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XALKORI(crizotinib) Capsules, oral
XALKORI - crizotinib capsule
Pfizer Laboratories Div Pfizer Inc
克里唑蒂尼胶囊（XALKORI）辉瑞肺癌新药克里唑替尼获FDA批准上市
crizotinib（克里唑蒂尼胶囊、克里唑替尼、克卓替尼，商品名：XALKORI® ）是6年来美国FDA批准的第一个治疗肺癌的新药。ALK酪氨酸激酶抑制剂Crizotinib（克里唑蒂尼，商品名：XALKORI ®胶囊，辉瑞公司）的加速新药申请，用于治疗间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移性非小细胞肺癌（NSCLC）。
crizotinib（克里唑蒂尼胶囊，商品名：XALKORI® ）是6年来美国FDA批准的第一个治疗肺癌的新药，该药已获得了欧盟的举荐。据悉去年八月份，该药物已经获得美国药监局的批准并且已经上市销售。
上周五时，辉瑞制药公司表示，公司需要进行更多的试验，提供额外的试验数据来完整申请书。
欧盟的此次举荐对于辉瑞制药公司而言是极为有利的。一旦该药物获批上市销售，预计2017年可创下15亿美元的年度销售总额。
Xalkori药物(亦作crizotinib)适用于体内出现特定基因变异的非小细胞型肺癌晚期患者，患者在接受该药物治疗之前，需要进行一种诊断测试来判断哪些患者可以从这种药物中获益。
据悉，非小细胞肺癌患者中，有一部分患者已经出现了异常间变性淋巴瘤激酶基因(ALK)，一般而言，这种基因常出现于不抽烟人群中，4%的非小细胞肺癌患者都会存在ALK基因变异，但是在这类肺癌患者中，10%-15%的患者从未抽烟。
美国食品和药物管理局（FDA）2011年8月26日批准了ALK酪氨酸激酶抑制剂Crizotinib（克里唑蒂尼，商品名：XALKORI ®胶囊，辉瑞公司）的加速新药申请，用于治疗间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移性非小细胞肺癌（NSCLC）。同时还批准了雅培公司生产的Vysis ALK Break-Apart FISH检测试剂盒，使用该试剂盒检测ALK阳性的非小细胞肺癌患者批准采用克里唑蒂尼治疗。
克里唑蒂尼是全球首个口服间变型淋巴瘤激酶（ALK）抑制剂。克里唑蒂尼通过抑制ALK可以阻断一系列关键的肿瘤细胞生长存活的通路。对于ALK基因重排的患者，克里唑蒂尼显示出了显着的活性，并可延长生存期。
克里唑蒂尼的有效性和安全性经2项多中心单组临床试验验证，临床研究结果显示，83%的患者的肿瘤某种程度上得到了缩小，其中有54%的患者的肿瘤缩小达1/3或1/3以上。
克里唑蒂尼不良反应轻微，最常见的不良反应为视力障碍、恶心、腹泻、呕吐、水肿和便秘。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XALKORI® safely and effectively. See full prescribing information for XALKORI.
XALKORI® (crizotinib) Capsules, oral
Initial U.S. Approval: August 2011
INDICATIONS AND USAGE
XALKORI is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. (1) This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.
DOSAGE AND ADMINISTRATION
250 mg taken orally twice daily with or without food. (2.1)
Dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required based on individual safety and tolerability, then to 250 mg taken orally once daily if further reduction is necessary. (2.2)
DOSAGE FORMS AND STRENGTHS
XALKORI Capsules: 250 mg and 200 mg. (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Pneumonitis: Severe, including fatal, treatment-related pneumonitis has been observed. Monitor patients for pulmonary symptoms indicative of pneumonitis. Permanently discontinue in patients diagnosed with treatment-related pneumonitis. (5.1)
Hepatic Laboratory Abnormalities: Concurrent elevations in ALT and total bilirubin have occurred. Monitor monthly and as clinically indicated with more frequent testing in patients with Grade 2–4 elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. (5.2)
QT Interval Prolongation: In patients who have a history of or predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered. (5.3)
ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. (5.4)
Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman. (5.5, 8.1)
ADVERSE REACTIONS
The most common adverse reactions (≥25%) are vision disorder, nausea, diarrhea, vomiting, edema, and constipation. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors. (7.1)
CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers. (7.2)
CYP3A Substrates: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 09/2011
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FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
2.2 Dose Modification
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1 Pneumonitis
5.2 Hepatic Laboratory Abnormalities
5.3 QT Interval Prolongation
5.4 ALK Testing
5.5 Pregnancy
6. ADVERSE REACTIONS
7. DRUG INTERACTIONS
7.1 Drugs That May Increase Crizotinib Plasma Concentrations
7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Cardiac Electrophysiology
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14. CLINICAL STUDIES
16. HOW SUPPLIED/STORAGE AND HANDLING
17. PATIENT COUNSELING INFORMATION
17.1 Gastrointestinal Effects
17.2 Visual Effects
17.3 Effects on Ability to Drive and Use Machines
17.4 Concomitant Medications
17.5 Instructions for Taking XALKORI
17.6 Pregnancy and Nursing
17.7 FDA-Approved Patient Labeling
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FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.
2. DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy. Capsules should be swallowed whole. XALKORI may be taken with or without food. If a dose of XALKORI is missed, then it should be taken as soon as the patient remembers unless it is less than 6 hours until the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.
2.2 Dose Modification
Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose of XALKORI should be reduced to 200 mg taken orally twice daily. If further dose reduction is necessary, then reduce the dosage to 250 mg taken orally once daily based on individual safety and tolerability. Dose reduction guidelines for hematologic and non-hematologic toxicities are provided in Tables 1 and 2.
Table 1: XALKORI Dose Modification – Hematologic Toxicities*
|
CTCAE† Grade |
XALKORI Dosing |
|
|
|
Grade 3 |
Withhold until recovery to Grade ≤2, then resume at the same dose schedule |
|
Grade 4 |
Withhold until recovery to Grade ≤2, then resume at 200 mg twice daily‡ |
Table 2: XALKORI Dose Modification – Non-Hematologic Toxicities
|
CTCAE Grade |
XALKORI Dosing |
|
|
|
Grade 3 or 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation with Grade ≤1 total bilirubin |
Withhold until recovery to Grade ≤1 or baseline, then resume at 200 mg twice daily* |
|
Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or hemolysis) |
Permanently discontinue |
|
Any Grade pneumonitis† |
Permanently discontinue |
|
Grade 3 QTc prolongation |
Withhold until recovery to Grade ≤1, then resume at 200 mg twice daily* |
|
Grade 4 QTc prolongation |
Permanently discontinue |
Complete blood counts including differential white blood cell counts should be monitored monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. Liver function tests should be monitored monthly and as clinically indicated, with more frequent repeat testing if Grade 2, 3 or 4 abnormalities are observed.
3. DOSAGE FORMS AND STRENGTHS
250 mg capsules
Hard gelatin capsule, size 0, pink opaque cap and body, with "Pfizer" on the cap and "CRZ 250" on the body.
200 mg capsules
Hard gelatin capsule, size 1, white opaque body and pink opaque cap, with "Pfizer" on the cap and "CRZ 200" on the body.
4. CONTRAINDICATIONS
None
5. WARNINGS AND PRECAUTIONS
5.1 Pneumonitis
XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients diagnosed with treatment-related pneumonitis [see Dosage and Administration (2.2)].
5.2 Hepatic Laboratory Abnormalities
Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and in 4% of patients in Study B. Grade 3 and 4 elevations were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient from Study B (less than 1%) required permanent discontinuation from treatment. Concurrent elevations in ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN without elevated alkaline phosphatase were detected in 1/255 (less than 0.5%) of patients with available laboratory data across both studies. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevation in patients who develop transaminase elevations [see Dosage and Administration (2.2) and Adverse Reactions (6)].
5.3 QT Interval Prolongation
QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms (ECGs) and electrolytes should be considered. Permanently discontinue XALKORI in patients who develop Grade 4 QTc prolongation. Withhold XALKORI in patients who develop Grade 3 QTc prolongation until recovery to less than or equal to Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation, withhold XALKORI until recovery to less than or equal to Grade 1, then resume XALKORI at 250 mg once daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs [see Dosage and Administration (2.2) and Clinical Pharmacology (12.4)].
5.4 ALK Testing
Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI [see Clinical Studies (14)].
Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.
Refer to an FDA-approved test's package insert for instructions on the identification of patients eligible for treatment with XALKORI.
5.5 Pregnancy
XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to and above those observed in humans at the recommended clinical dose of 250 mg twice daily. There are no adequate and well-controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
6. ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In Studies A and B, patients with locally advanced or metastatic ALK-positive NSCLC received crizotinib 250 mg orally twice daily continuously. Among the 255 patients for whom data on Grade 1–4 adverse reactions are available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted greater than 2 weeks in 13% and 19% of patients in Studies A and B, respectively. Dose reductions occurred in 44% and 29% of patients in Studies A and B, respectively. The rates of treatment-related adverse events resulting in permanent discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3–4 adverse reactions in at least 4% of patients in both studies included ALT increased and neutropenia.
Among the 397 patients for whom information on deaths and serious adverse reactions are available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1), pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock, DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in greater than or equal to 2% of patients included pneumonia, dyspnea, and pulmonary embolism.
Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI.
Table 3: Adverse Reactions in ≥10% of Patients with Locally Advanced or Metastatic ALK-Positive NSCLC on Studies A and B*
|
Adverse Event |
Treatment Emergent
N=255 |
Treatment Related
N=255 |
|
|
All Grades
n (%) |
Grade 3/4
n (%) |
All Grades
n (%) |
Grade 3/4
n (%) |
|
|
|
Eye Disorders |
|
|
|
|
|
Vision Disorder† |
163 (64%) |
0 |
159 (62%) |
0 |
|
Gastrointestinal Disorders |
|
|
|
|
|
Nausea |
145 (57%) |
2 (<1%) |
136 (53%) |
0 |
|
Diarrhea |
124 (49%) |
1 (<1%) |
109 (43%) |
0 |
|
Vomiting |
116 (45%) |
3 (1%) |
101 (40%) |
0 |
|
Constipation |
98 (38%) |
2 (<1%) |
69 (27%) |
1 (<1%) |
|
Esophageal Disorder‡ |
51 (20%) |
3 (1%) |
29 (11%) |
0 |
|
Abdominal Pain§ |
40 (16%) |
1 (<1%) |
20 (8%) |
0 |
|
Stomatitis¶ |
27 (11%) |
1 (<1%) |
15 (6%) |
1 (<1%) |
|
General Disorders |
|
|
|
|
|
Edema# |
97 (38%) |
2 (<1%) |
72 (28%) |
0 |
|
Fatigue |
80 (31%) |
6 (2%) |
51 (20%) |
4 (2%) |
|
Chest Pain/DiscomfortÞ |
30 (12%) |
1 (<1%) |
3 (1%) |
0 |
|
Fever |
30 (12%) |
1 (<1%) |
2 (<1%) |
0 |
|
Infections and Infestations |
|
|
|
|
|
Upper Respiratory Infectionß |
50 (20%) |
1 (<1%) |
4 (2%) |
0 |
|
Investigations |
|
|
|
|
|
Alanine Aminotransferase Increased |
38 (15%) |
17 (7%) |
34 (13%) |
14 (5%) |
|
Aspartate Aminotransferase Increased |
29 (11%) |
7 (3%) |
24 (9%) |
5 (2%) |
|
Metabolism and Nutrition |
|
|
|
|
|
Decreased Appetite |
69 (27%) |
3 (1%) |
49 (19%) |
0 |
|
Musculoskeletal |
|
|
|
|
|
Arthralgia |
29 (11%) |
3 (1%) |
4 (2%) |
0 |
|
Back Pain |
28 (11%) |
0 |
2 (<1%) |
0 |
|
Nervous System Disorders |
|
|
|
|
|
Dizzinessà |
60 (24%) |
0 |
42 (16%) |
0 |
|
Neuropathyè |
58 (23%) |
1 (<1%) |
34 (13%) |
1 (<1%) |
|
Headache |
34 (13%) |
1 (<1%) |
10 (4%) |
0 |
|
Dysgeusia |
33 (13%) |
0 |
30 (12%) |
0 |
|
Psychiatric Disorders |
|
|
|
|
|
Insomnia |
30 (12%) |
0 |
8 (3%) |
0 |
|
Respiratory Disorders |
|
|
|
|
|
Dyspnea |
57 (22%) |
16 (6%) |
5 (2%) |
3 (1%) |
|
Cough |
54 (21%) |
3 (1%) |
9 (4%) |
0 |
|
Skin Disorders |
|
|
|
|
|
Rash |
41 (16%) |
0 |
25 (10%) |
0 |
Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks of drug administration. Ophthalmological eva luation should be considered, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Caution should be exercised when driving or operating machinery by patients who experience vision disorder [see Patient Counseling Information (17)].
Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%) patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were all Grade 1 or 2 in severity.
Bradycardia has been reported in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2 in severity.
Complex renal cysts have been reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases.
Laboratory Abnormalities
Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia were seen in 5.2%, 0.4%, and 11.4% of patients, respectively.
7. DRUG INTERACTIONS
7.1 Drugs That May Increase Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. The concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole, should be avoided. Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.
7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort, should be avoided.
7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see "Warnings and Precautions" (5.5)]
XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies of XALKORI in pregnant women. In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to and above those observed in humans at the recommended clinical dose of 250 mg twice daily. Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥ 50 mg/kg/day (approximately 1.2 times the AUC at the recommended human dose) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 5 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day (approximately 3 times the AUC at the recommended human dose), though fetal body weights were reduced at these doses.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
8.3 Nursing Mothers
It is not known whether XALKORI is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from XALKORI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 10 times the AUC in adult patients at the recommended human dose). Other toxicities of potential concern to pediatric patients have not been eva luated in juvenile animals.
8.5 Geriatric Use
Of the 119 patients in Study A, 16 (13%) were 65 years or older. Of the 136 patients in Study B, 19 (14%) were 65 years or older. No overall differences in s |
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