Osimertinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tagrisso: 40 mg, 80 mg

Pharmacology

Mechanism of Action

Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which binds to select mutant forms of EGFR, including T790M, L858R, and exon 19 deletion at lower concentrations than wild-type. Osimertinib exhibits less activity against wild-type EGFR (as compared to other EGFR inhibitors) and is selective for sensitizing mutations and the T790M resistance mutation, which is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (Janne 2015).

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss/F: 918 L

Metabolism

Hepatic; predominantly oxidation (via CYP3A) and dealkylation to 2 active metabolites (AZ7550 and AZ5104)

Excretion

Feces (68%; ~2% as unchanged drug); Urine (14%; ~2% as unchanged drug)

Time to Peak

Median: 6 hours (range: 3 to 24 hours)

Half-Life Elimination

Mean (estimated): 48 hours

Protein Binding

95%

Use: Labeled Indications

Non-small cell lung cancer, metastatic:

First-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations as detected in tumor or plasma specimen by an approved test

Treatment of metastatic EGFR T790M mutation-positive (as detected in tumor or plasma specimen by an approved test) NSCLC in patients whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy

Contraindications

There are no contraindications listed in the US manufacturer's labeling.

Canadian labeling: Hypersensitivity to osimertinib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Prior to treatment, test tumor or plasma specimen to confirm tumor epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations (first-line treatment) or T790M EGFR mutation status (previously treated).

Non-small cell lung cancer, metastatic, first-line (EGFR exon 19 deletion- or exon 21 L858R mutation-positive): Oral: 80 mg once daily until disease progression or unacceptable toxicity (Soria 2018)

Non-small cell lung cancer, metastatic, previously treated (T790M EGFR mutation-positive): Oral: 80 mg once daily until disease progression or unacceptable toxicity (Jänne 2015; Mok 2017)

Missed doses: If a dose is missed, do not make up the missed dose, take the next dose as scheduled.

Dosage adjustment for concomitant strong CYP3A4 inducers: Avoid concomitant use. If coadministration with a strong CYP3A4 inducer cannot be avoided, increase osimertinib dose to 160 mg once daily. Reduce osimertinib dose to 80 mg once daily 3 weeks after discontinuation of the strong CYP3A4 inducer.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Cardiotoxicity:

QTc interval >500 msec on at least 2 separate ECGs: Withhold treatment until QTc interval is <481 msec or recovers to baseline (if baseline QTc ≥481 msec) and then resume at a dose of 40 mg once daily.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia: Permanently discontinue.

Symptomatic heart failure: Permanently discontinue.

Cutaneous: Stevens-Johnson syndrome, erythema multiforme major: Withhold treatment if suspected; permanently discontinue if confirmed.

Pulmonary toxicity: Interstitial lung disease/pneumonitis: Permanently discontinue.

Other toxicities: Grade 3 or higher adverse reaction: Withhold treatment for up to 3 weeks. If improves to ≤ grade 2 within 3 weeks, resume at either 80 mg once daily or 40 mg once daily. If not improved within 3 weeks, permanently discontinue.

Reconstitution

For patients who have difficulty swallowing tablets, disperse tablet in 60 mL of noncarbonated water (only), stir until tablet is dispersed into small pieces (will not dissolve completely) and use immediately; rinse container with 120 to 240 mL water and drink or administer immediately. For nasogastric administration, disperse the tablet in 15 mL of noncarbonated water; use an additional 15 mL of water to transfer residue to the syringe. Administer the 30 mL of liquid via the nasogastric tube and flush appropriately (with ~30 mL of water). Do not crush, heat, or ultrasonicate during preparation.

Administration

Oral: May be administered with or without food.

For patients who have difficulty swallowing tablets, disperse tablet in 60 mL of noncarbonated water (only), stir until tablet is dispersed into small pieces (will not dissolve completely) and immediately swallow. Rinse container with 120 to 240 mL of water and immediately drink. For nasogastric administration, disperse the tablet in 15 mL of noncarbonated water; use an additional 15 mL of water to transfer residue to the syringe. Administer the 30 mL of liquid via the nasogastric tube and flush appropriately (with ~30 mL of water). Do not crush, heat, or ultrasonicate during preparation.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCRP/ABCG2 Substrates: Osimertinib may increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Osimertinib. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Haloperidol: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Domperidone. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk). Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Osimertinib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>10%:

Dermatologic: Skin rash (58%), xeroderma (36%), nail disease (35%), pruritus (17%)

Endocrine & metabolic: Hypermagnesemia (30%), hypokalemia (16%)

Gastrointestinal: Diarrhea (58%), stomatitis (29%; grades 3/4: <1%), decreased appetite (20%), constipation (15%), nausea (14%), vomiting (11%)

Hematologic & oncologic: Lymphocytopenia (63%, grades 3/4: 6%), anemia (59%; grades 3/4: <1%), thrombocytopenia (51%, grades 3/4: <1%), neutropenia (41%, grades 3/4: 3%)

Hepatic: Increased serum aspartate aminotransferase (22%), increased serum alanine aminotransferase (21%), hyperbilirubinemia (14%)

Nervous system: Fatigue (21%), headache (12%)

Respiratory: Cough (17%), dyspnea (13%)

1% to 10%:

Cardiovascular: Prolonged QT interval on ECG (≤10%), decreased left ventricular ejection fraction (4%), cardiomyopathy (3%)

Respiratory: Upper respiratory tract infection (10%), interstitial pneumonitis (2% to 4%), pneumonia (3%), pulmonary embolism (2%)

Miscellaneous: Fever (10%)

<1%: Hyponatremia (Goss 2016), keratitis

Frequency not defined:

Dermatologic: Eczema, erythema of skin, leukonychia, nail bed changes, nail discoloration, nail hyperpigmentation, onychoclasis, onycholysis, onychomadesis, paronychia, skin erosion, skin fissure

Neuromuscular & skeletal: Asthenia

Ophthalmic: Eyelid pruritus

Postmarketing: Erythema multiforme, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Lymphopenia, thrombocytopenia, neutropenia, and anemia may occur (usually grades 1 and 2) with osimertinib.
• Cardiovascular toxicity: Cardiomyopathy (cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema, decreased ejection fraction, or stress cardiomyopathy) has been observed; some events were fatal. In patients who had baseline and at least one follow up assessment, a left ventricular ejection fraction (LVEF) decline of ≥10% from baseline to below 50% was noted. Assess LVEF prior to treatment, while on treatment in patients with cardiac risk factors, and in patients who develop cardiac signs/symptoms during treatment. Permanently discontinue for symptomatic heart failure. Prolongation of the QTc interval may occur; QTc >500 msec and an increase from baseline of >60 msec have been reported, although no QTc-related arrhythmias have been reported. Patients with a baseline QTc of ≥470 were excluded from clinical trials. Monitor ECG and electrolytes periodically in patients with a history of congenital long QTc syndrome, heart failure, electrolyte abnormalities, and/or those taking concurrent medications known to prolong the QTc interval. Permanently discontinue in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia.
• Cutaneous toxicity: Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported; withhold treatment if SJS or EMM is suspected and permanently discontinue if confirmed. Other skin reactions, including rash, dry skin, and itching may occur. Nail toxicity may also occur.
• Fertility effects: Osimertinib may impair fertility; effects may be reversible in females.
• GI toxicity: Diarrhea (usually grades 1 and 2) was observed in almost half the patients receiving osimertinib.
• Ocular toxicity: Keratitis has been reported (rarely) in clinical trials. Promptly refer patients for ophthalmologic evaluation if signs/symptoms of keratitis (eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) develop.
• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis were observed in clinical studies; some events were fatal. Withhold treatment with worsening respiratory symptoms (dyspnea, cough, fever) which may be indicative of ILD; permanently discontinue if ILD is confirmed. Cases of transient asymptomatic pulmonary opacities (TAPOs; apparent clinically benign areas of localized ground-glass opacities) have been observed with osimertinib. TAPOs may be mistaken for isolated pulmonary progression of disease or the beginning of more severe pneumonitis. Some TAPOs cases resolved during continued osimertinib treatment; monitor closely (Noonan 2016).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Confirm the presence of epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimen (if mutation is not detected in plasma, test tumor tissue if feasible) for first-line treatment of metastatic non-small cell lung cancer. Confirm the presence of a T790M EGFR mutation in tumor sample (preferred) or plasma specimen prior to treatment initiation in patients receiving treatment following progression on or after EGFR tyrosine kinase inhibitor therapy (mutation status should be determined from tumor sample; if tumor was not biopsied, a plasma sample may be used). Circulating tumor cells from plasma sample may be used as a surrogate marker for detection of T790M in tumor tissue (Remon 2017). If mutation is not detected in plasma sample, re-evaluate the feasibility of tumor biopsy for tissue testing. Information on diagnostic tests approved for detection of EGFR mutations may be found at www.fda.gov/companiondiagnostics.

Monitoring Parameters

Prior to treatment, test tumor or plasma specimen to determine epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation status (first-line treatment) or T790M EGFR mutation status (previously treated). Pregnancy test (in females of reproductive potential prior to therapy initiation). Monitor ECG and electrolytes periodically (in patients with a history of congenital long QTc syndrome, heart failure, electrolyte abnormalities, and/or those taking concurrent medications known to prolong the QTc interval). Assess left ventricular ejection fraction prior to treatment, while on treatment in patients with cardiac risk factors, and assess in patients who develop cardiac signs/symptoms. Monitor for signs/symptoms of interstitial lung disease or pneumonitis, dermatologic, and gastrointestinal toxicity. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on data from animal reproduction studies and the mechanism of action, use during pregnancy is expected to cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating osimertinib. Females of reproductive potential should use effective contraception during therapy and for 6 weeks after the last osimertinib dose. Males with female partners of reproductive potential should also use effective contraception during therapy and for 4 months after the last osimertinib dose.

Patient Education

What is this drug used for?

• It is used to treat lung cancer.

Frequently reported side effects of this drug

• Diarrhea
• Dry skin
• Nail changes
• Nausea
• Vomiting
• Lack of appetite
• Constipation
• Mouth sores
• Mouth irritation
• Headache
• Common cold symptoms
• Back pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Vision changes
• Eye pain
• Severe eye irritation
• Sensitivity to light
• Watery eyes
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Dizziness
• Passing out
• Fast heartbeat
• Abnormal heartbeat
• Severe loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.