TAGRISSO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TAGRISSO (TAGRISSO).
Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR exon 19 deletion or L858R substitution mutations, as well as T790M resistance mutations, with lower activity against wild-type EGFR.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP3A5. Forms active metabolites (AZ7550 and AZ5104) that also inhibit EGFR. |
| Excretion | Primarily fecal (68%) as unchanged drug and metabolites; renal excretion accounts for 14% (mostly metabolites, less than 1% unchanged). |
| Half-life | 48 hours (terminal elimination half-life); steady-state reached by 15 days with repeated daily dosing. |
| Protein binding | 94% bound to plasma proteins (albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Approximately 1191 L (about 17 L/kg for a 70 kg adult); extensive extravascular distribution. |
| Bioavailability | Oral: approximately 70% (fasting); high-fat meal reduces absorption by about 14% (clinically minor). |
| Onset of Action | Oral: Peak plasma concentration at 6 hours; clinical response observed within 2–4 weeks. |
| Duration of Action | Approximately 48 hours; once-daily dosing maintains therapeutic concentrations; continuous administration required for sustained effect. |
| Action Class | Tyrosine kinase inhibitors |
80 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >= 30 mL/min. For GFR < 30 mL/min, no specific dosing recommendation; use with caution. |
| Liver impairment | No dose adjustment for Child-Pugh A or B. For Child-Pugh C, no recommendation; use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment required for elderly patients; age-related monitoring recommended. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TAGRISSO (TAGRISSO).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions in nursing infants (e.g., diarrhea, skin reactions), advise women not to breastfeed during therapy and for 2 weeks after last dose. M/P ratio unknown. |
| Teratogenic Risk | Based on mechanism of action (EGFR inhibitor), there is potential for fetal harm. Animal studies show embryo-fetal lethality and teratogenicity at exposures below human clinical exposure. In humans, no adequate studies; however, EGFR inhibition is known to be associated with fetal developmental toxicity. Risk cannot be excluded; use only if maternal benefit justifies fetal risk. First trimester exposure carries highest risk for major malformations. Second and third trimester exposure may impair fetal growth and renal function. |
■ FDA Black Box Warning
No boxed warning is included in the FDA-approved prescribing information for osimertinib.
| Serious Effects |
["None known based on FDA labeling."]
| Precautions | ["Interstitial lung disease (ILD)/pneumonitis: Fatal or serious cases reported; permanently discontinue if ILD confirmed.","QTc interval prolongation: Monitor electrolytes and ECG in patients with risk factors.","Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before and during treatment.","Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception."] |
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| Fetal Monitoring | Monitor pregnancy status prior to initiation in women of childbearing potential. Confirm negative pregnancy test before starting. During pregnancy, monitor fetal growth and amniotic fluid volume by ultrasound every 4-6 weeks. Assess for oligohydramnios if exposure occurs in second or third trimester. |
| Fertility Effects | Based on animal studies, may impair male and female fertility. In female rats, ovarian effects including reduced primordial follicle numbers and prolonged estrous cycles. In male rats, testicular degeneration and decreased sperm motility observed. Reversibility not established. |