Zykadia^® (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Stein AG (Switzerland)

ATC Code

L01ED02 (Ceritinib)

Active Substance

Ceritinib (Rec.INN registered by WHO)

Dosage Form

Zykadia®

Capsules 150 mg: 50, 90, or 150 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin size 00, with a blue opaque cap and a white opaque body; the cap is radially printed in black with “LDK 150MG”, the body is radially printed in black with “NVR”; capsule contents: white or almost white powder.

Excipients: microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide.

Capsule shell composition: gelatin, titanium dioxide (E171), indigo carmine (E132).
Black printing ink composition: shellac, black iron oxide (E172), propylene glycol, ammonia solution.

10 pcs. – blisters (5) – cartons.
10 pcs. – blisters (9) – cartons.
10 pcs. – blisters (5) – cartons (3) – multipacks.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents, protein kinase inhibitors, anaplastic lymphoma kinase (ALK) inhibitors

Pharmacological Action

An inhibitor of anaplastic lymphoma kinase (ALK) for oral use. Ceritinib inhibits ALK autophosphorylation, ALK-mediated phosphorylation of signaling proteins, and the proliferation of ALK-dependent tumor cells both in vitro and in vivo. Translocation of the ALK gene results in the expression of a resulting hybrid protein and, consequently, aberrations in the ALK signaling pathway in non-small cell lung cancer (NSCLC). In most cases of NSCLC, the translocation partner for ALK is the EML4 gene; this leads to the formation of the EML4-ALK hybrid protein, containing the ALK protein kinase domain fused to the N-terminal portion of EML4. Ceritinib demonstrates efficacy against EML4-ALK kinase activity in an NSCLC cell line (H2228), leading to inhibition of cell proliferation in vitro and regression of H2228 cell line tumors in mouse and rat xenograft models.

Ceritinib dose-dependently inhibits ALK kinase activity and ALK-mediated signaling in Karpas 299 (lymphoma cell line) and H2228 (lung cancer cell line) cell lines. The inhibitory effect of ceritinib leads to inhibition of tumor cell proliferation in vitro and tumor regression in vivo in mouse and rat xenograft models. Ceritinib inhibits ALK kinase activity approximately 20 times more potently than crizotinib, as assessed by enzymatic inhibition of ALK kinase activity (the 50% inhibitory concentration (IC₅₀) for ALK inhibition is 0.15 nmol for ceritinib and 3 nmol for crizotinib). From a kinase panel consisting of 36 enzymes, Ceritinib inhibited only 2 other kinases with activity approximately 50 times less than that for ALK inhibition. Its activity against all other kinases in the panel was 500 times less compared to that against ALK, demonstrating a high degree of selectivity. In a single-dose pharmacodynamic study and a multiple-dose efficacy study in Karpas 299 lymphoma and H2228 lung cancer tumor models, it was shown that a 60-80% reduction in ALK signaling may be required to achieve tumor regression.

Pharmacokinetics

After a single oral dose, the C_max of ceritinib in plasma was reached approximately 4-6 hours after administration. Absorption was estimated as >25% based on the percentage of metabolite in feces. The absolute bioavailability of ceritinib has not been established. Daily oral administration of ceritinib leads to the achievement of steady state approximately after 15 days, which remains stable thereafter with a geometric mean accumulation ratio of 6.2 after 3 weeks of daily administration. After a single oral dose of ceritinib under fasting conditions, its plasma exposure, represented by C_max and AUC values, increased proportionally with the dose in the range from 50 to 750 mg. In contrast, after daily repeated administration, the concentration before the next dose (C_min) increased more than proportionally to the dose.

Systemic exposure of ceritinib increases when taken with food. The AUC value of ceritinib was 58% and 73% higher (C_max approximately 43% and 41% higher) in healthy subjects, with a single simultaneous intake of 500 mg ceritinib with low-fat (330 Kcal and 9 grams of fat) and high-fat (1000 Kcal and 58 grams of fat) food, respectively, compared to intake under fasting conditions.

Binding to human plasma proteins in vitro is dose-dependent from 50 ng/ml to 10000 ng/ml and is about 97%. V_d was 4230 L in patients after a single oral dose of 750 mg under fasting conditions. Furthermore, Ceritinib is more preferentially distributed into erythrocytes compared to plasma, with a mean in vitro blood/plasma ratio of 1.35. In vitro studies confirm that Ceritinib is a substrate of P-glycoprotein, but is not a substrate of breast cancer resistance protein (BCRP) or multidrug resistance protein 2 (MRP2). The apparent passive permeability for ceritinib in vitro was determined to be low.

In rats, Ceritinib penetrated the intact blood-brain barrier with a brain/plasma AUC_inf ratio of about 15%.

In vitro studies have shown that the CYP3A isoenzyme is the main isoenzyme involved in the metabolism of ceritinib. After a single oral dose of 750 mg under fasting conditions, Ceritinib is the main circulating component (82%) in human plasma. A total of 11 metabolites circulating in plasma were detected, with a mean contribution to the radioactivity AUC of <2.3% for each metabolite. The main metabolic pathways are monooxygenation, O-dealkylation, and N-formylation. Secondary biotransformation pathways involving primary metabolites are glucuronidation and dehydrogenation. Additionally, thiol group addition to O-dealkylated ceritinib was observed.

After a single oral dose of ceritinib under fasting conditions, the apparent terminal T_1/2 from plasma, calculated as the geometric mean, ranged from 31 to 41 hours in patients in the dose range from 400 to 750 mg. The geometric mean apparent clearance of ceritinib was lower at steady state (33.2 L/h) after daily oral administration of 750 mg than after a single 750 mg dose (88.5 L/h), thus suggesting that Ceritinib exhibits nonlinear pharmacokinetics over time.

Ceritinib and its metabolites are primarily excreted via the intestine. Fecal excretion accounts for 91% of the administered oral dose, with 68% of the dose excreted as unchanged ceritinib. Only 1.3% of the orally administered dose is excreted by the kidneys.

Pharmacokinetic/pharmacodynamic analysis suggests that Ceritinib may cause a dose-dependent prolongation of the QTc interval.

Indications

Locally advanced or metastatic non-small cell lung cancer, positive for anaplastic lymphoma kinase (ALK).

ICD codes

Dosage Regimen

Take orally.

Administer Zykadia once daily on an empty stomach. Take the dose at least 2 hours before or at least 2 hours after a meal due to increased systemic exposure when taken with food.

The recommended dose is 450 mg (three 150 mg capsules) once daily. The maximum daily dose is 450 mg.

Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Swallow capsules whole with water. Do not chew or dissolve the capsules.

If a dose is vomited, do not take an additional dose; resume the next scheduled daily dose.

If a dose is missed, take it unless the next scheduled dose is due within 12 hours.

For adverse reactions, manage with dose interruptions and/or reductions. Modify the dose according to the severity of the reaction.

First dose reduction: from 450 mg to 300 mg daily. Second dose reduction: from 300 mg to 150 mg daily. Discontinue if unable to tolerate 150 mg daily.

Monitor liver function tests (ALT, AST, bilirubin) before initiation and monthly during therapy. Monitor more frequently if elevated transaminases occur.

Monitor ECG and electrolytes (potassium) in patients with significant cardiac risk factors, before initiation, and periodically during treatment.

Monitor fasting serum glucose before initiation and periodically during therapy, especially in diabetic patients or those on corticosteroids.

Monitor lipase and amylase before initiation and as clinically indicated during treatment.

For symptomatic bradycardia, evaluate concomitant medications and adjust dose. For life-threatening bradycardia, discontinue Zykadia unless due to a concomitant medication.

For severe or persistent gastrointestinal toxicity (nausea, vomiting, diarrhea), provide antiemetic or antidiarrheal therapy and consider dose modification.

Discontinue permanently for confirmed treatment-related pneumonitis of any severity.

Adverse Reactions

Blood and lymphatic system disorders: very common – anemia; common – anemia (grades 3-4).

Metabolism and nutrition disorders very common – decreased appetite, weight loss; common – hyperglycemia, hypophosphatemia, decreased appetite (grades 3-4), weight loss (grades 3-4).

Eye disorders: common – vision impairment (blurred vision, visual acuity reduced, photopsia, vitreous floaters, visual acuity reduced, accommodation disorder, presbyopia).

Cardiac disorders common – pericarditis, bradycardia, QT interval prolongation on ECG.

Respiratory, thoracic and mediastinal disorders common – pneumonitis.

Gastrointestinal disorders very common – diarrhea, nausea, vomiting, abdominal pain, constipation, esophageal disorders; common – diarrhea (grades 3-4), abdominal pain (grades 3-4); uncommon – pancreatitis, constipation (grades 3-4), esophageal disorders (grades 3-4), increased lipase, increased amylase.

Hepatobiliary disorders common – abnormal liver function tests, hepatotoxicity; uncommon – hepatotoxicity (grades 3-4).

Skin and subcutaneous tissue disorders very common – skin rash; uncommon – skin rash (grades 3-4).

Renal and urinary disorders very common – increased creatinine; common – renal failure, renal impairment; uncommon – renal failure (grades 3-4), renal impairment (grades 3-4), uncommon – increased creatinine (grades 3-4).

General disorders and administration site conditions very common – fatigue; common – fatigue (grades 3-4).

Contraindications

Hypersensitivity to ceritinib; age under 18 years; pregnancy, breastfeeding period.

With caution

Patients with severe renal impairment, moderate and severe hepatic impairment, congenital long QT syndrome, QT interval prolongation, including in the medical history, or predisposition to QT interval prolongation, chronic heart failure, bradyarrhythmia, electrolyte imbalances, as well as in patients taking antiarrhythmic and other drugs that prolong the QT interval, drugs that can cause bradycardia (including beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); in patients with hyperglycemia, diabetes mellitus and/or taking corticosteroids; with concomitant use with potent inhibitors and inducers of the CYP3A isoenzyme/P-glycoprotein; with concomitant use with drugs affecting gastric juice pH.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Manifestations of hepatotoxicity are generally reversible upon interruption of therapy and/or reduction of the ceritinib dose; sometimes its discontinuation may be required.

Before starting treatment and monthly during therapy, it is recommended to monitor laboratory parameters of liver function (including AST, ALT activity, total bilirubin concentration). According to clinical indications, if liver transaminase activity increases, more frequent monitoring of these parameters should be performed.

Most cases of severe, life-threatening pneumonitis resolved or their course improved upon discontinuation of ceritinib. The patient’s condition should be monitored to identify symptoms indicative of the development of interstitial lung disease (ILD) and/or pneumonitis. If ILD and/or pneumonitis of any severity is detected during treatment, other possible causes of ILD and/or pneumonitis should be excluded and the use of ceritinib should be discontinued.

The use of ceritinib should be avoided in patients with congenital long QT syndrome, and caution should be exercised when using it in patients with QT interval prolongation, including in the medical history, or predisposition to QT interval prolongation, chronic heart failure, bradyarrhythmia, electrolyte imbalances, as well as in patients taking antiarrhythmic and other drugs that prolong the QT interval. Periodic monitoring of ECG and electrolyte levels (e.g., potassium) is recommended in this category of patients.

According to clinical indications, in case of vomiting, diarrhea, dehydration, or renal impairment, correction of water and electrolyte balance should be performed. Ceritinib should be discontinued if QTc prolongation > 500 msec or an increase of more than 60 msec from baseline occurs, as well as in case of torsades de pointes or polymorphic ventricular arrhythmia or in the presence of symptoms/signs of severe arrhythmia development. It is necessary to temporarily discontinue ceritinib in patients with QTc interval prolongation > 500 msec until baseline values are restored or until the QTc interval length decreases to < 481 msec according to at least two ECGs, and then resume ceritinib at a dose reduced by 150 mg.

Concomitant use of ceritinib and other drugs that can cause bradycardia (including beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin) should be avoided if possible. Heart rate and blood pressure should be regularly monitored. If symptoms of bradycardia (non-life-threatening) occur, it is necessary to temporarily discontinue ceritinib until they disappear or until the heart rate recovers to 60 bpm or higher, evaluate the impact of concomitantly used drugs that can cause bradycardia, and, if necessary, reduce the dose of ceritinib. Ceritinib should be discontinued in case of life-threatening bradycardia, if the influence of other drugs on the development of bradycardia is not established; however, if the influence of other concomitantly used drugs on the development of bradycardia is established, it is necessary to temporarily discontinue Ceritinib until the symptoms of bradycardia disappear or until a heart rate of 60 bpm or higher is achieved, and after adjusting the dose of concomitantly used drugs or after their discontinuation, resume treatment with ceritinib at a dose reduced by 150 mg, with more frequent monitoring of the condition.

The patient’s condition should be monitored and, if necessary, standard therapeutic measures should be applied, including antidiarrheal, antiemetic agents, as well as infusion therapy. If necessary, Ceritinib should be temporarily discontinued or its dose reduced.

The risk of developing hyperglycemia is higher in patients with diabetes mellitus and/or taking corticosteroids. Fasting serum glucose concentration should be monitored before starting therapy with ceritinib, and periodically during treatment as clinically indicated. If necessary, hypoglycemic therapy should be initiated or adjusted.
Lipase and amylase activity should be monitored before and during therapy with ceritinib according to clinical indications.
Effect on ability to drive vehicles and operate machinery

Ceritinib has a minor influence on the ability to drive vehicles and/or operate machinery. Given the possibility of developing some adverse reactions when using ceritinib (fatigue, vision disorders), patients should exercise caution when driving vehicles and/or operating machinery.

Drug Interactions

In healthy volunteers, simultaneous single administration of 450 mg ceritinib under fasting conditions with ketoconazole (200 mg twice daily for 14 days), a potent inhibitor of the CYP3A isoenzyme/P-glycoprotein, led to a 2.9 and 1.2-fold increase in AUC_inf and C_max of ceritinib, respectively, compared to the use of ceritinib as monotherapy. According to modeling results, the steady-state AUC of ceritinib at lower doses when used concomitantly with ketoconazole 200 mg twice daily for 14 days does not differ from that when using ceritinib as monotherapy. Concomitant use of ceritinib and potent CYP3A isoenzyme inhibitors should be avoided. If concomitant use with potent CYP3A isoenzyme inhibitors cannot be avoided, including, but not limited to, drugs such as ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone, the dose of ceritinib should be reduced by approximately one-third, rounded to the nearest multiple of 150 mg. Upon discontinuation of the potent CYP3A isoenzyme inhibitor, the dose of ceritinib should be returned to the original dose used before starting the potent CYP3A isoenzyme inhibitor.

When using ceritinib with drugs that inhibit Pgp, an increase in the concentration of ceritinib is possible. With this combination, caution and monitoring for adverse reactions are required.

In healthy volunteers, simultaneous single administration of 750 mg ceritinib under fasting conditions with rifampicin (600 mg once daily for 14 days), a potent inducer of the CYP3A isoenzyme/Pgp, led to a 70% and 44% decrease in AUC_inf and C_max of ceritinib, respectively, compared to the use of ceritinib as monotherapy. Concomitant use of ceritinib with potent inducers of the CYP3A isoenzyme/Pgp reduces the plasma concentration of ceritinib. Concomitant use with potent inducers of the CYP3A isoenzyme should be avoided, including, but not limited to, drugs such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John’s wort. Caution should be exercised when used concomitantly with Pgp inducers.

Based on in vitro data, Ceritinib competitively inhibits the metabolism of midazolam, a substrate of the CYP3A isoenzyme, and diclofenac, a substrate of the CYP2C9 isoenzyme. Time-dependent inhibition of the CYP3A isoenzyme was also observed. The C_max of ceritinib at steady state when used at a dose of 750 mg daily under fasting conditions may exceed the inhibition constant for the CYP3A and CYP2C9 isoenzymes, suggesting the ability of ceritinib to inhibit the clearance of other drugs metabolized by these isoenzymes. Dose reduction of drugs metabolized primarily by the CYP3A and CYP2C9 isoenzymes may be required. Concomitant use with known substrates of the CYP3A isoenzyme with a narrow therapeutic index (including astemizole, cisapride, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus) and known substrates of the CYP2C9 isoenzyme with a narrow therapeutic index (including phenytoin and warfarin) should be avoided.

Based on in vitro data, Ceritinib also inhibits the CYP2A6 and CYP2E1 isoenzymes at clinically relevant concentrations; therefore, Ceritinib may potentially increase the plasma concentration of co-administered drugs that are predominantly metabolized by these isoenzymes. Caution and careful monitoring for adverse reactions are necessary with such combinations.

The efficacy of oral contraceptives may be reduced when co-administered with ceritinib.

Based on in vitro data, it is assumed that at clinically relevant concentrations, Ceritinib may inhibit BCRP and P-gp in the intestinal wall. Caution and careful monitoring for adverse reactions are necessary when co-administered with drugs that are substrates of BCRP (rosuvastatin, topotecan, sulfasalazine) and P-gp (digoxin, dabigatran, colchicine, pravastatin).

Cases of QTc interval prolongation were observed in clinical studies with ceritinib; therefore, caution is advised when using ceritinib in patients taking Class I (quinidine, procainamide, disopyramide) or Class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs or other drugs that prolong the QT interval, such as astemizole, domperidone, droperidol, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, cisapride, and moxifloxacin. The QT interval duration should be carefully monitored in these patients.

Drugs that reduce gastric acidity (e.g., proton pump inhibitors, H₂-receptor blockers, antacids) may alter the solubility of ceritinib and reduce its bioavailability, as a pH-dependent solubility was noted, with the solubility of ceritinib decreasing as pH increases in vitro. In a clinical drug interaction study in healthy volunteers (n=22), co-administration of a single 750 mg dose of ceritinib on an empty stomach with esomeprazole (a proton pump inhibitor) at a dose of 40 mg daily for 6 days resulted in a decrease in ceritinib exposure (AUC_inf and C_max decreased to 76% and 79%, respectively). However, co-administration of a single 750 mg dose of ceritinib on an empty stomach with a proton pump inhibitor for 6 days in a subgroup of patients in a clinical study suggests a lesser effect on ceritinib exposure compared to healthy volunteers. A reduction in AUC (90% CI) of 30% (0%, 52%) and C_max (90% CI) of 25% (5%, 41%) was noted. No clinically significant effect on ceritinib exposure at steady state with once-daily dosing was observed. This is also supported by a subgroup analysis based on data from three clinical studies (n>400) involving patients both receiving and not receiving proton pump inhibitors, which demonstrated similar steady-state exposure, as well as clinical efficacy and safety.

Patients should be advised to avoid consuming grapefruit or grapefruit juice, as inhibition of the CYP3A isoenzyme activity in the intestinal wall may increase the bioavailability of ceritinib.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.