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. |
| Molecular Weight | 499.62 |
| 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 | Based on animal studies and its mechanism of action (EGFR inhibition), there is potential for fetal harm. There are no adequate and well-controlled studies in pregnant women. Use only if potential benefit justifies risk to fetus. |
| 2nd trimester | Same as first trimester. EGFR inhibition during organogenesis and fetal development may cause adverse effects. Limited human data. |
| 3rd trimester | Same as first and second trimesters. Potential risk of oligohydramnios and fetal renal impairment due to EGFR inhibition. |
Clinical note
Comprehensive clinical and safety monograph for TAGRISSO (TAGRISSO).
| Placental transfer | Osimeritinib and its metabolites are likely to cross the placenta based on molecular weight (<500 Da) and preclinical studies showing embryofetal toxicity; degree of transfer in humans is unknown. |
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions (e.g., diarrhea, skin reactions) in nursing infants, advise women not to breastfeed during treatment and for 2 weeks after last dose. |
■ FDA Black Box Warning
No boxed warning is included in the FDA-approved prescribing information for osimertinib.
| Serious Effects |
None known based on labeling; absolute contraindications are not specified in prescribing information, but use is contraindicated in patients with known severe hypersensitivity to osimertinib or any excipients.
| 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. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase drug levels. Take on an empty stomach: no food for at least 2 hours before and 1 hour after dose. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| Clinical Pearls | Monitor for interstitial lung disease (ILD) symptoms, especially in first weeks; discontinue if ILD confirmed. Assess LVEF at baseline and periodically due to risk of reduced ejection fraction. Administer on empty stomach (no food 2h before and 1h after) to avoid variable absorption. Check for prolonged QTc interval, particularly in patients with electrolyte abnormalities or concurrent QTc-prolonging drugs. Dose reductions may be needed for adverse events; avoid concomitant strong CYP3A4 inducers or inhibitors. |
| Patient Advice | Take TAGRISSO on an empty stomach, at least 2 hours before or 1 hour after a meal. · Notify your doctor immediately if you develop new or worsening shortness of breath, cough, or fever, as these may be signs of lung inflammation. · Report signs of heart problems such as chest pain, rapid heartbeat, or swelling in the legs. · Inform your doctor if you experience severe diarrhea, skin reactions, or nail changes. · Avoid grapefruit and grapefruit juice while taking this medication. · Do not take St. John's wort or any other herbal supplements without consulting your doctor. · Use effective contraception during treatment and for 6 weeks after the last dose. |