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Tagrisso

Generic Name: Osimertinib Mesylate
Class: Antineoplastic Agents
Chemical Name: N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate
Molecular Formula: C28H33N7O2•CH4O3S
CAS Number: 1421373-66-1

Introduction

Antineoplastic agent; a third-generation inhibitor of receptor tyrosine kinases.1 4 5 6 7

Uses for Tagrisso

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic NSCLC in patients with epidermal growth factor receptor (EGFR) T790M mutation (as detected by an FDA-approved diagnostic test) who have experienced disease progression during or after EGFR tyrosine kinase inhibitor therapy.1 2 3 17 19

Designated an orphan drug by FDA for treatment of EGFR mutation-positive NSCLC.13

Tagrisso Dosage and Administration

General

  • Confirm presence of EGFR T790M mutation in tumor or plasma specimens by an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test) prior to initiating therapy.1 20 Because of high rate of false-negative results, plasma testing is recommended only when a tumor biopsy cannot be obtained; patients with a negative plasma T790M result should be reevaluated for feasibility of biopsy.1 19 20

Restricted Distribution

  • Available through a limited network of specialty pharmacies.14 Consult the Tagrisso website () for specific availability information.14

Administration

Oral Administration

Administer orally once daily without regard to meals; swallow tablets whole and do not crush.1

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.1 To ensure full dose is administered, rinse container with an additional 120–240 mL of water and drink immediately.1 Do not crush, heat, or ultrasonicate tablet when preparing drug dispersion.1

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.1 Administer the resulting 30-mL drug dispersion through the nasogastric tube, then flush tube with appropriate volumes of water (approximately 30 mL).1

If a dose is missed, take next dose at regularly scheduled time; do not take missed dose.1

Dosage

Available as osimertinib mesylate; dosage expressed in terms of osimertinib.1

Adults

NSCLC
Oral

80 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity or Drug Interactions
Dosage Modification for Interstitial Lung Disease/Pneumonitis
Oral

If interstitial lung disease or pneumonitis occurs, permanently discontinue drug.1 (See Interstitial Lung Disease/Pneumonitis under Cautions.)

Dosage Modification for Cardiac Effects
Oral

If QTc interval >500 msec on at least 2 separate ECGs, withhold therapy.1 If QTc interval improves to <481 msec or returns to baseline (if baseline QTc interval ≥481 msec), may resume therapy at reduced dosage of 40 mg daily.1

If QTc-interval prolongation occurs concurrently with signs and/or symptoms of life-threatening arrhythmia, permanently discontinue drug.1 (See Prolongation of QT Interval under Cautions.)

If asymptomatic left ventricular (LV) dysfunction occurs and does not resolve within 4 weeks, permanently discontinue drug.1

If symptomatic congestive heart failure occurs, permanently discontinue drug.1 (See Cardiomyopathy under Cautions.)

Dosage Modification for Other Toxicity
Oral

If other grade 3 or higher adverse effects occur, withhold therapy for up to 3 weeks.1

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.1

Concomitant Use with CYP3A Inducers
Oral

If used concomitantly with a potent CYP3A inducer, increase osimertinib dosage to 160 mg daily.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (total bilirubin concentration less than ULN with AST concentration 1–1.5 times ULN, or total bilirubin concentration 1–3 times ULN with any AST concentration): No dosage adjustment needed.1

Severe hepatic impairment: Insufficient data to provide dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild to severe renal impairment (Clcr 15–89 mL/minute): No dosage adjustment needed.1

End-stage renal disease: Insufficient data to provide dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Tagrisso

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Severe or fatal interstitial lung disease or pneumonitis may occur.1

Temporarily interrupt therapy and promptly evaluate patient if any respiratory manifestations suggestive of interstitial lung disease occur; permanently discontinue if a diagnosis is confirmed.1

Prolongation of QT Interval

QTc-interval prolongation reported.1 Appears to occur in a concentration-dependent manner.1

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.1 (See Drugs that Prolong QT Interval under Interactions.)

If QT-interval prolongation occurs, dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.1 (See Dosage Modification for Cardiac Effects under Dosage and Administration.)

Permanently discontinue if QTc-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia.1

Cardiomyopathy

Cardiomyopathy (e.g., cardiac failure, CHF, pulmonary edema, decreased ejection fraction) reported.1

Assess cardiac function (including LVEF) in patients with cardiac risk factors prior to initiating therapy and periodically thereafter.1 Assess LVEF in any patient who develops cardiac complications during therapy.1

Permanently discontinue in patients who develop symptomatic CHF or asymptomatic LV dysfunction that does not resolve within 4 weeks.1

Keratitis

Keratitis reported.1 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.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., postimplantation loss and early embryonic death, decreased fetal weight) demonstrated in animals.1 Avoid pregnancy during therapy.1

Women of childbearing potential should use effective methods of contraception during therapy and for 6 weeks after drug discontinuance.1

Men with female partners of childbearing potential should use effective methods of contraception during therapy and for 4 months after drug discontinuance.1

Impairment of Fertility

Based on animal studies, may impair female and male fertility.1

Specific Populations

Pregnancy

No available data in pregnant women; animal studies and the drug's mechanism of action suggest possible fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.1

Lactation

Not known whether distributed into human milk or if drug has any effect on milk production or nursing infant.1 Discontinue nursing during therapy and for 2 weeks after drug is discontinued.1

Pediatric Use

Safety and efficacy not established.1

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.1

Hepatic Impairment

Population pharmacokinetic analysis suggests that pharmacokinetics of osimertinib not altered by mild (total bilirubin concentration less than ULN with AST concentration 1–1.5 times ULN, or total bilirubin concentration 1–1.5 times ULN with any AST concentration) or moderate (total bilirubin concentration 1.5–3 times ULN with any AST concentration) hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with severe (total bilirubin concentration 3–10 times ULN with any AST concentration) hepatic impairment.1

Renal Impairment

Population pharmacokinetic analysis suggests that pharmacokinetics of osimertinib not altered by mild (Clcr 60–89 mL/minute), moderate (Clcr 30–59 mL/minute), or severe (Clcr 15–29 mL/minute) renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Not studied in patients with end-stage renal disease (Clcr <15 mL/minute).1

Common Adverse Effects

Diarrhea,1 19 rash,1 19 dry skin,1 19 nail toxicity,1 19 fatigue.1 19

Interactions for Tagrisso

Metabolized principally by CYP3A.1 12 Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1

Induces CYP1A2.1 Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1

Inhibits BCRP, but does not inhibit P-gp, 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) 2.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma osimertinib concentrations).1 Avoid concomitant use.1 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).1 Monitor for adverse effects of BCRP substrate.1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).1 Periodically monitor ECG and electrolytes during concomitant use.1 (See Prolongation of QT Interval under Cautions.)

Drugs Affecting Gastric Acidity

Clinically important pharmacokinetic interactions unlikely.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenytoin)

Potential decrease in plasma osimertinib concentrations1

If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after anticonvulsant is discontinued1

Itraconazole

AUC of osimertinib increased by 24% and peak plasma concentrations decreased by 20%; not considered clinically important1

Omeprazole

No substantial effect on osimertinib exposure1

Rifampin

Decreased peak plasma concentrations and AUC of osimertinib by 73 and 78%, respectively15

If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after rifampin is discontinued1

Rosuvastatin

Increased peak concentrations and AUC of rosuvastatin by 72 and 35%, respectively16

Monitor for adverse effects of rosuvastatin1

Simvastatin

No substantial effect on pharmacokinetics of simvastatin16

St. John's wort

Potential decrease in plasma osimertinib concentrations1

If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after St. John's wort is discontinued1

Sulfasalazine

Potential increase in sulfasalazine exposure and toxicity1

Monitor for adverse effects of sulfasalazine 1

Topotecan

Potential increase in topotecan exposure and toxicity1

Monitor for adverse effects of topotecan1

Tagrisso Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 6 hours (range 3–24 hours) after oral administration.1 12

Dose-proportional increases in AUC and peak plasma concentration observed over a dose range of 20–240 mg.1 4 11

Steady-state concentrations are achieved in approximately 15 days.1 11

Food

Administration with a high-fat meal slightly increased AUC and peak plasma concentration by 19 and 14%, respectively; not considered clinically important.1 11

Distribution

Extent

Not known whether distributed into milk.1 Limited animal data suggest that drug distributes into brain.1

Plasma Protein Binding

Has not been determined, but likely high.1 12

Elimination

Metabolism

Principally metabolized by CYP3A.1 12

Metabolized to 2 active metabolites (AZ7550 and AZ5104), each accounting for approximately 10% of total drug exposure.1 11

AZ7550 has a similar potency to parent drug; AZ5104 exhibits higher potency against mutant EGFR and wild-type EGFR.1 10 11

Elimination Route

Eliminated in feces (68%) and urine (14%); 2% eliminated as unchanged drug.1

Half-life

Approximately 48 hours.1

Special Populations

Age, weight, gender, smoking status, and race do not substantially affect pharmacokinetics of osimertinib.1 11

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Binds irreversibly and selectively to mutant forms of EGFR including the EGFR-sensitizing mutations (e.g., exon 19 deletion [del19], exon 21 substitution [L858R]) and the secondary T790M mutation. 1 4 5 6 7 10 11

  • Also inhibits HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, ACK1, and BLK in vitro.1

  • Demonstrates antitumor activity against NSCLC cell lines expressing EGFR L858R/T790M, L858R, T790M/del19, and del19 and, to a lesser extent, wild-type EGFR.1

  • Exhibits approximately ninefold greater affinity for mutant forms of EGFR than wild-type EGFR.1 10

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • Risk of severe or fatal interstitial lung disease/pneumonitis.1 Importance of immediately informing clinician if new or worsening respiratory symptoms (e.g., difficulty breathing, shortness of breath, cough, fever) occur.1

  • Risk of QTc-interval prolongation.1 Importance of immediately informing clinician if any possible symptoms of QT-interval prolongation (e.g., dizziness, lightheadedness, syncope) occur.1

  • Risk of cardiomyopathy.1 Importance of immediately informing clinician if manifestations of heart failure (e.g., palpitations, shortness of breath, edema) occur.1

  • Risk of keratitis.1 Importance of informing clinician if manifestations of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, eye pain, red eye, changes in vision) occur.1

  • Risk of fetal harm.1 Advise women of childbearing potential to use effective methods of contraception during therapy and for 6 weeks after drug discontinuance.1 Advise men with female partners of childbearing potential to use effective methods of contraception during therapy and for 4 months after drug is discontinued.1 Importance of women informing their clinician if they are pregnant or think they may be pregnant.1 If pregnancy occurs, advise patient of potential fetal risk.1

  • Importance of advising women to avoid breast-feeding while receiving osimertinib therapy and for 2 weeks after the drug is discontinued.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of osimertinib is restricted. 14 (See Restricted Distribution under Dosage and Administration.)

Osimertinib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

40 mg (of osimertinib)

Tagrisso

AstraZeneca

80 mg (of osimertinib)

Tagrisso

AstraZeneca

AHFS DI Essentials. © Copyright 2017, Selected Revisions September 11, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca. Tagrisso (osimertinib) tablet prescribing information. Wilmington, DE; 2017 Mar.

2. Yang JC, Ahn M, Ramalingan SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study phase II extension cohort. Presented at the 16th World Conference on Lung Cancer. Denver, CO: 2015 Sep 6–9. Abstract 943.

3. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 phase II study. Presented at the 16th World Conference on Lung Cancer. Denver, CO: 2015 Sep 6–9. Abstract 1406.

4. Jänne PA, Yang JC, Kim DW et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015; 372:1689-99. [PubMed 25923549]

5. Greig SL. Osimertinib: First Global Approval. Drugs. 2016; 76:263-73. [PubMed 26729184]

6. Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016; 93:59-68. [PubMed 26898616]

7. Noda S, Kanda S. Addressing epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer. Expert Rev Respir Med. 2016; 10:547-56. [PubMed 26959310]

8. Song Z, Ge Y, Wang C et al. Challenges and Perspectives on the Development of Small-Molecule EGFR Inhibitors against T790M-Mediated Resistance in Non-Small-Cell Lung Cancer. J Med Chem. 2016; :.

9. Hirano T, Yasuda H, Tani T et al. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget. 2015; 6:38789-803. [PubMed 26515464]

10. Gao X, Le X, Costa DB. The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer. Expert Rev Anticancer Ther. 2016; 16:383-90. [PubMed 26943236]

11. Planchard D, Brown KH, Kim DW et al. Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother Pharmacol. 2016; 77:767-76. [PubMed 26902828]

12. Dickinson PA, Cantarini MV, Collier J et al. Metabolic Disposition of Osimertinib in Rat, Dog, and Man: insights into a drug designed to bind covalently to a cysteine residue of EGFR. Drug Metab Dispos. 2016; :. [PubMed 27226351]

13. US Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Silver Spring, MD. From FDA website. Accessed 2016 May 4.

14. AstraZeneca. Tagrisso (osimertinib) healthcare professionals website. Accessed 2016 Apr 28.

15. Vishwanathan K, Chih-Hsin J, Lee, JS, et al. Effect of itraconazole or rifampicin on the pharmacokinetics (PK) of osimertinib (AZD9291). Abstract e14100 (published in conjunction with the 2016 ASCO meeting). Chicago, IL.

16. Harvey RD, Isambert N, Rafii S, et al. Effect of multiple-dose osimertinib (AZD9291) on the pharmacokinetics (PK) of simvastatin and rosuvastatin. Abstract e14098 (published in conjunction with the 2016 ASCO meeting). Chicago, IL.

17. US Food and Drug Administration. Summary Review: NDA 208065. From FDA website.

19. Mok TS, Wu Y-L, Ahn M-J et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017; 376:629-640. [PubMed 27959700]

20. US Food and Drug Administration. Medical Devices: List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). From FDA website.

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