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Ceretinib Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician. Use
[Drug Name]
Generic Name: Ceretinib Capsules
Trade Name: Zantarelinib® Zykadia®
English name:Ceritinib Capsules
Hanyu Pinyin:Sairuitini Jiaonang
[Ingredients]
The active ingredient of this product is ceritinib.
Chemical name:5-chloro-N2-[2-isopropoxy -5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine
Chemical structure formula.
Molecular Formula:C28H36ClN5O3S
[Characteristic]
The content of this product is white to off-white powder.
[Indications]
[Specifications]
150mg
[dosage]
ALKDetection
This product must be used in a healthcare facility with experience in its use and under the This product must be used in a healthcare facility with experience in its use and under the direction of a specific technical professional.
Before taking this product, it must be administered by an accurate and well validated test methodALKmutation testing, confirmed asALKpositiveNSCLCpatients should only receive this product.
Dose
The recommended dose of this product is once daily, each time450mg, administered orally at the same time each day, and the drug should be taken with food.
Treatment should be continued as long as clinical benefit is observed until disease progression or the onset of intolerable toxicity.
If a dose is forgotten and the interval to the next dose 12hours or more, the patient should make up the missed dose. If vomiting occurs during treatment, the patient should not take the additional dose, but should continue with the next scheduled dose.
Dose Adjustment
For those who cannot tolerate daily dosing with meals150mgdose should be discontinued for patients who cannot tolerate daily dosing with meals.
Table1 summarizes the recommendations for discontinuation, dose reduction, or discontinuation of therapy for some adverse drug reactions to this product.
Table1 Recommendations for dose adjustment and management of some adverse reactions to this product
Determination criteriaCeretinib capsule doseGastrointestinal adverse effectsSevere or intolerable nausea or vomiting despite optimal antiemetic and antidiarrheal treatment or unbearable nausea, vomiting or diarrhea
Suspend treatment until the above response improves, then reduce150mgdose to restart treatment with this product. HepatotoxicityAlanine aminotransferase (ALT) or aspartate aminotransferase (AST) is elevated>Upper limit of normal (ULN)5 times the upper limit of normal and also a total bilirubin ≤. span>ULNof2timesSuspend use of this product untilALT/ASTreturns to baseline or ≤3timesULNlevels and then re-administered with a reduced dose of 150 mg. ALT orASTelevated>>3foldULN and concomitant elevated total bilirubin>2foldULN()
No cholestasis or hemolysis)Discontinue this product permanently. Interstitial Lung Disease (ILD)/Non-infectious PneumoniaAny degree of treatment-related interstitial lung disease/Non-infectious pneumoniaPermanently discontinue this product. Cardiac Arrhythmiaat least 2independent ECGs at ( ECG) in which heart rate correctedQTinterval (QTc)> 500msSuspend this product until return to baseline levels orQTc<481ms, check and correct electrolyte disturbances if necessary, then restart this treatment with reduced dosing150mg. QTc>500msor change from baseline>60mswith tip-twist ventricular tachycardia, polymorphic ventricular tachycardia or symptoms of severe arrhythmia/ signsPermanently discontinue this product. Bradycardiaa ()
symptomatic, possibly severe and clinically significant, requiring medical intervention)Suspend use of this product until bradycardia symptoms resolve (symptom rating ≤1) or heart rate reaches60times/. span>minutes (bpm) or more. .
Evaluate combination medications and antihypertensive drugs known to cause bradycardia.
If the combination medication causing bradycardia is identified and discontinued or its Dose, continue at the dose at which you previously returned to asymptomatic bradycardia or a heart rate of 60 bpm or greater.
If the combination of medications causing the above symptoms cannot be identified, or if the combination of medications causing the above symptoms cannot be discontinued. If the combination of drugs causing the above symptoms cannot be identified, or if the combination of drugs causing the above symptoms cannot be discontinued or the dose adjusted, wait until the patient’s bradycardia disappears or the heart rate returns to 60 bpm or more. Reduce150mgdose to restart treatment with this product. Bradycardiaa(Life-threatening consequences requiring urgent intervention)Permanently discontinue this product if a combination of medications causing bradycardia cannot be identified.
If the combination drug causing bradycardia is identified and discontinued or the dose is adjusted 60 bpmor more, when the patient’s bradycardia resolves or the heart rate returns to60 bpmor more, re-adjust to a dose lower than the pre-suspension dose 150 mg and closely monitoredb. HyperglycemiaPersistent hyperglycemia despite appropriate glucose-lowering therapy (>250 mg/dl)Suspend use of this product until blood glucose is adequately controlled, then lower 150 mgresume treatment with this product.
If blood glucose cannot be controlled at the desired level despite appropriate glucose-lowering therapy, discontinue this product permanently. Medical examLipase and amylase rose to2foldULNabove Suspend use of this product until lipase or amylase levels return to below 1.5 timesULN, reducing family:Times New Roman”>150mgResume treatment with this product. a
Heart rate below60 times (bpm)
b /sup>
Permanent discontinuation if relapse occurs again. Dose adjustment for potentCYP3Ainhibitors
Co-administration of potentinhibitors should be avoided during treatment with this productCYP3Ainhibitors. If a potentCYP3Ainhibitor must be used concurrently, the dose of ceritinib should be reduced by approximately one-third, rounded to the nearestinhibitor. span>150 mginteger multiple of the dose. Patient safety should be closely monitored. When the administration of a potentCYP3Ainhibitor is discontinued, the resumption of a potentCYP3Ainhibitor before the dosing of ceritinib.
Special Populations
Patients with kidney damage
There are no pharmacokinetic studies for patients with renal impairment No pharmacokinetic studies have been performed in patients with renal impairment. However, based on the available data, the elimination of this product through the kidney is negligible. Therefore, no dose adjustment is required in patients with mild to moderate renal insufficiency. This product should be used with caution in patients with severe renal insufficiency, as there is no experience with this population.
Patients with hepatic impairment
For patients with severe liver injury (Child-Pugh C), the dose should be adjusted downward by approximately one-third, rounded to the nearest150 mgdose Multiples of intensity. Mild (Child-Pugh A) or moderate (Child-Pugh B) patients with liver injury are not recommended for dose adjustment.
Dosing
This product should be administered orally once daily and at the same time each day with a meal. It can be taken with a regular meal or with a simple meal. Patients should swallow the capsule whole with water, not chewed or crushed.
[Adverse Reactions]
Safety profile overview
The following adverse drug reactions reflect 925 ALK-positive advanced NSCLC patients treated with a once-daily fasting oral dose of 750 mg NSCLC patients with exposure to ceritinib from 7 clinical studies, including 2 randomized, positive-controlled phase III studies [A2301 (ASCEND-4) and A2303 (ASCEND-5)]. The median exposure time for ceritinib 750 mg administered on an empty stomach was 44.9 weeks (range: 0.1 to 200.1 weeks). 62.2% of patients experienced dose down-titration and 74.8% experienced dose interruption. The incidence of adverse events leading to permanent discontinuation of treatment with this product was 12.1%. The most common adverse events (AEs) leading to discontinuation of therapy (>0.5%) were infectious pneumonia (0.6%) and respiratory failure (0.6%).
The drug-related adverse reactions (ADRs) with an incidence of ≥10% in patients given 750 mg on an empty stomach included diarrhea, nausea, vomiting, abnormal liver laboratory tests, fatigue abdominal pain, decreased appetite, weight loss, constipation, elevated blood creatinine, rash, anemia, and esophageal disease.
Grade 3/4 ADRs occurring in ≥5% of patients given 750 mg fasting included abnormal liver lab tests, fatigue, vomiting, hyperglycemia, nausea, and diarrhea.
In a dose optimization study A2112 (ASCEND-8) in previously treated and previously untreated patients with ALK-positive NSCLC,evaluated daily oral administration of ceritinib with a low-fat meal 450 mg or 600 mg relative to fasting administration750 mg in terms of systemic exposure, efficacy, and safety. Results showed that, with the exception of the gastrointestinal adverse effects described later, the overall safety profile of 450 mg (N=89) administered with food was consistent with fasting administration of 750 mg (N=90) while achieving comparable steady-state exposures. Compared with 750 mg fasting (diarrhea 76%, nausea 50%, vomiting 56%, Grade 3/4 adverse reactions reported by 12%), patients receiving 450 mg of this product with food had a reduced incidence and severity of gastrointestinal adverse drug reactions (diarrhea 56%, nausea 45%, vomiting 35%, Grade 3/4 adverse reactions reported by 1.1%). At least 1 adverse event requiring dose downward adjustment occurred in 10% of patients taking this product 450 mg with a meal, and at least 1 adverse event requiring interruption of dosing occurred in 42%. The median time to first dose down for any reason was 8weeks.
Summary of the list of adverse drug reactions in clinical trials
Table2Provides7 clinical studies in 750 mgdose Ceritinib-relatedN=925reported in patients treated with fasting dosing (N=925) font-family:Times New Roman”>ADRs occurred with frequency classification. For the frequency of selected gastrointestinal adverse reactions (diarrhea, nausea, vomiting), the frequency of once-daily dosing450 mgwith meal dose was also included The data for patients with N=89
According toMedDRAsystem organ classification listedADRs. Under each system organ classification, adverse drug reactions were ranked by frequency of occurrence, with the most common reactions ranked first. In addition, the corresponding frequency of each adverse drug reaction was classified based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100to<1/10); occasional (≥1/1000to 1/100); rare (≥1 /10000to 1/1000); very rare (1/10,000); unknown (cannot be estimated based on available data).
Table 2 Ceretinib-treated patients (N=925) with adverse drug reactions
Main System Organ ClassificationPreferred TerminologyAll levelsn (%)Frequency classification3/4level
n (%) Frequency classificationDiseases of the blood and lymphatic systemAnemia141 (15.2)very common28 (3.0)CommonMetabolic and Nutritional Disorders Loss of appetite =”padding-left: 7px; padding-right: 7px; border-top: none; border-left: none; border-bottom: solid 0.5pt; border-right: solid 0.5pt”>365 (39.5)very common20 (2.2)CommonHyperglycemia 87 (9.4)Common50 ( 5.4)CommonHypophosphatemia49 (5.3)Common21 (2.3) CommonOcular DiseasesVisual impairmentm65 (7.0) Common0 -Heart disease Pericarditish54 (5.8)Common24 (2.6)CommonBradycardiae21 (2.3)Common0
Medical ExamAbnormal liver lab testsb560 (60.5)very common347 (37.5)Very common Weight loss255 (27.6)very common26 (2.8)CommonElevated blood creatinine204 (22.1)Very common5 (0.5)occasionalECGQTinterval extension90 (9.7)Common19 (2.1)CommonElevated lipase44 (4.8)Common32 (3.5)CommonElevated amylase65 (7.0)Common29 (3.1)CommonaAbdominal pain includes the preferred terms (PT) abdominal pain, epigastric pain abdominal discomfort, epigastric discomfortb Abnormal liver laboratory tests include alanine aminotransferase elevated, elevated aspartate aminotransferase, elevated gamma glutamyl transferase, elevated blood bilirubin, elevated transaminases, elevated liver enzymes, abnormal liver function tests, elevated liver function test values, elevated blood alkaline phosphatasec Abnormal liver function tests include abnormal liver function, hyperbilirubinemia (PT)d Hepatotoxicity includes drug-related liver injury, cholestatic hepatitis, hepatocellular injury, hepatotoxicity (PT)eBradycardia includes bradycardia, sinus bradycardia (PT) fEsophageal disorders including dyspepsia, gastroesophageal reflux, dysphagia (PT) span style=”font-family:Arial”>)gFatigue includes tiredness, fatigue (PT)h Pericarditis includes pericardial effusion, pericarditis ( PT)i) family:Arial”>non-infectious pneumonia includes interstitial lung disease (ILD), non-infectious pneumonia (PT)jRashes include rashes, acne-like dermatitis, maculopapular rash (PT)k Renal failure includes acute kidney injury, renal failure (PT))lRenal damage including azotemia, damage (PT)mVisual impairment including impaired vision, blurred vision, flash hallucinations, vitreous fugacity, vision loss, dysregulation, presbyopia (PT)
nThese gastrointestinal adverse reactions included750 mgdose fasting (N=925) and 450mgdose with food (N=89) data from patients. The frequency of occurrence in front of the slash is based on patients with 750 mg doses administered on an empty stomach (N=925), the frequency of occurrence after the slash is based on A2112A2112(ASCEND-8) recommended dose in the study450mg food with (N=89) data from patients.
Special Populations
Senior population
In7 clinical studies In the 7 clinical studies, 168/925 cases (18.2%) of ceritinib-treated patients aged ≥65years. Safety characteristics among patients aged ≥65 years were similar to those among patients aged years. family:Times New Roman”>65 years of age were similar.
Adverse Reactions in Chinese Population- Safety of CLDK378A2109
A single-arm, multicenter study in ChinaA2109included103 patients previously treated with crizotinib and with or without chemotherapy (up to A maximum of 2lines of chemotherapy) were allowed for locally advanced or metastatic family:Times New Roman”>ALKpositiveNSCLCpatients. All patients started ceritinib treatment at 750 mgonce-daily fasting dose, with dose adjustment or suspension allowed for patients who could not tolerate the dosing schedule specified in the regimen. For patients who cannot tolerate the dosing schedule specified in the regimen, dose adjustment or suspension of dosing is allowed. The gradient of each dose downward adjustment is 150 mg, with a minimum maintenance dose of daily. “font-family:Times New Roman”>300 mg. The median duration of exposure as of the primary analysis date of the study was 7.06months ( =”font-family:Times New Roman”>0 to 18.8months),49 cases (47.6%) of patients had at least one dose reduction; among them15 patients had more than one dose reduction. The drug-related adverse reactions observed were similar to those found in other studies of ceritinib. See Table 3 for details.
Table3 A2109Observed in Ceritinib-treated patients in the study Incidence≥5% of adverse drug reactions (N=103, safety set)
Main System Organ Classification
Preferred TerminologyAll Levelsn (%)3/4level
n (%) Blood and lymphatic system disordersAnemia12 (11.7) 2 (1.9) Neurological Disorders Dizziness6 (5.8) 0 Gastrointestinal DisordersDiarrhea77 (74.8)3 (2.9) Nauseous55 (53.4) 0 Vomiting63 (61.2) 5 (4.9) epigastric pain29 (28.2) 1 (1.0) Loss of appetite26 (25.2) 1 ( 1.0) Abdominal pain20 (19.4) 1 (1.0) Abdominal discomfort 10 (9.7) 0 Bloating10 (9.7) 0 Dermal and subcutaneous tissue disordersRash9 (8.7) 0 Systemic disease and site condition of administration Fatigue