XALKORI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XALKORI (XALKORI).
Selective tyrosine kinase inhibitor targeting ALK, ROS1, and MET, inhibiting downstream signaling pathways (PI3K/AKT, MAPK/ERK) leading to reduced tumor cell proliferation and survival.
| Metabolism | Primarily via CYP3A4/5; forms inactive metabolites. Active parent drug accounts for >50% of total exposure. |
| Excretion | Primarily hepatic metabolism, with 53% of the dose recovered in feces (mostly as metabolites) and 22% in urine (1.1% unchanged). |
| Half-life | Terminal elimination half-life is approximately 72 hours (range 47-108 hours) in patients, supporting once-daily dosing. |
| Protein binding | 91% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Apparent Vd is approximately 2200 L (or ~32 L/kg for a 70 kg patient), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is 43% (range 32-56%) under fasting conditions; increased by 85% with a high-fat meal (avoid coadministration). |
| Onset of Action | Oral: ~2 weeks for initial clinical response; maximum effect may require several weeks. |
| Duration of Action | Sustained for 8-12 hours post-dose; continuous inhibition of ALK and c-Met receptors requires regular twice-daily dosing, but half-life allows steady-state within 15 days. |
| Molecular Weight | 450.34 |
250 mg orally twice daily.
| Dosage form | CAPSULE |
| Renal impairment | For severe renal impairment (CrCl <30 mL/min), reduce dose to 200 mg orally twice daily. |
| Liver impairment | For Child-Pugh A: no adjustment. For Child-Pugh B: reduce dose to 200 mg orally twice daily. For Child-Pugh C: reduce dose to 200 mg orally twice daily; further reduce to 150 mg orally twice daily if not tolerated. |
| Pediatric use | For age ≥1 year: 230 mg/m2 orally twice daily. Maximum dose: 250 mg orally twice daily. |
| Geriatric use | No specific dose adjustment required; monitor renal function and consider dose reduction if CrCl <30 mL/min. |
| 1st trimester | There are no adequate and well-controlled studies in pregnant women. Based on animal studies, crizotinib can cause fetal harm when administered to a pregnant woman. Animal studies at exposures below the recommended human dose resulted in embryofetal toxicity including fetal malformations (e.g., abnormal heart development) and increased post-implantation loss. Therefore, crizotinib is contraindicated in the first trimester unless the potential benefit justifies the potential risk to the fetus. |
| 2nd trimester | Crizotinib is not recommended during the second trimester unless absolutely necessary. Animal studies show embryofetal toxicity and teratogenicity. If used, women of childbearing potential should be advised to avoid pregnancy and use adequate contraception. |
| 3rd trimester | Use in the third trimester is not recommended. There is a potential risk of fetal harm based on animal data. If treatment is necessary, close monitoring of fetal development is advised. |
Clinical note
Comprehensive clinical and safety monograph for XALKORI (XALKORI).
| Placental transfer | Based on animal studies, crizotinib crosses the placenta and is transferred to the fetus. There is evidence of embryofetal toxicity at maternal exposures below the recommended human dose. In rats, crizotinib was detected in fetal plasma, indicating placental transfer. |
■ FDA Black Box Warning
Risk of severe, life-threatening hepatotoxicity; monitor liver function tests before and during treatment.
| Serious Effects |
Hypersensitivity to crizotinib or any of its excipientsPregnancy (based on animal reproductive toxicity)
| Precautions | Hepatotoxicity: elevated transaminases, bilirubin, and drug-induced liver injury; fatal cases reported., Interstitial lung disease/pneumonitis: monitor for pulmonary symptoms; discontinue if confirmed., QT prolongation: avoid in congenital long QT syndrome; monitor electrolytes and ECG., Bradycardia: monitor heart rate, especially in combination with other bradycardic agents., Vision disorders: include vitreous floaters, photopsia, and blurred vision; evaluate ophthalmologically., Fetal harm: can cause fetal harm; advise effective contraception. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase crizotinib levels and risk of toxicity. No other significant food interactions identified, but take consistently with or without food. |
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| Breastfeeding | It is not known whether crizotinib 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 crizotinib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. It is recommended to avoid breastfeeding during treatment and for 45 days after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Based on animal studies and its mechanism of action (ALK inhibitor), crizotinib is expected to cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, crizotinib was embryotoxic and fetotoxic at maternal exposures below the recommended human dose. The risk is present throughout all trimesters. Use effective contraception during treatment and for at least 45 days after the last dose in females of reproductive potential and for at least 90 days after the last dose in males with female partners of reproductive potential. |
| Fetal Monitoring | Monitor pregnant women for pregnancy-related complications due to potential fetal harm. Perform pregnancy testing in females of reproductive potential prior to initiating treatment. Monitor for signs of hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, and bradycardia during pregnancy as these adverse reactions may be exacerbated. Consider fetal monitoring (ultrasound) to assess for growth abnormalities if exposure occurs. |
| Fertility Effects | Based on animal studies, crizotinib may impair fertility in males and females. In female rats, crizotinib caused disruption of estrous cycles and reduced fertility at exposures similar to human exposure. In male rats, crizotinib caused decreased sperm motility, count, and increased abnormal sperm morphology, leading to reduced fertility. The effects on human fertility are unknown. |
| Clinical Pearls | Monitor liver function tests (ALT, AST, bilirubin) monthly for first 3 months, then periodically; dose reduction or interruption may be required for hepatotoxicity. Use with caution in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease on dialysis, as crizotinib exposure is increased. Crizotinib is a moderate CYP3A inhibitor; avoid concomitant use with sensitive CYP3A substrates (e.g., midazolam, triazolam) or CYP3A substrates with narrow therapeutic index (e.g., cyclosporine, fentanyl). For non-small cell lung cancer (NSCLC), confirm ALK or ROS1 rearrangement via FDA-approved test before initiation. QTc prolongation possible; monitor ECG and electrolytes in patients at risk. Advise patients to avoid grapefruit juice during treatment. |
| Patient Advice | Take XALKORI exactly as prescribed, with or without food. Do not crush or chew capsules. · Avoid grapefruit juice and products containing grapefruit while on this medication. · Report symptoms of liver problems: yellowing of skin/eyes, dark urine, abdominal pain, or unusual bleeding/bruising. · Common side effects include vision changes (blurred vision, floaters, light sensitivity), nausea, diarrhea, constipation, and swelling in hands/feet. · Use effective contraception during treatment and for at least 45 days after the last dose if female, or 90 days if male. · Inform your doctor if you have a history of heart problems, especially QTc prolongation or arrhythmias. · Do not change dose or stop without consulting your healthcare provider. |