LORBRENA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LORBRENA (LORBRENA).
LORBRENA (lorlatinib) is a potent, selective, brain-penetrant inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinases. It inhibits ALK phosphorylation and downstream signaling pathways (STAT3, PI3K/AKT, MAPK/ERK), and shows activity against most known ALK resistance mutations.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A4; minor contributions from CYP2C8, CYP2C19, CYP3A5, and CYP2D6. |
| Excretion | Primarily fecal (95%), with unchanged drug accounting for approximately 7% of the dose. Renal excretion is minimal (<1%). |
| Half-life | Terminal elimination half-life is approximately 24 hours (range 20-30 hours), supporting once-daily dosing. |
| Protein binding | 99.8% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 305 L (3.9 L/kg for a 78 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 81% (range 60-100%). |
| Onset of Action | Time to peak concentration (Tmax) is approximately 2 hours after oral administration. Clinical response (tumor regression) typically observed within 6-8 weeks. |
| Duration of Action | Duration of clinical effect is continuous with daily dosing. Steady-state achieved in approximately 5 days. |
100 mg orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >= 30 mL/min). For severe renal impairment (CrCl < 30 mL/min), reduce dose to 75 mg once daily. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). For moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, reduce dose to 75 mg once daily. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended based on age; monitor renal function and potential increased risk of adverse events. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LORBRENA (LORBRENA).
| Breastfeeding | No data are available on the presence of lorlatinib in human milk, its effects on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with LORBRENA and for at least 7 days after the final dose. M/P ratio unknown. |
| Teratogenic Risk | LORBRENA (lorlatinib) is an ALK inhibitor. Based on its mechanism of action and animal studies, it is expected to cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women. Animal studies demonstrated embryofetal toxicity including increased post-implantation loss, reduced fetal body weights, and external and visceral malformations at exposures below the clinical dose. Therefore, LORBRENA is contraindicated in pregnancy. If used during pregnancy or if patient becomes pregnant while taking this drug, apprise of potential hazard to fetus. |
■ FDA Black Box Warning
None
| Serious Effects |
["Concomitant use with strong CYP3A inducers","Concomitant use with strong CYP3A inhibitors"]
| Precautions | ["Hepatotoxicity: Elevations of AST, ALT, and bilirubin; monitor liver function tests.","Interstitial lung disease (ILD)/pneumonitis: Monitor for pulmonary symptoms; discontinue if ILD is suspected.","Hyperlipidemia: Monitor serum cholesterol and triglycerides; manage with lipid-lowering agents.","Central nervous system effects: Seizures, hallucinations, changes in cognitive function, mood disorders; monitor and manage.","Hypertension: Monitor blood pressure; manage with antihypertensive therapy.","AV block: PR interval prolongation; monitor ECG in patients with predisposing conditions.","Fetal harm: Can cause fetal harm; advise effective contraception.","Risk of hepatotoxicity with concomitant use of strong CYP3A inducers/ inhibitors."] |
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| Fetal Monitoring | Monitor complete blood counts for anemia, neutropenia, and thrombocytopenia. Monitor hepatic function (ALT, AST, bilirubin) monthly and as clinically indicated. Monitor serum uric acid levels for hyperuricemia. Monitor for hyperlipidemia (fasting serum cholesterol and triglycerides). Monitor for hypertension. Monitor for peripheral neuropathy and neurotoxicity (including CNS effects). Monitor for pneumonitis. In pregnant women, perform fetal ultrasound to assess for growth abnormalities and oligohydramnios if drug must be used (though contraindicated). |
| Fertility Effects | Fertility studies have not been conducted with lorlatinib. However, based on animal studies, LORBRENA may impair female fertility. In female rats, decreased corpora lutea and increased post-implantation loss were observed at doses ≥ 10 mg/kg (approximately 4.5 times the clinical AUC at the recommended human dose). Effects on male fertility have not been evaluated in animals. |