Dosing & Uses
Dosage Forms & Strengths
tablet
- 40mg
- 80mg
Non-Small Cell Lung Cancer
Indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
Also indicated for metastatic EGFR T790M mutation positive NSCLC, as detected by an FDA approved test, in patients who have progressed on or after EGFR TKI therapy
80 mg PO qDay; continue until disease progression or unacceptable toxicity
Dosage Modifications
Renal impairment
- Mild-to-moderate (CrCl 15-89 mL/min): No dose adjustment required
- End-stage renal disease (ESRD): There is no recommended dose
Hepatic impairment
- Mild (total bilirubin ≤upper limit of normal (ULN) and AST >ULN or total bilirubin between 1-1.5x ULN and any AST) or moderate (total bilirubin between 1-3x ULN and any AST): No dose adjustment required
- Severe ((total bilirubin between 3-10x ULN and any AST): There is no recommended dose
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
- QTc interval prolongation with signs/symptoms of life-threatening arrhythmia: Permanently discontinue
- Symptomatic CHF: Permanently discontinue
Other adverse effects
- Adverse reaction≥Grade 3: Withhold for up to 3 weeks
- If improvement to grade 0-2 within 3 weeks: Resume at 80 mg or 40 mg daily
- If no improvement within 3 weeks: Permanently discontinue
Coadministration of CYP3A4 inducers
- Strong CYP3A4 inducer: Avoid use; If coadministration is unavoidable, increase osimertinib dosage to 160 mg daily when coadministering with a strong CYP3A inducer; resume osimertinib at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer
- Moderate and/or weak CYP3A inducers: No dose adjustments required
- Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics
Geriatric Dosing and Indications
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
Dosing Considerations
First-line treatment of metastatic EGFR-positive NSCLC: Confirm the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens
Metastatic EGFR T790M mutation-positive NSCLC: Confirm the presence of T790M mutation in tumor specimens prior to initiating treatment
Safety and efficacy not established
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
Warnings
Contraindications
None
Cautions
Interstitial lung disease (ILD)/pneumonitis reported in 3.3% of patients during clinical trials; 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; withhold then restart at a reduced dose or permanently discontinue
Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of 1142 osimertinib-treated patients; 0.1% of cardiomyopathy cases were 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
Can cause fetal harm; advise females of reproductive potential to use effect contraception during treatment and for 6 weeks after the final dose; males should use effective contraception for 4 months after the final dose
Drug interaction overview
- See Dosage Modifications
- Coadministration with a strong CYP3A4 inducer decreased the exposure of osimertinib
- Concurrent use with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone; monitor for adverse reactions of BCRP substrate
Pregnancy & Lactation
Pregnancy
Based on data from animal studies and its mechanism of action, osimertinib can cause fetal harm when administered to a pregnant woman
There are no available data in humans
Administration of osimertinib to pregnant rats was associated with embryo lethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose
Infertility
- Based on animal studies, may impair fertility in females and males of reproductive potential
Contraception
- Females: Advise females of reproductive potential to use effective contraception during treatment with and for 6 weeks after the final dose
- Males: Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the 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
Because of the potential for serious adverse reactions in breastfed infants, advise a lactating woman not to breastfeed during treatment and for 2 weeks after the 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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