osimertinib

High Alert

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.
First-line treatment of locally advanced or metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations (in combination with pemetrexed and platinum-based chemotherapy).
Adjuvant therapy after tumor resection of NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.
Locally advanced, unresectable (stage III) NSCLC in patients whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and 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 effects:

Improved progression-free survival.

Pharmacokinetics ⬆ ⬇

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 95%.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP3A4 isoenzyme to two 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 ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Oral	unknown	6 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

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 in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: cutaneous vasculitis, DEEP VEIN THROMBOSIS, HF, QT interval prolongation

Derm: dry skin, nail disorders, pruritus, rash, ERYTHEMA MULTIFORME (EM), STEVENS-JOHNSON SYNDROME (SJS), urticaria

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

F and E: hypermagnesemia, hyponatremia

GI: constipation, diarrhea, nausea, stomatitis

Hemat: anemia, lymphopenia, neutropenia, thrombocytopenia, APLASTIC ANEMIA

Metab: ↓appetite

MS: back pain

Neuro: fatigue, headache, STROKE

Resp: cough, interstitial lung disease (ILD)/pneumonitis, PULMONARY EMBOLISM

Interactions ⬆ ⬇

Drug-drug:

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

Drug-Natural Products:

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

Route/Dosage ⬆ ⬇

PO (Adults ): 80 mg once daily. In patients with metastatic disease, continue until disease progression or unacceptable toxicity. In adjuvant setting, continue until disease progression, unacceptable toxicity, or for up to 3 yr.

Availability ⬆ ⬇

Tablets: 40 mg; 80 mg

Assessment ⬆ ⬇

Assess for worsening respiratory symptoms (dyspnea, cough, hypoxia, fever) during therapy; may indicate ILD or pneumonitis. If signs and symptoms occur, hold medication. If ILD confirmed, permanently discontinue osimertinib. Dosage adjustments for ILD/pneumonitis in patients who have not recently received platinum-based chemoradiation: Any Grade ILD/pneumonitis: permanently discontinue osimertinib; Dosage adjustments for ILD/pneumonitis in patients who have recently received platinum-based chemoradiation: Grade 1: Hold therapy or continue as clinically appropriate; Grade ≥2 ILD/pneumonitis: Permanently discontinue osimertinib.
Assess cardiac history and ECG at baseline. Monitor ECG 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 ≥2 separate ECGs, hold therapy until QTc interval <481 msec or recovery to baseline (if baseline QTc is ≥481 msec but <500 msec); then resume at 40-mg dose. If QTc interval prolongation occurs with signs and symptoms of life-threatening arrhythmia, permanently discontinue osimertinib.
Assess for signs and symptoms of cardiomyopathy (HF, pulmonary edema, ↓ left ventricular ejection fraction [LVEF], stress cardiomyopathy) by echocardiogram and multigated acquisition scan prior to starting therapy and every 3 mo during therapy, especially in patients with cardiac risk factors. If asymptomatic and absolute ↓ in LVEF of 10% from baseline and <50%, withhold therapy for up to 4 wk. If improved to baseline, resume. If not improved to baseline, permanently discontinue osimertinib. If symptomatic HF develops, permanently discontinue osimertinib.
Monitor for symptoms of keratitis (eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, red eye) during therapy. If symptoms occur, refer to an ophthalmologist.
Assess for rash or signs and symptoms of SJS or EM periodically during therapy (fever, general malaise, fatigue, muscle or joint aches, red patches, blisters, oral lesions, conjunctivitis). If SJS or EM suspected, hold therapy. If SJS or EM confirmed, permanently discontinue osimertinib.
Monitor for signs and symptoms of cutaneous (leukocytoclastic, urticarial vasculitis, IgA) vasculitis (multiple nonblancheable red papules on forearms, lower legs, or buttocks or large urticaria on trunk that do not go away within 24 hr and develop a bruised appearance). Interrupt therapy if suspected and evaluate; permanent discontinuation may be necessary.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy. Patient selection is based on presence of EGFR exon mutations in tumor specimens. Confirm EGFR mutation by an FDA-approved test prior to treatment. Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics.
Monitor CBC with differential before starting and periodically during therapy. May cause lymphopenia, thrombocytopenia, anemia, and neutropenia. If Grade ≥3 reaction occurs, withhold osimertinib for up to 3 wk. If improved to Grade <2, resume at 80 mg or 40 mg daily. If no improvement in 3 wk, permanently discontinue osimertinib.
Monitor electrolytes periodically during therapy. May cause hyponatremia and hypermagnesemia.

Implementation ⬆ ⬇

PO: Administer once daily without regard to food.
- For patients with difficulty swallowing, disperse tablet in 60 mL (2 oz) of only noncarbonated water. Stir until tablet is completely dispersed and swallow immediately; do not crush, heat, or ultrasonicate during preparation. Rinse container with 4–8 oz of water and drink or administer through nasogastric (NG) tube immediately. If administered via NG tube, disperse tablet in 15 mL of noncarbonated water; then use an additional 15 mL of water to transfer any residues in syringe. Administer 30 mL of solution via NG tube with 30 mL of water flushes.
- Higher incidence of Grade 3 or 4 adverse events have been reported, requiring more frequent dosage adjustments in older adults.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of osimertinib to patient. Instruct them to take medication as directed. Do not share medication with others, even if they have similar symptoms; may be harmful. Keep out of children's reach. Advise patient to read Patient Information prior to starting therapy and with each Rx dose refill in case of changes.
Inform patient that side effects may include diarrhea, dry skin, stomatitis, fatigue, and ↓ appetite. Maintain adequate hydration and good oral hygiene.
Advise patient to notify health care professional if signs and symptoms of lung problems (worsening lung symptoms, trouble breathing, shortness of breath, cough, fever), heart problems (pounding or racing heart, shortness of breath, swollen ankles or feet, light-headedness, fainting), eye symptoms, rash (target lesions, severe blistering or peeling of skin), cutaneous vasculitis (multiple nonblanching red papules on forearms, lower legs, or buttocks or large hives on trunk that do not go away within 24 hr and develop a bruised appearance), and aplastic anemia (new or persistent fevers, bruising, bleeding, pallor) 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 cause fetal harm. Caution women of reproductive potential to use effective contraception during therapy and for 6 wk after final dose. Advise men with female partners of reproductive potential to use effective contraception during and for 4 mo after final dose. Advise patients to avoid breastfeeding during and for 2 wk after final dose. May impair fertility in women and men.

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Pronunciation ⬇

Classifications ⬆ ⬇

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