dose should be interrupted until recovery to Grade ≤2 and then Ribociclib should be resumed at the same dose level. If Grade 3 neutropenia without fever recurs, Ribociclib dose should be interrupted until recovery, then Ribociclib should be resumed at the next lower dose level. In patients who develop Grade 3 febrile neutropenia (ANC 500 to <1,000/mm3 with a single episode of fever >38.3°C (or) above 38°C for more than one hour and/or concurrent infection), or patients who develop Grade 4 neutropenia, Ribociclib dose should be interrupted until recovery to Grade ≤2, then Ribociclib should be resumed at the next lower dose level. Hepatobiliary toxicity In the phase III clinical studies, increases in transaminases were observed. Grade 3 or 4 increases in ALT (9.7% vs. 1.5%) and AST (6.7% vs. 2.1%) were reported in the Ribociclib plus any combination and placebo plus any combination arms respectively. Grade 4 increases in ALT (1.9% vs. 0.1%) and AST (1.1% vs. 0.1%) were reported in the Ribociclib plus any combination treatment and placebo plus any combination treatment arms respectively. In the phase III clinical studies, 83.2% ( 89/107) of Grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment (see section ADVERSE DRUG REACTIONS). The majority of increases in ALT and AST were reported without concurrent elevations of bilirubin. Among the patients who had Grade 3 or 4 ALT/AST elevation, the median time-to-onset was 85 days for the Ribociclib plus any combination treatment group. The median time to resolution (to normalization or Grade ≤2) was 22 days in the Ribociclib plus any combination treatment group. Concurrent elevations of ALT or AST greater than three times the upper limit of normal and of total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase levels, and in the absence of cholestasis occurred in 6 patients (4 patients in Study A2301, whose levels recovered to normal within 154 days; and 2 patients in Study F2301, whose levels recovered to normal within 121 and 532 days, respectively, after discontinuation of Ribociclib. There were no such cases reported in Study E2301. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 5 of 25Liver function tests (LFTs) should be performed before initiating therapy with Ribociclib. The LFTs should be monitored every 2 weeks for first 2 cycles, at the beginning of each of the subsequent 4 cycles, then 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 – Hepatobiliary toxicity (see section DOSAGE AND ADMINISTRATION). Recommendations for patients who have elevated AST/ALT Grade >3 at baseline have not been established. QT interval prolongation In the phase III clinical studies, in patients with advanced or metastatic breast cancer who received the Ribociclib plus any combination partners, review of ECG data showed 14 patients (1.3%) had >500 msec post- baseline QTcF value, and 59 patients (5.6%) had a >60 msec QTcF interval increase from baseline. There were no reported cases of Torsade de Pointes. In E2301 (MONALEESA-7), the observed mean QTcF increase from baseline was approximately more than 10 msecs higher in the tamoxifen plus placebo subgroup compared with NSAI plus placebo subgroup, suggesting that tamoxifen had a QTcF prolongation effect which can contribute to the QTcF observed in the ribociclib plus tamoxifen group (see section Clinical pharmacology- Cardiac electrophysiology). In the placebo arm, an increase of >60 msec from baseline occurred in 6/90 (6.7%) of the patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of >60 msec from baseline in the QTcF interval was observed in 14/87 (16.1%) patients receiving ribociclib plus tamoxifen and in 18/245 (7.3%) of the patients receiving ribociclib plus an NSAI. The ECG should be assessed prior to initiation of treatment. Treatment with Ribociclib should be initiated only in patients with QTcF values less than 450 msec. The ECG should be repeated at approximately Day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated. Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorous and magnesium) should be performed prior to initiation of treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before and during Ribociclib therapy. Ribociclib should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients with: • long QT syndrome • uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias • electrolyte abnormalities Ribociclib should be avoided with medicinal products known to prolong the QTc interval and/or strong CYP3A inhibitors as this may lead to clinically meaningful prolongation of the QTcF interval (see sections DOSAGE AND ADMINISTRATION, INTERACTIONS and CLINICAL PHARMACOLOGY). Based on the findings in E2301, Ribociclib is not recommended for use in combination with tamoxifen (see section Clinical pharmacology). Based on the observed QT prolongation during treatment, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 4-4 Dose Modification and Management-QT prolongation (see sections DOSAGE AND ADMINISTRATION, ADVERSE DRUG REACTIONS and CLINICAL PHARMACOLOGY). Reproductive toxicity Based on animal findings and its mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman. Women of reproductive potential should be advised to use effective contraception during therapy with Ribociclib and for at least 21 days after the last dose (see sections PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL). India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 6 of 25ADVERSE DRUG REACTIONS Summary of the safety profile The overall safety profile of Ribociclib reported below is based on the pooled data set of 1065 patients who received Ribociclib in combination with endocrine therapy (N=582 in combination with aromatase inhibitor, and N=483 in combination with fulvestrant), in double blind, placebo controlled phase III clinical studies (MONALEESA-2, MONALEESA-7-NSAI arm, MONALEESA-3) in HR-positive, HER2-negative advanced or metastatic breast cancer. The median duration of exposure to Ribociclib treatment across the pooled phase III studies dataset was 16.53 months with 61.7% patients exposed for >12 month. Dose reductions due to adverse events (AEs), regardless of causality occurred in 37.3% of patients receiving Ribociclib in phase III clinical studies regardless of the combination and in 3.4% of patients receiving placebo. Permanent discontinuations due to adverse events was reported in 7.0% of patients receiving Ribociclib plus any combination and 2.9% in patients receiving placebo plus any combination. The most common AEs leading to permanent discontinuation of both Ribociclib with any combination treatment partner were ALT increased (2.0%), AST increased (1.4%) and vomiting (0.8%). In the pooled analysis of three phase III studies, on treatment deaths, were reported in 21 cases (2.0%) of patients treated with Ribociclib plus any combination vs 16 cases (2.0%) of patients treated with placebo plus any combination treatment Excluding the most frequent cause of death disease progression, three treatment related cause of deaths were reported in patients treated with Ribociclib plus any combination treatment. Causes of death were acute respiratory distress syndrome 1 (0.1%), acute respiratory failure 1 (0.1%), and sudden death (in the setting of Grade 3 hypokalaemia and Grade 2 QT prolongation) 1 (0.1%).The most common adverse drug reactions (ADRs) across the pooled phase III studies (reported at a frequency >20% and for which the rate for Ribociclib exceeds the frequency for placebo) were infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhoea, vomiting, constipation, alopecia and rash. The most common Grade 3/4 ADRs in the pooled data (reported at a frequency >2% and for which the frequency for Ribociclib exceeds the frequency for placebo) were infections, neutropenia, leukopenia, anaemia, abnormal liver function tests, lymphopenia, hypophosphataemia, and vomiting. Tabulated summary of adverse drug reactions based on pooled dataset from 3 phase III clinical studies ADRs from the phase-III clinical studies (Table 6) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Table 6 Adverse drug reactions based on pooled data set from 3 phase III clinical studies Ribociclib Placebo Ribociclib Placebo Frequency N=1065 N=818 N=1065 N=818 category Adverse drug reactions n (%) n (%) n (%) n (%) All Grades All Grades Grades 3/4 Grades 3/4 All Grades Infections and infestations Infections1 434 (40.8) 245 (30.0) 41 (3.8) 8 (1.0) Very common Blood and lymphatic system disorders Neutropenia 785 (73.7) 41 (5.0) 624 (58.6) 11 (1.3) Very common Leukopenia 314 (29.5) 24 (2.9) 165 (15.5) 4 (0.5) Very common Anaemia 200 (18.8) 51 (6.2) 30 (2.8) 12 (1.5) Very common Lymphopenia 95 (8.9) 18 (2.2) 56 (5.3) 5 (0.6) Common India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 7 of 25Ribociclib Placebo Ribociclib Placebo Frequency N=1065 N=818 N=1065 N=818 category Adverse drug reactions n (%) n (%) n (%) n (%) All Grades All Grades Grades 3/4 Grades 3/4 All Grades Thrombocytopenia 95 (8.9) 11 (1.3) 8 (0.8) 1 (0.1) Common Febrile neutropenia 15 (1.4) 2 (0.2) 15 (1.4) 2 (0.2) Common Eye disorders 0 Lacrimation increased 0 Common 59 (5.5) 9 (1.1) Dry eye 54 (5.1) 18 (2.2) 0 0 Common Metabolism and nutrition disorders Decreased appetite 163 (15.3) 101 (12.3) 6 (0.6) 1 (0.1) Very common Hypocalcaemia 45 (4.2) 14 (1.7) 11 (1.0) 0 Common Hypokalaemia 33 (3.1) 21 (2.6) 12 (1.1) 5 (0.6) Common Hypophosphataemia 34 (3.2) 11 (1.3) 22 (2.1) 7 (0.9) Common Nervous system disorders Headache 253 (23.8) 177 (21.6) 5 (0.5) 4 (0.5) Very common Dizziness 125 (11.7) 83 (10.1) 1 (0.1) 0 Very common Vertigo 46 (4.3) 10 (1.2) 1 (0.1) 0 Common Cardiac disorders Syncope 19 (1.8) 9 (1.1) 12 (1.1) 7 (0.9) Common Respiratory, thoracic and mediastinal disorders Dyspnoea 132 (12.4) 81 (9.9) 15 (1.4) 7 (0.9) Very common Cough 218 (20.5) 132 (16.1) 0 0 Very common Musculoskeletal and connective tissue disorders Back pain 211 (19.8) 153 (18.7) 20 (1.9) 7 (0.9) Very common Gastrointestinal disorders Nausea 475 (44.6) 219 (26.8) 15 (1.4) 4 (0.5) Very common Diarrhoea 317 (29.8) 176 (21.5) 16 (1.5) 5 (0.6) Very common Vomiting 284 (26.7) 128 (15.6) 21 (2.0) 3 (0.4) Very common Constipation 253 (23.8) 129 (15.8) 8 (0.8) 0 Very common Stomatitis 122 (11.5) 53 (6.5) 3 (0.3) 1 (0.1) Very common Abdominal pain2 182 (17.1) 107 (13.1) 14 (1.3) 4 (0.5) Very common Dysgeusia 71 (6.7) 36 (4.4) 1 (0.1) 0 Common Dyspepsia 88 (8.3) 35 (4.3) 1 (0.1) 0 Common Hepatobiliary disorders Hepatotoxicity3 19 (1.8) 7 (0.9) 15 (1.4) 4 (0.5) Common India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 8 of 25Ribociclib Placebo Ribociclib Placebo Frequency N=1065 N=818 N=1065 N=818 category Adverse drug reactions n (%) n (%) n (%) n (%) All Grades All Grades Grades 3/4 Grades 3/4 All Grades Skin and subcutaneous tissue disorders Alopecia 256 (24.0) 97 (11.9) 0 0 Very common Rash4 227 (21.3) 70 (8.6) 10 (0.9) 0 Very common Pruritus 177 (16.6) 48 (5.9) 3 (0.3) 0 Very common Erythema 43 (4.0) 8 (1.0) 2 (0.2) 0 Common Dry skin 88 (8.3) 18 (2.2) 0 0 Common Vitiligo 16 (1.5) 0 0 0 Common General disorders and administration site conditions Fatigue 348 (32.7) 249 (30.4) 20 (1.9) 4 (0.5) Very common Peripheral oedema 147 (13.8) 71 (8.7) 1 (0.1) 0 Very common Asthenia 145 (13.6) 103 (12.6) 7 (0.7) 3 (0.4) Very common Pyrexia 139 (13.1) 52 (6.4) 4 (0.4) 0 Very common Dry mouth 74 (6.9) 44 (5.4) 1 (0.1) 0 Common Oropharyngeal pain 67 (6.3) 33 (4.0) 0 0 Common Investigations Abnormal liver function 66 (8.1) 16 (2.0) Very common 184 (17.3) 93 (8.7) tests5 Blood creatinine increased 67 (6.3) 15 (1.8) 4 (0.4) 0 Common Electrocardiogram QT 13 (1.6) 2 (0.2) Common prolonged 69 (6.5) 13 (1.2) 1 Infections: Urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (<1%). 2 Abdominal pain: Abdominal pain, abdominal pain upper. 3Hepatotoxicity: hepatocellular injury, drug induced liver injury, hepatotoxicity, hepatic failure, autoimmune hepatitis (single case). 4Rash: rash, rash maculopapular, rash pruritic. 5Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased. Laboratory abnormalities Clinically relevant abnormalities of routine haematological or biochemical laboratory values from the dataset of 3 pooled phase III studies, are presented in Table 7. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 9 of 25Table 7 Laboratory abnormalities based on pooled dataset from phase III clinical studies Laboratory abnormalities Ribociclib Placebo Ribociclib Placebo Frequency N=1065 N=818 N= 1065 N=818 category n (%) n (%) n (%) n (%) (all Grades) All Grades All Grades Grades 3/4 Grades 3/4 Hematological parameters Leukocyte count decreased 1002 (94.1) 243 (29.7) 336 (31.5) 8 (1.0) Very common Neutrophil count decreased 985 (92.5) 207 (25.3) 622 (58.4) 13 (1.6) Very common Haemoglobin decreased 698 (65.5) 309 (37.8) 36 (3.4) 13 (1.6) Very common Lymphocyte count decreased 649 (60.9) 209 (25.6) 163 (15.3) 30 (3.7) Very common Platelet count decreased 332 (31.2) 73 (8.9) 12 (1.1) 3 (0.4) Very common Biochemical parameters Alanine aminotransferase 466 (43.8) 291 (35.6) 103 (9.7) 12 (1.5) Very increased common Aspartate aminotransferase 498 (46.8) 308 (37.7) 71 (6.7) 17 (2.1) Very increased common Creatinine increased 409 (38.4) 107 (13.1) 7 (0.7) 1 (0.1) Very common Phosphorous decreased 165 (15.5) 66 (8.1) 44 (4.1) 8 (1.0) Very common Potassium decreased 95 (8.9) 68 (8.3) 17 (1.6) 9 (1.1) Common Gamma glutamyl transferase 357 (48.8) 220 (45.1) 53 (7.3) 47 (9.6) Very increased common Albumin decreased 112 (10.5) 45 (5.5) 1 (0.1) 1 (0.1) Very common Glucose serum decreased 184 (17.3) 100 (12.2) 1 (0.1) 1 (0.1) Very common Bilirubin increased 54 (5.1) 44 (5.4) 9 (0.8) 9 (1.1) Common Description of selected adverse drug reactions Neutropenia Neutropenia was most frequently reported by laboratory findings in the phase III studies. Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Treatment discontinuation due to neutropenia was low (0.8%) in patients receiving Ribociclib plus any combination partner (see sections DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS). Hepatobiliary toxicity In the phase III clinical studies, hepatobiliary toxicity events occurred in a higher proportion of patients in the Ribociclib plus any combination arms vs the placebo plus any combination arms (23.2% vs 16.5%, India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 10 of 25respectively), with more Grade 3/4 adverse events reported in the patients treated with Ribociclib plus any combination treatment (11.4% vs 5.4%, respectively). Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 10.4% of Ribociclib treated patients, primarily due to ALT increased (6.9%) and/or AST increased (6.1%). Discontinuation of treatment with Ribociclib due to abnormal liver function tests, hepatotoxicity were 2.3% and 0.4% respectively (see section WARNINGS AND PRECAUTIONS). QT prolongation In the phase III clinical studies, 8.4% of patients in the Ribociclib arm and 3.2% in the placebo arm had at least one event of QT interval prolongation (including ECG QT prolonged, syncope). Dose interruptions-adjustments were reported in 2.3% of Ribociclib treated patients due to electrocardiogram QT prolonged and syncope. A central analysis of ECG data (average of triplicate) showed 52 patients (4.9%) and 11 patients (1.4%) with at least one post-baseline QTcF >480 m sec for the Ribociclib tretament arm and the placebo arm respectively. Among the patients who had QTcF prolongation of >480 m secs, the median time to onset is 15 days, regardless of combination and these changes were reversible with dose interruption and/or dose reduction (see sections DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY). INTERACTIONS Ribociclib is primarily metabolized by CYP3A and is a time-dependent inhibitor of CYP3A in vivo. Therefore, medicinal products which can influence CYP3A enzyme activity may alter the pharmacokinetics of ribociclib. Medicinal products that may increase ribociclib plasma concentrations Co-administration of a strong CYP3A4 inhibitor (ritonavir) increased ribociclib exposure in healthy subjects by 3.21-fold. Concomitant use of strong CYP3A inhibitors including but not limited to clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole (see section WARNINGS AND PRECAUTIONS) should be avoided. Alternative concomitant medications with low potential to inhibit CYP3A should be considered and patients should be monitored for ADRs (see sections DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY). If co-administration of Ribociclib with a strong CYP3A inhibitor cannot be avoided, Ribociclib dose should be reduced to 200 mg. However, there are no clinical data with this dose adjustment (see section DOSAGE AND ADMINISTRATION). If the strong inhibitor is discontinued, the Ribociclib dose should be resumed (after at least 5 half-lives of the CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ADRs is recommended. In the event of Ribociclib related toxicity, dose should be modified (see section DOSAGE AND ADMINISTRATION), or treatment should be interrupted until toxicity is resolved (see sections DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY) Patients should be instructed to avoid grapefruits or grapefruit juice, all of which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to ribociclib. Medicinal products that may decrease ribociclib plasma concentrations Co-administration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers, including but not limited to phenytoin, rifampin, carbamazepine and St John’s Wort (Hypericum perforatum). An alternate concomitant medication with no or minimal potential to induce CYP3A should be considered (see sections WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY). Medicinal products that may have their plasma concentrations altered by ribociclib Co-administration of midazolam (CYP3A4 substrate) with multiple doses of Ribociclib (400 mg) increased the midazolam exposure by 280% (3.80-fold) in healthy subjects, compared with administration of midazolam alone. Simulations using physiologically-based PK (PBPK) models suggested that Ribociclib given at the clinically relevant dose of 600 mg is expected 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 India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 11 of 25dose 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 has the potential to increase their exposure (see section CLINICAL PHARMACOLOGY). Co-administration of caffeine (CYP1A2 substrate) with multiple doses of Ribociclib (400 mg) increased caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of caffeine alone. At the clinically relevant dose of 600 mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (<2-fold increase in AUC) (see section CLINICAL PHARMACOLOGY). Medicinal products that are substrates of transporters In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OAT1/3, OATP1B1/B3, and OCT1 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see section CLINICAL PHARMACOLOGY). Drug-food interactions Ribociclib can be administered with or without food (see section DOSAGE AND METHOD OF ADMINISTRATION). 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 had no effect on the rate and extent of absorption of ribociclib (C GMR: 1.00; max 90% CI: 0.898, 1.11; AUC GMR: 1.06; 90% CI: 1.01, 1.12 (see section CLINICAL PHARMACOLOGY). inf Gastric pH elevating medications Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co- administration of Ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in the population pharmacokinetic analysis nor in simulations using PBPK models (see section CLINICAL PHARMACOLOGY). Anticipated interactions Anti-arrhythmic medicines and other medicinal products that may prolong the QT interval: Co- administration of Ribociclib should be avoided with medicinal products with known potential to prolong the QT interval such as anti-arrhythmic medicines. Concomitant use of anti-arrhythmic medicines (including but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol), other medicinal products that are known to prolong the QT interval, including but not limited to, chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron (i.v), should be avoided (see section WARNINGS AND PRECAUTIONS). Ribociclib is not recommended for use in combination with tamoxifen (see section WARNINGS AND PRECAUTIONS). PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Pregnancy Risk summary Based on animal data and its mechanism of action, it is possible that Ribociclib can cause fetal harm when administered to a pregnant woman. The patient should be advised of the risk to a fetus, if Ribociclib is used during pregnancy or if the patient becomes pregnant while taking this medicinal product. There are no adequate and well-controlled studies in pregnant women. Reproductive studies in rats and rabbits have demonstrated ribociclib induced embryotoxicity, fetotoxocity and teratogenicity. Following prenatal exposure, increased incidences of post-implantation loss and reduced fetal weights were observed in rats and ribociclib was teratogenic in rabbits as evidenced by increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants) at exposures lower than or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC. There are no available human data informing the drug-associated risk. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 12 of 25Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ribociclib up to 1,000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, 1,000 mg/kg/day was lethal in the maternal animals. At 300 mg/kg/day, a slight, non-adverse trend towards reduced maternal body weight gain and fetal toxicity evidenced by reduced fetal weights accompanied by skeletal changes were considered to be transitory and/or related to the lower fetal weights. There were no effects upon embryo-fetal mortality or adverse effects on fetal morphology at 50 or 300 mg/kg/day. The no- observed-adverse-effect level (NOAEL) for maternal toxicity was considered to be 300 mg/kg/day. The no- observed-effect-level (NOEL) for embryo-fetal development was considered to be 50 mg/kg/day. In rabbits at doses ≥30 mg/kg/day, there were adverse effects on embryo-fetal development as evidenced by 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 and additional vessel on the aortic arch and diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes and reduced/small accessory lung lobe (30 and 60 mg/kg), extra/rudimentary 13th ribs and misshapen hyoid bone and reduced number of phalanges in the pollex. There was no evidence of embryo-fetal mortality. The no-observed-effect level (NOEL) for maternal toxicity was considered to be at least 30 mg/kg/day and the NOEL for the embryo- fetal development was 10 mg/kg/day. At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 13,800 ng*hr/mL and 36,700 ng*hr/mL, lower than or at 1.5 times, the one achieved 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 child or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from Ribociclib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women taking Ribociclib should not breastfeed for at least 21 days after the last dose. Data Animal data In lactating rats administered a single dose of 50 mg/kg, exposure to ribociclib was 3.56 fold higher in milk than in maternal plasma. Females and males of reproductive potential Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman (see section NON CLINICAL SAFETY DATA). Pregnancy testing For females of reproductive potential the pregnancy status should be verified prior to initiating treatment with Ribociclib. Contraception Females of reproductive potential should be advised that animal studies have been performed showing ribociclib to be harmful to the developing fetus. Sexually active females of reproductive potential should use effective contraception (methods that result in < 1 % pregnancy rates) when using Ribociclib during treatment and for 21 days after stopping treatment with Ribociclib. Infertility In a fertility study in female rats, ribociclib did not affect the reproductive function, fertility or early embryonic development at any dose up to 300 mg/kg/day (likely at an exposure lower than or equal to patients clinical exposure, at the highest recommended dose of 600 mg/day based on AUC). India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 13 of 25A fertility study in male rats has not been performed, however atrophic changes in testes were reported in repeated dose toxicity studies in rats and dogs at exposures that were less or equal to the human exposure at the highest recommended daily dose of 600 mg/day based on AUC (see section NON CLINICAL SAFETY DATA). There are no clinical data available regarding the effects of Ribociclib on fertility. Based on animal studies, Ribociclib may impair fertility in males of reproductive potential. OVERDOSAGE There is limited experience with reported cases of Ribociclib overdose in humans. General symptomatic and supportive measures should be initiated in all cases of overdosage where necessary. CLINICAL PHARMACOLOGY Mechanism of action (MOA) Ribociclib is a selective 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 led to tumor regressions which correlated with inhibition of pRb phosphorylation at well tolerated doses. In vivo studies using patient-derived estrogen positive breast cancer xenograft models combination of ribociclib and antiestrogens (i.e. letrozole) resulted in superior inhibition of tumor growth compared to each drug alone. Tumor regrowth was delayed for 33 days after stopping dosing. Pharmacodynamics (PD) Ribociclib inhibits the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes with concentration resulting in 50% inhibition (IC ) values of 0.01 (4.3 ng/mL) and 0.039 micro molar (16.9 ng/mL) in biochemical assays, 50 respectively. In cell-based assays, ribociclib inhibits CDK4/6-dependent pRb phosphorylation with an average IC of 0.06 50 micro molar (26 ng/mL). Ribociclib halts G1 to S phase cell cycle progression measured by flow cytometry with an average IC of 0.11 micro molar (47.8 ng/mL). Ribociclib also inhibits cellular proliferation measured by 50 bromodeoxyuridine (BrdU) uptake with an IC of 0.8 micro molar (34.8 ng/mL). The similar IC values 50 50 obtained from the target modulation, cell cycle and proliferation assays confirms that the blockade of the pRb phosphorylation by ribociclib directly leads to G1 to S phase arrest and subsequent inhibition of cellular proliferation. When tested in a panel of breast cancer cell lines with known ER status, ribociclib demonstrated to be more efficacious in ER+ breast cancer cell lines than in the ER- ones. Cardiac electrophysiology Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1,200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. Pharmacokinetics (PK) The pharmacokinetics of ribociclib were investigated in patients with advanced cancer following oral daily doses of 50 mg to 1,200 mg. Healthy subjects received single oral doses ranging of 400 or 600 mg or repeated daily oral doses (8 days) of 400 mg. Absorption Following oral administration of Ribociclib to patients with advanced solid tumors or lymphomas peak plasma levels (C ) of ribociclib were achieved between 1 and 4 hours (time to reach maximum concentration, T ). max max Ribociclib exhibited slightly over-proportional increases in exposure (C and AUC) across the dose range max India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 14 of 25tested (50 to 1,200 mg). Following repeated once daily dosing, 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). Food effect: Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablet formulation with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib (C GMR: 1.00; 90% CI: 0.898, 1.11; AUC GMR: 1.06; 90% CI: 1.01, 1.12) (see section max inf INTERACTIONS). 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 1,090 L based on the population pharmacokinetic analysis. Biotransformation/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 [14C]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 (43.5%). The major circulating metabolites included metabolite M13 (CCI284, N- hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9.39%, 8.60%, and 7.78% of total radioactivity, and 21.6%, 19.8%, and 17.9% of ribociclib exposure, respectively. Clinical activity (pharmacological and safety) of ribociclib was primarily due to parent drug, with negligible contribution from circulating metabolites. Ribociclib was extensively metabolized with the unchanged drug accounting for 17.3% and 12.1% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤2.78% 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 plasma terminal half-life (T ) of ribociclib ranged from 29.7 to 1/2 54.7 hours and the 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 the feces, with a small contribution from the renal route. In 6 healthy male subjects, following a single oral dose of [14C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 21 days; feces was the major route of excretion (69.1%), with 22.6% of the dose recovered in the urine. Linearity/non-linearity Ribociclib exhibited slightly over-proportional increases in exposure (C and AUC) across the dose range of max 50 mg to 1,200 mg following both single dose and repeated doses. This analysis is limited by the small sample sizes for most of the dose cohorts with a majority of the data coming from the 600 mg dose cohort. Special populations Renal impairment No dose adjustment is necessary in patients with mild or moderate renal impairment. Based on a population pharmacokinetic analysis that included 438 patients with normal renal function (eGFR ≥90 mL/min/1.73 m2), 488 patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73 m2) and 113 patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2), mild and moderate renal impairment had no effect on the exposure of ribociclib (see section DOSAGE AND ADMINISTRATION). India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 15 of 25The effect of renal impairment on the pharmacokinetics of ribociclib was also assessed in a renal impairment study that included 7 subjects with normal renal function (eGFR ≥90 mL/min/1.73 m2), 7 subjects with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2), and 3 subjects with end stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2) at single ribociclib dose of 400 mg/day. The geometric mean AUC (geometric %CV, n) inf of 5570 ng*hr/mL (22.8%, 7), 10900 ng*hr/mL (38.1%, 7), 13600 ng*hr/mL (20.9%, 3) and Cmax (geometric %CV, n) of 356 ng/mL (15%, 7), 538 ng/mL (43.3%, 7), 593 ng/mL (11.3%, 3) was observed in subjects with normal renal function, severe renal impairment and ESRD, respectively . In subjects with severe renal impairment AUC increased by 1.96 fold, and C increased by 1.51 fold compared to subjects with normal inf max renal function. Based on this study, a starting dose of 200 mg is recommended for patients with severe renal impairment (see section 4 Dosage and administration). Hepatic impairment No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A); a dose adjustment is required in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) and a starting dose of 400 mg is recommended (see section DOSAGE AND ADMINISTRATION). Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib (see section DOSAGE AND ADMINISTRATION). The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for C ; 1.28 for max AUC ) and severe (GMR: 1.32 for C ; 1.29 for AUC ) hepatic impairment. Based on a population inf max inf 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 (see section DOSAGE AND ADMINISTRATION). Effect of age, weight, gender and race The population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib that would require a dose adjustment. Geriatric use Of 334 patients who received Ribociclib in the phase III study (MONALEESA 2, in ribocilib plus letrozole arm), 150 patients (44.9%) were ≥65 years of age and 35 patients (10.5%) were ≥75 years of age. No overall differences in safety or effectiveness of Ribociclib were observed between these patients and younger patients (see section DOSAGE AND ADMINISTRATION). Interactions Strong CYP3A inhibitors: A drug interaction study in healthy subjects was conducted with ritonavir (strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg b.i.d for 14 days) increased ribociclib C max and AUC by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. C and AUC inf max last for LEQ803 (a prominent metabolite of ribociclib, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. Simulations using physiologically-based pharmacokinetic modeling (PBPK) suggested that a moderate CYP3A4 inhibitor (erythromycin) may increase C and AUC of ribociclib 400 mg max single dose by 1.3-fold and 1.9-fold, respectively (see sections DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and INTERACTIONS). Strong CYP3A inducers: A drug interaction study in healthy subjects was conducted with rifampicin (strong CYP3A4 inducer). Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib C and AUC by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 C max inf max increased 1.7-fold and AUC decreased by 27%, respectively. Simulations using PBPK suggested that a inf moderate CYP3A inducer (efavirenz) may decrease ribociclib single dose C and AUC by 37% and 60%, max respectively (see section INTERACTIONS). Cytochrome P450 enzymes (CYP3A4 and CYP1A2 substrates): A drug interaction study 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 C and AUC by 2.1-fold and 3.8-fold, respectively. Simulations using max inf PBPK suggested that at a 600 mg ribociclib dose, midazolam C and AUC may increase 2.4-fold and 5.2-fold, max respectively. The effect of multiple doses of ribociclib on caffeine was minimal, with C decreasing by 10% max India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 16 of 25and AUC increasing slightly by 20%. Simulations using PBPK suggested only weak inhibitory effects on inf CYP1A2 substrates at a 600 mg ribociclib dose (see section INTERACTIONS). Ribociclib exhibited no capacity to inhibit CYP2E1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and showed no apparent time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6 at clinically relevant concentrations. No induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4 was observed in vitro at clinically relevant concentrations (see section INTERACTIONS). Gastric pH-elevating agents: Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in population pharmacokinetic analysis nor in simulations using PBPK models (see sections DOSAGE AND ADMINISTRATION AND INTERACTIONS). Letrozole: Data from clinical trials in patients with breast cancer and population PK analysis indicated no drug interaction between ribociclib and letrozole following co-administration of the drugs (see section INTERACTIONS). 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 Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrazole following coadministration of the drugs. Tamoxifen: Data from a clinical trial in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2 fold following coadministration of ribociclib and tamoxifen. 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, MATE2K at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see section INTERACTIONS). 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 (see section INTERACTIONS). CLINICAL STUDIES Study CLEE011A2301 Ribociclib was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III clinical study in the treatment of postmenopausal women with HR positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease in combination with letrozole versus letrozole alone. A total of 668 patients were randomized in a 1:1 ratio to receive either Ribociclib 600 mg and letrozole (n= 334) or placebo and letrozole (n= 334), stratified according to the presence of liver and/or lung metastases [Yes (n=292 (44%))] vs No [n=376 (56%))]). Demographics and baseline disease characteristics were balanced and comparable between study arms. Ribociclib was given orally at a dose of 600 mg daily for 21 consecutive days followed by 7 days off treatment in combination with letrozole 2.5 mg once daily for 28 days. Patients were not allowed to cross over from placebo to Ribociclib during the study or after disease progression. Patients enrolled in this study had a median age of 62 years (range 23 to 91). 44.2% patients were of age 65 years and older including 69 patients (10.3%) of age 75 years and older. The patients included were Caucasian (82.2%), Asians (7.6%), and Black (2.5%). All patients had an ECOG performance status of 0 or 1. A total of 43.6% of patients had received chemotherapy in the neoadjuvant or adjuvant setting and 51.8% had received antihormonal therapy in the neo/adjuvant setting prior to study entry. 34.1% of patients had de novo metastatic disease. 20.7% of patients had bone only disease and 59.0% of patients had visceral disease. The primary endpoint for the study was met at the planned interim analysis conducted after observing 80% of targeted progression-free survival (PFS) events using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in the full population (all randomized patients) and confirmed by a blinded independent central radiological assessment. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 17 of 25The efficacy results (29 January 2016 cut-off) demonstrated a statistically significant improvement in PFS in patients receiving Ribociclib plus letrozole compared to patients receiving placebo plus letrozole in the full analysis set (hazard ratio [HR] = 0.556 with 95% CI: 0.429, 0.720, one sided stratified log-rank test p-value 0.00000329), with an estimated 44% reduction in risk of progression for patients treated with the combination of reduction in Ribociclib plus letrozole. The median PFS was not reached in the Ribociclib plus letrozole arm (95% CI: 19.3 – NE) at the time of primary analysis. The median PFS was 14.7 months (95% CI, 13.0, and 16.5) for placebo plus letrozole arm. Results were consistent across the subgroups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, bone only metastasis disease. Progression free survival is summarized in Table 8 and the Kaplan-Meier curve for PFS is provided in Figure 1. The results for PFS based on the blinded independent central radiological assessment were consistent with the primary efficacy results based on the investigator’s assessment (hazard ratio: 0.592 with 95% CI: (0.412, 0.852). The one-sided stratified log-rank test p-value was 0.002. The global health status/QoL showed no relevant difference between the Ribociclib plus letrozole arm and the placebo plus letrozole control arm. Overall survival (OS) was a key secondary endpoint. At the time of primary PFS analysis, overall survival was not mature with 11% of events. A more mature update of efficacy data (02 January 2017 cutoff) is provided in Table 9. Median PFS was 25.3 months (95% CI: 23.0, 30.3) for ribociclib plus letrozole treated patients and 16.0 months (95% CI: 13.4, 18.2) for patients receiving placebo plus letrozole. 54.7% of patients receiving ribociclib plus letrozole were estimated to be progression free at 24 months compared with 35.9% in the placebo plus letrozole arm. There was no statistically significant difference in overall survival (OS) between the Ribociclib plus letrozole arm and the placebo plus letrozole arm (HR 0.746 [95% CI 0.517, 1.078]). OS data remain immature. Hazard ratios based on pre-specified subgroup analysis (29 January 2016 cut-off) are in favor of the Ribociclib plus letrozole arm, demonstrating that patients benefit independent of age, race, prior adjuvant/ neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone only metastasis disease. Table 8 CLEE011A2301 primary efficacy results (PFS) based on Investigator radiological assessment (29 January 2016 cut-off) Ribociclib plus letrozole Placebo plus letrozole N=334 N=334 Progression free survival Median PFS [months] (95% CI) NE (19.3 – NE) 14.7 (13.0 – 16.5) Hazard ratio (95% CI) 0.556 (0.429 to 0.720) p-valuea 0.00000329 CI=confidence interval; N=number of patients; NE = Not estimable. a p-value is obtained from the one-sided stratified log-rank test. Table 9 CLEE011A2301 primary efficacy results (PFS) based on investigator radiological assessment (02 January 2017 cut-off) Ribociclib plus letrozole Placebo plus letrozole N=334 N=334 Progression free survival Median PFS [months] (95% CI) 25.3 (23.0-30.3) 16.0 (13.4-18.2) Hazard ratio (95% CI) 0.568 (0.457-0.704) p-valuea 9.63×10-8 CI=confidence interval; N=number of patients; ap-value is obtained from the one-sided stratified log-rank test. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 18 of 25Figure 1 Kaplan-Meier plot of PFS based on Investigator review – Study A2301 (Full analysis set) (29 January 2016 cut-off) 100 80 60 40 Censoring Times Ribociclib (N = 334) Placebo (N = 334) 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Months) Number of patients still at risk Time 0 2 4 6 8 10 12 14 16 18 20 22 24 Ribociclib 334 294 277 257 240 226 164 119 68 20 6 1 0 Placebo 334 279 264 237 217 192 143 88 44 23 5 0 0 Figure 2 Kaplan-Meier plot of PFS based on Investigator assessment – Study A2301 (Full analysis set 02 January 2017 cut-off) Other secondary endpoints included overall response rate (ORR), time to deterioration of ECOG performance status, safety and tolerability and change in patient-reported outcomes (PROs) for health related quality of life. In full analysis set (FAS), the overall response rate according to local radiologist assessment was 40.7% of patients (95% CI: 35.4%, 46.0%) in the Ribociclib plus letrozole arm and 27.5% (95% CI: 22.8%, 32.3%) in the placebo plus letrozole arm (p=0.000155) the clinical benefit rate (CBR) was 79.6% of patients (95% CI: 75.3%, India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 19 of 25 )%( ytilibaborp eerf-tnevE84.0%) in the Ribociclib plus letrozole arm and 72.8% (95% CI: 68.0%, 77.5%) in the placebo plus letrozole arm (p=0.018). In patients with measurable disease, the overall response rate according to local radiologists assessment was 52.7% of patients (95% CI: 46.6%, 58.9%) in the Ribociclib plus letrozole and 37.1% (95% CI: 31.1%, 43.2%) in the placebo plus letrozole arm (p=0.00028). The clinical benefit rate was 80.1% (95% CI: 75.2%, 85.0%) in the Ribociclib plus letrozole arm and 71.8% (95% CI: 66.2%, 77.5%) in the placebo plus letrozole arm (p=0.018) (see Table 10). A series of pre-specified subgroup PFS analyses was performed (02 January 2017 cut-off) based on prognostic factors and baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in favour of the ribociclib plus letrozole arm was observed in all individual patient subgroups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease. This was evident for patients with liver and/or lung disease (HR of 0.561 [95% CI: 0.424, 0.743], median progression-free survival [mPFS] 24.8 months versus 13.4 months respectively for ribociclib and placebo arm, the same for next) or without liver and/or lung disease (HR of 0.597 [95% CI: 0.426, 0.837], mPFS 27.6 months versus 18.2 months). Updated results (02 January 2017 cut-off) for overall response and clinical benefit rates are displayed in Table 11. Table 10 CLEE011A2301 efficacy results (ORR, CBR) based on Investigator assessment (29 January 2016 cut-off) Analysis Ribociclib plus Placebo plus letrozole p-valuec letrozole (%, 95% CI) (%, 95% CI) Full analysis set N=334 N=334 Overall Response Ratea 40.7 (35.4, 46.0) 27.5 (22.8, 32.3) 0.000155 Clinical Benefit Rateb 79.6 (75.3, 84.0) 72.8 (68.0, 77.5) 0.018 Patients with measurable disease N=256 N=245 Overall Response Ratea 52.7 (46.6, 58.9) 37.1 (31.1, 43.2) 0.00028 Clinical Benefit Rateb 80.1 (75.2, 85.0) 71.8 (66.2, 77.5) 0.020 aORR: proportion of patients with complete response + partial response bCBR: proportion of patients with complete response + partial response + (stable disease or non-complete response/Non-progressive disease >=24 weeks) c p-values are obtained from one sided Cochran-Mantel-Haenszel chi-square test. Table 11 CLEE011A2301 efficacy results (ORR, CBR) based on investigator assessment (02 January 2017 cut-off) Analysis Ribociclib + letrozole Placebo + letrozole p-valuec (%, 95% CI) (%, 95% CI) Full analysis set N=334 N=334 Overall response ratea 42.5 (37.2, 47.8) 28.7 (23.9, 33.6) 9.18 × 10-5 Clinical benefit rateb 79.9 (75.6, 84.2) 73.1 (68.3, 77.8) 0.018 Patients with measurable N=257 N=245 disease Overall response ratea 54.5 (48.4, 60.6) 38.8 (32.7, 44.9) 2.54 × 10-4 Clinical benefit rateb 80.2 (75.3, 85.0) 71.8 (66.2, 77.5) 0.018 a ORR: Overall response rate = proportion of patients with complete response + partial response b CBR: Clinical benefit rate = proportion of patients with complete response + partial response (+ stable disease or non-complete response/Non-progressive disease ≥24 weeks) c p-values are obtained from one-sided Cochran-Mantel-Haenszel chi-square test India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 20 of 25Study CLEE011E2301 (MONALEESA-7) Ribociclib was evaluated in a randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of pre and perimenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer. A total of 672 [ML7-CSR-Section 10.1] patients were randomized to receive either Ribociclib 600 mg plus tamoxifen or NSAI plus goserelin (n= 335) or placebo plus tamoxifen or NSAI plus goserelin (n= 337), stratified according to the presence of liver and/or lung metastases (Yes [n=344 (51.2%)] versus No [n=328 (48.8%)]), prior chemotherapy for advanced disease (Yes [n=120 (17.9%)] versus No [n=552 (82.1%)]) and endocrine combination partner (NSAI and goserelin) [n=493 (73.4%)] versus tamoxifen and goserelin [n=179 (26.6%)]). Demographics and baseline disease characteristics were balanced and comparable between study arms. Tamoxifen 20 mg or NSAI (letrozole 2.5 mg or anastrazole 1 mg) were given orally once daily on a continuous schedule, goserelin 3.6 mg administered as 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. Patients were not allowed to cross over from placebo to Ribociclib during the study or after disease progression. Patients were not allowed to switch between endocrine combination partners. Patients enrolled in the study had a median age of 44 (range 25 to 58) and 27.7% of patients were younger than 40 years of age. The majority of patients were Caucasian (57.7%), Asian (29.5%), or Black (2.8%) and nearly all patients (99.0%) had an ECOG performce status of 0 or 1 of these 672 patients, 14.0% had received prior chemotherapy for metastatic disease. Of the 672 patients, 32.6% of patients had received chemotherapy in the adjuvant vs 18.0% in neo-adjuvant setting and 39.6% had received endocrine therapy in the adjuvant vs 0.7% in neo-adjuvant setting prior to study entry 40.2% of patients had de novo metastatic disease, 23.7% had bone only disease, and 56.7% had visceral disease. Overall study The primary endpoint for the study was performed after observing 318 progression-free survival (PFS) events using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, based on the investigator assessment in the full analysis set (all randomized patients) and confirmed by blinded independent central radiological assessment of a randomly selected subset of approximately 40% of randomized patients. The median follow-up time at the time of primary PFS analysis was 19.2 months. In the overall study population, the median PFS (95% CI) was 23.8 months (19.2, NE) in the Ribociclib plus tamoxifen or NSAI arm and 13.0 months (11.0, 16.4) in the placebo plus tamoxifen or NSAI arm, [HR: 0.553 (95% CI: 0.441, 0.694), one-sided stratified long-rank test p-value of 9.83x10-8]. Efficacy results are summarized in the Kaplan-Meier curve for PFS in Figure 3. At the time of primary PFS analysis, overall survival data were not mature with 89 (35 %) events (N=252, HR 0. 916 [95% CI: 0.601, 1.396 ]). The results for PFS based on the blinded independent central radiological assessment of a randomly selected subset of approximately 40% of randomized patients were supportive of the primary efficacy results based on the investigator’s assessment (hazard ratio of 0.427; 95% CI: 0.288, 0.633). Overall response rate (ORR) per Investigator assessment based on RECISTv1.1 was higher in the Ribociclib arm (40.9%; 95% CI: 35.6, 46.2) compared to the placebo arm (29.7%; 95% CI: 24.8, 34.6, p = 0.00098). The main prespecified QoL measure was Time-To-Deterioration (TTD) in global health status. Definitive 10% deterioration was defined as a worsening in score (EORTC QLQ-C30 global health scale score) by at least 10% compared to baseline, with no later improvement above this threshold observed during the treatment period, or death due to any cause. Addition of Ribociclib to tamoxifen or NSAI resulted in delaying time-to-deterioration in EORTC QLQ-C30 global health scale score compared with placebo plus tamoxifen or NSAI (median not estimable versus 21.2 months; HR of 0.699 [95% CI: 0.533, 0.916]; p=0.004. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 21 of 25Figure 3 Kaplan-Meier plot of PFS from Monaleesa-7 overall study CLEE011E2301 100 80 Censoring Times 60 Ribociclib (N = 335) Placebo (N = 337) No. of events Ribociclib: 131, Placebo: 187 40 Hazard Ratio = 0.553 95 % CI [0.441, 0.694] Kaplan-Meier median 20 Ribociclib: 23.8 Months Placebo: 13.0 Months Log-rank p-value = 9.83*10^(-8) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (Months) Number of patients still at risk Time 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Ribociclib 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0 Placebo 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0 NSAI sub-group only In the pre-specified subgroup analysis of 495 patients who had received Ribociclib or placebo in combination with with NSAI plus goserelin, the median PFS (95% CI) was 27.5 months (19.1, NE) in the Ribociclib plus NSAI sub-group and 13.8 months (12.6, 17.4) in the placebo plus NSAI sub-group [HR: 0.569 (95% CI: 0.436, 0.743)]. Efficacy results are summarized in Table 12 and the Kaplan-Meier curves for PFS are provided in Figure 4. Results, in the Ribociclib plus NSAI sub-group were consistent across sub-groups of age, race, prior adjuvant/ neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone only metastatic disease. In the NSAI subgroup, the median time to response (TTR) was not reached in either the Ribociclib arm or the placebo arm, and the probability of response by 6 months was 34.7% (95% CI: 29.0, 41.1) in the Ribociclib arm and 23.7% (95% CI: 18.8, 29.6) in the placebo arm, indicating that a larger proportion of patients derived earlier benefit in the Ribociclib arm. In the NSAI subgroup, the median duration of response (DOR) was not reached (95% CI: 18.3 months, NE) in the Ribociclib arm and was 17.5 months (95% CI: 12.0, NE) in the placebo arm. Among patients with confirmed complete response or partial response, the probability of subsequent progression was 23.5% (95% CI: 15.6, 34.5) in the Ribociclib arm and 36.4% (95% CI: 25.6, 49.8) in the placebo arm at 12 months. Table 12 CLEE011E2301 efficacy results (PFS) from Monaleesa-7 study (E2301) in patients who received NSAI Ribociclib plus NSAI plus goserelin Placebo plus NSAI plus goserelin N=248 N=247 Progression free survivala Median PFS [months] (95% CI) 27.5 (19.1, NE) 13.8 (12.6, 17.4) Hazard ratio (95% CI) 0.569 (0.436, 0.743) CI=confidence interval; N=number of patients; NE = Not estimable. a – PFS based on investigator radiological assessment India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 22 of 25 )%( ytilibaborp eerf-tnevEFigure 4 Kaplan-Meier plot of PFS based on investigator assessment – Study CLEE011E2301 in patients who received NSAI Table 13 CLEE011E2301 efficacy results (ORR, CBR) based on investigator assessment in patients who received NSAI Analysis Ribociclib plus NSAI plus Placebo plus NSAI plus goserelin goserelin (%, 95% CI) (%, 95% CI) Full analysis set N=248 N=247 Overall Response Ratea 39.1 (33.0 , 45.2) 29.1 (23.5 , 34.8) Clinical Benefit Rateb 80.2 (75.3, 85.2) 67.2 (61.4 , 73.1) Patients with measurable disease N=192 N=199 Overall Response Ratea 50.5 (43.4 , 57.6) 36.2 (29.5 , 42.9) Clinical Benefit Rateb 81.8 (76.3 , 87.2) 63.8 (57.1 , 70.5) aORR: proportion of patients with complete response + partial response bCBR: proportion of patients with complete response + partial response + (stable disease or non-complete response/Non-progressive disease >=24 weeks) NON-CLINICAL SAFETY DATA Ribociclib was evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity studies. Safety pharmacology Ribociclib did not have effects on CNS or respiratory functions. In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure that would be expected to India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 23 of 25be achieved in patients following the recommended dose of 600 mg. As well, there is potential to induce incidences of PVCs at elevated exposures (approximately 5 fold the anticipated clinical C ). max Repeated dose toxicity Repeated dose toxicity studies (treatment schedule of 3 weeks on/1 week off) in rats up to 26 weeks duration and dogs up to 39 weeks duration, revealed the hepatobiliary system (proliferative changes, cholestasis, sand- like gallbladder calculi, and inspissated bile) as the primary target organ of toxicity of ribociclib. Target organs associated with the pharmacological action of ribociclib in repeat dose studies include bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation), kidney (concurrent degeneration and regeneration of tubular epithelial cells) and testes (atrophy). Besides the atrophic changes seen in the testes, which showed a trend towards reversibility, all other changes were fully reversible after a 4-week treatment free period. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules. Exposure to ribociclib in animals in the toxicity studies was generally less than or equal to that observed in patients receiving multiple doses of 600 mg/day (based on AUC). Reproductive toxicity/Fertility See section PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL. Genotoxicity Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems with and without metabolic activation did not reveal any evidence for a mutagenic potential of ribociclib. Phototoxicity Ribociclib was shown to absorb light in the UV-B and UV-A range. An in vitro phototoxicity test did not identify a relevant phototoxicity potential for ribociclib. The risk that ribociclib causes photosensitization in patients is considered very low. Carcinogenesis No carcinogenesis studies have been conducted with ribociclib. INCOMPATIBILITIES Not applicable. STORAGE See folding box. KRYXANA should not be used after the date marked “EXPIRY DATE” on the pack. KRYXANA must be kept out of the sight and reach of children. INSTRUCTIONS FOR USE AND HANDLING N/A. Manufacturer: See folding box. Importer: Sandoz Private Limited, Gala no.11, Building no.27, Arihant Commercial Complex, Kopar Bus stop, Purna, Tal- Bhiwandi, Dist- Thane - 421 302, India. India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 24 of 25Marketed By: Novartis Healthcare Pvt. Ltd., Gala No. 1-A & 2-A, Bldng No.. 28, Arihant Comp., Kopar, Purna Tal Bhiwandi-14 (Thane Z5), Maharashtra, Thane- 421302 (India). Information issued: India package insert dtd 11 Dec 18 based on the international package leaflet (IPL) dtd 9 Jul 18 ® Registered trademark of Novartis AG, Basel, Switzerland India package insert dtd 11 Dec 18 based on IPL dtd 9 Jul 18 Page 25 of 25