Osimertinib is an irreversible inhibitor of both Epidermal Growth Factor Receptor (EGFR) with activity in clinically relevant sensitizing mutations as well as T790M.
|Peak plasma levels||
median tmax of 6 (3-24) hours
|Effects with food||
Food does not alter osimertinib bioavailability to a clinically significant extent. The drug may be taken with or without food.
|Time to reach steady state||
Extensive tissue distribution
|Cross blood brain barrier?||
Brain penetration and activity in the CNS have been observed in animal studies.
|Main enzymes involved||
CYP3A4 and CYP3A5
yes (10% of osimertinib exposure at steady state)
68% (~2% unchanged)
14% (~2% unchanged)
First-line treatment in patients with locally advanced (not amenable to curative therapies) or metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations (either alone or in combination with other EGFR mutations).
- A validated test is required to identify EGFR mutation-positive status prior to treatment.
Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR tyrosine kinase inhibitor therapy*.
- A validated test is required to confirm T790M mutation-positive status prior to treatment.
Approval was based on a randomized phase III study demonstrating improvement in progression free survival compared to chemotherapy.
Extravasation Potential: Not applicable
The following table lists adverse effects that occurred in previously untreated patients, or previously treated patients (marked with #), in phase III trials treated with osimertinib. Adverse events from other trial data or severe / post-marketing events may also be included.
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Arterial thromboembolism (rare)||E|
|Cardiotoxicity (4%)||E D|
|QT interval prolonged (1%) (> 500 msec)||E|
|Venous thromboembolism (1%)||E D|
|Dermatological||Dry skin (36%)||E|
|Nail disorder (35%)||E D|
|Rash, pruritus (58%) (may rarely be severe)||E|
|Gastrointestinal||Anorexia (18%) #||E|
|Constipation (14%) #||E|
|Nausea, vomiting (16%) #||E|
|General||Fatigue (16%) #||E|
|Hematological||Myelosuppression ± infection, bleeding (72%) (6% severe)||E|
|Hepatobiliary||↑ LFTs (22%)||E|
|Musculoskeletal||Musculoskeletal pain (10%) #||E|
|Nervous System||Headache (10%) #||E|
|Ophthalmic||Conjunctivitis (8%) # (related to ocular surface events)||E|
|Renal||Creatinine increased (9%)||E|
|Respiratory||Cough, dyspnea (17%) #||E|
|Epistaxis (5%) #||E|
|Other (bronchiolitis obliterans organizing pneumonia; rare)||E|
|Pneumonitis (4%)||E D|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for osimertinib include myelosuppression ± infection, bleeding, diarrhea, rash, pruritus, dry skin, nail disorder, mucositis, ↑ LFTs, anorexia, cough, dyspnea, fatigue, nausea and vomiting.
Skin effects observed with osimertinib have mainly been mild in nature, including rash, dry skin pruritus and nail effects. There were no reports of ≥ Grade 4 events. Rare, non-fatal post-marketing case reports of Stevens-Johnson syndrome have been reported with osimertinib.
QTc interval prolongation has been observed and may lead to an increased risk of ventricular arrhythmias, including Torsade de pointes, although no QT-associated arrhythmias were reported in clinical trials. A pharmacokinetic/ pharmacodynamic analysis with osimertinib predicted a concentration-dependent increase in QTc prolongation. Patients with significant rhythm or conduction abnormalities and those with resting QTc > 470 msec were excluded from clinical trials.
Left ventricular dysfunction has been reported. Across clinical trials, 4% of patients had decreases in LVEF ≥ 10% and drops in LVEF to below 50%. Three percent of patients reported cardiomyopathy events, including 1 case of fatal congestive heart failure.
Interstitial lung disease (ILD) and/or pneumonitis were reported in 4% of patients with a median onset of about 3 months, and may be fatal. Patients with a history of or active ILD, or those with radiation pneumonitis requiring steroids were excluded from clinical trials.
Ocular surface events (i.e. conjunctivitis, blepharitis and dry eye) were usually mild and rarely required dose modification. Keratitis has been rarely reported.
Refer to protocol by which patient is being treated.
A validated test is required to identify EGFR mutation-positive status prior to first-line NSCLC treatment.
A validated test is required to confirm EGFR T790M mutation-positive status prior to treatment of NSCLC that has progressed on or after EGFR TKI.
Electrolyte abnormalities should be corrected prior to treatment.
|Dose Level||Osimertinib Dose (mg/day)|
|ILD/pneumonitis||Hold and investigate. Discontinue permanently if confirmed.|
|Asymptomatic LVEF < 50% and absolute decrease of 10% from baseline||
Hold for up to 4 weeks.
If recovery to baseline, restart.
If no recovery to baseline, discontinue permanently.
|QTc interval > 500 msec on at least 2 separate ECGs||
Hold until QTc interval is < 481 msec or recovery to baseline if baseline is ≥ 481 msec.
Then restart at 1 dose level ↓.
QTc interval prolonged with signs/symptoms of serious arrhythmia (e.g. Torsade de pointes, polymorphic VT)
OR Symptomatic congestive heart failure
|Signs & symptoms suggestive of keratitis||Refer promptly to an ophthalmology specialist.|
|Other ≥ grade 3 toxicity||
Hold for up to 3 weeks.
If recovery to ≤ grade 2, restart at the same dose or at 1 dose level ↓.
If no recovery, discontinue permanently.
|Hepatic impairment||Osimertinib dose|
Mild (total bilirubin ≤ ULN and AST > ULN OR total bilirubin 1-1.5 x ULN and any AST) or
Moderate (total bilirubin 1.5 to 3 x ULN and any AST)
|No dosage adjustment required|
|Severe||No data; use with caution|
Renal impairment (creatinine clearance)
Mild to moderate (30 to <60 mL/min)
No dosage adjustment required
Severe (15 to < 30 mL/min)
End stage renal disease (<15 mL/min)
No dosage adjustment is required.
No overall differences in efficacy or predicted steady state exposure of osimertinib were observed between patients ≥ 65 years of age and younger patients.
Patients ≥ 65 years of age experienced more ≥ Grade 3 adverse reactions compared to younger patients (13% versus 9%) and had more reported adverse reactions that led to drug dose interruptions or reductions (13% versus 8%).
No dosage adjustment required due to ethnicity.
In clinical trials, the incidence of ILD was higher in Japanese patients compared to other Asians and non-Asian patients (10.4% vs. 1.9% and 2.8 %, respectively).
Safety and efficacy are not established in children under 18 years.
Osimertinib may be taken orally with or without food at the same time once a day.
The tablet should be swallowed whole with water and not crushed, split or chewed.
If a dose is missed, it may be taken within 12 hours. If there are less than 12 hours until the next dose, the missed dose should be skipped and the next dose should be taken at the scheduled time.
If the patient has difficulty swallowing, the tablet may be dispersed in 50 ml of non-carbonated water (room temperature) and swallowed immediately. An additional 50 ml of water should be added to capture drug residue and immediately swallowed. No other liquids should be added.
For nasogastric administration, the tablet may be dispersed in 15 mL of noncarbonated water; using an additional 15 mL of water for residue rinses. The 30 mL of liquid should be administered within 30 minutes via the nasogastric tube and flush appropriately as per the nasogastric tube manufacturer’s instructions.
- Store tablets at room temperature (15-30oC)
- Patients who are hypersensitive to this drug or to ingredients in the formulation or component in the container
Not recommended in patients with congenital long QT syndrome or those taking other medications know to prolong QTc
Patients at risk for prolonged QTc such as those with cardiac disease, history of arrhythmias, electrolyte disturbances or conditions leading to electrolyte disturbances, bradycardia, acute neurological events, diabetes mellitus and autonomic neuropathy should be monitored closely and electrolyte abnormalities corrected prior to treatment.
Patients with abnormal LVEF or those with significant cardiac history were excluded from clinical trials.
Exercise caution in patients with cardiac risk factors and those with conditions that can affect LVEF.
Patients with a history of ILD/pneumonitis, evidence of clinically active ILD or those with radiation pneumonitis requiring steroids were excluded from clinical trials.
Ocular events have been reported. Contact lens use is risk factor for ocular toxicity, including keratitis. Caution should be used when driving or operating machinery in patients who experience visual disturbances.
Other Drug Properties:
Carcinogenicity studies have not been performed.
Osimertinib is not recommended for use in pregnancy. Adequate contraception (including a barrier method in females using hormonal contraception and/or a change to a non-oral method of contraception) should be used by both sexes during treatment, and for at least 2 months after the last dose (for females) and 4 months after the last dose (for males).
Excretion into breast milk:
Breastfeeding is not recommended.
Documented in animals
Osimertinib is metabolised primarily by CYP3A4/5. It does not inhibit P-gp, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2.
Strong CYP3A4 inhibitors decreased the osimertinib maximum plasma concentration (Cmax) by approximately 20% and increased the area under the curve (AUC) by approximately 24%. Given the inter-patient variability of 46% in the osimertinib exposure in the population PK analysis, this change of 24% is not clinically significant.
Clinical pharmacokinetic interactions with CYP3A4 substrates are unlikely.
There are no interactions with gastric pH modifying agents.
|Strong CYP3A4 inducers (i.e. phenytoin, rifampin, carbamazepine, St. John’s Wort, etc)||↓ osimertinib concentration and/or efficacy (e.g. rifampin ↓ osimertinib exposure by 78%)||↑ metabolism of osimertinib||Avoid. If coadministration is unavoidable, closely monitor therapy and increase osimertinib dose to 160mg daily during concurrent use. Continue this dose for 3 weeks after discontinuation of the strong CYP3A4 inducer. Then, resume osimertinib dose at 80mg daily.|
|Moderate CYP3A4 inducers (i.e. bosentan, efavirenz, etravirine, phenobarbital, primidone)||↓ osimertinib concentration and/or efficacy||↑ metabolism of osimertinib||Monitor therapy if co-administered. No dose adjustments required.|
|BCRP and P-gp substrates (e.g. certain HMG-CoA reductase inhibitors, digoxin, fexofenadine, dabigatran)||↑ substrate concentration and/or toxicity||osimertinib is a competitive inhibitor of BCRP||Avoid co-administration with substrates with narrow therapeutic indices. Monitor closely if used together. Starting and maintenance doses of statins should be as low as possible.|
|CYP3A4, CYP1A2, CYP2C substrates||↓ substrate concentration and/or efficacy. Potential reduced effectiveness of oral hormonal contraceptives.||osimertinib induced these enzymes in vitro||Consider alternatives to oral hormonal contraception. Closely monitor substrates with narrow therapeutic indices for reductions in effectiveness.|
|Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)||↑ risk of QT prolongation and arrhythmias||Additive||Avoid if possible; closely monitor if co-administered|
|Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids)||↑ risk of QT prolongation and arrhythmias||Additive||Avoid if possible; closely monitor if co-administered|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
Liver function tests
|Baseline and at each visit|
Renal function tests
|Baseline and at each visit; more frequent in patients with severe renal impairment|
|Baseline and at each visit|
ECG and electrolytes (calcium, potassium and magnesium), especially in patients at risk of electrolyte abnormalities
|Baseline and as clinically indicated|
LVEF; in patients with cardiac risk factors or those who develop cardiac signs/symptoms during treatment
|Baseline, during treatment* and as clinically indicated|
Clinical toxicity assessment for GI, skin and respiratory effects, signs and symptoms of CHF, infection, bleeding, thromboembolism and ocular effects
|At each visit|
*LVEF was monitored every 12 weeks while on treatment in some clinical trials
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- osimertinib - For the treatment of locally advanced (not amenable to curative therapies) or metastatic non-small cell lung cancer (NSCLC) according to clinical criteria
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, et al.; AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629-640.
Tagrisso (osimertinib) product monograph. AstraZeneca Canada Ltd., August 2019.
August 2020 Updated Monitoring section.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.