Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
XALKORI as monotherapy is indicated for:
Treatment with XALKORI should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
An accurate and validated assay for either ALK or ROS1 is necessary for the selection of patients for treatment with XALKORI (see section 5.1 for information on assays used in the clinical studies).
ALK-positive NSCLC, ROS1-positive NSCLC, ALK-positive ALCL or ALK-positive IMT status should be established prior to initiation of crizotinib therapy. Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised (see section 4.4).
The recommended dose schedule of crizotinib is 250 mg twice daily (500 mg daily) taken continuously.
The recommended starting dose schedule of crizotinib in paediatric patients is based on body surface area (BSA). The recommended dosage of crizotinib for paediatric patients with ALCL or IMT is 280 mg/m² orally twice daily until disease progression or unacceptable toxicity.
The recommended dosage for paediatric patients with BSA ≥1.34 m² is provided in Table 1. If needed, attain the desired dose by combining different strengths of crizotinib capsules.
Table 1. Paediatric patients with body surface area (BSA) ≥1.34 m²: Recommended crizotinib capsules* starting dosage:
| Body Surface Area (BSA)** | Dose (Twice Daily) | Total Daily Dose |
|---|---|---|
| 1.34 – 1.51 m² | 400 mg (2×200 mg capsule) | 800 mg |
| 1.52 – 1.69 m² | 450 mg (1×200 mg capsule + 1×250 mg capsule) | 900 mg |
| ≥1.70 m² | 500 mg (2×250 mg capsule) | 1000 mg |
* Refers to the XALKORI 200 mg and 250 mg hard capsules.
** For paediatric patients with BSA <1.34 m², refer to Table 2.
For paediatric patients with BSA <1.34 m², the granules in capsules for opening formulation of XALKORI should be used. The recommended dosage for paediatric patients with BSA <1.34 m² is provided in Table 2.
The granules are encapsulated into 3 dosage strengths: 20 mg, 50 mg and 150 mg crizotinib. If needed, attain the desired dose by combining different strengths of crizotinib granules in capsules for opening. No more than 4 capsules will be required for a single dose (see Table 2).
Table 2. Paediatric patients with body surface area (BSA) of 0.38 m² to 1.33 m²: Recommended crizotinib granules* starting dosage:
| Body Surface Area (BSA)** | Dose (Twice Daily) | Total Daily Dose |
|---|---|---|
| 0.38 to 0.46 m² | 120 mg (1 × 20 mg + 2 × 50 mg) | 240 mg |
| 0.47 to 0.51 m² | 140 mg (2× 20 mg + 2 × 50 mg) | 280 mg |
| 0.52 to 0.61 m² | 150 mg (1 × 150 mg) | 300 mg |
| 0.62 to 0.80 m² | 200 mg (1 × 50 mg + 1 × 150 mg) | 400 mg |
| 0.81 to 0.97 m² | 250 mg (2 × 50 mg + 1 × 150 mg) | 500 mg |
| 0.98 to 1.16 m² | 300 mg (2 × 150 mg) | 600 mg |
| 1.17 to 1.33 m² | 350 mg (1 × 50 mg + 2 × 150 mg) | 700 mg |
* Refers to the 20 mg, 50 mg and 150 mg crizotinib granules in capsules for opening.
** The recommended dosage for patients with a BSA less than 0.38 m² has not been established. For paediatric patients with BSA ≥1.34 m², refer to Table 1.
Administer crizotinib to paediatric patients under adult supervision.
Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.
In 1722 adult patients treated with crizotinib with either ALK-positive or ROS1-positive NSCLC across clinical studies, the most frequent adverse reactions (≥3%) associated with dosing interruptions were neutropenia, elevated transaminases, vomiting, and nausea. The most frequent adverse reactions (≥3%) associated with dose reductions were elevated transaminases and neutropenia. If dose reduction is necessary for patients treated with crizotinib 250 mg orally twice daily, then the dose of crizotinib should be reduced as below.
Dose reduction guidelines for haematological and non-haematological toxicities are provided in Tables 3 and 4. For patients treated with a lower dose of crizotinib than 250 mg twice daily, then follow the dose reduction guidelines provided in Tables 3 and 4 accordingly.
Table 3. Adult patients: XALKORI dose modification – haematological toxicitiesa,b:
| CTCAEc Grade | XALKORI treatment |
|---|---|
| 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 the next lower dosed,e |
a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
b For patients who develop neutropenia and leukopenia, see also sections 4.4 and 4.8.
c National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
d In case of recurrence, dosing should be withheld until recovery to Grade ≤2, then dosing should be resumed at 250 mg once daily. XALKORI must be permanently discontinued in case of further Grade 4 recurrence.
e For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation.
Table 4. Adult patients: XALKORI dose modification – non-haematological toxicities:
| CTCAEa Grade | XALKORI treatment |
|---|---|
| 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 250 mg once daily and escalate to 200 mg twice daily if clinically toleratedb,c |
| 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 haemolysis) | Permanently discontinue |
| Any Grade Interstitial lung disease (ILD)/pneumonitis | Withhold if ILD/pneumonitis is suspected, and permanently discontinue if treatment-related ILD/pneumonitis is diagnosedd |
| Grade 3 QTc prolongation | Withhold until recovery to Grade ≤1, check and if necessary correct electrolytes, then resume at the next lower doseb,c |
| Grade 4 QTc prolongation | Permanently discontinue |
| Grade 2, 3 Bradycardiad,e Symptomatic, may be severe and medically significant, medical intervention indicated | Withhold until recovery to Grade ≤1 or to heart rate 60 or above Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to Grade ≤1 or to heart rate 60 or above If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dosec upon recovery to Grade ≤1 or to heart rate 60 or above |
| Grade 4 Bradycardiad,e,f Life-threatening consequences, urgent intervention indicated | Permanently discontinue if no contributing concomitant medicinal product is identified If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at 250 mg once dailyc upon recovery to Grade ≤1 or to heart rate 60 or above, with frequent monitoring |
| Grade 4 Ocular disorder (Visual loss) | Discontinue during evaluation of severe vision loss |
a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events.
b XALKORI must be permanently discontinued in case of further Grade ≥3 recurrence. See sections 4.4 and 4.8.
c For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation.
d See sections 4.4 and 4.8.
e Heart rate less than 60 beats per minute (bpm).
f Permanently discontinue for recurrence.
If a dose reduction is necessary for paediatric patients treated at the recommended starting dose, then the dose of XALKORI for paediatric patients with BSA ≥1.34 m² should be reduced as shown in Table 5.
Table 5. Paediatric patients with body surface area (BSA) ≥1.34 m²: Recommended XALKORI capsules*dose reductions:
| Body Surface Area (BSA)** | First Dose Reduction | Second Dose Reduction*** | ||
|---|---|---|---|---|
| Dose (Twice daily*) | Total Daily Dose | Dose (Twice daily*) | Total Daily Dose | |
| 1.34 – 1.69 m² | 250 mg | 500 mg | 200 mg | 400 mg |
| ≥1.70 m² | 400 mg | 800 mg | 250 mg | 500 mg |
* Refers to the XALKORI 200 mg and 250 mg hard capsules.
** For paediatric patients with BSA <1.34 m², refer to Table 6.
*** Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions.
If a dose reduction is necessary for paediatric patients treated at the recommended starting dose, then the dose of XALKORI for paediatric patients with BSA <1.34 m² should be reduced as shown in Table 6.
Table 6. Paediatric patients with body surface area (BSA) of 0.38 m² to 1.33 m²: Recommended XALKORI granules* dose reductions:
| Body Surface Area (BSA)** | First Dose Reduction | Second Dose Reduction*** | ||
|---|---|---|---|---|
| Dose (Twice Daily) | Total Daily Dose | Dose (Twice Daily) | Total Daily Dose | |
| 0.38 to 0.46 m² | 90 mg (2 × 20 mg + 1 × 50 mg) | 180 mg | 70 mg (1 × 20 mg + 1 × 50 mg) | 140 mg |
| 0.47 to 0.51 m² | 100 mg (2 × 50 mg) | 200 mg | 80 mg (4 × 20 mg) | 160 mg |
| 0.52 to 0.61 m² | 120 mg (1 × 20 mg + 2 × 50 mg) | 240 mg | 90 mg (2 × 20 mg + 1 × 50 mg) | 180 mg |
| 0.62 to 0.80 m² | 150 mg (1 × 150 mg) | 300 mg | 120 mg (1 × 20 mg + 2 × 50 mg) | 240 mg |
| 0.81 to 0.97 m² | 200 mg (1 × 50 mg + 1 × 150 mg) | 400 mg | 150 mg (1 × 150 mg) | 300 mg |
| 0.98 to 1.16 m² | 220 mg (1 × 20 mg + 1 × 50 mg + 1 × 150 mg) | 440 mg | 170 mg (1 × 20 mg + 1 × 150 mg) | 340 mg |
| 1.17 to 1.33 m² | 250 mg (2 × 50 mg + 1 × 150 mg) | 500 mg | 200 mg (1 × 50 mg + 1 × 150 mg) | 400 mg |
* Refers to the 20 mg, 50 mg, and 150 mg crizotinib as granules in capsules for opening.
** For paediatric patients with BSA ≥1.34 m², refer to Table 5.
*** Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions.
Recommended dosage modifications for haematologic and non-haematologic adverse reactions for paediatric patients with ALK-positive ALCL or ALK-positive IMT are provided in Tables 7 and 8, respectively.
Table 7. Paediatric patients: XALKORI dosage modification for haematologic adverse reactions:
| CTCAEa Grade | XALKORI Dosing |
|---|---|
| Absolute Neutrophil Count (ANC) | |
| Grade 4 Neutrophil count decreased | First occurrence: Withhold until recovery to Grade ≤2, then resume at the next lower dosage. Second occurrence: • Permanently discontinue for recurrence complicated by febrile neutropenia or infection. • For uncomplicated Grade 4 neutropenia, either permanently discontinue, or withhold until recovery to Grade ≤2, then resume at the next lower dosage.b |
| Platelet Count | |
| Grade 3 platelet count decreased (with concurrent bleeding) | Withhold until recovery to Grade ≤2, then resume at the same dosage. |
| Grade 4 platelet count decreased | Withhold until recovery to Grade ≤2, then resume at the next lower dosage. Permanently discontinue for recurrence. |
| Grade 3 | Withhold until recovery to Grade ≤2, then resume at the same dosage. |
| Grade 4 | Withhold until recovery to Grade ≤2, then resume at the next lower dosage. Permanently discontinue for recurrence. |
a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
b Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated in Tables 5 and 6.
It is recommended to monitor complete blood counts, including differential counts, weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur.
Table 8. Paediatric patients: XALKORI dosage modification for non-haematologic adverse reactions:
| CTCAEa Grade | XALKORI Dosing |
|---|---|
| Grade 3 or 4 ALT or AST elevation with Grade ≤1 total bilirubin | Withhold until recovery to Grade ≤1, then resume at next lower dose. |
| 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 haemolysis) | Permanently discontinue. |
| Any Grade drug-related Interstitial lung disease/pneumonitis | Permanently discontinue. |
| Grade 3 QTc prolongation | Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage. |
| Grade 4 QTc prolongation | Permanently discontinue. |
| Grade 2, 3 Bradycardiab Symptomatic, may be severe and medically significant, medical intervention indicated | Withhold until recovery to a resting heart rate according to the patient’s age (based on the 2.5th percentile per age-specific norms) as follows: • 1 to <2 years: 91 bpm or above • 2 to 3 years: 82 bpm or above • 4 to 5 years: 72 bpm or above • 6 to 8 years: 64 bpm or above • >8 years: 60 bpm or above |
| Grade 4 Bradycardiab,c Life-threatening consequences, urgent intervention indicated | Permanently discontinue if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at the second dose reduction level in Table 5c upon recovery to Grade ≤1 or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring. |
| Grade 3 Nausea Inadequate oral intake for more than 3 days, medical intervention required | Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d |
| Grade 3, 4 Vomiting More than 6 episodes in 24 hours for more than 3 days, medical intervention required, i.e., tube feeding or hospitalisation; life-threatening consequences, urgent intervention indicated | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d |
| Grade 3, 4 Diarrhoea Increase of 7 or more stools per day over baseline, incontinence, hospitalisation indicated; life-threatening consequences, urgent intervention indicated | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d |
| Grade 1 (mild symptoms), 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living) Ocular disorder | Grade 1 or 2: Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders. |
| Grade 3, 4 Ocular disorder (visual loss, marked decrease in vision) | Grade 3 or 4: Withhold pending evaluation of severe visual loss. Permanently discontinue, if no other cause found on evaluation. |
a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
b Resting heart rate less than the 2.5th percentile per age-specific norms.
c Permanently discontinue for recurrence.
d Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions, unless otherwise indicated in Tables 5 and 6.
Crizotinib is extensively metabolised in the liver. Treatment with crizotinib should be used with caution in patients with hepatic impairment (see Tables 4 and 8, and sections 4.4, 4.8 and 5.2).
Based on the National Cancer Institute (NCI) classification, no starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST >Upper Limit of Normal (ULN) and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5 × ULN). The starting crizotinib dose for patients with moderate hepatic impairment (any AST and total bilirubin >1.5 × ULN and ≤3 × ULN) is recommended to be 200 mg twice daily. The starting crizotinib dose for patients with severe hepatic impairment (any AST and total bilirubin >3 × ULN) is recommended to be 250 mg once daily (see section 5.2). Crizotinib dose adjustment according to Child-Pugh classification has not been studied in patients with hepatic impairment.
Adjustments for paediatric patients are based on the clinical study conducted in adult patients (see section 5.2). No starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST >ULN and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5 × ULN). The recommended starting dose of crizotinib in patients with moderate hepatic impairment (any AST and total bilirubin >1.5 × ULN and ≤3 × ULN) is the first dose reduction based on BSA as shown in Tables 5 and 6. The recommended starting dose of crizotinib in patients with severe hepatic impairment (any AST and total bilirubin >3 × ULN) is the second dose reduction based on BSA as shown in Tables 5 and 6.
No starting dose adjustment is recommended for patients with mild (60 ≤creatinine clearance [CLcr] <90 mL/min) or moderate (30 ≤CLcr <60 mL/min) renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CLcr <30 mL/min). The crizotinib starting dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or haemodialysis. The dose may be increased to 200 mg twice daily based on individual safety and tolerability after at least 4 weeks of treatment (see sections 4.4 and 5.2).
Adjustments for paediatric patients are based on information in adult patients (see section 5.2). No starting dose adjustment is needed for patients with mild (60 ≤creatinine clearance [CLcr] <90 mL/min) or moderate (30 ≤CLcr <60 mL/min) renal impairment calculated using the Schwartz equation. The recommended starting dose of crizotinib in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis is the second dose reduction based on BSA as shown in Tables 5 and 6. The dose may be increased to the first dose reduction based on BSA as shown in Tables 5 and 6 and on individual safety and tolerability after at least 4 weeks of treatment.
No starting dose adjustment is required (see sections 5.1 and 5.2).
The safety and efficacy of crizotinib in paediatric patients with ALK-positive or ROS1-positive NSCLC have not been established. No data are available.
The safety and efficacy of crizotinib have been established in paediatric patients with relapsed or refractory systemic ALK-positive ALCL from 3 to <18 years of age or with unresectable, recurrent, or refractory ALK-positive IMT from 2 to <18 years of age (see sections 4.8 and 5.1). No safety or efficacy data are available for crizotinib treatment in ALK-positive ALCL paediatric patients below 3 years of age or ALK-positive IMT paediatric patients below 2 years of age.
For oral use.
XALKORI may be taken either after a meal or while fasted. The Xalkori granules should not be sprinkled on food. Grapefruit or grapefruit juice should be avoided since it may increase crizotinib plasma concentration. St. John’s wort should be avoided since it may decrease crizotinib plasma concentration (see section 4.5).
If a dose is missed, then it should be taken as soon as the patient or caregiver remembers unless it is less than 6 hours until the next scheduled 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.
The XALKORI 200 mg and 250 mg hard capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened.
The granules in capsules for opening should not be chewed, crushed or sprinkled on food. The capsule shell must not be swallowed but carefully be opened as follows:
If the entire prescribed dose of granules in capsules for opening cannot be taken at one time, then the granules in capsules for opening are to be administered in portions until the entire prescribed dose is given. Immediately after administration of each portion, a sufficient amount of water should be given to ensure that all medication is swallowed. After the medication has been swallowed, other liquids or foods can be ingested (except as noted in section 4.5, Agents that may increase crizotinib plasma concentrations).
Detailed pictograms on how to administer the granules in capsules for opening are provided in the Package Leaflet.
The use of antiemetics prior to and during treatment with crizotinib is recommended to prevent nausea and vomiting for paediatric patients with ALK-positive ALCL or ALK-positive IMT. Standard antiemetic and antidiarrhoeal agents are recommended to manage gastrointestinal toxicities. Supportive care such as intravenous or oral hydration, electrolyte supplementation and nutritional support are recommended as clinically indicated (see section 4.4).
Treatment of overdose with the medicinal product consists of general supportive measures. There is no antidote for XALKORI.
XALKORI 200 mg and 250 mg hard capsules:
4 years.
XALKORI 20 mg, 50 mg and 150 mg granules in capsules for opening:
2 years.
XALKORI 200 mg and 250 mg hard capsules:
This medicinal product does not require any special storage conditions.
XALKORI 20 mg, 50 mg and 150 mg granules in capsules for opening:
Store below 25°C.
XALKORI 200 mg and 250 mg hard capsules:
HDPE bottles with a polypropylene closure containing 60 hard capsules.
PVC-foil blisters containing 10 hard capsules.
Each carton contains 60 hard capsules.
Not all pack sizes may be marketed.
XALKORI 20 mg, 50 mg and 150 mg granules in capsules for opening:
XALKORI granules are supplied in high density polyethylene (HDPE) bottles with a polypropylene child-resistant (CR) closure and an aluminum foil/polyethylene heat induction seal containing 60 capsules for opening.
Any unused product or waste material, e.g., capsule shell from granules in capsule for opening formulation, should be disposed of in accordance with local requirements. The empty XALKORI granules capsule shell(s) should be discarded in the household waste.
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