Introduction

Antineoplastic agent; a third-generation inhibitor of receptor tyrosine kinases.

Uses for Osimertinib (Systemic)

Non-small Cell Lung Cancer (NSCLC)

Adjuvant treatment after tumor resection in patients with NSCLC harboring epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations (as detected by an FDA-approved diagnostic test).

First-line treatment of metastatic NSCLC harboring EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution mutations (as detected by an FDA-approved diagnostic test).

Treatment of metastatic NSCLC harboring EGFR T790M mutation (as detected by an FDA-approved diagnostic test) in patients who have experienced disease progression during or after EGFR tyrosine kinase inhibitor therapy.

Designated an orphan drug by FDA for treatment of EGFR mutation-positive NSCLC.

Osimertinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Adjuvant therapy of NSCLC: Confirm presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in tumor specimens using an FDA-approved companion diagnostic test (e.g., cobas EGFR Mutation Test).

• First-line treatment of metastatic NSCLC: Confirm presence of EGFR del19 or L858R substitution mutations in tumor or plasma specimens using an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Patients with a negative plasma del19 or L858R mutation result should be reevaluated for feasibility of a tumor biopsy.

• Previously treated metastatic NSCLC: Confirm presence of EGFR T790M mutation in tumor or plasma specimens by an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Because of the high rate of false-negative results, plasma testing is recommended only when a tumor biopsy cannot be obtained; patients with a negative plasma result should be reevaluated for feasibility of a tumor biopsy.

• Baseline left ventricular ejection fraction (LVEF) in patients with cardiac risk factors.

• Peform a CBC with differential before initiating therapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for symptoms of interstitial lung disease and pneumonitis during therapy.

• Monitor for corrected QT (QT_c) interval prolongation in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Periodic monitoring of electrolyte concentrations recommended in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Patients with cardiac risk factors: Monitor for signs and symptoms of cardiomyopathy during therapy; assess LVEF in patients with cardiac risk factors at baseline and in those who develop signs or symptoms of cardiomyopathy during therapy.

• Perform a CBC with differential periodically during therapy, and more frequently if clinically indicated.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), osimertinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally once daily without regard to meals; swallow tablets whole and do not crush.

For patients with difficulty swallowing solids, may disperse tablet in a container with 60 mL (2 ounces) of noncarbonated water (do not use other liquids); immediately swallow. To ensure full dose is administered, rinse container with an additional 120–240 mL of water and drink immediately. Do not crush, heat, or ultrasonicate tablet when preparing drug dispersion.

Alternatively, for administration through a nasogastric tube, disperse tablet in a container with 15 mL of noncarbonated water and draw dispersion into a syringe; rinse container with additional 15 mL of water to transfer any residue to the syringe. Administer the resulting 30-mL drug dispersion through the nasogastric tube, then flush tube with appropriate volumes of water (approximately 30 mL).

If a dose is missed, take next dose at regularly scheduled time; do not take missed dose.

Dosage

Available as osimertinib mesylate; dosage expressed in terms of osimertinib.

Adults

NSCLC

Adjuvant Treatment of NSCLC

80 mg once daily. Continue therapy for up to 3 years or until disease recurrence or unacceptable toxicity occurs.

First-line Treatment of Metastatic NSCLC

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Previously Treated Metastatic NSCLC

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification

Interstitial Lung Disease/Pneumonitis

If interstitial lung disease or pneumonitis occurs, permanently discontinue drug.

Cardiac Effects

If QT_c interval >500 msec on at least 2 separate ECGs, withhold therapy. If QT_c interval improves to <481 msec or returns to baseline (if baseline QT_c interval ≥481 msec), may resume therapy at reduced dosage of 40 mg daily.

If QT_c-interval prolongation occurs concurrently with signs and/or symptoms of life-threatening arrhythmia, permanently discontinue drug.

If symptomatic congestive heart failure occurs, permanently discontinue drug.

Cutaneous Toxicity

If Stevens-Johnson syndrome or erythema multiforme major is suspected, withhold osimertinib. Permanently discontinue osimertinib if diagnosis confirmed.

If cutaneous vasculitis is suspected, withhold osimertinib and evaluate patient for systemic involvement; consider consultation with a dermatologist. Consider permanent discontinuance based on severity when no other etiology is identified.

Other Toxicity

If other grade 3 or higher adverse effects occur, withhold therapy for up to 3 weeks.

If adverse effect improves to grade 0–2, resume therapy at original dosage or reduced dosage (40 mg daily); if no improvement within 3 weeks, permanently discontinue drug.

Concomitant Use with CYP3A Inducers

If used concomitantly with a potent CYP3A inducer, increase osimertinib dosage to 160 mg daily.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN; or total bilirubin concentration 1–3 times ULN with any AST concentration): No dosage adjustment needed.

Severe hepatic impairment: Insufficient data to provide dosage recommendations.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): No dosage adjustment needed.

End-stage renal disease: Insufficient data to provide dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Severe or fatal interstitial lung disease or pneumonitis may occur.

Temporarily interrupt therapy and promptly evaluate patient if any respiratory manifestations suggestive of interstitial lung disease occur; permanently discontinue if a diagnosis is confirmed.

Prolongation of QT Interval

QT_c-interval prolongation reported. Appears to occur in a concentration-dependent manner.

Periodically monitor ECG and serum electrolytes in patients with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities and in those receiving concomitant drugs known to prolong the QT interval with known risk of torsades de pointes.

If QT-interval prolongation occurs, dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.

Permanently discontinue if QT_c-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia.

Cardiomyopathy

Cardiomyopathy (e.g., acute or chronic cardiac failure, CHF, pulmonary edema, decreased ejection fraction) reported.

Assess cardiac function (including LVEF) in patients with cardiac risk factors prior to initiating therapy and periodically thereafter. Assess LVEF in any patient who develops cardiac complications during therapy.

Permanently discontinue in patients who develop symptomatic CHF.

Keratitis

Keratitis reported. If manifestations suggestive of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain, red eye) occur, promptly refer patient to an ophthalmologist for evaluation.

Erythema Multiforme and Stevens-Johnson Syndrome

Erythema multiforme and Stevens-Johnson syndrome reported in postmarketing case reports.

Withhold osimertinib if erythema multiforme or Stevens-Johnson syndrome suspected; permanently discontinue if diagnosis confirmed.

Cutaneous Vasculitis

Cutaneous vasculitis (e.g., leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis) reported in postmarketing case reports.

Withhold osimertinib if cutaneous vasculitis suspected and evaluate for systemic involvement; consider consultation with a dermatologist. Consider permanently discontinuing osimertinib based on severity when no other etiology is identified.

Aplastic Anemia

Aplastic anemia reported; some cases resulted in fatal outcomes. Advise patients of signs and symptoms of aplastic anemia (e.g., new or persistent fevers, bruising, bleeding, pallor). If suspected, withhold osimertinib and obtain a hematology consultation. If diagnosis is confirmed, permanently discontinue osimertinib. Perform CBC with differential before initiating therapy, periodically throughout treatment, and more frequently if indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity (e.g., postimplantation loss and early embryonic death, decreased fetal weight) demonstrated in animals.

Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Females of reproductive potential should use effective methods of contraception during therapy and for 6 weeks after drug discontinuance.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 4 months after drug discontinuance.

Impairment of Fertility

Based on animal studies, may impair female and male fertility.

Specific Populations

Pregnancy

No available data in pregnant women; animal studies and the drug's mechanism of action suggest possible fetal harm. If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.

Lactation

Not known whether distributed into human milk or if drug has any effect on milk production or nursing infant. Discontinue nursing during therapy and for 2 weeks after drug is discontinued.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy based on age; however, a higher incidence of grade 3 or 4 adverse reactions and more frequent dosage modifications for adverse reactions observed in patients ≥65 years of age relative to younger adults.

Hepatic Impairment

Pharmacokinetics of osimertinib not altered by mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN; or total bilirubin concentration 1–3 times ULN with any AST concentration).

Not studied in patients with severe (total bilirubin concentration 3–10 times ULN with any AST concentration) hepatic impairment.

Renal Impairment

Pharmacokinetics of osimertinib not altered by mild to severe renal impairment (Cl_cr 15–89 mL/minute).

Not studied in patients with end-stage renal disease (Cl_cr <15 mL/minute).

Common Adverse Effects

Adverse effects reported in >20% of patients: Diarrhea, rash, musculoskeletal pain, dry skin, nail toxicity, stomatitis, fatigue, cough. Laboratory abnormalities reported in ≥20% of patients: Leukopenia, lymphopenia, anemia, thrombocytopenia, neutropenia.

General

Pretreatment Screening

• Adjuvant therapy of NSCLC: Confirm presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in tumor specimens using an FDA-approved companion diagnostic test (e.g., cobas EGFR Mutation Test).

• First-line treatment of metastatic NSCLC: Confirm presence of EGFR del19 or L858R substitution mutations in tumor or plasma specimens using an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Patients with a negative plasma del19 or L858R mutation result should be reevaluated for feasibility of a tumor biopsy.

• Previously treated metastatic NSCLC: Confirm presence of EGFR T790M mutation in tumor or plasma specimens by an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Because of the high rate of false-negative results, plasma testing is recommended only when a tumor biopsy cannot be obtained; patients with a negative plasma result should be reevaluated for feasibility of a tumor biopsy.

• Baseline left ventricular ejection fraction (LVEF) in patients with cardiac risk factors.

• Peform a CBC with differential before initiating therapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for symptoms of interstitial lung disease and pneumonitis during therapy.

• Monitor for corrected QT (QT_c) interval prolongation in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Periodic monitoring of electrolyte concentrations recommended in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Patients with cardiac risk factors: Monitor for signs and symptoms of cardiomyopathy during therapy; assess LVEF in patients with cardiac risk factors at baseline and in those who develop signs or symptoms of cardiomyopathy during therapy.

• Perform a CBC with differential periodically during therapy, and more frequently if clinically indicated.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), osimertinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally once daily without regard to meals; swallow tablets whole and do not crush.

For patients with difficulty swallowing solids, may disperse tablet in a container with 60 mL (2 ounces) of noncarbonated water (do not use other liquids); immediately swallow. To ensure full dose is administered, rinse container with an additional 120–240 mL of water and drink immediately. Do not crush, heat, or ultrasonicate tablet when preparing drug dispersion.

Alternatively, for administration through a nasogastric tube, disperse tablet in a container with 15 mL of noncarbonated water and draw dispersion into a syringe; rinse container with additional 15 mL of water to transfer any residue to the syringe. Administer the resulting 30-mL drug dispersion through the nasogastric tube, then flush tube with appropriate volumes of water (approximately 30 mL).

If a dose is missed, take next dose at regularly scheduled time; do not take missed dose.

Dosage

Available as osimertinib mesylate; dosage expressed in terms of osimertinib.

Adults

NSCLC

Adjuvant Treatment of NSCLC

80 mg once daily. Continue therapy for up to 3 years or until disease recurrence or unacceptable toxicity occurs.

First-line Treatment of Metastatic NSCLC

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Previously Treated Metastatic NSCLC

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification

Interstitial Lung Disease/Pneumonitis

If interstitial lung disease or pneumonitis occurs, permanently discontinue drug.

Cardiac Effects

If QT_c interval >500 msec on at least 2 separate ECGs, withhold therapy. If QT_c interval improves to <481 msec or returns to baseline (if baseline QT_c interval ≥481 msec), may resume therapy at reduced dosage of 40 mg daily.

If QT_c-interval prolongation occurs concurrently with signs and/or symptoms of life-threatening arrhythmia, permanently discontinue drug.

If symptomatic congestive heart failure occurs, permanently discontinue drug.

Cutaneous Toxicity

If Stevens-Johnson syndrome or erythema multiforme major is suspected, withhold osimertinib. Permanently discontinue osimertinib if diagnosis confirmed.

If cutaneous vasculitis is suspected, withhold osimertinib and evaluate patient for systemic involvement; consider consultation with a dermatologist. Consider permanent discontinuance based on severity when no other etiology is identified.

Other Toxicity

If other grade 3 or higher adverse effects occur, withhold therapy for up to 3 weeks.

If adverse effect improves to grade 0–2, resume therapy at original dosage or reduced dosage (40 mg daily); if no improvement within 3 weeks, permanently discontinue drug.

Concomitant Use with CYP3A Inducers

If used concomitantly with a potent CYP3A inducer, increase osimertinib dosage to 160 mg daily.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN; or total bilirubin concentration 1–3 times ULN with any AST concentration): No dosage adjustment needed.

Severe hepatic impairment: Insufficient data to provide dosage recommendations.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): No dosage adjustment needed.

End-stage renal disease: Insufficient data to provide dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Metabolized principally by CYP3A. Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Induces CYP1A2. Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

Inhibits BCRP, but does not inhibit organic anion transporter (OAT) 1 and OAT3, organic anion transporter polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion transporter (MATE) 1 and MATE2K, or organic cation transporter (OCT) 2.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma osimertinib concentrations). Avoid concomitant use. If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after the potent CYP3A inducer is discontinued.

Drugs Transported by Breast Cancer Resistance Protein

Possible pharmacokinetic interaction (increased plasma concentrations of substrate). Monitor for adverse effects of BCRP substrate.

Drugs Affected by the P-gp Transport System

Possible pharmacokinetic interaction (increased plasma concentrations of substrate). Monitor for adverse effects of P-gp substrate.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation). Avoid concomitant use. If concomitant use cannot be avoided, periodically monitor ECG and electrolytes. (See Prolongation of QT Interval under Cautions.)

Drugs Affecting Gastric Acidity

Clinically important pharmacokinetic interactions unlikely.

Specific Drugs