Tagrisso

/ Astra Zeneca

The recommended dose is 80 mg osimertinib once a day until disease progression or unacceptable toxicity.
If a dose of Osimertinib is missed, the dose should be made up unless the next dose is due within 12 hours.
Osimertinib can be taken with or without food at the same time each day.
Dose adjustments: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose should be reduced to 40 mg taken once daily.
For dose adjustment information for adverse reactions- See prescribing information for full details.
No dosage adjustment is required due to patient age, body weight, gender, ethnicity and smoking status.
Hepatic impairment: No dose adjustment is recommended in patients with mild hepatic impairment (total bilirubin <upper limit of normal (ULN) and aspartate aminotransferase (AST) between 1 to 1.5x ULN or total bilirubin between 1.0 to 1.5x ULN and any AST) but caution should be used when administering Osimertinib to these patients. The safety and efficacy of this medicinal product has not been established in patients with moderate or severe hepatic impairment. Until additional data become available, use in patients with moderate or severe hepatic impairment is not recommended.
Renal impairment: No dose adjustment is recommended in patients with mild and moderate renal impairment. Limited data are available in patients with severe renal impairment. The safety and efficacy of this medicinal product has not been established in patients with end-stage renal disease [creatinine clearance (CLcr) <15 mL/min, calculated by the Cockcroft and Gault equation], or on dialysis. Caution should be exercised when treating patients with severe and end stage renal impairment.
Paediatric population: The safety and efficacy of Osimertinib in children or adolescents aged less than 18 years have not been established. No data are available.
Method of administration: This medicinal product is for oral use. The tablet should be swallowed whole with water and it should not be crushed, split or chewed.
If the patient is unable to swallow the tablet, the tablet may first be dispersed in 50 mL of noncarbonated water. It should be dropped in the water, without crushing, stirred until dispersed and immediately swallowed. An additional half a glass of water should be added to ensure that no residue remains and then immediately swallowed. No other liquids should be added.
If administration via nasogastric tube is required, the same process as above should be followed but using volumes of 15 mL for the initial dispersion and 15 mL for the residue rinses. The resulting 30 mL of liquid should be administered as per the naso-gastric tube manufacturer’s instructions with appropriate water flushes. The dispersion and residues should be administered within 30 minutes of the addition of the tablets to water.

Tagrisso as monotherapy is indicated for:
– the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.
– the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

Hypersensitivity to the active substance or to any of the excipients.
St. John’s wort should not be used together with Osimertinib.

Assessment of EGFR T790M mutation status: When considering the use of Osimertinib as a treatment for locally advanced or metastatic NSCLC, it is important that the EGFR T790M mutation status is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample.
Interstitial lung disease (ILD): Severe, life-threatening or fatal Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) have been observed in patients treated with Osimertinib in clinical studies. Most cases improved or resolved with interruption of treatment. Patients with a past medical history of ILD, drug induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from clinical studies.
Severe Cutaneous Adverse Reactions (SCARs)
Case reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with frequency categories of rare and not known, respectively, in association with treatment. Before initiating treatment, patients should be advised of signs and symptoms of SJS and TEN. If signs and symptoms suggestive of SJS or TEN appear, osimertinib should be interrupted. This medical product should be discontinued immediately if SJS or TEN are diagnosed.
QTc interval prolongation: QTc interval prolongation occurs in patients treated with Osimertinib. QTc interval prolongation may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. No arrhythmic events were reported in AURAex or AURA2.
Changes in cardiac contractility
Across clinical studies, left ventricular ejection fraction (LVEF) decreases greater than or equal to 10 percentage points and a drop to less than 50% occurred in 4.2% of patients treated with monotherapy who had baseline and at least one follow-up LVEF assessment. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered.
In an adjuvant placebo-controlled study, 1.5% (5/325) of patients treated with osimertinib and 1.5% (5/331) of patients treated with placebo experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In another study, following platinum-based chemoradiation therapy, 3.0% (4/135) of patients treated with osimertinib and no patients treated with placebo, who had both a baseline and post-baseline LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In a different study, 8.0% (21/262) of patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.
Keratitis
Keratitis was reported in 0.6% (n=11) of the 1956 patients treated with osimertinib monotherapy. Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.
Aplastic Anaemia
Rare cases of aplastic anaemia, including fatal events, have been reported in association with osimertinib treatment. Before initiating treatment, patients should be advised of signs and symptoms of aplastic anaemia including but not limited to persistent fever, bruising, bleeding, pallor, infection and fatigue. If signs and symptoms suggestive of aplastic anaemia develop, close patient monitoring and drug interruption or discontinuation should be considered.
Age and body weight
Elderly patients (>65 years) or patients with low body weight (<50 kg) may be at increased risk of developing adverse events of Grade 3 or higher. Close monitoring is recommended in these patients.
Hepatitis B Virus (HBV) reactivation
Hepatitis B virus reactivation can occur in patients treated with osimertinib, and in some cases, may result in fulminant hepatitis, hepatic failure, and death. Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation while receiving osimertinib. In patients who develop reactivation of HBV while on osimertinib, treatment should be withheld.
See prescribing information for full details. 

Very common: Diarrhoea, Stomatitis, Rash, Dry skin, Paronychia, Pruritus,
Platelet count decreased, Leucocytes decreased, Lymphocytes decreased, Neutrophils decreased.
Common: Interstitial lung disease.
See prescribing information for full details.

Pharmacokinetic interactions: Strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may increase the exposure of breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) substrates.
See prescribing information for full details.

Pregnancy:  There are no or limited amount of data from the use of osimertinib in pregnant women. TAGRISSO should not be used during pregnancy unless the clinical condition of the woman requires treatment with osimertinib.
Lactation: Is not known whether osimertinib or its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with TAGRISSO.
See prescribing information for full details.                

In phase I/II clinical trials a limited number of patients were treated with Osimertinib daily doses of up to 240 mg without dose limiting toxicities. In these studies, patients who were treated with Osimertinib daily doses of 160 mg and 240 mg experienced an increase in the frequency and severity of a number of typical EGFR-induced AEs (primarily diarrhoea and skin rash) compared to the 80 mg dose. There is limited experience with accidental overdoses in humans. All cases were isolated incidents of patients taking an additional daily dose of Osimertinib in error, without any resulting clinical consequences. There is no specific treatment in the event of Osimertinib overdose. In case of suspected overdose, Osimertinib should be withheld and symptomatic treatment initiated.

Storage: Do not store above 30°C.