Dosing and uses of Tagrisso (osimertinib)
Adult dosage forms and strengths
tablet
- 40mg
- 80mg
Non-small Cell Lung Cancer
Indicated for metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non-small cell lung cancer (NSCLC), as detected by an FDA approved test, in patients who have progressed on or after EGFR TKI therapy
80 mg PO qDay until disease progression or unacceptable toxicity
Dosage modifications
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dose adjustment required
- Severe or ESRD (CrCl <30 mL/min): There is no recommended dose
Hepatic impairment
- Mild (TB <ULN and AST 1-1.5 ULN, or TB 1-1.5 ULN and any AST): No dose adjustment required
- Moderate or severe: 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
- Asymptomatic, absolute decrease in LVEF of 10% from baseline and below 50%: Withhold for up to 4 weeks; resume if improved to baseline LVEF; if not improved to baseline, permanently discontinue
- Symptomatic congestive heart failure: Permanently discontinue
Other adverse effects ≥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
Dosing Considerations
This indication is approved under accelerated approval based on tumor response rate and duration of response
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
Confirm the presence of T790M mutation in tumor specimens prior to initiating treatment
Pediatric dosage forms and strengths
Safety and efficacy not established
Tagrisso (osimertinib) adverse (side) effects
>10%
Lymphopenia (63%)
Thrombocytopenia (54%)
Anemia (44%)
Diarrhea (42%)
Rash (41%)
Neutropenia (33%)
Dry skin (31%)
Hyponatremia (26%)
Nail toxicity (25%)
ypermagnesemia (20%)
Eye disorders (18%)
Nausea (17%)
Decreased appetite (16%)
Constipation (15%)
Pruritus (14%)
Fatigue (14%)
Cough (14%)
Back pain (13%)
Stomatitis (12%)
1-10%
Headache (10%)
Venous thromboembolism (7%)
Pneumonia (4%)
Interstitial lung disease/pneumonitis (3.3%)
QTc increased from baseline >60 msec (2.7%)
Cardiomyopathy (1.4%)
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
Cardiomyopathy reported; assess LVEF before treatment and then every 3 months thereafter
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
- Osimertinib is a substrate of CYP3A and P-gp; avoid coadministration with strong CYP3A inhibitors or inducers
- Osimertinib is a competitive inhibitor of CYP3A and BCRP; avoid coadministration with drugs that are sensitive substrates of CYP3A or BCRP
- Osimertinib is inducers CYP3A4 and CYP1A2; avoid coadministration with drugs that are sensitive substrates of CYP3A or with drugs with narrow therapeutic indices that are substrates of CYP1A2
Pregnancy and 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 embryolethality 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 of Tagrisso (osimertinib)
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: Likely high based on its physiochemical properties
Vd: 986 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: 14.2 L/hr
Excretion: 68% feces; 14% urine
Administration
Instructions
May take with or without food
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 or administer through the nasogastric tube in order to assure taking the complete dose
