What Is Crizotinib?

Crizotinib capsules, crizotinib capsules can be used in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) positive as determined by a CFDA-approved test. ^[1] .

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Drug Name: Crizotinib capsules

Hanyu Pinyin: Kezuotini Jiaonang
Use classification: Small molecule targeted therapy

Crizotinib capsule ingredients

The main ingredient of this product is crizotinib and its chemical name is:
(R) -3- [1- (2,6-dichloro-3-fluoro-benzene) -ethoxy] -5- (1-piperidin-4-hydrocarbyl-1 hydrogen-pyrazole-4-hydrocarbyl ) -Pyrimidine-2-indane chemical structure:
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Molecular formula: C ₂₁ H ₂₂ C _l2 FN ₅ O
Molecular weight: 450.34 Dalton Name of excipients: silicon dioxide, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, magnesium stearate.

Crizotinib Capsules

This product is a capsule, the content is white to light yellow powder.

Crizotinib capsule indications

Crizotinib capsules can be used in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) positive as determined by a CFDA-approved test.

Crizotinib capsule specifications

(1) 250 mg; (2) 200 mg

Crizotinib capsules dosage

Patient Selection < br This product must be used in medical institutions with experience and under the guidance of specific professional and technical personnel. Before taking this product, you must obtain a positive evaluation of ALK confirmed by a fully validated test method.
Recommended dose < br The recommended dose of crizotinib is 250 mg orally, twice daily until the disease progresses or the patient cannot tolerate it. For patients with severe renal impairment who do not need dialysis (creatinine clearance <30ml / min), the recommended dose of crizotinib is 250 mg orally once daily. Capsules should be swallowed whole. Crizotinib can be taken with or without food. If you miss a dose of crizotinib, take the missed dose of the drug unless it is less than 6 hours from the next dose. If you vomit after taking the medicine, take the next dose at the normal time.
Dose adjustments < br If a patient has a Grade 3 or 4 adverse event as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version 4.0), dose reduction is required , Reduce the dose as follows:
· First dose reduction: oral, 200 mg, twice daily · Second dose reduction: oral, 250 mg, once daily · If 250 mg crizotinib is not tolerated once daily, then See Table 1 and Table 2 for guidelines on permanent dose reduction.
Table 1. Dose adjustments for crizotinib capsules-hematological toxicity *
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* Except for lymphopenia (unless accompanied by a clinical event, such as an opportunistic infection).
Table 2. Dose adjustment of crizotinib capsules-non-hematological toxicity http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201506110956120501.jpg
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Whole blood counts including white blood cell counts should be monitored monthly and at the time of clinical symptoms, and should be monitored more frequently in the presence of grade 3 or 4 abnormalities or fever or infection.
Patients with liver damage <br The use of crizotinib in patients with liver damage has not been studied. Because crizotinib is primarily metabolized in the liver, liver damage is likely to increase the plasma concentration of crizotinib. Therefore, patients with liver damage should be treated with caution when using crizotinib capsules. (See [Pharmacokinetics])
Patients with Renal Impairment Based on a population pharmacokinetic analysis, for patients with mild (Cr Patients do not need to make initial dose adjustments. In patients with severe kidney injury ([CLcr] less than 30 ml / min) who do not need dialysis, crizotinib exposure is increased. The recommended starting dose of crizotinib is 250 mg, orally once daily. (See "Special population" under [Pharmacokinetics])

Crizotinib adverse reactions

The following adverse reactions are discussed in more detail elsewhere in the description:
· Hepatotoxicity [see note].
· Interstitial lung disease / non-infectious pneumonia [see precautions]
· QT interval extended [see note]
Bradycardia [see note]
The safety data are mainly from more than 1,200 patients with ALK-positive metastatic non-small cell lung cancer who received crizotinib capsules as a single agent. The initial dose was 250 mg, taken orally, twice daily, and continuously administered. In study A8081005, A8081007, and A8081014, 252 Chinese patients were included.
Because the conditions of each clinical study are not the same, it is inappropriate to directly compare the incidence of adverse reactions between two drugs in different clinical studies. The incidence of adverse reactions in clinical studies may also be different from that in clinical practice.
The most common adverse reactions (25%) in crizotinib capsules were visual abnormalities, nausea, diarrhea, vomiting, constipation, edema, elevated transaminase, and fatigue.
ALK-positive metastatic non-small cell lung cancer-Study A8081007
The data in Table 3 are from a randomized, multicenter, active drug controlled, open trial (Study A8081007) of 343 patients with ALK-positive metastatic non-small cell lung cancer. Patients in the crizotinib capsule group (n = 172) received 250 mg of crizotinib orally,
Twice daily until disease progression is documented, intolerable treatment is not identified, or the investigator determines that the patient is no longer receiving clinical benefit. A total of 171 patients in the chemotherapy group received pemetrexed 500 mg / m ² (n = 99) or docetaxel 75 mg / m (n = 72), given by intravenous infusion, every three weeks Until documented disease progression, intolerable treatment, or researcher determines that the patient no longer receives clinical benefit. Patients in the chemotherapy group all received pemetrexed, unless they have received pemetrexed in first-line or maintenance therapy. The median study duration for patients receiving crizotinib capsules and receiving chemotherapy was 7.1 months and 2.8 months, respectively.
Serious adverse reactions were reported in 64 (37.2%) patients treated with crizotinib capsules and in 40 (23.4%) patients in the chemotherapy group. The most common serious adverse reactions reported by patients receiving crizotinib capsules were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and interstitial lung disease (ILD; 2.9%). Nine patients (5%) who received crizotinib capsules had fatal adverse reactions, including: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, non-infectious pneumonia, pulmonary embolism, ILD, Respiratory failure and sepsis.
In addition, current EU instructions ** also report that the most common adverse reactions that led to discontinuation were neutropenia (8%), elevated aminotransferase (8%), nausea (5%), and vomiting ( 3%).
Of the patients treated with crizotinib capsules, 16% needed dose reductions due to adverse reactions. The most common adverse reactions that led to a reduction in crizotinib capsules were elevated ALT (7.6%), and also included those accompanied by increased AST, prolonged QTc interval (2.9%), and decreased neutrophils (2.3%). patient.
Among patients receiving crizotinib, 17.0% discontinued treatment due to adverse reactions. The most common adverse reactions in patients discontinuing treatment with crizotinib capsules were ILD (1.7%), elevated ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in patients receiving crizotinib capsules.
Table 3. Incidence of adverse reactions reported in the crizotinib capsule group compared to the chemotherapy group in study A8081007 (5% for all grades, or 2% for grade 3/4)
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In patients receiving crizotinib capsules, other adverse reactions with an overall incidence between 1% and 30% include loss of appetite (27%), fatigue (27%), neuropathy (19%; dullness, stepping Dysfunction, hypoesthesia, muscle weakness, neuralgia, peripheral neuropathy, sensory disturbance, peripheral sensory neuropathy, polyneuropathy, skin burning sensation), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, non-infectious pneumonia), renal cysts (4%), and liver failure (1%).
Table 4. Abnormal summary of grade 3 or 4 laboratory test results in patients receiving crizotinib capsules after treatment (incidence rate 4%)
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Current EU instructions ** also report adverse reactions in the following A8081007 studies: gastrointestinal perforation (1%)-uncommon ( 1/1000 to <1/100); elevated serum alkaline phosphatase (8%) -Common ( 1/100 to <1/10).
A8081007 Safety information of Chinese subjects in the study (data as of March 30, 2012)
In study A8081007, 29 patients with ALK-positive metastatic non-small cell lung cancer (identified by the Vysis ALK Break-Apart FISH test) in China (including mainland China, Taiwan, and Hong Kong) were randomly assigned to receive crizotinib (12 patients, 250 mg orally twice daily) or chemotherapy (17 patients). As of March 30, 2012, 10 patients (9 received crizotinib and 1 received chemotherapy) are still under study. No unexpected safety-related findings were found in this small group. One patient receiving crizotinib and three patients receiving chemotherapy were discontinued due to treatment-related adverse events. The most common serious adverse reactions (30%) include diarrhea (67%), vomiting (67%), visual abnormalities * (50%), neutropenia * (50%), elevated aminotransferases * (42%) , Nausea (33%), cough * (33%), dizziness * (33%), anemia * (33%), stomatitis * (33%), hypoproteinemia (33%), and leukopenia (33 %).
ALK-positive metastatic non-small cell lung cancer-Study A8081005
The safety analysis population in Study A8081005 included 934 patients with ALK-positive metastatic non-small cell lung cancer who were treated with crizotinib in clinical trials. Their median duration of treatment was 23 weeks. Medication discontinuation and dose reduction were due to treatment-related adverse events in 23% and 12% of patients, respectively. Percent discontinuation due to treatment-related adverse events was 5%. The most common adverse reactions (25%) included visual abnormalities (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), and constipation (38%)
And tired (26%).
In addition, the current EU leaflet ** also reports the following adverse reactions: The most common grade 3 or 4 adverse reactions (> 3%) studied in A8081005 are neutropenia, elevated transaminase, and constipation.
A8081005 Safety information of Chinese subjects in the study (data as of November 30, 2013)
The safety analysis population in Study A8081005 included 234 patients with ALK-positive metastatic non-small cell lung cancer (identified by any type of ALK diagnostic test) from China (including mainland China, Taiwan, and Hong Kong) who had received clinical trials. Zotinib treatment (250 mg orally twice daily. By the deadline, 64 patients (27.4%) were still being studied. Their median duration of treatment was 42.1 weeks. There were 19.2% and 10.3% of patients, respectively Discontinuation and dose reduction due to treatment-related adverse events. Percent discontinuation of treatment due to treatment-related adverse events was 5.1%. The most common serious adverse reactions (30%) included elevated transaminase * (55%), and vomiting ( 54%), visual abnormalities * (50%), constipation (45%), diarrhea (44%), nausea (37%), leukopenia * (34%), loss of appetite (34%), edema * (32 %).
* Cluster terms (Because the frequency of certain specific medical concepts or situations may be underestimated by relying on a single MedDRA preferred term, some adverse events are analyzed using the US cluster term.)
Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics Study in Patients with Advanced Oncology A8081001
As indicated in the current EU instructions **, the safety analysis population in Study A8081001 included 149 patients treated with crizotinib. Their median duration of treatment was 43 weeks. The most common adverse reactions (25%) in study A8081001 included nausea, visual abnormalities, diarrhea, vomiting, edema, constipation, dizziness, fatigue, and loss of appetite.
Description of specific adverse drug reactions < br Visual abnormalities < br In clinical trials (n = 1225), 691 patients (56%) had visual abnormalities, the most common of which were visual impairment, flash illusion, and blurred vision Or vitreous mosquito. Most (99%) patients had grade 1 or 2 visual adverse reactions. In a clinical study, 1 patient had Grade 3 treatment-related visual abnormalities.
In addition, the current EU instructions ** report the following adverse reactions:
In study A8081007, study A8081001, and study A8081005, 103 (60%), 99 (66%), and 513 (55%) patients had all-causal visual abnormalities during treatment, the most common being visual impairment , Flash illusion, blurred vision and vitreous mosquito. Studies A8081007, A8081001, and A8081005 reported the events as mild (96%), moderate (3%), and severe (<1%), with median occurrence times of 5 days, 15 days, and 7 days, respectively. Study A8081007, A8081001, and Study A8081005 had temporary interruptions in treatment in 0, 1, and 4 patients, respectively. One patient in Study A8081007 and Study A8081005 each had a dose reduction due to visual abnormalities. None of the patients in studies A8081007, A8081001, and A8081005 required permanent discontinuation of crizotinib due to visual abnormalities. If visual abnormalities continue to appear or worsen, an eye examination should be considered (see [Precautions]).
According to the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in study A8081007 reported a higher incidence of visual disturbances than patients in the chemotherapy group. Visual abnormalities usually begin within the first week of medication. Most patients (> 50%) in the crizotinib capsule group in study A8081007 reported visual impairment; according to the results obtained in the patient questionnaire, the incidence of these visual impairments was 4-7 days per week, with a maximum duration of 1 Minutes, with little or no impact on daily life (scores 0-3, with a maximum score of 10).
Neuropathy < br Of the 1,225 patients, 235 (19%) developed neuropathy. The most common is actually sensory neuropathy. Most events (95%) had a severity of 1 or 2.
Current EU instructions also report that taste disorders are also a very common adverse event reported by these studies, with a severity of mainly Grade 1.
Renal cysts < br In study A8081007, renal cysts occurred in 7 (4%) and 1 (1%) patients in the crizotinib capsule treatment group and the chemotherapy group, respectively. Most renal cysts in patients treated with crizotinib capsules are complex renal cysts. Observed local cystic invasion and kidneys,
In some cases, imaging features indicate abscess formation. However, no microbiological testing in clinical trials confirmed renal abscesses.
In addition, the current EU instructions report that patients with renal cysts should be considered for regular monitoring through imaging and urinalysis.
Hepatotoxicity < br At present, lethal liver toxicity caused by drugs has occurred. It is found in less than 1% of patients receiving crizotinib in clinical studies. Less than 1% of patients in clinical studies observed an increase in ALT> 3 times ULN with total bilirubin> 2 times ULN without an increase in alkaline phosphatase.
In study A8081007, 17% of patients in the crizotinib-treated group observed elevations in grade 3 or 4 ALT, compared with 4% in the chemotherapy group. In study A8081001 and study A8081005, 7% and 8% of patients had grade 3 or 4 ALT elevations, respectively.
Elevated transaminase (ALT, AST) usually occurs during the first 2 months of treatment. In study A8081001, study A8081005, and study A8081007, the median time to a level 1 or 2 transaminase elevation was 22 to 26 days. The median time to a level 3 or 4 transaminase elevation is 30 to 43 days. Grade 3 and 4 elevations usually recover after interrupted dosing. In study A8081007, 8% of patients experienced reduced dose-related transaminase elevations, compared to 3% in study A8081001 and study A8081005. Of the patients participating in study A8081007, study A8081001, and study A8081005, 2 (1%), 1 (<1%), and 5 (<1%) patients required permanent discontinuation of this product.
This product should not be used in patients with severe liver damage (see [Contraindications]). Monitor liver function tests (including ALT, AST, and total bilirubin) once a week for the first 2 months of treatment, and then routinely and once a month when clinical indications occur. For Grade 2, 3, or 4 upgrades High, the inspection needs to be repeated more frequently.
Patients should be monitored and managed for liver toxicity according to the recommendations of [Usage and Dosage] and [Precautions].
Gastrointestinal effects < br Nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal events. The median duration of nausea and vomiting was 2 to 3 days. Most events were mild to moderate and decreased in frequency after 3 to 4 weeks of treatment. Supportive treatment should include the use of antiemetics. The severity of diarrhea and constipation is mainly mild to moderate. Supportive treatment for diarrhea and constipation should include the use of commonly used antidiarrheal and laxatives, respectively.
Gastrointestinal perforation events have been reported in clinical studies using crizotinib. During the post-marketing use of crizotinib capsules, there have been reports of fatal cases of gastrointestinal perforation (see [Precautions]).
QT interval prolongation < br In study A8081007 and study A8081005, the average change of QTcF (QT adjusted by Fridricia method) from baseline values of 8.3 ms and 8.7, respectively, on day 1 of treatment 1 and day 1 of treatment 2 ms (The upper limits of the 90% CI for both sides of QTcF are 13.1 ms and 10.2 ms, respectively, both less than 15 ms, so it is unlikely that QTc changes will have a clinical impact). In studies A8081007 and A8081005, 5 (3.4%) and 10 (1.1%) patients recorded QTcF 500 ms, respectively, and the patients with the highest increase in QTcF from baseline in these two studies 9 60 ms were 9 patients ( 6.3%) and 38 cases (4.3%). Study A8081007 reported 6 patients (3.5%) with an all-causal grade 3 or 4 ECG QT interval prolongation (see [Precautions] and [Pharmacokinetics]).
Prolonged QT interval can cause arrhythmias and is a risk factor for sudden death. The clinical manifestations of prolonged QT interval are bradycardia, dizziness, and syncope. Electrolyte disturbances, dehydration, and bradycardia can further increase the risk of prolonged QTc intervals, so patients with gastrointestinal toxicity are advised to regularly monitor ECG and electrolyte levels (see [Cautions]).
Bradycardia < br In study A8081007, study A8081001, and study A8081005, 8 (5%), 13 (9%), and 108 (10%) patients reported all-causal tachycardia during the treatment period slow.
Of the 170, 144, and 890 patients studied in A8081007, A8081001, and A8081005, 19 (11%), 26 (18%), and 90 (10%) patients had a heart rate of <50 bpm. Care should be taken to evaluate the combination of bradycardia-causing drugs. Patients with symptomatic bradycardia should be managed according to the recommendations in the "Dose Adjustment" and "Precautions" sections (see [Dosage and Administration] and [Precautions]).
Neutropenia and leukocytopenia < br In study A8081007, study A8081001, and study A8081005, 13%, 6%, and 11% of patients treated with crizotinib developed grade 3 or 4 neutrality, respectively. Granulocytopenia. The median time to occurrence of neutropenia at all levels was 43, 197, and 47 days, and the median time to occurrence of grade 3 or 4 neutropenia was 165, 197, and 64 days. Of the patients receiving study A8081007, study A8081001, and study A8081005 who were treated with crizotinib, 2%, 1%, and 3% of them had reduced doses due to neutropenia. Study <1% of patients in A8081005 due to neutropenia need to permanently discontinue treatment with this product. There were no permanent discontinuations in studies A8081001 and A8081007 due to neutropenia. Less than 1% of patients with crizotinib have developed febrile neutropenia in clinical studies.
In study A8081007 and study A8081005, 2% of patients each had grade 3 or 4 leukopenia; the proportion of such patients in study A8081001 was <1%. In Study A8081007, Study A8081001, and Study A8081005, the median time to occurrence of leukopenia at all levels was 64, 75, and 43 days; the median time to occurrence of grade 3 or 4 leukopenia was 373, 299, and 75 days, respectively. .
In study A8081007 and study A8081005, the incidence of leukocytopenia that led to reduced doses was <1%. Study A8081001 did not show dose reductions due to leukocytopenia. None of study A8081007, study A8081001, and study A8081005 were permanently discontinued due to leukopenia.
In study A8081007, patients had grade 3 or 4 reductions in leukocytes and neutrophils at a frequency of 5% and 13%, respectively. In study A8081001, patients had grade 3 or 4 reductions in leukocytes and neutrophils at a frequency of <3% and 8%, respectively. Study A8081005
In patients, grade 3 or 4 reductions in leukocytes and neutrophils occurred at a frequency of <3% and 8%, respectively.
Whole blood counts, including differential counts of white blood cells, should be monitored monthly and at the time of clinical indications and should be repeated more frequently if there is a grade 3 or 4 abnormality or fever or infection. For patients with abnormal hematology laboratory tests, please refer to [Dosage and Administration].
** It is important to note that because the statistical data selected by different review agencies (FDA and EMA) are calculated differently, the data in the US and EU instructions also show some differences.

Crizotinib contraindications

It is contraindicated in patients who are allergic to crizotinib or any of the ingredients in this product (see [Ingredients]-Excipient Name). Disabled in patients with severe liver damage (see [Precautions]).

Crizotinib Capsules

Evaluation of ALK-positive conditions <br brWhen evaluating whether a patient is ALK-positive, you must choose a fully validated and reliable method to avoid false negative or false-positive results.
Hepatotoxicity < br In three major clinical trials, two of the 1,225 patients treated with crizotinib (0.2%) experienced a fatal hepatotoxic reaction caused by the drug. Seven patients (0.6%) experienced an increase in ALT greater than three times the upper limit of normal, while total bilirubin increased more than two times the upper limit, and alkaline phosphatase was normal. In addition, 109 patients (9.2%) had an increase in ALT five times greater than the upper limit of normal. Eight patients (0.7%) required permanent discontinuation due to elevated transaminases. These laboratory results are usually asymptomatic and generally recover after interrupted dosing. Elevated aminotransferases usually occur within the first 2 months of treatment.
Liver function tests include ALT, AST and total bilirubin, which should be tested weekly during the first two months of treatment and monthly thereafter, and patients with elevated aminotransferase levels should be tested more frequently based on clinical status Elevated levels of transaminase, alkaline phosphatase, or total bilirubin. Temporarily suspend, reduce or permanently discontinue dosing according to the instructions in Table 2. (See [Usage and dosage] and [Adverse reactions])
In addition, the EU instructions ** report the following considerations:
In the randomized study A8081007, 17% of patients in the crizotinib-treated group observed elevations in grade 3 or 4 ALT, compared with 4% in the chemotherapy group. Elevation of grade 3 or 4 ALT was observed in 7% of patients in Study A8081001, while it was observed in 8% of patients in Study A8081005. After discontinuation of the dose, grade 3 and 4 elevations usually recover. Two patients (1%) in the randomized study A8081007, one patient (<1%) in the study A8081001, and five patients (<1%) in the study A8081005 required permanent discontinuation of treatment.
Interstitial lung disease (non-infectious pneumonia)
Patients receiving crizotinib capsules may develop severe, life-threatening or fatal interstitial lung disease (ILD) / non-infectious pneumonia. In clinical trials A8081007, A8081001, and A8081005 (n = 1225), 31 patients (2.5%) received crizotinib capsules with different levels of ILD, and 11 (0.9%) patients had grade 3 or 4 Grade ILD, 6 patients (0.5%) had fatal events. These events usually occur within the first 2 months after starting treatment.
The EU manual ** also states: When differential diagnosis of interstitial lung disease-like diseases (eg: non-infectious pneumonia, radiation pneumonia, allergic pneumonia, interstitial pneumonia, pulmonary fibrosis, acute respiratory distress syndrome [ARDS], alveoli Inflammation, pulmonary infiltration, pneumonia, pulmonary edema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, occlusive bronchitis, and bronchiectasis should be considered drug-induced interstitial lung disease / pneumonia.
Patients should be closely monitored for indicators of pulmonary symptoms of ILD / non-infectious pneumonia. And exclude other potential causes of ILD / non-infectious pneumonia. Once patients have treatment-related ILD / non-infectious pneumonia, treatment with crizotinib should be stopped permanently (see [Dosage and Administration] and [Adverse Reactions])
Prolonged QT interval <br Patients receiving crizotinib capsules may experience prolonged QTc interval (see [Dosage and Administration] and [Pharmacokinetics]), which can lead to ventricular tachycardia (such as twisted tip Type of ventricular tachycardia) or increased risk of sudden death. In clinical trials (n = 1225), 34 (2.7%) patients experienced prolonged QTc intervals (all levels), and 17 (1.4%) patients had QTc greater than 500 ms in at least 2 separate ECGs.
Patients with congenital long QT syndrome should avoid taking crizotinib capsules. For patients with congestive heart failure, bradyarrhythmias and electrolyte abnormalities, as well as patients who are taking antiarrhythmic drugs or other drugs known to cause QT interval prolongation, their ECG, electrolytes and kidneys should be monitored regularly when using this product Features. When taking this product, you should closely monitor ECG and electrolytes (such as calcium, magnesium, and potassium) before the first dose, and it is recommended to regularly monitor ECG and electrolytes, especially when vomiting, diarrhea, In cases of dehydration or impaired kidney function.
Patients with QTc greater than 500 ms or a change from baseline greater than or equal to 60 ms with torsional ventricular tachycardia, polymorphic ventricular tachycardia, or severe arrhythmia symptoms / signs should permanently discontinue crizotinib capsule. The advice of a cardiologist must be consulted immediately. Patients with QTc greater than 500 ms on at least 2 separate ECGs should suspend the use of crizotinib capsules until QTc is less than or equal to 480 ms, and then continue to reduce the dose as described in Table 2 (see [Dosage and Administration] and [ Pharmacokinetics) .
Bradycardia < br In the EU data sheet **, clinical studies report that 5% to 10% of patients treated with crizotinib develop all-causal bradycardia during treatment.
Patients receiving crizotinib capsules may experience symptomatic bradycardia (eg, syncope, dizziness, hypotension). Of the 1174 patients treated with crizotinib in different clinical trials, bradycardia and a heart rate of <50 beats / min were 11%. In Study A8081007, 2.9% of patients treated with XALKORI capsules developed grade 3 syncope, and patients receiving chemotherapy did not experience such events. EU instructions also report that crizotinib did not have a full impact on heart rate decline until a few weeks after starting treatment.
Try to avoid crizotinib and other drugs known to cause bradycardia (such as beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine And digoxin). Heart rate and blood pressure should be monitored regularly. If you experience symptomatic bradycardia that is not life-threatening, suspend the use of crizotinib until you return to asymptomatic bradycardia or a heart rate of 60 bpm or above. dose. If crizotinib causes life-threatening bradycardia, this drug should be permanently discontinued; if it is associated with a combination of medications known to cause bradycardia or hypotension, crizotinib should be suspended until it returns to no Symptomatic bradycardia or a heart rate of 60 bpm or above, if you can stop or adjust the combined dose, you can continue to use crizotinib capsules 250 mg once daily (see [Dosage and Administration] and Adverse reactions) .
Embryo toxicity < br According to the mechanism of action of crizotinib capsules, pregnant women may cause harm to the fetus after taking it. In non-clinical studies in rats, crizotinib capsules are embryotoxic and fetal toxic at exposures approximately equal to human clinically recommended doses (250 mg, twice daily). There are currently no adequate and well-controlled studies of crizotinib capsules in pregnant women. If taking crizotinib capsules during pregnancy, or if the patient becomes pregnant while taking the drug, the potential harm of the drug to the fetus should be informed (see [Medication for pregnant and lactating women]).
ALK test "Consensus for the diagnosis of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer" (2013 edition), "Chinese epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase fusion gene positive," published in June 2013 Guidelines for the diagnosis and treatment of non-small cell lung cancer
(2013 edition) recommends that there are currently three methods commonly used for ALK fusion gene detection: fluorescence in situ hybridization (FISH), technology based on polymerase chain reaction (PCR) amplification, and immune tissues for fusion protein expression Chemical method (IHC). According to the advantages and disadvantages of the current ALK fusion gene detection methods, the characteristics of clinical samples, and the conditions of the laboratory, a suitable detection method should be selected according to a reasonable detection process.
In the selection of patients treated with crizotinib, ALK-positive non-small cell lung cancer (NSCLC) must be diagnosed by a trained professional technician using a well-proven test. In clinical studies A8081005, A8081007, and A8081014, the ALK Gene Recombination Assay Kit (Fluorescent In Situ Hybridization) (Vysis ALK Break Apart FISHProbe Kit) was used. In China, Roche Diagnostics (Shanghai) Co., Ltd. Ventana anti-ALK Antibody Diagnostic Kit (Immunohistochemistry), Abbott Trading (Shanghai) Co., Ltd. ALK Recombination Detection Kit (Fluorescence In Situ Hybridization) and Xiamen Aide Biomedical Technology Co., Ltd.'s EML4-ALK fusion gene detection kit (fluorescent PCR method) has been approved by the CFDA for the detection of ALK fusion genes.
In addition, the following notes are reported in the EU instructions **:
Neutropenia and leukocytopenia grade 3 or 4 neutropenia are very common adverse events reported in the clinical studies of crizotinib (study A8081007, study A8081001, and study A8081005) (6% -13 %). Grade 3 or 4 leukopenia is a common adverse event (2%) (see [Adverse Reactions]). Less than 1% of patients with crizotinib have developed febrile neutropenia in clinical studies. A complete blood count including a differential count of white blood cells should be monitored every month and at the time of clinical indications. If there is a grade 3 or 4 abnormality or fever or infection, repeat the test more frequently (see [Dosage and Administration]).
Gastrointestinal Perforation < br Gastrointestinal perforation has been reported in clinical studies using crizotinib. There have been reports of fatal cases of gastrointestinal perforation during the use of Secori (see [Adverse Reactions]).
Patients at risk for gastrointestinal perforation (history of diverticulitis, tumor metastasis to the gastrointestinal tract, and concurrent use of drugs with a defined risk of gastrointestinal perforation) should be used with caution with crizotinib.
Crizotinib should be discontinued in patients with gastrointestinal perforation. Patients should be informed of the initial signs of gastrointestinal perforation and advised to seek medical attention promptly if gastrointestinal perforation occurs.
Visual effects < br The patients who participated in Study A8081007, Study A8081001, and Study A8081005 developed visual abnormalities. If visual abnormalities continue to appear or worsen, eye examinations (such as visual acuity, fundus examination, and slit lamp examination) should be considered (see [Adverse Reactions]).
Non-Adenocarcinoma NSCLC
Data on patients with ALK-positive NSCLC with non-adenocarcinoma components are limited.
** It is important to note that because the statistical data selected by different review agencies (FDA and EMA) are calculated differently, the data in the US and EU instructions also show some differences.

Crizotinib capsules for pregnant and lactating women

Pregnant women < br Based on the mechanism of action of crizotinib capsules, pregnant women may cause harm to the fetus. There are currently no adequate and well-controlled studies of crizotinib capsules in pregnant women. Embryotoxicity and fetal toxicity in non-clinical studies in rats when exposed to approximately human clinically recommended doses (250 mg, twice daily). Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects of the drug on embryo / fetal development. When rats were administered with 50 mg / kg / day (approximately 0.6 times the recommended human clinical dose based on the area under the curve), there was an increase in post-implantation abortion. When the dosage of rats reaches 200 mg / kg / day (based on the area under the curve, approximately 2.7 times the recommended human clinical dose) or the dosage of rabbits reaches 60 mg / kg / day (the area under the curve is approximately the recommended human clinical At 1.6 times the dose), the weight of the embryo was reduced, but no teratogenic effect was observed.
Women of childbearing age should avoid pregnancy when taking crizotinib capsules for treatment.
Women of childbearing age who are taking this medicine, or partners of women of childbearing age who are taking this medicine, should use appropriate methods for contraception during treatment and for at least 90 days after completion of treatment. If this medicine is taken during pregnancy, or if the patient or her partner becomes pregnant during the administration of this medicine, they should be informed that this medicine is potentially harmful to the fetus.
Breastfeeding women < br It is not clear whether crizotinib and its metabolites are secreted from milk. Because most drugs are usually secreted from breast milk, and potentially serious adverse reactions can occur if infants are exposed to crizotinib, it is important to decide whether to stop breastfeeding or stop taking medications during breastfeeding.

Crizotinib capsules for children

There are no data on the effectiveness and safety of crizotinib capsules in pediatric patients. The study found that after giving crizotinib 150 mg / kg / day to young rats once a day for 28 consecutive days (based on the area under the curve, approximately 5.4 times the recommended human clinical dose), bone formation was reduced during long bone growth. Other potential toxicities in pediatric patients have not been evaluated in young animals.

Crizotinib capsules for the elderly

Twenty-seven (16%) of patients treated with crizotinib in study A8081007 were 65 or older; 152 (16%) of patients in study A8081005 were 65 or older; in study A8081001, there were Sixteen patients (13%) were 65 years or older. There were no overall differences in safety or effectiveness between these patients and younger patients.

Crizotinib capsule drug interactions

Drugs that may increase crizotinib blood concentration Combination of crizotinib with a strong CYP3A inhibitor may lead to an increase in crizotinib blood concentration (see [Pharmacokinetics]). Concomitant use of the following strong inhibitors of CYP3A (including but not limited to): atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, rivar Tonavir, saquinavir, clarithromycin, telithromycin, aceandromycin, and voriconazole. Grapefruit or grapefruit juice may also increase the blood concentration of crizotinib and should be avoided at the same time. Caution should be used in combination with moderate CYP3A inhibitors.
Drugs that may lower the blood concentration of crizotinib Combination of crizotinib with a strong inducer of CYP3A may cause a decrease in the blood concentration of crizotinib (see [Pharmacokinetics]). Concomitant use of the following strong CYP3A inducers (including but not limited to): carbamazepine, phenobarbital, phenytoin, rifampicin, rifampin, and St. John's wort.
Crizotinib is a drug that may change its blood concentration. Crozotinib can inhibit CYP3A in vivo or in vitro (see [Pharmacokinetics]). Patients taking crizotinib should avoid CYP3A substrates with a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, Quinidine, sirolimus, and tacrolimus). If patients taking crizotinib need to use these CYP3A substrates with a narrow therapeutic index, the dose of CYP3A substrates may need to be reduced because the combination of drugs can cause adverse reactions.

Crizotinib capsule overdose

There are no known cases of overdose of crizotinib capsules. There is currently no antidote for crizotinib capsules.

Crizotinib capsule clinical trial

Randomized Controlled Study-Study A8081007
A randomized, multicenter, open, active drug controlled study (A8081007) demonstrated the efficacy and safety of crizotinib capsules as a single drug in 347 patients with ALK-positive metastatic non-small cell lung cancer. In this study, patients had previously been treated with a platinum-containing chemotherapy regimen. The primary outcome was progression-free survival (PFS) as determined by independent radiological evaluation (IRR). Other outcomes include objective response rate (ORR) and overall survival (OS) as assessed by independent imaging.
Patients were randomly assigned to receive crizotinib (250 mg orally, twice daily) (n = 173) or chemotherapy (n = 174). Chemotherapy includes pemetrexed 500 mg / m 2 (if not previously treated with pemetrexed; n = 99) or docetaxel 75 mg / m 2 (n = 72), intravenous (IV), 21 ECOG 0-12EGFR ALK FDA Vysis ALK Break-Apart FISH
56%50 ECOG 0 39%1 52% 52%45%4%33%63%95%93%
A8081007 112 64%5 1
5. ALK - http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201506111024450847.jpg
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201506111025260114.jpg
A8081007 2012 3 30
A8081007 29 ALK Vysis ALK Break-Apart FISH 12 250 mg17 5.6 95% CI: 2.9, 8.51.5 95% CI: 1.3,4.00.0795% CI: 0.01, 0.52P 0.00068 66.7% 6 2 15 88.2% 141 PFS 4 33.3%0 0%P 0.001975%95% CI: 43%, 95%6%95% CI: 0.1%,29%24.1 5.6
-A8081005 A8081001
A8081005 A8081001ALK RECIST250 mg
A8081005 n=934 57% 52 ECOG 0/1 82%2/3 18%52%44%4%30%66%92%94%
A8081005 934 ALK 765 Vysis ALK Break-Apart FISHALK 5.5 8357 48%95% CI44%51%11.0
A8081005 2013 11 30
A8081005 209 ALK Vysis ALK Break-Apart FISH 250 mg 2 96 47% 95% CI: 40%,54%36.0 157 75.1%PFS 131 26 6.9 95% CI: 5.5, 8.3 31 14.8%
A8081001 n=119 50% 51 ECOG 0 35%1 53%62%29%1%27%72%96%98%13%
A8081001 119 ALK 32 61%95% CI52%70%11.1
2
A8081014 III 250 mg BID //ALK NSCLC 334 11 A B //
in.2015 4
A8081029 III ALK NSCLC // Patients were enrolled from China, Taiwan, Hong Kong, Thailand and Malaysia.200 11A B //150 50 2015 4
ALK NSCLC CFDA

ALK HGFR c-Met ROS1 c-cosRONALK ALK ALK ROS1c-Met EML4-ALK NPM-ALK c-Met
 Ames
28 >50
mg/kg/AUC 1.7 3 500 mg/kg/AUC 10

4~6 250 mg 154.8200~300 mg Cmin AUC
250 mg 43%32%~66%AUC inf C max 14%
 50 mg Vss1772
91%P-P-gp-1
 CYP3A4/5 O-O-
 42
250 mg 63%22%53%2.3%
250 mg CL/F60 / 250mg100 /CYP3A
CYP3A 150 mgCYP3A 200 mgAUC infC max 3.2 1.4 CYP3A
CYP3A 250 mgCYP3A 600 mgAUC inf C max 82%69%CYP3A
PH 5 40 mg 250 mg AUC _inf10%Cmax
CYP3A 250 mg28 AUC inf 3.7 CYP3A

CYP CYP1A2CYP2C8CYP2C9CYP2C19 CYP2D6
CYP2B6 CYP2B6
CYP1A2CYP2B6CYP2C8CYP2C9CYP2C19 CYP3A
UGT UGT1A1UGT1A4UGT1A6UGT1A9UGT2B7
 P-P-gp P-
1OCT12OCT2OCT1 OCT2
OATP1B1 OATP1B3 OAT1 OAT3
 BSEP
 Because crizotinib is primarily metabolized in the liver, liver damage is likely to increase the plasma concentration of crizotinib.AST ALT>2.5 >5.0 >1.5 Therefore, patients with liver damage should be treated with caution when using crizotinib capsules.A8081007A8081005 A8081001 0.1 2.1 mg/dLAST 7 124 U/L
A8081007A8081005A8081001 [CLcr]60 89 ml/N=433[CLcr]30 59 ml/N=1377 CLcr<30 ml /8 [CLcr] 90 ml/250 mg AUC inf C max 79%34% AUC _infCmax
N=523N=691
A8081007A8081005 A8081001
A8081007A8081005 A8081001
 250 mgQT QT 1167 16 1.4%QTcF500 msFridericia QT 1136 514.4%QTcF 60 ms/QTcF

30°C

1HDPE 14 /28 /60 /
2PVC 10 /30 /60 /

36 months

JX20120233