Ceritinib hard gelatin capsules 150 mg

For the use of only Registered Medical Practitioners or a Hospital or a Laboratory. Ceritinib hard gelatin capsules 150 mg Spexib TM Protein kinase inhibitors DESCRIPTION AND COMPOSITION Pharmaceutical form Hard gelatin capsules 150 mg: Size #00 hard gelatin capsule with blue opaque cap with black imprint “LDK 150MG” and white opaque body with black imprint “NVR”, containing white to almost white powder. Active substance Ceritinib Each capsule contains 150 mg ceritinib. Excipients Hard gelatin capsule: Capsule content: silica, colloidal anhydrous; low-substituted hydroxypropylcellulose; magnesium stearate; microcrystalline cellulose; sodium starch glycolate Capsule shell: gelatin; indigotine (E132); titanium dioxide (E171) Printing ink: ammonium hydroxide; iron oxide black (E172); propylene glycol; shellac glaze INDICATIONS Spexib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Spexib as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). DOSAGE REGIMEN AND ADMINISTRATION Dosage regimen General target population The recommended dose of Spexib is 450 mg taken orally once daily with food at the same time each day. The maximum recommended dose is 450 mg taken orally once daily with food. Continue treatment as long as the patient is deriving clinical benefit from therapy. Dose adjustments Temporary dose interruption and/or dose reduction of Spexib therapy may be required based on individual safety and tolerability. If dose reduction is required due to an adverse drug reaction not listed in Table 1, then the daily India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 1 of 26dose of Spexib should be reduced by decrements of 150 mg. Early identification and management of adverse drug reactions with standard supportive care measures should be considered. Spexib should be discontinued in patients unable to tolerate 150 mg taken once daily with food. Table 1 summarizes recommendations for dose interruption, reduction, or discontinuation of Spexib in the management of selected adverse drug reactions (ADRs). Table 1 - Spexib dose adjustment and management recommendations for selected adverse drug reactions Criteria Spexib Dosing Severe or intolerable nausea, vomiting, or Withhold Spexib until improved, then reinitiate Spexib by diarrhea despite optimal anti-emetic or anti- reducing dose by 150 mg diarrheal therapy Alanine aminotransferase (ALT) or aspartate Withhold Spexib until recovery to baseline ALT/AST aminotransferase (AST) elevation greater than 5 levels or to less than or equal to 3 times ULN, then times upper limit of normal (ULN) with reinitiate Spexib by reducing dose by 150 mg concurrent total bilirubin less than or equal to 2times ULN ALT or AST elevation greater than 3 times ULN Permanently discontinue Spexib with concurrent total bilirubin elevation greater than 2 times ULN (in the absence of cholestasis or hemolysis) Any Grade treatment-related ILD/pneumonitis Permanently discontinue Spexib QTc greater than 500 msec on at least 2 separate Withhold Spexib until recovery to baseline or to a QTc less electrocardiograms (ECGs) than 481 msec, then reinitiate Spexib by reducing dose by 150 mg QTc greater than 500 msec or greater than 60 Permanently discontinue Spexib msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Bradycardiaa (symptomatic, may be severe and Withhold Spexib until recovery to asymptomatic medically significant, medical intervention bradycardia or to a heart rate of 60 bpm or above indicated) Evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications If contributing concomitant medication is identified and discontinued, or its dose is adjusted, reinitiate Spexib at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, reinitiate Spexib by reducing dose by 150 mg upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above Bradycardiaa (life-threatening consequences, Permanently discontinue Spexib if no contributing urgent intervention indicated) concomitant medication is identified If contributing concomitant medication is identified and discontinued, or its dose is adjusted, reinitiate Spexib by reducing dose by 150 mg upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoringb India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 2 of 26Persistent hyperglycemia greater than 250 mg/dL Withhold Spexib until hyperglycemia is adequately despite optimal anti-hyperglycemic therapy controlled, then reinitiate Spexib by reducing dose by 150 mg If adequate glucose control cannot be achieved with optimal medical management, permanently discontinue Spexib Elevated lipase or amylase greater than or equal Withhold Spexib until lipase or amylase returns to less than to grade 3 or equal to grade 1, then reinitiate by reducing dose by 150 mg a Heart rate less than 60 beats per minute (bpm) b Permanently discontinue for recurrence Strong CYP3A inhibitors Avoid concurrent use of strong CYP3A inhibitors during treatment with Spexib (see section INTERACTIONS). If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the Spexib dose by approximately one- third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the Spexib dose that was taken prior to initiating the strong CYP3A inhibitor. Special populations Renal impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Caution should be used in patients with severe renal impairment as there is no experience with Spexib in this population (see section CLINICAL PHARMACOLOGY). Hepatic impairment For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of Zykadia by approximately one- third, rounded to the nearest multiple of the 150 mg dosage strength. No dose adjustment is necessary in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. (see section CLINICAL PHARMACOLOGY). Pediatric patients (below 18 years) The safety and efficacy of Spexib have not been established in pediatric patients. Geriatric patients (65 years or above) The limited data on the safety and efficacy of Spexib in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see section CLINICAL PHARMACOLOGY). Method of administration Spexib should be administered orally once daily with food at the same time every day. Food can range from a snack to a full meal (see section INTERACTIONS and section CLINICAL PHARMACOLOGY). Spexib capsules should be swallowed whole with water. The capsules should not be chewed or crushed. If a dose is missed, the patient should make up that dose, unless the next dose is due within 12 hours. If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose. CONTRAINDICATIONS None. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 3 of 26WARNINGS AND PRECAUTIONS Hepatotoxicity Cases of hepatotoxicity occurred in 1.1 % of patients treated with Spexib in clinical studies (see section ADVERSE DRUG REACTIONS). Increases to grade 3 or 4 ALT elevations were observed in 25% of patients receiving Spexib. Concurrent elevations in ALT/AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, occurred in less than 1% of patients in clinical studies. The majority of cases were manageable with dose interruption and/or dose reduction. Few events required discontinuation of Spexib. Monitor with liver laboratory tests (including ALT, AST, and total bilirubin) prior to the start of treatment and monthly thereafter. In patients who develop transaminase elevations, more frequent monitoring of liver transaminases and total bilirubin should be done as clinically indicated (see section DOSAGE REGIMEN AND ADMINISTRATION). Interstitial lung disease (ILD)/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis have been observed in patients treated with Spexib in clinical studies (see section ADVERSE DRUG REACTIONS). Most of these severe/life- threatening cases improved or resolved with interruption of Spexib. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue Spexib in patients diagnosed with any grade treatment-related ILD/pneumonitis (see section DOSAGE REGIMEN AND ADMINISTRATION). QT interval prolongation QTc prolongation has been observed in clinical studies in patients treated with Spexib, which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de pointes) or sudden death (see section ADVERSE DRUG REACTIONS). A categorical outlier analysis of ECG data demonstrated new QTc >500 msec in 12 patients (1.3%), among which six had elevated QTc>450 msec at baseline. There were 58 patients (4.46.3%) with a QTc increase from baseline >60 msec. A pharmacokinetic/pharmacodynamic analysis suggested that ceritinib causes concentration-dependent increases in QTc. Avoid use of Spexib in patients with congenital long QT syndrome. Periodic monitoring with ECGs and periodic monitoring of electrolytes (e.g., potassium) is recommended in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in patients who are taking medications that are known to prolong the QT interval. In case of vomiting, diarrhea, dehydration, or impaired renal function, correct electrolytes as clinically indicated. Permanently discontinue Spexib in patients who develop QTc greater than 500 msec or greater than 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold Spexib in patients who develop QTc greater than 500 msec on at least 2 separate ECGs until recovery to baseline or a QTc less than 481 msec, then reinitiate Spexib by reducing dose by 150 mg (see section DOSAGE REGIMEN AND ADMINISTRATION and section CLINICAL PHARMACOLOGY). Bradycardia Asymptomatic cases of bradycardia have been observed in patients treated with Spexib in clinical studies (see section ADVERSE DRUG REACTIONS). Avoid use of Spexib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non- dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Spexib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Spexib if necessary. Permanently discontinue Spexib for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with concomitant medication known to cause bradycardia or hypotension, withhold Spexib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medication can be adjusted or discontinued, reinitiate Spexib by reducing dose by 150 mg upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring (see section DOSAGE REGIMEN AND ADMINISTRATION). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 4 of 26Gastrointestinal adverse reactions Diarrhea, nausea, or vomiting occurred in 74.2% of 89 patients treated with Spexib at the recommended dose of 450 mg taken with food in a dose optimization study A2112 (ASCEND-8) and were mainly grade 1 events (49.4%). One patient (1.1%) experienced grade 3 diarrhea. Seven patients (7.9%) required study drug interruption due to diarrhea or nausea. No patients required dose reduction or discontinuation of Spexib due to diarrhea, nausea, or vomiting (see section ADVERSE DRUG REACTIONS). Monitor and manage patients using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Dose interruption and dose reduction may be employed as necessary. If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose (see section DOSAGE REGIMEN AND ADMINISTRATION). Hyperglycemia Events of hyperglycemia (all grades) have been reported in less than 10% of patients treated with Spexib in clinical studies; 5% of patients reported a grade 3/4 event (see section ADVERSE DRUG REACTIONS). The risk of hyperglycemia was higher in patients with diabetes mellitus and/or concurrent steroid use. Monitor fasting serum glucose prior to the start of Spexib treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated (see section DOSAGE REGIMEN AND ADMINISTRATION). Lipase and/or amylase elevations Elevations of lipase and/or amylase have occurred in patients receiving Spexib in clinical studies (see section ADVERSE DRUG REACTIONS). Monitor lipase and amylase prior to the start of Spexib treatment and periodically thereafter as clinically indicated (see section DOSAGE REGIMEN AND ADMINISTRATION). ADVERSE DRUG REACTIONS Summary of the safety profile Adverse drug reactions described below reflect exposure to Spexib 750 mg once daily fasted in 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies, including two randomized, active- controlled, Phase 3 studies (Studies A2301 and A2303). The median duration of exposure to Spexib 750 mg fasted was 44.9 weeks (range 0.1 to 200.1 weeks). Dose reductions occurred in 62.2% of patients and dose interruptions in 74.8% of patients. The rate of adverse events (AEs) resulting in permanent discontinuation of Spexib was 12.1%. The most frequent AEs (>0.5%) leading to discontinuation of Spexib were pneumonia (0.6%) and respiratory failure (0.6%). Adverse drug reactions (ADRs) with an incidence of ≥10% in patients treated with Spexib 750 mg fasted were diarrhoea, nausea, vomiting, liver laboratory test abnormalities, fatigue, abdominal pain, decreased appetite, weight decreased, constipation, blood creatinine increased, rash, anaemia and esophageal disorder. Grade 3/4 ADRs with an incidence of ≥5% in patients treated with Spexib 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea. In the dose optimization study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK- positive advanced NSCLC, the overall safety profile of Spexib at the recommended dose of 450 mg with food (N=89) was consistent with Spexib 750 mg fasted (N=90), except for a reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure (see section CLINICAL PHARMACOLOGY). The incidence and severity of gastrointestinal adverse drug reactions (diarrhoea 56%, nausea 45%, vomiting 35%; 1.1% reported a grade 3/4 event) were reduced for patients treated with Spexib 450 mg with food compared to 750 mg fasted (diarrhoea 76%, nausea 50%, vomiting 56%; 12% reported a grade 3/4 event). In patients treated with Spexib 450 mg with food, 10% of patients had at least one adverse event that required dose reduction and 42% of patients had at least one adverse event that required study drug interruption. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 5 of 26Tabulated summary of adverse drug reactions from clinical trials Table 2 presents the frequency category of ADRs reported for Spexib in patients treated at a dose of 750 mg fasted (N=925) in 7 clinical studies. The frequency of selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) are based on patients treated with a dose of 450 mg once daily with food (N=89). ADRs are listed according to MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: 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); and not known (cannot be estimated from the available data). Table 2 Adverse drug reactions in patients (N=925) treated with Spexib Primary System Organ Class All grades Frequency Grades 3/4 Frequency Preferred Term n (%) category n (%) category Blood and lymphatic system disorders Anaemia 141 (15.2) Very Common 28 (3.0) Common Metabolism and nutrition disorders Decreased appetite 365 (39.5) Very common 20 (2.2) Common Hyperglycaemia 87 (9.4) Common 50 (5.4) Common Hypophosphataemia 49 (5.3) Common 21 (2.3) Common Eye disorders Vision disorderm 65 (7.0) Common 0 Cardiac disorders Pericarditish 54 (5.8) Common 24 (2.6) Common Bradycardiae 21 (2.3) Common 0 Respiratory, thoracic and mediastinal disorders Pneumonitisi 19 (2.1) Common 11 (1.2) Common Gastrointestinal disorders Diarrhoean 50 (56.2) Very common 1 (1.1) Common Nausean 40 (44.9) Very common 0 Vomitingn 31 (34.8) Very common 0 Abdominal paina 426 (46.1) Very common 23 (2.5) Common Constipation 222 (24.0) Very common 3 (0.3) Uncommon Oesophageal disorderf 130 (14.1) Very common 4 (0.4) Uncommon Pancreatitis 5 (0.5) Uncommon 5 (0.5) Uncommon Hepatobiliary disorders Abnormal liver function testsc 20 (2.2) Common 9 (1.0) Common Hepatotoxicityd 10 (1.1) Common 4 (0.4) Uncommon Skin and subcutaneous tissue disorders Rashj 181 (19.6) Very common 4 (0.4) Uncommon Renal and urinary disorders Renal failurek 17 (1.8) Common 2 (0.2) Uncommon Renal impairmentl 9 (1.0) Common 1 (0.1) Uncommon General disorders and administration site conditions Fatigueg 448 (48.4) Very common 71 (7.7) Common Investigations Liver laboratory test 560 (60.5) Very common 347 (37.5) Very common India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 6 of 26Primary System Organ Class All grades Frequency Grades 3/4 Frequency Preferred Term n (%) category n (%) category abnormalitiesb Weight decreased 255 (27.6) Very common 26 (2.8) Common Blood creatinine increased 204 (22.1) Very common 5 (0.5) Uncommon Electrocardiogram QT 90 (9.7) Common 19 (2.1) Common prolonged Lipase increased 44 (4.8) Common 32 (3.5) Common Amylase increased 65 (7.0) Common 29 (3.1) Common a Abdominal pain includes PTs of Abdominal Pain, Abdominal Pain Upper, Abdominal Discomfort, Epigastric Discomfort b Liver laboratory test abnormalities includes PTs of Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased, Gamma-Glutamyltransferase Increased, Blood Bilirubin Increased, Transaminases Increased, Hepatic Enzyme Increased, Liver Function Test Abnormal, Liver Function Test Increased, Blood Alkaline Phosphatase Increased c Abnormal liver function tests includes PTs of Hepatic Function Abnormal, Hyperbilirubinaemia d Hepatotoxicity includes PTs of Drug-Induced Liver Injury, Hepatitis Cholestatic, Hepatocellular Injury, Hepatotoxicity e Bradycardia includes PTs of Bradycardia and Sinus Bradycardia f Esophageal Disorder includes PTs of Dyspepsia, Gastroesophageal Reflux Disease, Dysphagia g Fatigue includes PTs of Fatigue and Asthenia h Pericarditis includes PTs of Pericardial Effusion and Pericarditis i Pneumonitis includes PTs of Interstitial Lung Disease (ILD) and Pneumonitis j Rash includes PTs of Rash, Dermatitis Acneiform, Rash Maculo-Papular k Renal Failure includes PTs of Acute Renal Injury and Renal Failure l Renal Impairment includes PTs of Azotaemia and Renal Impairment m Vision disorder includes PTs of Visual Impairment, Vision Blurred, Photopsia, Vitreous Floaters, Visual Acuity Reduced, Accommodation Disorder, Presbyopia n The frequency of these selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) is based on patients treated with the recommended dose of 450 mg with food (N=89) in Study A2112 (ASCEND-8) Special populations Geriatric population Across seven clinical studies, 168 of 925 patients (18.2%) treated with Spexib were aged 65 years and older. The safety profile in patients aged 65 years and older was similar to that in patients less than 65 years of age (see section DOSAGE REGIMEN AND ADMINISTRATION). INTERACTIONS Agents that may increase ceritinib plasma concentrations Strong CYP3A inhibitors In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold increase in ceritinib AUCinf and C , respectively, compared to when ceritinib was given alone. The steady-state AUC of ceritinib at max reduced doses after co-administration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone. Avoid concurrent use of strong CYP3A inhibitors during treatment with Spexib. If concomitant use of strong CYP3A inhibitors is unavoidable, including but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, and nefazodone, reduce the Spexib dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 7 of 26inhibitor, resume the Spexib dose that was taken prior to initiating the strong CYP3A inhibitor (see section DOSAGE REGIMEN AND ADMINISTRATION). P-gp inhibitors Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If Spexib is administered with drugs that inhibit P-gp, an increase in ceritinib concentration is likely. Exercise caution with concomitant use of P-gp inhibitors and carefully monitor adverse drug reactions. Agents that may decrease ceritinib plasma concentrations Strong CYP3A and P-gp inducers In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampin (600 mg daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib AUCinf and C , max respectively, compared to when ceritinib was given alone. Co-administration of Spexib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Avoid concomitant use of strong CYP3A inducers, including but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort (Hypericum perforatum). Exercise caution with concomitant use of P-gp inducers. Agents whose plasma concentration may be altered by ceritinib CYP3A and CYP2C9 substrates Based on in vitro data, ceritinib competitively inhibits the metabolism of a CYP3A substrate, midazolam, and a CYP2C9 substrate, diclofenac. Time-dependent inhibition of CYP3A was also observed. Co-administration of a single dose of midazolam (a sensitive CYP3A substrate) following 3 weeks of Spexib dosing in patients (750 mg daily fasted) increased the midazolam AUCinf (90% CI) by 5.4-fold (4.6, 6.3) compared to midazolam alone. Avoid co-administration of Spexib with substrates primarily metabolized by CYP3A or CYP3A substrates known to have narrow therapeutic indices (e.g., ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus). If unavoidable, consider dose reduction for co-administered medicines that are CYP3A substrates with narrow therapeutic indices. Co-administration of a single dose of warfarin (a CYP2C9 substrate) following 3 weeks of Spexib dosing in patients (750 mg daily fasted) increased the S-warfarin AUC (90% CI) by 54% (36%, 75%) compared to inf warfarin alone. Avoid co-administration of Spexib with substrates primarily metabolized by CYP2C9 or CYP2C9 substrates known to have narrow therapeutic indices (e.g., phenytoin and warfarin). If unavoidable, consider dose reduction for co-administered medicines that are CYP2C9 substrates with narrow therapeutic indices. Increase the frequency of international normalized ratio (INR) monitoring if co-administration with warfarin is unavoidable as the anti-coagulant effect of warfarin may be enhanced. CYP2A6 and CYP2E1 substrates Based on in vitro data, ceritinib also inhibits CYP2A6 and CYP2E1 at clinically relevant concentrations. Therefore, ceritinib may have the potential to increase plasma concentrations of co-administered drugs that are predominantly metabolized by these enzymes. Exercise caution with concomitant use of CYP2A6 and CYP2E1 substrates and carefully monitor adverse drug reactions. Agents that are substrates of transporters Based on in vitro data, ceritinib does not inhibit apical efflux transporters, BCRP, P-gp or MRP2, hepatic uptake transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations. Therefore, clinical drug-drug interactions as a result of ceritinib-mediated inhibition of substrates for these transporters are unlikely to occur. Agents that affect gastric pH Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of ceritinib and reduce its bioavailability as ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. In a drug interaction study in healthy subjects (N=22), co- administration of a single dose of 750 mg of ceritinib fasted and esomeprazole (a proton pump inhibitor) at 40 mg daily for 6 days decreased the ceritinib exposure (AUCinf and Cmax decreased by 76% and 79%, respectively). However, coadministration of a single 750 mg ceritinib dose fasted with proton pump inhibitors for 6 days in a subgroup of patients from Study X2101 suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC (90% CI) decreased by 30% (0%, 52%) and Cmax (90% CI) decreased by India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 8 of 2625% (5%, 41%) and no clinically meaningful effect on ceritinib exposure was observed at steady-state after ceritinib once daily dosing. This is further confirmed by a subgroup analysis based on three clinical studies (N >400) in which patients with and without proton pump inhibitors showed similar steady-state exposure and clinical efficacy and safety. Drug-food/drink interactions Spexib should be taken with food. The bioavailability of ceritinib is increased in the presence of food (see section CLINICAL PHARMACOLOGY). Patients should be instructed to avoid grapefruit or grapefruit juice as they may inhibit CYP3A in the gut wall and may increase the bioavailability of ceritinib. PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Pregnancy Risk summary There are insufficient data regarding the use of Spexib in pregnant women. Reproductive toxicology studies (i.e., embryo-fetal development studies) in pregnant rats and rabbits indicated no fetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however, maternal plasma exposure was less than that observed at the recommended human dose. The potential risk in humans is unknown. Spexib should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. Lactation Risk Summary It is unknown whether ceritinib is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse drug reactions in breastfed newborns/infants, a decision should be made whether to discontinue breast-feeding or discontinue using Spexib taking into account the importance of Spexib to the mother. Females and males of reproductive potential Contraception Females Females of reproductive potential should be advised to use an effective method of contraception (methods that result in less than 1% pregnancy rates) while receiving Spexib and for up to 3 months after discontinuing treatment. Infertility Formal non-clinical studies on the potential effects of ceritinib on fertility have not been conducted. The potential for Spexib to cause infertility in male and female patients is unknown. OVERDOSAGE There is limited reported experience with overdose in humans. General supportive measures should be initiated in all cases of overdose. CLINICAL PHARMACOLOGY Mechanism of action (MOA) Ceritinib is an orally highly selective and potent ALK kinase inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signaling proteins, and proliferation of ALK-dependent cancer cells both in vitro and in vivo. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 9 of 26ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the N-terminal part of EML4. Ceritinib was demonstrated effective against EML4-ALK kinase activity in a NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of tumors in H2228 derived xenografts in mouse and rat. Pharmacodynamics (PD) Ceritinib inhibition of ALK kinase activity and ALK-mediated signaling pathways in Karpas 299 (lymphoma cell line) and in H2228 (lung cancer cell line) was demonstrated to be dose-dependent. The inhibitory effect of ceritinib led to inhibition of cancer cell proliferation in vitro and tumor regression in vivo in mouse and rat xenograft models. Ceritinib is approximately 20-fold more potent than crizotinib in enzymatic inhibition assays of the ALK kinase activity (IC50 for inhibition of ALK of 0.15 nanomolar for ceritinib and 3 nanomolar for crizotinib). In a kinase panel of 36 enzymes, ceritinib inhibited only 2 other kinases with approximately 50-fold less potency for ALK inhibition. All other kinases in the panel had greater than 500-fold less potency when compared with ALK, demonstrating a high degree of selectivity. A single-dose pharmacodynamic study and multiple-daily dose efficacy study performed in Karpas 299 lymphoma and H2228 lung cancer tumor models indicated that a 60% to 80% reduction in the ALK signaling pathway may be required to achieve tumor regression. Pharmacokinetics (PK) Absorption Peak plasma levels (C ) of ceritinib are achieved approximately 4 to 6 hours after a single oral administration max in patients. Oral absorption was estimated to be ≥25% based on metabolite percentages in the feces. The absolute bioavailability of ceritinib has not been determined. Daily oral dosing of ceritinib results in achievement of steady-state by approximately 15 days and remains stable afterwards, with a geometric mean accumulation ratio of 6.2 after 3 weeks of daily dosing. After a single oral administration of ceritinib in patients, plasma exposure to ceritinib, as represented by C and max AUC , increased dose-proportionally over the 50 to 750 mg dose range under fasted conditions. In contrast last with single-dose data, pre-dose concentration (Cmin) after repeated daily dosing appeared to increase in a greater than dose-proportional manner. Food effect: Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUC values were inf approximately 58% and 73% higher (C approximately 43% and 41% higher) in healthy subjects when a single max 500 mg ceritinib dose (capsule) was administered with a low fat meal (containing approximately 330 calories and 9 grams of fat) and a high fat meal (containing approximately 1000 calories and 58 grams of fat), respectively, as compared with the fasted state. Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUC values were inf approximately 39% and 64% higher (C approximately 42% and 58% higher) in healthy subjects when a single max 750 mg ceritinib dose (tablet) was administered with a low fat meal (containing approximately 330 calories and 9 grams of fat) and a high fat meal (containing approximately 1000 calories and 58 grams of fat), respectively, as compared with the fasted state. In a dose optimization study A2112 (ASCEND-8) in patients comparing Spexib 450 mg or 600 mg daily with food (approximately 100 to 500 calories and 1.5 to 15 grams of fat) to 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib for the 450 mg with food arm (N=36) compared to the 750 mg fasted arm (N=31), with only small increases in steady-state AUC (90% CI) by 4% (-13%, 24%) and C (90% CI) by 3% (-14%, 22%). In contrast, the steady-state AUC max (90% CI) and C (90% CI) for the 600 mg with food arm (N=30) increased by 24% (3%, 49%) and 25% (4%, max 49%), respectively, compared to the 750 mg fasted arm. The maximum recommended dose of Spexib is 450 mg taken orally once daily with food (see section DOSAGE REGIMEN AND ADMINISTRATION). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 10 of 26Distribution Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentration independent manner, from 50 ng/mL to 10,000 ng/mL. The apparent volume of distribution (Vd/F) is 4230 L in patients after a single 750 mg fasted dose of Spexib. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35. In vitro studies suggest that ceritinib is a substrate for P-glycoprotein (P-gp), but not of breast cancer resistance protein (BCRP) or multi-resistance protein 2 (MRP2). The in vitro apparent passive permeability of ceritinib was determined to be low. In rats, ceritinib crosses the intact blood brain barrier with a brain-to-blood exposure (AUCinf) ratio of about 15%. There are no data related to brain-to-blood exposure ratio in humans. Biotransformation/metabolism In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following a single oral administration of radioactive ceritinib dose at 750 mg fasted, ceritinib was the main circulating component (82%) in human plasma. A total of 11 metabolites were found circulating in plasma at low levels with mean contribution to the radioactivity AUC of ≤2.3% for each metabolite. Main biotransformation pathways identified in healthy subjects included mono-oxygenation, O-dealkylation, and N- formylation. Secondary biotransformation pathways involving the primary biotransformation products included glucuronidation and dehydrogenation. Addition of a thiol group to O-dealkylated ceritinib was also observed. Elimination Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasma terminal half-life (T1/2) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg dose range. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/hr) after 750 mg daily oral dosing than after a single 750 mg oral dose (88.5 L/hr) suggesting that ceritinib demonstrates non-linear PK over time. The primary route of excretion of ceritinib and its metabolites is in the feces. Recovery in the feces accounts for 91% of the administered oral dose (with a mean 68% of an oral dose as unchanged parent compound). Only 1.3% of the administered oral dose is recovered in the urine. Special populations Effects of age, gender, and race Population pharmacokinetic analyses showed that age, gender, and race had no clinically meaningful influence on ceritinib exposure. Hepatic impairment The effect of hepatic impairment on the single dose pharmacokinetics of ceritinib (750 mg fasted) was evaluated in subjects with mild (Child-Pugh class A; N = 8), moderate (Child-Pugh class B; N = 7), or severe (Child-Pugh class C; N = 7) hepatic impairment and in 8 healthy subjects with normal hepatic function. The geometric mean systemic exposure (AUC ) of ceritinib was increased by 18% and 2% in subjects with mild and moderate inf hepatic impairment, respectively, compared to subjects with normal hepatic function. No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section DOSAGE REGIMEN AND ADMINISTRATION). The geometric mean systemic exposure (AUC ) of ceritinib was increased by 66% in subjects with severe inf hepatic impairment compared to subjects with normal hepatic function. For patients with severe hepatic impairment, reduce the dose of Spexib by approximately one-third rounded to the nearest multiple of the 150 mg dosage strength (see section DOSAGE REGIMEN AND ADMINISTRATION). Renal impairment Ceritinib has not been studied in patients with renal impairment. However, based upon available data, ceritinib elimination via the kidney is negligible (1.3% of a single oral administered dose). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 11 of 26Based on a population pharmacokinetic analysis of 345 patients with mild renal impairment (CLcr 60 to <90 mL/min), 82 patients with moderate renal impairment (CLcr 30 to <60 mL/min) and 546 patients with normal renal function (≥90 mL/min), ceritinib exposures were similar in patients with mild and moderate renal impairment and normal renal function, suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment (see section DOSAGE REGIMEN AND ADMINISTRATION). Patients with severe renal impairment (CLcr <30 mL/min) were not included in the clinical trial. Cardiac electrophysiology The potential for QT interval prolongation of ceritinib was assessed in 7 clinical studies with Spexib. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in 925 patients treated with Spexib 750 mg once daily fasted. A categorical outlier analysis of ECG data demonstrated new QTc >500 msec in 12 patients (1.3%). There were 58 patients (6.3%) with a QTc increase from baseline >60 msec. A central tendency analysis of the QTc data at average steady-state concentrations from a global phase 3 study (Study A2301) demonstrated that the upper bound of the 2-sided 90% CI for QTc was 15.3 msec at ceritinib 750 mg fasted. A pharmacokinetic/ pharmacodynamic analysis suggested that ceritinib causes concentration-dependent increases in QTc (see section WARNINGS AND PRECAUTIONS). CLINICAL STUDIES Previously untreated ALK-positive locally advanced or metastatic NSCLC - Randomized Phase 3 Study A2301 (ASCEND-4) The efficacy and safety of Spexib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients with and without brain metastasis, who have not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with the exception of neo-adjuvant or adjuvant therapy, was demonstrated in a global multicenter, randomized, open-label Phase 3 Study A2301. The primary efficacy endpoint was progression-free survival (PFS), as determined by a Blinded Independent Review Committee (BIRC), according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The key secondary endpoint was Overall Survival (OS). Other secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR), disease control rate (DCR), and time to response (TTR) determined by BIRC and by Investigators and patient reported outcomes (PROs), including disease-related symptoms, functioning, and health-related quality of life. Intracranial ORR (OIRR), intracranial DCR (IDCR) and duration of intracranial response (DOIR) determined by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. up to 5 lesions in the brain) were used to assess the antitumor activity in the brain. Patients were allowed to continue the assigned study treatment beyond initial progression in case of continued clinical benefit as per the Investigator's opinion. Patients randomized to the chemotherapy arm could crossover to receive ceritinib upon RECIST-defined disease progression by BIRC. A total of 376 patients were randomized in a 1:1 ratio (stratified by WHO performance status, prior adjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receive either ceritinib (750 mg once daily, fasted) or chemotherapy (based on Investigator’s choice - pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC 5-6), administered every 21 days). Patients who completed 4 cycles of chemotherapy (induction) without progressive disease subsequently received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. One hundred and eighty-nine (189) patients were randomized to ceritinib and one hundred eighty-seven (187) were randomized to chemotherapy. The overall median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. A total of 57.4% of patients were female. 53.7% of the study population was Caucasians, 42.0%, Asians, 1.6%, Blacks and 2.6% other races. The majority of patients had adenocarcinoma (96.5%) and had either never smoked or were former smokers (92.0%). The Eastern Cooperative Oncology Group (ECOG) performance status was 0/1/2 in 37.0%/56.4%/6.4% of patients respectively, and 32.2% had neurologically stable (symptomatic or not) brain metastasis at baseline. Baseline disease characteristics were well-balanced between the two treatment arms. The median duration of follow-up was 19.7 months (from randomization to data cut-off date). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 12 of 26The study met its primary objective demonstrating a statistically significant and clinically meaningful improvement in PFS by BIRC with an estimated 45% risk reduction in the ceritinib arm compared to the chemotherapy arm (HR: 0.55 with 95% CI: 0.42, 0.73, p<0.001). The median PFS was 16.6 months (95% CI: 12.6, 27.2) and 8.1 months (95% CI: 5.8, 11.1) for the ceritinib arm and chemotherapy arm, respectively (see Table 3 and Figure 1). The PFS benefit of ceritinib over chemotherapy was robust and consistent by Investigator assessment and across various subgroups including age, gender, race, smoking class, Eastern Cooperative Oncology Group (ECOG) performance status and disease burden. Ceritinib also significantly improved BIRC-assessed ORR as compared to chemotherapy with durable response (see Table 3). The overall survival (OS) data was not mature at the time of primary PFS analysis. There were fewer deaths in the ceritinib arm (48 events, 25.4%) than in the chemotherapy arm (59 events, 31.6%), indicating a trend favoring ceritinib. The median OS was not estimable in the ceritinib arm and was 26.2 months (95% CI: 22.8, NE) in the chemotherapy arm. The estimated OS rate (95% CI) at 24 months was 70.6% (62.2, 77.5) and 58.2% (47.6, 67.5) for ceritinib arm and chemotherapy arm, respectively. Eighty-one patients (43.3%) in the chemotherapy arm received subsequent ceritinib as first antineoplastic therapy after study treatment discontinuation. Efficacy data from Study A2301 are summarized in Table 3, and the Kaplan-Meier curves for PFS and OS are shown in Figure 1 and Figure 2, respectively. Table 3 ASCEND-4 (Study A2301) - Efficacy results in patients with previously untreated ALK-positive locally advanced or metastatic NSCLC Ceritinib Chemotherapy (N=189) (N=187) Progression-Free Survival (based on BIRC) Number of events, n (%) 89 (47.1) 113 (60.4) Median, monthsd (95% CI) 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) HR (95% CI)a 0.55 (0.42, 0.73) p-valueb <0.001 Overall Survivalc Number of events, n (%) 48 (25.4) 59 (31.6) Median, monthsd (95% CI) NE (29.3, NE) 26.2 (22.8, NE) OS rate at 24 monthsd, % (95% CI) 70.6 (62.2, 77.5) 58.2 (47.6, 67.5) HR (95% CI)a 0.73 (0.50,1.08) p-valueb 0.056 Tumor Response (based on BIRC) Objective response rate (95% CI) 72.5% (65.5, 78.7) 26.7% (20.5, 33.7) Duration of response (based on BIRC) Number of responders 137 50 Median, monthsd (95% CI) 23.9 (16.6, NE) 11.1 (7.8, 16.4) Event-free rate at 18 monthsd, % (95% CI) 59.0 (49.3, 67.4) 30.4 (14.1, 48.6) HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; NE=not estimable; CR=compete response; PR=partial response a Based on the Cox proportional hazards stratified analysis. b Based on the stratified log-rank test. c OS analysis was not adjusted for the effects of cross over. d Estimated using the Kaplan-Meier method. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 13 of 26Figure 1 ASCEND-4 (Study A2301) - Kaplan-Meier plot of progression-free survival as assessed by BIRC 100 Hazard Ratio = 0.55 95% CI (0.42, 0.73) e 80 Kaplan-Meier medians (95% CI) (Months) e ceritinib750 mg: 16.6 (12.6, 27.2) r f- Chemotherapy: 8.1 (5.8, 11.1) t en 60 v Logrank p-value = <.001 e f o ) % 40 ( y it li ab 20 Censoring Times b ceritinib 750 mg (n/N = 89/189) o r P Chemotherapy (n/N = 113/187) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (Months) No. of patients still at risk Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 LDK378 750 mg 189 155 139 125 116 105 98 76 59 43 32 23 16 11 1 1 1 0 Chemotherapy 187 136 114 82 71 60 53 35 24 16 11 5 3 1 1 0 0 0 India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 14 of 26Figure 2 ASCEND-4 (Study A2301) - Kaplan-Meier plot of overall survival 100 e e r 80 f- tn Hazard Ratio = 0.73 e 95% CI (0.50, 1.08) v f oe 60 Kaplan-Meier medians (95% CI) (Months) ) ceritinib 750 mg: NE (29.3, NE) % Chemotherapy: 26.2 (22.8, NE) ( y40 it li b Logrank p-value = 0.056 a b o 20 Censoring Times r P ceritinib 750 mg (n/N = 48/189) Chemotherapy (n/N = 59/187) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (Months) No. of patients still at risk Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 LDK378 750 189 180 175 171 165 155 150 138 103 77 56 39 26 18 6 3 2 0 mg Chemotherapy 187 172 161 150 146 141 134 124 97 69 49 35 19 10 5 1 0 0 Ceritinib significantly prolonged time to deterioration for lung cancer specific symptoms as shown by the composite endpoint of cough, pain and dyspnea in the Lung Cancer Symptom Score (LCSS) (HR = 0.61, 95% CI: 0.41, 0.90) and QLQ-LC13 (HR = 0.48, 95% CI: 0.34, 0.69) instruments compared to chemotherapy. Median time to definitive deterioration for the LC13 composite endpoint (pain, cough, shortness of breath) was 23.6 months (95% CI: 20.7, NE) in the ceritinib arm versus 12.6 months (95% CI: 8.9, 14.9) in the chemotherapy arm. Patients receiving ceritinib showed significant improvements over chemotherapy in General Quality of Life (LCSS, p <0.001), Global Health Status/QoL (QLQ-C30, p <0.001) as well as in EQ-5D-5L index (p <0.001) and EQ-5D-5L VAS (p < 0.05 from each treatment cycle from 13 until 49). Overall, these results suggest improvements in lung cancer specific symptoms as well as general health status benefits for ALK-positive NSCLC patients treated with ceritinib versus chemotherapy. In Study A2301, 44 out of 121 patients had active and measurable brain metastasis at baseline and at least one post-baseline brain radiological assessment (22 in the ceritinib arm and 22 patients in the chemotherapy arm). An active brain metastasis is defined as an untreated brain metastasis, new brain metastasis or an existing brain metastasis with documented progression after the end of the brain radiotherapy. These 44 patients were assessed for intracranial response by BIRC neuro-radiologist. The intracranial ORR (OIRR) was higher with ceritinib (72.7%, 95% CI: 49.8, 89.3) as compared to the chemotherapy arm (27.3%, 95% CI: 10.7, 50.2). Among these patients, 59.1% (13/22) in the ceritinib arm and 81.8% (18/22) in the chemotherapy arm did not receive prior radiotherapy to the brain. The median PFS by BIRC and Investigator using RECIST 1.1 was longer in the ceritinib arm compared to the chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases (based on the extent of cancer CRF, see Table 4). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 15 of 26Table 4 ASCEND-4 (Study A2301) – PFS with and without brain metastases BIRC Investigator Ceritinib Chemotherapy Ceritinib Chemotherapy With Brain Metastases N=59 N=62 N=59 N=62 Progression Free Survival Median, months (95% CI) 10.7 (8.1, 16.4) 6.7 (4.1, 10.6) 13.5 (9.0, 16.7) 6.7 (4.2, 10.6) HR (95% CI) 0.70 (0.44, 1.12) 0.58 (0.36, 0.92) Without Brain Metastases N=130 N=125 N=130 N=125 Progression Free Survival Median, months (95% CI) 26.3 (15.4, 27.7) 8.3 (6.0, 13.7) 25.2 (13.9, NE) 8.3 (5.8, 11.1) HR (95% CI) 0.48 (0.33, 0.69) 0.44 (0.31, 0.63) Previously treated ALK-positive locally advanced or metastatic NSCLC - Randomized Phase 3 Study A2303 (ASCEND-5) The efficacy and safety of Spexib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients with and without brain metastasis, who have received previous treatment with crizotinib, was demonstrated in a global multicenter, randomized, open-label Phase 3 Study A2303. The primary efficacy endpoint was PFS, as determined by BIRC, according to RECIST 1.1. The key secondary endpoint was Overall Survival (OS). Other secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR), disease control rate (DCR), and time to response (TTR) determined by BIRC and by Investigator, PFS by Investigator and patient reported outcomes (PROs), including disease-related symptoms, functioning, and health-related quality of life. Intracranial ORR (OIRR), intracranial DCR (IDCR) and duration of intracranial response (DOIR) determined by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. up to 5 lesions in the brain) were used to assess the antitumor activity in the brain. Patients were allowed to continue the assigned study treatment beyond initial progression in case of continued clinical benefit as per the Investigator's opinion. Patients randomized to the chemotherapy arm could crossover to receive ceritinib upon RECIST-defined disease progression confirmed by BIRC. A total of 231 patients with advanced ALK positive NSCLC who have received prior treatment with crizotinib and chemotherapy (one or two regimen including a platinum-based doublet) were included in the analysis. 115 patients were randomized to ceritinib and 116 were randomized to chemotherapy. 73 patients received docetaxel and 40 received pemetrexed. In the ceritinib arm, 115 patients were treated with 750 mg once daily fasted. Baseline disease characteristics were well-balanced between the two treatment arms. The median age was 54.0 years (range: 28 to 84 years); 77.1% of patients were younger than 65 years. A total of 55.8% of patients were female. 64.5% of the study population were Caucasians, 29.4% Asians, 0.4% Blacks and 2.6% other races. The majority of patients had adenocarcinoma (97.0%) and had either never smoked or were former smokers (96.1%). The ECOG performance status was 0/1/2 in 46.3%/47.6%/6.1% of patients respectively, and 58.0% had brain metastasis at baseline. All patients were treated with prior crizotinib. 198 patients (81.8%) received crizotinib as last treatment. All except one patient received prior chemotherapy (including a platinum doublet) for advanced disease; 11.3% of the patients in the ceritinib arm and 12.1% of the patients in the chemotherapy arm were treated with two prior chemotherapy regimen for advanced disease. The median duration of follow-up was 16.5 months (from randomization to data cut-off date). The study met its primary objective demonstrating a statistically significant and clinically meaningful improvement in PFS by BIRC with an estimated 51% risk reduction in the ceritinib arm compared to chemotherapy arm (HR: 0.49 with 95% CI: 0.36, 0.67). The median PFS was 5.4 months (95% CI: 4.1, 6.9) and 1.6 months (95% CI: 1.4, 2.8) for the ceritinib arm and chemotherapy arm, respectively (see Table 5 and Figure 3). The PFS benefit of ceritinib over chemotherapy was robust and consistent by Investigator assessment and across various subgroups including age, gender, race, smoking class, ECOG performance status, and presence of brain metastases or prior response to crizotinib. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 16 of 26Ceritinib also significantly improved BIRC-assessed ORR as compared to chemotherapy with durable response (see Table 5). The OS data was not mature at the time of primary PFS analysis. In addition, 81 patients (69.8%) in the chemotherapy arm received subsequent ceritinib as first antineoplastic therapy after study treatment discontinuation. Efficacy data from Study A2303 are summarized in Table 5, and the Kaplan-Meier curves for PFS and OS are shown in Figure 3 and Figure 4, respectively. Table 5 ASCEND-5 (Study A2303) – Efficacy result in patients with previously treated ALK- positive locally advanced or metastatic NSCLC Ceritinib Chemotherapy (N=115) (N=116) Progression-free survival (based on BIRC) Number of events, n (%) 83 (72.2%) 89 (76.7%) Median, months (95% CI) 5.4 (4.1, 6.9) 1.6 (1.4, 2.8) HR (95% CI)a 0.49 (0.36, 0.67) p-valueb <0.001 Overall survivalc Number of events, n (%) 48 (41.7%) 50 (43.1%) Median, months (95% CI) 18.1 (13.4, 23.9) 20.1 (11.9, 25.1) HR (95% CI)a 1.00 (0.67,1.49) p-valueb 0.496 Tumor response (based on BIRC) Objective response rate (95% CI) 39.1% (30.2, 48.7) 6.9% (3.0, 13.1) Duration of response Number of responders 45 8 Median, monthsd (95% CI) 6.9 (5.4, 8.9) 8.3 (3.5, NE) Event-free probability estimate at 9 monthsd 31.5% (16.7%, 47.3%) 45.7% (6.9%, 79.5%) (95% CI) HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; NE=not estimable; a Based on the Cox proportional hazards stratified analysis. b Based on the stratified log-rank test. c OS analysis was not adjusted for the effects of cross over. d Estimated using the Kaplan-Meier method. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 17 of 26Figure 3 ASCEND-5 (Study A2303) - Kaplan-Meier plot of progression-free survival as assessed by BIRC 100 Censoring Times Ceritinib 750 mg (n/N = 83/115) Chemotherapy (n/N = 89/116) 80 ee Hazard Ratio = 0.49 f-r 95% CI (0.36; 0.67) nt e 60 ev Kaplan-Meier medians (95% CI) (Months) of Ceritinib 750 mg: 5.4 (4.1; 6.9) %) Chemotherapy: 1.6 (1.4; 2.8) ( y 40 bilit Log rank p-value = <0.001 a b o r P 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Months) No. of patients still at risk Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 LDK378 750 mg 115 87 68 40 31 18 12 9 4 3 2 1 0 Chemotherapy 116 45 26 12 9 6 2 2 2 0 0 0 0 India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 18 of 26Figure 4 ASCEND-5 (Study A2303) - Kaplan-Meier plot of overall survival 100 e80 e r f- nt e v e of 60 Censoring Times %) Ceritinib 750 mg (n/N = 48/115) y ( Chemotherapy (n/N = 50/116) bilit 40 a Hazard Ratio = 1.00 b o 95% CI (0.67; 1.49) Pr Kaplan-Meier medians (95% CI) (Months) 20 Ceritinib 750 mg: 18.1 (13.4; 23.9) Chemotherapy: 20.1 (11.9; 25.1) Log rank p-value = 0.496 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 24 24 Time (Months) No. of patients s till at risk Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 LDK378 115 107 92 83 71 61 52 37 28 23 13 8 2 2 0 0 750 mg Chemotherapy 116 109 91 78 66 53 43 39 29 22 17 7 5 2 1 0 Significant improvements were reported for the majority of lung cancer specific symptoms for Spexib versus chemotherapy (LCSS and QLQ-LC13 scores). Time to deterioration for cough, pain and dyspnea was significantly prolonged for the individual scales (p-value<0.05) or when combined into a composite score (p- value <0.001) in the LCSS and LC13 instruments. Median time to definitive deterioration for the LCSS composite endpoint (pain, cough, shortness of breath) was 18 months (95% CI: 13.4, NE) in the ceritinib arm versus 4.4 months (95% CI: 1.6, 8.6) in the chemotherapy arm. Median time to definitive deterioration for the same endpoint in the LC13 instrument was 11.1 months (95% CI 7.1, 14.2) in the ceritinib arm versus 2.1 months (95% CI: 1.0, 5.6) in the chemotherapy arm. The EQ-5D questionnaire showed a significant overall health status improvement for Spexib in comparison to the chemotherapy. In Study A2303, 133 patients with baseline brain metastasis (66 patients in the ceritinib arm and 67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-radiologist. The intracranial ORR (OIRR) in patients with measurable disease in the brain at baseline and at least one post-baseline assessment was higher with ceritinib (35.3%, 95% CI: 14.2, 61.7) compared to chemotherapy (5.0%, 95% CI: 0.1, 24.9). The median PFS by BIRC and Investigator using RECIST 1.1 was longer in the ceritinib arm compared to the chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases (based on the extent of cancer CRF, see Table 6). India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 19 of 26Table 6 ASCEND-5 (Study A2303) – PFS with and without brain metastases BIRC Investigator Ceritinib Chemotherapy Ceritinib Chemotherapy With Brain Metastases N=65 N=69 N=65 N=69 Progression Free Survival Median, months (95% CI) 4.4 (3.4, 6.2) 1.5 (1.3, 1.8) 5.4 (3.9, 7.0) 1.5 (1.3, 2.1) HR (95% CI) 0.54 (0.36, 0.80) 0.45 (0.31, 0.66) Without Brain Metastases N=50 N=47 N=50 N=47 Progression Free Survival Median, months (95% CI) 8.3 (4.1, 14.0) 2.8 (1.4, 4.1) 8.3 (5.6, 13.4) 2.6 (1.4, 4.2) HR (95% CI) 0.41 (0.24, 0.69) 0.32 (0.19, 0.54) Dose optimization Study A2112 (ASCEND-8) The efficacy of Spexib 450 mg with food was evaluated in a multicenter, open-label dose optimization Study A2112 (ASCEND-8). A total of 81 previously untreated patients with ALK-positive locally advanced or metastatic NSCLC were randomized to receive Spexib 450 mg once daily with food (N=41) or Spexib 750 mg once daily under fasted conditions (N=40). ALK-positivity was identified by VENTANA IHC. A key secondary efficacy endpoint was overall response rate (ORR) according to RECIST 1.1 as evaluated by a Blinded Independent Review Committee (BIRC). The population characteristics across the two arms were: mean age 53 years, age less than 65 (79%), female (57%), Caucasian (54%), Asian (33%), never or former smoker (95%), WHO PS 0 or 1 (93%), adenocarcinoma histology (94%), and metastases to the brain (33%). Efficacy results from ASCEND-8 are summarized in Table 7 below. Table 7 ASCEND-8 (Study A2112) - Efficacy results in patients with previously untreated ALK positive locally advanced or metastatic NSCLC by BIRC Efficacy Parameter Spexib 450 mg with food Spexib 750 mg fasted (N=40) (N=41) Overall Response Rate (ORR: 32 (78.0) 28 (70.0) CR+PR), n (%) (95% CI)a (62.4, 89.4) (53.5, 83.4) BIRC: Blinded Independent Review Committee; CI: Confidence Interval CR, PR confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met Overall response rate determined based on BIRC assessment per RECIST 1.1 aExact binomial 95% confidence interval Single-arm studies X2101, A2203 and A2201 The use of Spexib in the treatment of ALK-positive NSCLC patients was investigated in 3 global, multicenter, open-label, single-arm studies (Study X2101, Study A2203, and Study A2201). The primary efficacy endpoint for these studies was overall response rate (ORR) by investigator for patients who were treated with a Spexib dose of 750 mg fasted, defined as the proportion of patients with best response of complete response (CR) or partial response (PR) confirmed by repeat assessments performed not less than 4 weeks after the criteria for response was first met. Additional evaluations included duration of response (DOR) and progression-free survival (PFS) by Investigator assessment, and overall survival (OS). Tumor evaluations were performed by the Investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 in Study X2101 and RECIST 1.1 in Studies A2203 and A2201. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 20 of 26Study X2101 was a global, multicenter, open-label, phase 1 study which included a dose-escalation phase and an expansion phase, at a dose of 750 mg on an empty stomach. All patients enrolled in the study had locally advanced or metastatic malignancy that had progressed despite standard therapy and all patients were previously tested for ALK rearrangement. Patients with controlled or asymptomatic brain metastases were eligible for the study. Prior ALK inhibitor therapy was permitted. Two-hundred and ninety of the 304 patients enrolled in the study were ALK-positive NSCLC patients. A total of 246 ALK-positive NSCLC patients were enrolled who were treated at a Spexib dose of 750 mg fasted: 163 who had received prior treatment with an ALK inhibitor and 83 who were ALK inhibitor naïve. Across the 246 ALK-positive NSCLC patients treated at a dose of 750 mg fasted in the study, the median age was 53 years (range: 22 to 80 years); 84.1% of patients were younger than 65 years. A total of 53.7% of patients were female. Caucasians comprised 63.4% of the study population, Asians 33.3%, Blacks 1.6%, and other races 1.6%. The vast majority of patients had adenocarcinoma (92.7%) and were either never or former smokers (97.6%). More than two-thirds (67.5%) of the patients were treated with 2 or more regimens prior to enrollment into the study, 26.0% with 1 prior regimen, and 6.5% with 0 prior regimens. Both Study A2203 and Study A2201were global, multicenter, open-label, single-arm, phase 2 studies designed to evaluate the efficacy and safety of 750 mg ceritinib fasted in patients with locally advanced or metastatic ALK-positive NSCLC. Study A2203 enrolled 124 crizotinib-naïve patients who were either chemotherapy-naïve or who had been previously treated with up to 3 lines of cytotoxic chemotherapy. Study A2201 enrolled 140 patients who had been previously treated with 1 to 3 prior lines of cytotoxic chemotherapy followed by treatment with crizotinib, and then progressed on crizotinib. In Study A2203, 124 patients were treated at a dose of 750 mg fasted. The median age was 56 years (range: 27 to 82 years); 75.8% of patients were younger than 65 years. A total of 59.7% of patients were female. Asians comprised 59.7% of the study population, Caucasians 38.7%, Blacks 0.8%, and other races 0.8%. The vast majority of patients had adenocarcinoma (96.8%). All patients, except 2 who were naïve to anti-cancer treatment, were treated with prior chemotherapy. 54 (43.5%) patients were treated with 1 regimen and 68 (54.8%) were treated with 2 or more regimens prior to enrollment into this study. All patients were ALK inhibitor naïve. In Study A2201, 140 patients were treated at a dose of 750 mg fasted. The median age was 51 years (range: 29 to 80 years); 87.1% of patients were younger than 65 years. A total of 50.0% of patients were female. Caucasians comprised 60.0% of the study population, Asians 37.9% and other races 2.1%. The vast majority of patients had adenocarcinoma (92.1%). All patients were treated with 2 or more regimens prior to enrollment into the study. All patients had received prior treatment with an ALK inhibitor. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 21 of 26Main efficacy results from Studies X2101, A2203 and A2201 In Study A2203, the median OS was 51.3 months (95% CI: 42.7, 55.3) at the final analysis (data cut-off date: 22-Jan-2018) and a high proportion of patients were censored (68 patients; 54.8%). The OS rate was 67.3% (95% CI: 58.1, 75.0) at 30 months. The main efficacy data for all 3 studies are summarized in Table 8 for ALK-positive NSCLC patients who are ALK inhibitor naïve and in Table 9 for ALK-positive NSCLC patients with prior ALK inhibitor treatment. Patients responded to Spexib regardless of whether they received a prior ALK inhibitor as shown in Tables 8 and 9. With longer follow-up (median duration > two years), patients continued to demonstrate a clinical response to Spexib. Table 8 Overview of efficacy data in ALK-positive NSCLC patients who are ALK inhibitor naïve per Investigator assessment Study X2101 Study A2203 ceritinib 750 mg ceritinib 750 mg N=83 N=124 Duration of follow-up Median (months) (min – max) 12.5* 39.8** 9.3** 25.9** (0.4 – 22.2) (33.1 – 52.5) (5.6 – 17.2) (22.2 – 33.8) Overall response rate (CR + PR), 60 (72.3) 61 (73.5) 79 (63.7) 84 (67.7) n (%) (95% CI) (61.4, 81.6) (62.7, 82.6) (54.6, 72.2) (58.8, 75.9) Duration of response*** Median (months) (95% CI) 17.0 14.2 9.3 22.1 (11.3, NE) (11.3, 22.1) (9.1, NE) (14.8, NE) % Event-free probability 37.6 42.8 NE 55.7 estimate (95% CI) at 18 (9.7, 66.3) (29.9, 55.1) (44.2, 65.7) months Progression-free survival Median (months) (95% CI) 18.4 15.2 11.1 16.6 (11.1, NE) (12.1, 19.5) (9.3, NE) (11.0, 22.1) % Event-free probability 50.6 44.2 NE 49.1 estimate (95% CI) at 18 (36.1, 63.5) (32.8, 55.1) (39.7, 57.9) months Overall survival Median (months) (95% CI) NE 39.1 NE NE (19.6, NE) (32.9, NE) (NE, NE) (NE, NE) % Event-free probability 79.6 75.2 NE 73.4 estimate (95% CI) at 18 (66.5, 88.0) (63.8, 83.5) (64.6, 80.4) months Data cut-off date 14-Apr-2014 3-May-2016 27-Jun-2014 15-Nov-2015 NE = not estimable Study X2101: Responses assessed by Investigator; Overall response rate determined per RECIST 1.0 Study A2203: Responses assessed by Investigator; Overall response rate determined per RECIST 1.1 CR, PR confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met *From start date of study treatment to date of death or censoring **From start date of study treatment to cut-off date ***Includes only patients with confirmed CR, PR India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 22 of 26Table 9 Overview of efficacy data in ALK-positive NSCLC patients with prior ALK inhibitor treatment per Investigator assessment Study X2101 Study A2201 ceritinib 750 mg ceritinib 750 mg N=163 N=140 Duration of follow-up Median (months) (min – max) 10.2* 40.0** 8.3** 33.4** (0.1 – 24.1) (33.1 – 52.7) (5.6 – 14.8) (30.6 – 39.8) Overall response rate (CR + PR), 92 (56.4) 92 (56.4) 52 (37.1) 57 (40.7) n (%) (95% CI) (48.5, 64.2) (48.5, 64.2) (29.1, 45.7) (32.5, 49.3) Duration of response*** Median (months) (95% CI) 8.3 8.3 9.2 10.6 (6.8, 9.7) (6.8, 9.7) (5.6, NE)# (7.4, 14.7) Progression-free survival Median (months) (95% CI) 6.9 6.9 5.7 5.8 (5.6, 8.7) (5.6, 8.5) (5.3, 7.4) (5.4, 7.6) Overall survival Median (months) (95% CI) 16.7 20.3 14.0 15.6 (14.8, NE)## (15.2, 24.3) (10.3, 14.0) (13.6, 24.2) Data cut-off date 14-Apr-2014 3-May-2016 26-Feb-2014 29-Mar-2016 NE = not estimable Study X2101: Responses assessed by Investigator; Overall response rate determined per RECIST 1.0 Study A2201: Responses assessed by Investigator; Overall response rate determined per RECIST 1.1 CR, PR confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met *From start date of study treatment to date of death or censoring **From start date of study treatment to cut-off date ***Includes only patients with confirmed CR, PR # DOR rate at 8 months is 51.3% (32.7, 67.1) ## OS rate at 18 months is 47.5% (36.4, 57.8) The majority of patients treated with Spexib, who had measurable disease at baseline and at least one valid post- baseline assessment, had a reduction in measurable lesions as best percentage change from baseline based on Investigator assessment, i.e. 207 (90.79%), 94 (75.81%) and 108 (94.74%) in Study X2101, A2201 and A2203 respectively. Patients with brain metastases In the analysis of Studies X2101, A2203, and A2201 at an early cut off date, brain m etastases were seen in 50.0%, 40.3%, and 71.4% of patients, respectively. The main efficacy data for patients with brain metastases at baseline for all 3 studies are summarized in Table 10. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 23 of 26Table 10 Overview of efficacy data in ALK-positive NSCLC patients with brain metastases at baseline Patients who are ALK inhibitor Patients with prior ALK naïve inhibitor treatment Study X2101 Study A2203 Study X2101 Study A2201 ceritinib ceritinib ceritinib ceritinib 750 mg 750 mg 750 mg 750 mg N=26 N=50 N=98 N=100 Overall response rate (CR + PR), n (%) 19 (73.1) 29 (58.0) 50 (51.0) 33 (33.0) (95% CI) (52.2, 88.4) (43.2, 71.8) (40.7, 61.3) (23.9, 43.1) Duration of response* 12.6 9.1 6.9 6.1 (5.5, NE) (7.5, NE) (5.4, 8.3) (5.4, NE) Median (months) (95% CI) Progression-free survival 9.7 10.8 6.9 5.4 Median (months) (95% CI) (4.6, NE) (7.3, NE) (4.9, 8.4) (4.7, 6.4) Data cut-off date 14-Apr-2014 27-Jun-2014 14-Apr-2014 26-Feb-2014 NE = not estimable Study X2101: Responses assessed by Investigator; Overall response rate determined per RECIST 1.0 Studies A2203 and A2201: Responses assessed by Investigator; Overall response rate determined per RECIST 1.1 CR, PR confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met *Includes only patients with confirmed CR, PR Intracranial response In Study X2101, there were 14 ALK-positive NSCLC patients with investigator-assessed measurable brain metastases at baseline in the 750 mg dose group. The overall intracranial response rate (OIRR) at the cut-off date 14-Apr-2014 as assessed by the Investigator was 50.0% (95% CI: 23.0, 77.0), including 2 patients having a CR in the brain and 5 patients with a confirmed PR in the brain; in addition, 3 patients had stable disease (SD). In Study A2203, 10 out of the 124 patients with ALK-positive NSCLC had brain metastases at baseline considered to be target lesions by the Investigator. In these patients, the OIRR at the cut-off date 27-Jun-2014 based on Investigator assessment was 20.0% (95% CI: 2.5, 55.6), including 2 patients with a confirmed PR in the brain. In Study A2201, 20 out of the 140 patients with ALK-positive NSCLC had brain metastases at baseline considered to be target lesions by the Investigator. In these patients, the OIRR at the cut-off date 26-Feb-2014 based on Investigator assessment was 35.0% (95% CI: 15.4, 59.2), including 2 patients with a confirmed CR in the brain and 5 patients with a confirmed PR in the brain. Intracranial response without prior irradiation In addition, for ALK-positive NSCLC patients with measurable brain lesions at baseline that had not been irradiated, Spexib induced responses in the brain that matched or exceeded the systemic tumor responses in the majority of ALK-positive NSCLC patients previously treated with an ALK inhibitor and in ALK inhibitor naïve patients. In Study X2101, 41 ALK-positive NSCLC patients were enrolled with brain metastases that were not irradiated (30 previously treated with an ALK inhibitor and 11 ALK inhibitor naïve), 4 of whom had measurable brain lesions at baseline (3 previously treated with an ALK inhibitor and 1 ALK inhibitor naïve). At the cut-off date 14-Apr-2014, all 4 of the patients (100%) with measurable brain lesions at baseline that had not been irradiated had responses in the brain that matched or exceeded the systemic tumor responses including 2 complete brain metastases responses (1 for a patient previously treated with an ALK inhibitor and 1 for an ALK inhibitor naïve patient). In addition to the 2 CRs, there was 1 PR and 1 SD. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 24 of 26In Study A2203, 23 ALK-positive NSCLC patients were enrolled with brain metastases that were not irradiated, 6 of whom had measurable brain lesions at baseline. At the cut-off date 27-Jun-2014, all 6 of the patients (100%) had responses in the brain that matched the systemic tumor responses. There were 2 PRs, 3 SDs, and 1 “Unknown”. In Study A2201, 28 ALK-positive NSCLC patients were enrolled with brain metastases that were not irradiated, 6 of whom had measurable brain lesions at baseline. At the cut-off date 26-Feb-2014, 4 of the 6 patients (66.7%) had responses in the brain that matched or exceeded the systemic tumor responses including 2 complete brain metastases responses. In addition to the 2 CRs, there were 2 PRs and 2 SDs. NON-CLINICAL SAFETY DATA Safety pharmacology and repeat dose toxicity Safety pharmacology studies indicate that ceritinib is unlikely to interfere with vital functions of the respiratory and central nervous systems. In vitro data show that the IC for the inhibitory effect of ceritinib on the hERG 50 potassium channel was 0.4 micromolar at 33°C to 35°C (near body temperature). An in vivo telemetry study in monkeys showed a modest QT prolongation in 1 of 4 animals after receiving the highest dose of ceritinib. ECG studies in monkeys after 4- or 13-weeks of dosing with ceritinib have not shown QT prolongation or abnormal ECGs. The principal toxicity related to ceritinib administration in rats and monkeys was inflammation of the extra- hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixed cell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum at higher doses. GI toxicity was observed in both species characterized by body weight loss, decreased food consumption, emesis (monkey), diarrhea, and at high doses, by histopathologic lesions including erosion, mucosal inflammation, and foamy macrophages in the duodenal crypts and submucosa. Liver was also affected in both species, but only at the highest dose levels studied, and included minimal increases in liver transaminases in a few animals, and vacuolation of the intra-hepatic bile duct epithelium. Alveolar foamy macrophages (confirmed phospholipidosis) were seen in the lungs of rats, but not in monkeys, and the lymph nodes of rats and monkeys had macrophage aggregates. Target organ effects showed partial to complete recovery. Carcinogenicity and mutagenicity Carcinogenicity studies have not been performed with ceritinib. The Ames assay for ceritinib indicated it was not a potential mutagen, and the chromosomal aberration assay in cultured human peripheral blood lymphocytes did not indicate the potential to cause structural chromosomal aberrations. The micronucleus test using cultured human peripheral blood lymphocytes was negative. An in vivo rat micronucleus test revealed no adverse chromosomal effects on the bone marrow at any dose level after oral dosing in the rat. Fertility and Reproductive toxicity For information on fertility and reproductive toxicity, see section PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL. STORAGE Special precautions for storage See folding box. Spexib should not be used after the date marked “EXPIRY” on the pack. Spexib must be kept out of the reach and sight of children. Instructions for use and handling There are no special requirements for use or handling of this product. Manufacturer: See folding box. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 25 of 26Information issued: India pack insert dtd 22 Jan 19 based on International Package Leaflet (IPL) dtd 26 Nov 18. TM = Trademark of Novartis AG, Basle, Switzerland. India pack insert dtd 22 Jan 19 based on IPL dtd 26 Nov 18 Page 26 of 26