osimertinib

General

Genetic Implications:

Pronunciation:
oh-si-mer-ti-nib

Trade Name(s)

• Tagrisso

Ther. Class.
antineoplastics

Pharm. Class.
epidermal growth factor receptor (EGFR) inhibitors

Indications

•   Treatment of metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non–small-cell lung cancer (NSCLC) in patients who have progressed on or after EGFR tyrosine kinase inhibitor therapy.
•   First-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.

Action

 Irreversibly binds to select mutant forms of EGFR (including T790M), resulting in inactivation of kinases that regulate proliferation and transformation; the T790M mutation is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors.

Therapeutic Effect(s):

Decreased spread of NSCLC

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 95%.

Metabolism and Excretion: Mostly metabolized by the liver (CYP3A4 enzyme system) to 2 active metabolites; 68% excreted in feces (2% as unchanged drug); 14% excreted in urine (2% as unchanged drug).

Half-life: 48 hr.

TIME/ACTION PROFILE (blood levels)

Contraindication/Precautions

Contraindicated in:

• Concurrent use of strong CYP3A4 inhibitors or inducers;
• OB:  Pregnancy (may cause fetal harm);
• Lactation: Breast feeding should be avoided during treatment and for 2 wk after therapy.

Use Cautiously in:

• Congenital long QT syndrome, HF, electrolyte abnormalities, or taking QT interval prolonging medications;
• End-stage renal disease (CCr <15 mL/min);
• Severe hepatic impairment;
• Rep:  Women of reproductive potential and men with female partners of reproductive potential;
• Pedi:  Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: STROKE, fatigue, headache

CV: CARDIOMYOPATHY, QT INTERVAL PROLONGATION, VENOUS THROMBOEMBOLISM

Derm: dry skin, nail disorders, pruritus, rash

EENT: blepharitis, blurred vision, cataracts, dry eye, eye pain, ↑ lacrimation, keratitis

F and E: hypermagnesemia, hyponatremia

GI: constipation, ↓ appetite, diarrhea, nausea, stomatitis

Hemat: NEUTROPENIA, THROMBOCYTOPENIA, anemia, lymphopenia

MS: back pain

Resp: INTERSTITIAL LUNG DISEASE, cough

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Strong CYP3A4 inhibitors, including itraconazole, nefazodone, and  ritonavir  may ↑ levels and the risk of toxicity; avoid concurrent use.
• Strong CYP3A4 inducers, including carbamazepine, rifampin, and  phenytoin  may ↓ levels and its effectiveness; avoid concurrent use.
• May ↑ or ↓ carbamazepine, cyclosporine, ergot derivatives, fentanyl, phenytoin, or  quinidine ; avoid concurrent use.
•  QT interval prolonging drugs  may ↑ risk of torsade de pointes; avoid concurrent use.
• May ↑ levels of P-gp substrates, including  fexofenadine.
• May ↑ levels of breast cancer resistant protein (BCRP) substrates, including  rosuvastatin.

Drug-Natural Products:

 St. John's wort  may ↓ levels and its effectiveness; avoid concurrent use.

Route/Dosage

PO (Adults): 80 mg once daily until disease progression or unacceptable toxicity

Availability

Tablets: 40 mg, 80 mg

Assessment

• Assess for worsening respiratory symptoms (dyspnea, coughing, fever) during therapy; may indicate interstitial lung disease or pneumonitis. If signs and symptoms occur, permanently discontinue osimertinib.
• Monitor cardiac status (ECG, electrolytes) periodically during therapy, especially in patients with congenital long QTc syndrome, HF, electrolyte abnormalities, or taking medications that prolong QTc interval.  If QTc interval >500 msec on at least 2 separate ECGs,  withhold therapy until QTc interval is <481 msec or recovery to baseline if baseline is ≥481 msec, resume at 40 mg dose.  If QTc interval prolongation occurs with signs and symptoms of life threatening arrhythmia,  permanently discontinue therapy.
• Assess for signs and symptoms of cardiomyopathy (cardiac failure, pulmonary edema, ejection fraction decreased, stress cardiomyopathy) by echo cardiogram, multigated acquisition (MUGA) scan prior to starting therapy and every 3 mo during therapy.  If asymptomatic and absolute decrease in LVEF of 10% from baseline and below 50%,  withhold therapy for up to 4 wk. If improved to baseline, resume. If not improved to baseline, permanently discontinue.  If symptomatic HF develops,  permanently discontinue therapy.

Lab Test Considerations:

Obtain a negative pregnancy test before starting therapy.

• May cause hyponatremia and hypermagnesemia.

Potential Diagnoses

• Ineffective breathing pattern (Indications)  (Adverse Reaction) 
• Decreased cardiac output (Adverse Reaction) 

Implementation

• PO Administer once daily without regard to food.
  • For patients with difficulty swallowing, disperse tablet in 4 tbsp (50 mL) of only non-carbonated water. Stir until tablet is completely dispersed and swallow or administer through NG tube immediately; do not crush, heat, or ultrasonicate during preparation. Rinse container with 4–8 oz of water and drink or administer through NG tube immediately.

Patient/Family Teaching

• Instruct patient to take osimertinib as directed. If dose missed, omit and take next dose as scheduled. Advise patient to read  Patient Information prior to starting therapy and with each Rx dose refill in case of changes.
• Advise patient to notify health care professional if signs and symptoms of lung problems (worsening lung symptoms, trouble breathing, shortness of breath, cough, fever) or heart problems (pounding or racing heart, shortness of breath, swollen ankles or feet, lightheadedness) occur.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
• Rep:  May be teratogenic and may impair fertility in males and females. Caution women of reproductive potential to use effective contraception during and for at least 6 wk after final dose. Advise males with female partners of reproductive potential to use effective contraception during and for at least 4 mo after final dose. Advise females patient to avoid breast feeding during and for at least 2 wk after final dose.

Evaluation/Desired Outcomes

Decreased spread of NSCLC.