Dosing & Uses
Dosage Forms & Strengths
tablet
- 40mg
- 80mg
Non-Small Cell Lung Cancer
Adjuvant therapy
- Indicated as adjuvant therapy after tumor resection for non-small cell lung cancer (NSCLC) in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations
- 80 mg PO qDay
- Continue until disease recurrence, or unacceptable toxicity, or for up to 3 years
First-line treatment for metastatic NSCLC
- Indicated for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations
- 80 mg PO qDay
- Continue until disease progression or unacceptable toxicity, or for up to 3 years
Previously treated metastatic NSCLC
- Indicated for metastatic EGFR T790M mutation-positive NSCLC in patients whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy
- 80 mg PO qDay
- Continue until disease progression or unacceptable toxicity, or for up to 3 years
Dosage Modifications
Pulmonary adverse effects
- Interstitial lung disease/pneumonitis: Permanently discontinue
Cardiac adverse effects
QTc interval >500 msec on at least 2 separate ECGs: Withhold until QTc interval <481 msec or recovery to baseline if baseline QTc is ≥481 msec, then resume at 40 mg dose
Permanently discontinue
- QTc interval prolongation with signs/symptoms of life-threatening arrhythmia
- Symptomatic congestive heart failure
Other adverse effects
- Grade ≥3: Withhold for up to 3 weeks
- If improvement to Grade ≤2 within 3 weeks: Resume at 80 mg or 40 mg qDay
- If no improvement within 3 weeks: Permanently discontinue
Cutaneous adverse effects
- Stevens Johnson syndrome (SJS), erythema multiforme major (EMM): Withhold if suspected and permanently discontinue if confirmed
CYP3A4 inducers
- Moderate and/or weak CYP3A inducers: No dose adjustments required
-
Strong CYP3A4 inducers
- Avoid coadministration
- If coadministration is unavoidable, increase osimertinib to 160 mg/day when used with a strong CYP3A inducer
- Resume osimertinib at 80 mg 3 weeks after discontinuing the strong CYP3A4 inducer
Renal impairment
- Mild-to-moderate (CrCl 15-89 mL/min): No dosage adjustment necessary
- End-stage renal disease (CrCl <15 mL/min): No recommended dose
Hepatic impairment
- Mild-to-moderate (Child-Pugh A and B or total bilirubin ≤3x ULN and any AST): No dose adjustment necessary
- Severe (total bilirubin 3-10x ULN and any AST): No recommended dose
Dosing Considerations
Patient selection
First-line treatment of metastatic EGFR-positive NSCLC: Confirm presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens
Metastatic EGFR T790M mutation-positive NSCLC: Confirm presence of T790M mutation in tumor specimens prior to initiating treatment
Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics
Safety and efficacy not established
No overall differences in effectiveness were observed based on age
Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent dose modifications for adverse reactions (13.4% versus 7.6%) in patients ≥65 years as compared to those <65 year
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
Adverse drug reactions listed are all grades of severity unless listed otherwise
>10%
Lymphopenia (63%)
Thrombocytopenia (46%)
Anemia (43%)
Diarrhea (41%)
Rash (34%)
Neutropenia (27%)
Hypermagnesemia (27%)
Hyponatremia (26%)
Dry skin (23%)
Nail toxicity (22%)
Fatigue (22%)
Hypoglycemia (20%)
Eye disorders (18%)
Decreased appetite (18%)
Cough (17%)
Nausea (16%)
Stomatitis (15%)
Constipation (14%)
Pruritus (14%)
Vomiting (11%)
1-10%
Back pain (10%)
Headache (10%)
Hypokalemia (9%)
Lymphopenia, Grade 3 or 4 (8.2%)
Venous thromboembolism (7%)
Pneumonia (4%)
Interstitial lung disease/pneumonitis (3.3%)
QTc increased from baseline >60 msec (2.7%)
Neutropenia, Grade 3 or 4 (2.2%)
Hyponatremia, Grade 3 or 4 (1.8%)
Hypomagnesemia, Grade 3 or 4 (1.8%)
Hypokalemia, Grade 3 or 4 (1.8%)
Fatigue, Grade 3 or 4 (1.8%)
Cardiomyopathy (1.4%)
Diarrhea, Grade 3 or 4 (1.1%)
Decreased appetite, Grade 3 or 4 (1.1%)
<1%
Keratitis
Nausea
Vomiting
Rash
Back pain
Thrombocytopenia
Postmarketing Reports
Erythema multiforme and Stevens-Johnson syndrome, cutaneous vasculitis
Warnings
Contraindications
None
Cautions
Interstitial lung disease (ILD)/pneumonitis reported; permanently discontinue if diagnosed with ILD/pneumonitis
May prolong QTc interval; monitor ECG and electrolytes in patients with a history or predisposition for QTc prolongation or in those who are taking medications that are known to prolong the QTc interval
Cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred, some fatal; assess LVEF before treatment and then every 3 months thereafter
Keratitis reported; promptly refer patients with signs and symptoms suggestive of keratitis (eg, eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, red eye) to an ophthalmologist
May cause fetal harm
Postmarketing cases consistent with SJS and EMM reported
Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported
Drug interaction overview
- Osimertinib is a CYP3A4 substrate; a P-gp and BCRP inhibitor
-
CYP3A4 inducers
- Avoid use; if concurrent use is unavoidable, increase osimertinib dose
- Coadministration with a strong CYP3A4 inducer decreased osimertinib systemic exposure
-
BCRP and P-gp substrates
- Monitor for adverse effects of BCRP and P-gp substrates
- Coadministration with a BCRP or P-gp substrate increased exposure and risk of toxicities of BCRP or P-gp substrate
-
Drugs that prolong QTC interval
- Avoid use; if unavoidable, monitor ECG periodically
- Effects of coadministration with QT prolonging drugs is unknown
Pregnancy & Lactation
Pregnancy
Based on data from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females
No data available in humans
Animal data
- Administration to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5x the exposure at the recommended human dose
Infertility
- Based on animal studies, may impair fertility in females and males of reproductive potential
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 6 weeks after final dose
- Males with female partners of reproductive potential: Use effective contraception during and for 4 months following final dose
Lactation
Unknown if distributed in human breast milk
Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death
Advise lactating women not to breastfeed during treatment and for 2 weeks after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at ~9-fold lower concentrations than wild-type
Absorption
Peak plasma time: 6 hr
Distribution
Protein bound: 95%
Vd, steady-state: 918 L
Metabolism
Main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro
Metabolites: Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating at approximately 10% of the parent) with similar inhibitory profiles to osimertinib have been identified
Elimination
Half-life: 48 hr
Clearance: 14.3 L/hr
Excretion: 68% (feces); 14% (urine); ~2% (unchanged osimertinib)
Administration
Oral Administration
Administer with or without food
Missed dose: Do not make up the missed dose and take the next dose as scheduled
Administration to patients with swallowing difficulty
- Disperse tablet in 4 tablespoons of noncarbonated water only
- Stir until tablet is completely dispersed and swallow or administer through nasogastric tube immediately
- Do not crush, heat, or ultrasonicate during preparation
- Rinse the container with 4-8 ounces of water and immediately drink
Nasogastric tube administration
- Disperse tablet as above in 15 mL of noncarbonated water, then use an additional 15 mL of water to transfer any residues to the syringe; administer resulting 30 mL liquid as per the nasogastric tube instructions with appropriate water flushes (~30 mL)
Storage
Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
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Patient Handout
Formulary
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