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Osimertinib

Pronunciation

(oh si mer ti nib)

Index Terms

  • AZD9291
  • Tagrisso

Dosage Forms

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

Tablet, Oral:

Tagrisso: 40 mg, 80 mg

Brand Names: U.S.

  • Tagrisso

Pharmacologic Category

  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

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 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).

Distribution

Vss/F: 986 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

Binding is likely high.

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an approved test, in patients who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to osimertinib or any component of the formulation.

Dosing: Adult

Note: Confirm tumor T790M EGFR mutation status prior to treatment initiation (in the absence of tumor biopsy, a plasma specimen may be utilized).

Non-small cell lung cancer, metastatic (T790M EGFR mutation-positive): Oral: 80 mg once daily until disease progression or unacceptable toxicity

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: Renal Impairment

Note: Renal function may be estimated using the Cockcroft Gault formula.

CrCl 30 to 89 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute and end stage renal disease: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate (total bilirubin 1.5 to 3 times ULN and any AST) or severe impairment (total bilirubin 3 to 10 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

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.

Asymptomatic absolute decrease in left ventricular ejections fraction (LVEF) of 10% from baseline and below 50%: Withhold treatment for up to 4 weeks. If improved to baseline, resume treatment; if not improved to baseline, permanently discontinue.

Symptomatic heart failure: Permanently discontinue.

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 or lower within 3 weeks, resume at either 80 mg once daily or 40 mg once daily. If not improved within 3 weeks, permanently discontinue.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2016 criteria). 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. When it is necessary to manipulate the tablets (eg, to prepare an oral liquid), it is recommended to double glove, wear a protective gown, and prepare in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended (NIOSH 2016).

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.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2016 criteria). NIOSH recommends single gloving for administration of intact tablets. Avoid exposure to crushed tablets. When it is necessary to manipulate the tablets (eg, to prepare an oral liquid), it is recommended to double glove, wear a protective gown, and prepare in a controlled device. NIOSH recommends double-gloving, a protective gown, and (if there is a potential for vomit or spit up), eye/face protection for administration of a liquid (NIOSH 2016).

Storage

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

Drug Interactions

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

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

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

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of Osimertinib. Avoid combination

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Consider therapy modification

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

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. Avoid combination

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (14%), headache (10%)

Dermatologic: Skin rash (41%, including erythematous rash, macular rash, maculopapular rash, papular rash, pustular rash, erythema, folliculitis, acne vulgaris, dermatitis, dermatitis acneiform), xeroderma (31%), nail disease (25%), pruritus (14%)

Endocrine & metabolic: Hyponatremia (26%), hypermagnesemia (20%)

Gastrointestinal: Diarrhea (42%), nausea (17%), decreased appetite (16%), constipation (15%), stomatitis (12%)

Hematologic & oncologic: Lymphopenia (63%, grades 3/4: 3%), thrombocytopenia (54%, grades 3/4: 1%), anemia (44%, grades 3/4: <1%), neutropenia (33%, grades 3/4: 3%)

Neuromuscular & skeletal: Back pain (13%)

Ophthalmic: Eye disorder (19%, including dry eyes, blurred vision, keratitis, cataract, eye irritation, blepharitis, eye pain, increased lacrimation, vitreous floaters, <1% other ocular toxicity)

Respiratory: Cough (14%)

1% to 10%:

Cardiovascular: Venous thromboembolism (7%, including deep vein thrombosis, internal jugular thrombosis), cerebrovascular accident (3%), prolonged Q-T interval on EKG (≤3%; prolonged from baseline), pulmonary embolism (≤2%), reduced ejection fraction (<2%), cardiomyopathy (≤1%)

Respiratory: Pneumonia (≤4%; grade 3/4: 2%), interstitial pneumonitis (3%)

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, 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% and a drop to below 50% was noted. Assess LVEF (by echocardiogram or multigated acquisition [MUGA] scan) prior to treatment and then every 3 months while on treatment. Withhold treatment if ejection fraction decreases by 10% from baseline and is <50%. Permanently discontinue for symptomatic heart failure or persistent, asymptomatic left ventricular dysfunction that does not resolve within 4 weeks. Prolongation of the QTc interval may occur; QTc >500 msec and an increase from baseline of >60 msec 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.

• Dermatologic toxicity: 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.

• Gastrointestinal toxicity: Diarrhea (usually grades 1 and 2) was observed in almost half the patients receiving osimertinib.

• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis was 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.

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2016 criteria).

Other warnings/precautions:

• Appropriate use: Confirm the presence of a T790M epidermal growth factor receptor (EGFR) mutation prior to treatment initiation. Mutation status should be determined from tumor sample; if tumor was not biopsied, a plasma sample may be used (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 T790M mutations may be found at www.fda.gov/companiondiagnostics.

Monitoring Parameters

T790M epidermal growth factor receptor (EGFR) mutation status (prior to treatment). 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 LVEF (by echocardiogram or multigated acquisition [MUGA] scan) prior to treatment and then every 3 months while on treatment. Monitor for signs/symptoms of interstitial lung disease or pneumonitis, dermatologic, and gastrointestinal toxicity.

Pregnancy Considerations

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, dry skin, nail changes, nausea, lack of appetite, constipation, mouth sores, back pain, or headache. Have patient report immediately to prescriber signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of high magnesium levels (confusion, feeling sluggish, slow movements, shortness of breath, nausea, severe dizziness, or passing out), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of heart problems (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), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), dizziness, passing out, tachycardia, abnormal heartbeat, coughing up blood, angina, severe loss of strength and energy, chills, pharyngitis, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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