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 is 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, DIG, 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 B1
|Adverse Event|| Treatment Emergent
| Treatment Related
| All Grades
| Grade 3/4
| All Grades
| Grade 3/4
|Vision Disorder2||163 (64%)||0||159 (62%)||0|
|Nausea||145 (57%)||2 ( < 1%)||136 (53%)||0|
|Diarrhea||124 (49%)||1 ( < 1%)||109 (43%)||0|
|Constipation||98 (38%)||2 ( < 1%)||69 (27%)||1 ( < 1%)|
|Esophageal Disorder3||51 (20%)||3 (1%)||29(11%)||0|
|Abdominal Pain4||40 (16%)||1 ( < 1%)||20 (8%)||0|
|Stomatitis5||27(11%)||1 ( < 1%)||15 (6%)||1 ( < 1%)|
|Edema6||97 (38%)||2 ( < 1%)||72 (28%)||0|
|Fatigue||80(31%)||6 (2%)||51 (20%)||4 (2%)|
|Chest Pain/Discomfort7||30 (12%)||1 ( < 1%)||3(1%)||0|
|Fever||30 (12%)||1 ( < 1%)||2 ( < 1%)||0|
|Infections and Infestations|
|Upper Respiratory Infection8||50 (20%)||1 ( < 1%)||4 (2%)||0|
|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|
|Arthralgia||29(11%)||3 (1%)||4 (2%)||0|
|Back Pain||28(11%)||0||2 ( < 1%)||0|
|Nervous System Disorders|
|Dizziness9||60 (24%)||0||42 (16%)||0|
|Neuropathy10||58 (23%)||1 ( < 1%)||34 (13%)||1 ( < 1%)|
|Headache||34 (13%)||1 ( < 1%)||10 (4%)||0|
|Dysgeusia||33 (13%)||0||30 (12%)||0|
|Insomnia||30 (12%)||0||8 (3%)||0|
|Dyspnea||57 (22%)||16 (6%)||5 (2%)||3(1%)|
|Cough||54(21%)||3 (1%)||9 (4%)||0|
|Rash||41 (16%)||0||25 (10%)||0|
|1 Study A used CTCAE v4.0, and Study B used CTCAE
2 Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual brightness, and visual acuity reduced.
3 Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer, gastroesophageal reflux, odynophagia, and reflux esophagitis.
4 Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness.
5 Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain, and stomatitis.
6 Includes edema, edema localized, and peripheral edema.
7 Includes chest pain, chest discomfort, and musculoskeletal chest pain.
8 Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection.
9 Includes balance disorder, dizziness, and presyncope.
10 Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensory neuropathy.
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. Consider ophthalmological evaluation, 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. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder [see PATIENT INFORMATION].
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 occurred in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2 in severity.
Complex renal cysts occurred in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases.
Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 5.2%, 0.4%, and 11.4% of patients, respectively.
Read the Xalkori (crizotinib) Side Effects Center for a complete guide to possible side effects »
Drugs That May Increase Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see CLINICAL PHARMACOLOGY]. Avoid concomitant use of strong CYP3 A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors.
Drugs That May Decrease Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong CYP3 A inducers decreases crizotinib plasma concentrations [see CLINICAL PHARMACOLOGY]. Avoid concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort.
Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
Crizotinib inhibits CYP3A both in vitro and in vivo [see CLINICAL PHARMACOLOGY]. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3 A. Avoid 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.
Last reviewed on RxList: 3/15/2012
This monograph has been modified to include the generic and brand name in many instances.
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