May 27, 2016
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Xalkori

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Xalkori




Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Clinical Trials Experience

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 clinical practice.

The data in the WARNINGS AND PRECAUTIONS section reflect exposure to XALKORI in 1719 patients who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154) [see WARNINGS AND PRECAUTIONS].

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions ( ≥ 25%) of XALKORI are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1

The data in Table 3 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m²in combination with cisplatin 75 mg/m²(n=91) or carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 or 6 mg min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 58 patients (34%) treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.

Dose reductions due to adverse reactions were required in 6.4% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8.2%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 3: Adverse Reactions Reported at a Higher Incidence ( ≥ 5% Higher for All Grades or ≥ 2% Higher for Grades 3-4) with XALKORI than Chemotherapy in Study 1†

Adverse Reaction XALKORI
(N=171)
Chemotherapy (Pemetrexed/ Cisplatin or Pemetrexed/ Carboplatin)
(N=169)
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Cardiac Disorders
  Electrocardiogram QT prolonged 6 2 2 0
  Bradycardiaa 14 1 1 0
Eye Disorders
  Vision disorderb 71 1 10 0
Gastrointestinal Disorders
  Vomiting 46 2 36 3
  Diarrhea 61 2 13 1
  Constipation 43 2 30 0
  Dyspepsia 14 0 2 0
  Dysphagia 10 1 2 1
  Abdominal painc 26 0 12 0
General Disorders and Administration Site Conditions
  Edemad 49 1 12 1
  Pyrexia 19 0 11 1
Infections and Infestations
  Upper respiratory infectione 32 0 12 1
Investigations
  Increased weight 8 1 2 0
Musculoskeletal and Connective Tissue Disorders
  Pain in extremity 16 0 7 0
  Muscle spasm 8 0 2 1
Nervous System Disorders
  Dizzinessf 18 0 10 1
  Dysgeusia 26 0 5 0
  Headache 22 1 15 0
†Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases reported within the clustered terms:
a Bradycardia (Bradycardia, Sinus bradycardia).
b Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).
c Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).
d Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
e Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
f Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; which included gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), and syncope (1%).

Table 4: Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥ 4% in XALKORI-Treated Patients in Study 1

Laboratory Abnormality XALKORI Chemotherapy
Any Grade (%) Grade 3-4(%) Any Grade (%) Grade 3-4(%)
Hematology
  Neutropenia 52 11 59 16
  Lymphopenia 48 7 53 13
Chemistry
  ALT elevation 79 15 33 2
  AST elevation 66 8 28 1
  Hypophosphatemia 32 10 21 6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2

The data in Table 5 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m²(n=99) or docetaxel 75 mg/m²(n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.

The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.

Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were ALT elevation (7.6%) including some patients with concurrent AST elevation, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 5: Adverse Reactions Reported at a Higher Incidence ( ≥ 5% Higher for All Grades or ≥ 2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 2†

Adverse Reaction XALKORI
(N=172)
Chemotherapy (Pemetrexed or Docetaxel)
(N=171)
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Nervous System Disorders
  Dizzinessa 22 1 8 0
  Dysgeusia 26 0 9 0
  Syncope 3 3 0 0
Eye Disorders
  Vision disorderb 60 0 9 0
Cardiac Disorders
  Electrocardiogram QT prolonged 5 3 0 0
  Bradycardiac 5 0 0 0
Investigations
  Decreased weight 10 1 4 0
Gastrointestinal Disorders
  Vomiting 47 1 18 0
  Nausea 55 1 37 1
  Diarrhea 60 0 19 1
  Constipation 42 2 23 0
  Dyspepsia 8 0 3 0
Infections and Infestations
  Upper respiratory infectiond 26 0 13 1
Respiratory, Thoracic and Mediastinal Disorders
  Pulmonary embolisme 6 5 2 2
General Disorders and Administration Site Conditions
  Edemaf 31 0 16 0
†Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases reported within the clustered terms:
a Dizziness (Balance disorder, Dizziness, Postural dizziness).
b Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
c Bradycardia (Bradycardia, Sinus bradycardia).
d Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
e Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
f Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).

Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).

Table 6: Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥ 4% in XALKORI-Treated Patients in Study 2

Laboratory Abnormality XALKORI Chemotherapy
Any Grade (%) Grade 3-4 (%) Any Grade (%) Grade 3-4 (%)
Hematology
  Neutropenia 49 12 28 12
  Lymphopenia 51 9 60 25
Chemistry
  ALT elevation 76 17 38 4
  AST elevation 61 9 33 0
  Hypokalemia 18 4 10 1
  Hypophosphatemia 28 5 25 6

ROS1-Positive Metastatic NSCLC - Study 3

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description Of Selected Adverse Drug Reactions

Vision Disorders

Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 1084 (63.1%) of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) patients with Grade 4 visual impairment.

Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 ( > 50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in the VSAQ-ALK questionnaire.

Neuropathy

Neuropathy, most commonly sensory in nature, occurred in 435 (25%) of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal Cysts

Renal cysts were experienced by 52 (3%) of 1719 patients.

The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.

Read the Xalkori (crizotinib) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Drugs That May Increase Crizotinib Plasma Concentrations

Coadministration of crizotinib with strong cytochrome P450 (CYP) 3A inhibitors increases crizotinib plasma concentrations [see CLINICAL PHARMACOLOGY]. Avoid concomitant use of strong CYP3A 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 CYP3A inducers decreases crizotinib plasma concentrations [see CLINICAL PHARMACOLOGY]. Avoid concomitant 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]. Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Read the Xalkori Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/9/2016

Side Effects
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