your corporation [481:<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 concentrations 1 If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after anticonvulsant is discontinued 1 Itraconazole AUC of osimertinib increased by 24% and peak plasma concentrations decreased by 20%; not considered clinically important 1 Omeprazole No substantial effect on osimertinib exposure 1 Rifampin Decreased peak plasma concentrations and AUC of osimertinib by 73 and 78%, respectively 15 If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after rifampin is discontinued 1 Rosuvastatin Increased peak concentrations and AUC of rosuvastatin by 72 and 35%, respectively 16 Monitor for adverse effects of rosuvastatin 1 Simvastatin No substantial effect on pharmacokinetics of simvastatin 16 St. John's wort Potential decrease in plasma osimertinib concentrations 1 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 discontinued 1 Sulfasalazine Potential increase in sulfasalazine exposure and toxicity 1 Monitor for adverse effects of sulfasalazine 1 Topotecan Potential increase in topotecan exposure and toxicity 1 Monitor for adverse effects of topotecan 1 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 QT c -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. Next Interactions Print this page Add to My Med List More about Tagrisso (osimertinib) Side Effects During Pregnancy Dosage Information Drug Images Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: EGFR inhibitors Consumer resources Tagrisso Tagrisso (Advanced Reading) Professional resources Tagrisso (FDA) Osimertinib Mesylate (AHFS Monograph) Related treatment guides Non-Small Cell Lung Cancer> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only N/A CSA Schedule Not a controlled drug 2 years Approval History FDA approved 2015 Manufacturer AstraZeneca Drug Class EGFR inhibitors Related Drugs Non-Small Cell Lung Cancer Avastin , methotrexate , Taxol , Opdivo , cisplatin , Taxotere , Tarceva , Keytruda , paclitaxel , nivolumab , gemcitabine , Gemzar , Abraxane , docetaxel , Alimta , bevacizumab , pembrolizumab , pemetrexed , erlotinib , Trexall , Tecentriq , crizotinib , Cyramza , atezolizumab , More... 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