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osimertinib

( OH sim ER ti nib )
Funding:
Exceptional Access Program
  • osimertinib - For the treatment of locally advanced (not amenable to curative therapies) or metastatic non-small cell lung cancer (NSCLC) according to clinical criteria
Other Name(s): Tagrisso®
Appearance: tablet in various strengths, shapes and colours
A - Drug Name

osimertinib

COMMON TRADE NAME(S):   Tagrisso®

 
B - Mechanism of Action and Pharmacokinetics

Osimertinib is an irreversible inhibitor of both Epidermal Growth Factor Receptor (EGFR) with activity in clinically relevant sensitizing mutations as well as T790M.



Absorption
Bioavailability

70%

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

15 days


Distribution

Extensive tissue distribution

PPB

94.7%

Cross blood brain barrier?

Brain penetration and activity in the CNS have been observed in animal studies.

Metabolism
Main enzymes involved

CYP3A4 and CYP3A5

Active metabolites

yes (10% of osimertinib exposure at steady state)

Inactive metabolites

yes

Elimination
Feces

68% (~2% unchanged)

Urine

14% (~2% unchanged)

Half-life

44 hours

 
C - Indications and Status
Health Canada Approvals:

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.

*Note:

Approval was based on a randomized phase III study demonstrating improvement in progression free survival compared to chemotherapy.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

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
Diarrhea (58%) E
Mucositis (29%) 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
Keratitis (<1%) 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.

 
E - Dosing

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.



Adults:

Oral: 80 mg Daily

Dosage with Toxicity:

Dose Levels:

Dose Level Osimertinib Dose (mg/day)
0 80
-1 40

 

Toxicity Dose modification
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

Discontinue permanently.
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.



Dosage with Hepatic Impairment:

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

 



Dosage with Renal Impairment:

Renal impairment (creatinine clearance)

Osimertinib dose

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 data

 



Dosage in the elderly:

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%).

 



Dosage based on ethnicity:

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).



Children:

Safety and efficacy are not established in children under 18 years.



 
F - Administration Guidelines

  • 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)
 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to this drug or to ingredients in the formulation or component in the container

Other Warnings/Precautions:

  • 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: Unknown

    Carcinogenicity studies have not been performed.

Pregnancy and Lactation:
  • Embryotoxicity: Yes
  • Fetotoxicity: Yes

    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: Unknown

    Breastfeeding is not recommended.

  • Fertility effects: Documented in animals
 
H - Interactions

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.

AGENT EFFECT MECHANISM MANAGEMENT
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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring

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

CBC

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



 
J - Supplementary Public Funding

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

 
K - References

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.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

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