Tagrisso

Osimertinib is used to treat a certain type of non-small-cell lung cancer (NSCLC) that has spread to other parts of the body that has worsened after treatment with another chemotherapy medication. Osimertinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop or slow the spread of cancer cells and may help shrink tumors.

Dosage Forms & Strengths

tablet

• 40mg
• 80mg

Non-small Cell Lung Cancer

Indicated for metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non-small cell lung cancer (NSCLC), as detected by an FDA approved test, in patients who have progressed on or after EGFR TKI therapy

80 mg PO qDay until disease progression or unacceptable toxicity

Dosage Modifications

Renal impairment

• Mild-to-moderate (CrCl 30-89 mL/min): No dose adjustment required
• Severe or ESRD (CrCl <30 mL/min): There is no recommended dose

Hepatic impairment

• Mild (TB <ULN and AST 1-1.5 ULN, or TB 1-1.5 ULN and any AST): No dose adjustment required
• Moderate or severe: There is no recommended dose

Pulmonary adverse effects

• Interstitial lung disease/pneumonitis: Permanently discontinue

Cardiac adverse effects

• QTc interval >500 msec on at least 2 separate ECGs: Withhold until QTc interval <481 msec or recovery to baseline if baseline QTc is ≥481 msec, then resume at 40 mg dose
• QTc interval prolongation with signs/symptoms of life-threatening arrhythmia: Permanently discontinue
• Symptomatic CHF or asymptomatic left ventricular dysfunction that persists ≥4 wk: Permanently discontinue

Other adverse effects ≥grade 3

• Withhold for up to 3 weeks
• If improvement to grade 0-2 within 3 weeks: Resume at 80 mg or 40 mg daily
• If no improvement within 3 weeks: Permanently discontinue

Dosing Considerations

Confirm the presence of T790M mutation in tumor specimens prior to initiating treatment

Safety and efficacy not established

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• medications that block a protein in the body (CYP3A4) such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan (Vaprisol), delavirdine (Rescriptor), and nefazodone. When taken together with Tagrisso, these medications can increase the levels of Tagrisso and cause more side effects or toxicity. 
•   medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, and nimodipine (Nimotop). When taken together with Tagrisso, these medications can decrease Tagrisso levels in the body. 

This is not a complete list of Tagrisso drug interactions. Ask your doctor or pharmacist for more information.

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Severe or fatal interstitial lung disease or pneumonitis may occur.1

Temporarily interrupt therapy and promptly evaluate patient if any respiratory manifestations suggestive of interstitial lung disease occur; permanently discontinue if a diagnosis is confirmed.1

Prolongation of QT Interval

QTc-interval prolongation reported.1 Appears to occur in a concentration-dependent manner.1

Periodically monitor ECG and serum electrolytes in patients with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities and in those receiving concomitant drugs known to prolong the QT interval.1 (See Drugs that Prolong QT Interval under Interactions.)

If QT-interval prolongation occurs, dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.1 (See Dosage Modification for Cardiac Effects under Dosage and Administration.)

Permanently discontinue if QTc-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia.1

Cardiomyopathy

Cardiomyopathy (e.g., cardiac failure, CHF, pulmonary edema, decreased ejection fraction) reported.1

Assess cardiac function (including LVEF) in patients with cardiac risk factors prior to initiating therapy and periodically thereafter.1 Assess LVEF in any patient who develops cardiac complications during therapy.1

Permanently discontinue in patients who develop symptomatic CHF or asymptomatic LV dysfunction that does not resolve within 4 weeks.1

Keratitis

Keratitis reported.1 If manifestations suggestive of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain, red eye) occur, promptly refer patient to an ophthalmologist for evaluation.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., postimplantation loss and early embryonic death, decreased fetal weight) demonstrated in animals.1 Avoid pregnancy during therapy.1

Women of childbearing potential should use effective methods of contraception during therapy and for 6 weeks after drug discontinuance.1

Men with female partners of childbearing potential should use effective methods of contraception during therapy and for 4 months after drug discontinuance.1

Impairment of Fertility

Based on animal studies, may impair female and male fertility.1

Specific Populations

No available data in pregnant women; animal studies and the drug's mechanism of action suggest possible fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.1

Not known whether distributed into human milk or if drug has any effect on milk production or nursing infant.1 Discontinue nursing during therapy and for 2 weeks after drug is discontinued.1

Safety and efficacy not established.1

No overall differences in efficacy based on age; however, a higher incidence of grade 3 or 4 adverse reactions and more frequent dosage modifications for adverse reactions observed in patients ≥65 years of age relative to younger adults.1

Population pharmacokinetic analysis suggests that pharmacokinetics of osimertinib not altered by mild (total bilirubin concentration less than ULN with AST concentration 1–1.5 times ULN, or total bilirubin concentration 1–1.5 times ULN with any AST concentration) or moderate (total bilirubin concentration 1.5–3 times ULN with any AST concentration) hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with severe (total bilirubin concentration 3–10 times ULN with any AST concentration) hepatic impairment.1

Population pharmacokinetic analysis suggests that pharmacokinetics of osimertinib not altered by mild (Clcr 60–89 mL/minute), moderate (Clcr 30–59 mL/minute), or severe (Clcr 15–29 mL/minute) renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Not studied in patients with end-stage renal disease (Clcr <15 mL/minute).1

Common Adverse Effects

Diarrhea,1 19 rash,1 19 dry skin,1 19 nail toxicity,1 19 fatigue.1 19

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

Storage

Oral

25°C (may be exposed to 15–30°C).1

• 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

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.)

In the U.S.

• Tagrisso

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Tyrosine Kinase Inhibitor

• Tell all of your health care providers that you take Tagrisso. This includes your doctors, nurses, pharmacists, and dentists.
• You will need to have heart function tests while taking this medicine. Talk with the doctor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• This medicine may cause a type of abnormal heartbeat (prolonged QT interval). If this happens, the chance of other unsafe and sometimes deadly abnormal heartbeats may be raised. Talk with the doctor.
• If you are 65 or older, use Tagrisso with care. You could have more side effects.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. In both men and women, this may go back to normal but sometimes it may not. Talk with your doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for at least 4 months after stopping this medicine. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant while you take Tagrisso or within 4 months after your last dose, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking this medicine and for 6 weeks after your last dose.
• If you get pregnant while taking Tagrisso or within 6 weeks after your last dose, call your doctor right away.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

NDC 0310-1349-30

30 Tablets

Each tablet contains 40 mg osimertinib.
USUAL ADULT DOSAGE:
See Prescribing Information.
WARNING: As with all medications, keep out of the reach of children.
Store at room temperature between 68°F to 77°F (20°C to 25°C).

Rx only

AstraZeneca

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Applies to osimertinib: oral tablet

Along with its needed effects, osimertinib (the active ingredient contained in Tagrisso) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking osimertinib:

• Anxiety
• cough
• dizziness, lightheadedness, or fainting
• eye or vision changes
• fast, pounding, or uneven heartbeat
• pain in the chest, groin, or legs, especially the calves
• pain, redness, or swelling in the arm or leg
• slurred speech
• sudden loss of coordination
• sudden, severe headache
• sudden, severe weakness or numbness in the arm or leg
• troubled breathing

• Blurred vision
• fever or chills
• general feeling of discomfort or illness
• inability to speak
• seizures
• sneezing
• sore throat
• sudden, severe weakness on one side of the body
• temporary blindness
• thickening of bronchial secretions

• Eye redness, irritation, or pain

Some side effects of osimertinib may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• changes in the fingernails or toenails, including brittleness, inflammation, pain, redness, tenderness, separation from nail bed, or shedding of nails
• constipation
• decreased appetite
• diarrhea
• headache
• nausea
• skin rash, dryness, or itching
• swelling or inflammation of the mouth
• unusual tiredness or weakness