OSIMERTINIB MESYLATE
Clinical safety rating
cautionComprehensive clinical and safety monograph for OSIMERTINIB MESYLATE (OSIMERTINIB MESYLATE).
Comprehensive clinical and safety monograph for OSIMERTINIB MESYLATE (OSIMERTINIB MESYLATE).
FDA-approved: Adjuvant therapy after tumor resection in patients with EGFR exon 19 deletions or exon 21 L858R mutations; first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations; metastatic NSCLC with EGFR T790M mutation after progression on EGFR TKI therapy.Off-label: Treatment of leptomeningeal carcinomatosis from EGFR-mutant NSCLC.
Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that selectively inhibits EGFR exon 19 deletion and L858R substitution mutations, as well as T790M resistance mutations, with less activity against wild-type EGFR.
| Metabolism | Metabolized primarily by CYP3A4; minor contributions from CYP3A5 and CYP1A1. Forms active metabolites (AZ5104 and AZ7550) that contribute to clinical activity. |
| Excretion | Osimertinib is eliminated primarily via feces (67.8%, with 1.2% as unchanged drug) and urine (13.8%, with 0.8% as unchanged drug). The remainder is recovered as metabolites. |
| Half-life | Terminal elimination half-life is approximately 48 hours (range 36-60 h) based on population pharmacokinetic analysis, supporting once-daily dosing. |
| Protein binding | Approximately 95% bound to human plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 956 L, suggesting extensive tissue distribution. Not expressed per kg, but corresponds to a very large Vd (approximately 13.7 L/kg for a 70 kg person). |
| Bioavailability | Oral bioavailability is estimated to be approximately 70% based on mass balance and absorption studies. Absorption is unaffected by food. |
| Onset of Action | Clinical effect (tumor response) typically observed after 6-8 weeks of daily oral dosing, although pharmacodynamic changes (EGFR phosphorylation inhibition) occur within hours. |
| Duration of Action | Duration of action is sustained throughout the 24-hour dosing interval due to long half-life. Median progression-free survival is approximately 18.9 months in first-line setting (FLAURA trial). |
| Molecular Weight | 499.61 |
80 mg orally once daily, with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >=15 mL/min; insufficient data for GFR <15 mL/min or dialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: 80 mg once daily; Child-Pugh C: not recommended due to lack of data. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; clinical studies included patients >=65 years with no overall differences in safety or efficacy. |
| 1st trimester | Avoid use in first trimester. Human data are limited but animal studies have shown teratogenicity including skeletal abnormalities and fetal death. Use only if maternal benefit outweighs fetal risk. |
| 2nd trimester | Avoid use in second trimester. May cause fetal harm based on mechanism of action (EGFR inhibition) and animal data. Use only if clearly needed. |
| 3rd trimester | Avoid use in third trimester. Potential for oligohydramnios, fetal renal impairment, and neonatal respiratory depression. Use only if maternal benefit outweighs fetal risk. |
Clinical note
Comprehensive clinical and safety monograph for OSIMERTINIB MESYLATE (OSIMERTINIB MESYLATE).
| Placental transfer | Osimertinib crosses the placenta. Human data are limited, but based on molecular weight and animal studies, significant transfer is expected. |
| Breastfeeding | Osimertinib and its metabolites are excreted in human milk. Due to potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment and for 2 weeks after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Based on its mechanism of action (EGFR tyrosine kinase inhibition) and animal studies, osimertinib is expected to cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib was embryotoxic and teratogenic at exposures below the recommended human dose. First trimester exposure poses the highest risk for major malformations. Second and third trimester exposure may cause fetal growth retardation and oligohydramnios. Use is contraindicated in pregnancy unless no alternative therapy exists. |
| Fetal Monitoring | Women of reproductive potential should undergo pregnancy testing prior to initiation of therapy. During pregnancy, monitor fetal growth by ultrasound for growth restriction and amniotic fluid volume. Additionally, monitor liver function tests, serum creatinine, and electrolytes monthly. Assess for interstitial lung disease (ILD) symptoms (cough, dyspnea) and dermatologic toxicities (rash, dry skin). |
| Fertility Effects | Osimertinib may impair fertility in females based on animal studies showing reduced fertility and embryonic loss. However, no specific human data are available. Men should consider sperm preservation prior to therapy as osimertinib may affect spermatogenesis (based on animal data). Reversibility after discontinuation is unknown. |
■ FDA Black Box Warning
Black Box Warning: Interstitial lung disease (ILD)/pneumonitis, which can be fatal. Monitor for new or worsening respiratory symptoms. Withhold or permanently discontinue based on severity.
| Serious Effects |
Hypersensitivity to osimertinib or any excipients
| Precautions | Interstitial lung disease (ILD)/pneumonitis: Monitor pulmonary symptoms; withhold or permanently discontinue based on severity., QTc interval prolongation: Monitor electrolytes and ECG in patients with risk factors; withhold or permanently discontinue for QTc >500 ms., Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before and during treatment; withhold for symptomatic congestive heart failure., Keratitis: Evaluate for signs of keratitis, especially in patients with prior ocular conditions., Fetal harm: Can cause fetal harm; advise females of reproductive potential of effective contraception during and for 6 weeks after treatment., Embryo-fetal toxicity: Verify pregnancy status before initiation. |
| Food/Dietary | Avoid grapefruit and grapefruit juice, Seville oranges, and star fruit due to potential CYP3A4 inhibition. No other dietary restrictions. |
| Clinical Pearls | Osimertinib is a third-generation EGFR-TKI selective for both sensitizing and T790M resistance mutations. Monitor for interstitial lung disease (ILD) and QTc prolongation. Dose reduction or interruption may be needed for adverse reactions. Avoid concurrent use with strong CYP3A4 inducers. |
| Patient Advice | Take exactly as prescribed, once daily with or without food. · Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit during treatment. · Report new or worsening respiratory symptoms (cough, dyspnea, fever) immediately. · Notify your doctor if you experience palpitations, dizziness, or fainting (QT prolongation risk). · Use effective contraception during treatment and for 6 weeks after the last dose. · Breastfeeding is not recommended while on this medication. |
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