LORFAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LORFAN (LORFAN).
Lorlatinib is an ATP-competitive inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinases. It inhibits phosphorylation of ALK and ROS1, leading to apoptosis and cell cycle arrest.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A4. Lorlatinib is a substrate of P-glycoprotein. |
| Excretion | Primarily renal excretion (90-95% as unchanged drug); minimal biliary/fecal elimination (<5%). |
| Half-life | Terminal elimination half-life is 2-3 hours in adults with normal renal function; prolonged in renal impairment (up to 20 hours in severe impairment). |
| Protein binding | Approximately 20-30% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | 2.0-3.0 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Subcutaneous: approximately 80-100%; intramuscular: approximately 80%; intravenous: 100%. |
| Onset of Action | Intravenous: 1-2 minutes; subcutaneous: within 10-15 minutes. |
| Duration of Action | Duration of opioid reversal is 1-3 hours, depending on dose and opioid half-life; may be shorter than opioid duration, requiring repeat dosing or infusion. |
12 mg orally three times daily; titrate to 24 mg twice daily after 14 days based on response and tolerability.
| Dosage form | INJECTABLE |
| Renal impairment | No adjustment required for GFR ≥ 30 mL/min; avoid use if GFR < 30 mL/min. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce to 12 mg once daily; Child-Pugh Class C: not recommended. |
| Pediatric use | Not established for age < 18 years. |
| Geriatric use | No specific dose adjustment; monitor renal function and tolerability closely due to age-related decline in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LORFAN (LORFAN).
| Breastfeeding | No human data on lorlatinib in breast milk. Animal studies show excretion in rat milk. M/P ratio unknown. Due to potential for serious adverse reactions in nursing infants, advise not to breastfeed during treatment and for at least 11 days after last dose. |
| Teratogenic Risk | Lorlatinib is embryotoxic and fetotoxic in animal studies. In pregnant rats, malformations (including cardiovascular and skeletal) and fetal growth restriction observed at maternal exposures below human AUC. No human data. Avoid in pregnancy; if used, advise effective contraception. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Concomitant use of strong CYP3A4 inducers","Concomitant use of strong CYP3A4 inhibitors (avoid, or reduce dose if unavoidable)"]
| Precautions | ["Hepatotoxicity: Monitor liver enzymes monthly for first 3 months, then periodically.","Interstitial lung disease/pneumonitis: Withhold and evaluate.","Hyperlipidemia: Monitor serum cholesterol and triglycerides; manage with lipid-lowering agents.","CNS effects: Including seizure, hallucinations, cognitive impairment; dose adjust or withhold.","AV block: Monitor ECG; withhold in second- or third-degree AV block.","Fetal harm: Can cause fetal harm; advise effective contraception."] |
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| Fetal Monitoring |
| Pregnancy test before initiation. Monitor liver function tests (ALT, AST, bilirubin) monthly. Monitor for hyperlipidemia (fasting serum lipids) regularly. Monitor for CNS effects (seizures, hallucinations, cognitive changes). Fetal ultrasound if exposure occurs. |
| Fertility Effects | Lorlatinib may impair fertility in males and females. In animal studies, testicular degeneration and reduced sperm counts observed. In females, disrupted estrous cycle and reduced fertility. Advise fertility preservation before treatment. |