Osimertinib

Osimertinib is used for 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. Osimertinib is also used 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.

Osimertinib is available under the following different brand names: Tagrisso.

Dosages of Osimertinib:

Dosage Forms and Strengths

Tablet

• 40mg
• 80mg

Dosage Considerations – Should be Given as Follows:

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 orally once daily; continue until disease progression or unacceptable toxicity

Dosage Modifications

Renal impairment

• Mild-to-moderate (CrCl 15-89 mL/minute): No dose adjustment required
• End-stage renal disease (ESRD): There is no recommended dose

Hepatic impairment

• Mild (total bilirubin up to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1-1.5x ULN and any AST) or moderate (total bilirubin between 1-3 times ULN and any AST): No dose adjustment required
• Severe ((total bilirubin between 3-10 times ULN and any AST): There is no recommended dose

Pulmonary adverse effects

• Interstitial lung disease/pneumonitis: Permanently discontinue

Cardiac adverse effects

• QTc interval greater than 500 milliseconds on at least 2 separate ECGs: Withhold until QTc interval <481 msec or recovery to baseline if baseline QTc is 481 milliseconds or greater, 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 or greater: 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 coadministered 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 are required
• Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics

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 before initiating treatment
• Geriatric: 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 and older as compared to those under 65 years
•  Safety and efficacy not established in pediatric patients

Common side effects of osimertinib include:

• Low white blood cell count (lymphopenia, neutropenia)
• Low platelets (thrombocytopenia)
• Anemia
• Diarrhea
• Rash
• High blood magnesium (hypermagnesemia)
• Low blood sodium (hyponatremia)
• Dry skin
• Nail toxicity
• Fatigue
• Low blood sugar (hypoglycemia)
• Eye disorders
• Decreased appetite
• Cough
• Nausea
• Inflammation of mouth and lips
• Constipation
• Itching
• Vomiting
• Back pain
• Headache
• Low blood potassium (hypokalemia)
• Venous thromboembolism
• Pneumonia
• Interstitial lung disease/pneumonitis
• QTc increased from a baseline greater than 60 milliseconds
• Low blood magnesium (hypomagnesemia)
• Cardiomyopathy

Less common side effects of osimertinib include:

• Keratitis

Postmarketing side effects of osimertinib reported include:

• Erythema multiforme and Stevens-Johnson syndrome

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Severe interactions of osimertinib include:
  • doravirine
• Osimertinib has serious interactions with at least 79 different drugs.
• Osimertinib has moderate interactions with at least 166 different drugs.
• Mild interactions of osimertinib include:
  • estradiol vaginal

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains osimertinib. Do not take Tagrisso if you are allergic to osimertinib or any ingredients contained in this drug.
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• None

Effects of Drug Abuse

• No information available

Short-Term Effects

• See "What Are Side Effects Associated with Using Osimertinib?”

Long-Term Effects

• See "What Are Side Effects Associated with Using Osimertinib?”

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 (e.g., 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 effective contraception during treatment and for 6 weeks after the final dose; males should use effective contraception for 4 months after the final dose
• Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) reported in patients receiving therapy; withhold therapy if SJS or EMM is suspected and permanently discontinue if confirmed

Drug interaction overview

• 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 and Lactation

• Based on data from animal studies and its mechanism of action, osimertinib can cause fetal harm when administered to a pregnant woman. 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. There are no available data in humans. Consult your doctor.
• Females of reproductive potential are advised to use effective contraception during treatment with osimertinib and for 6 weeks after the final dose. Males with female partners of reproductive potential are advised to use effective contraception during treatment with osimertinib and for 4 months following the final dose.

It is unknown if osimertinib is 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, lactating women are advised not to breastfeed during treatment with osimertinib and for 2 weeks after the final dose.