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. |
| Molecular Weight | 166.2 |
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 | Contraindicated due to teratogenicity (Valproate syndrome, neural tube defects). |
| 2nd trimester | Contraindicated due to continued risk of major malformations and neurodevelopmental delay. |
| 3rd trimester | Contraindicated due to risk of fetal hemorrhage, liver toxicity, and withdrawal syndrome. |
Clinical note
Comprehensive clinical and safety monograph for LORFAN (LORFAN).
| Placental transfer | Valproate readily crosses the placenta with cord blood levels exceeding maternal levels, leading to high fetal exposure and known teratogenic effects. |
| Breastfeeding | Valproate is excreted in breast milk at low concentrations (1-10% of maternal serum). However, due to potential hepatotoxicity and hematologic adverse effects in the infant, valproate is not recommended unless the benefit justifies the risk. Monitor infant for jaundice, bruising, and lethargy. |
■ FDA Black Box Warning
None.
| Serious Effects |
Pregnancy (unless no alternative for bipolar disorder)Active liver diseaseSevere hepatitis or family history of severe hepatitisKnown hypersensitivity to valproateUrea cycle disordersMitochondrial disorders (POLG mutations)
| 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. |
| Food/Dietary | Take on empty stomach with water only. Must follow a low-fat diet (<20% of total calories from fat) throughout treatment. Avoid grapefruit and grapefruit juice (CYP3A4 inhibition). Avoid alcohol due to hepatotoxicity risk. |
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| Lactation Rating | L4 (Possibly Hazardous) |
| 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. |
| 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. |
| Clinical Pearls | LORFAN (lomitapide) is a microsomal triglyceride transfer protein inhibitor used for homozygous familial hypercholesterolemia. Monitor hepatic function monthly due to risk of elevated transaminases and hepatic steatosis. Must be taken with a low-fat diet (<20% of calories from fat) to reduce gastrointestinal adverse effects. Concomitant use with strong CYP3A4 inhibitors is contraindicated. Dose adjustments needed with moderate CYP3A4 inhibitors. Administer with water only, no food, at least 2 hours after evening meal and 2 hours before next meal. |
| Patient Advice | Take lomitapide with a low-fat diet; avoid high-fat meals to reduce stomach side effects. · Take the medication with a glass of water only, at least 2 hours after your evening meal and 2 hours before your next meal. · Do not eat grapefruit or drink grapefruit juice while taking this medication. · Inform your doctor immediately if you experience yellowing of eyes/skin, dark urine, or abdominal pain. · You will need regular blood tests to check liver function; do not miss these appointments. · Avoid alcohol consumption during treatment. |