Tagrisso Drug Information

Recommended Evaluation and Testing Before Initiating TAGRISSO TAGRISSO Monotherapy • Before initiating TAGRISSO monotherapy in patients with cardiac risk factors, conduct cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF). • Before initiating TAGRISSO, perform complete blood count with differential. TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy • Before initiating TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of left ventricular ejection fraction (LVEF). • Before initiating TAGRISSO, perform complete blood count with differential.

Patient Selection Table 1 below presents the patient selection criteria for treatment with TAGRISSO. Table 1: Patient Selection

Recommended Dosage and Administration Recommended Dosage Table 2 provides the recommended dosage of TAGRISSO by indication. Table 2:. Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration.

Missed Dose If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.

Administration to Patients Who Have Difficulty Swallowing Solids Disperse TAGRISSO tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation.

If administration via nasogastric tube is required, disperse the TAGRISSO tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Repeat this step until no pieces remain in the syringe.

This will help to ensure that the full prescribed dose of the TAGRISSO is given. The dispersion and residues should be administered within 30 minutes of the addition of the tablets to water.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 3. Table 3. Recommended Dosage Modifications for TAGRISSO Target Organ Adverse Reaction Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).

Dosage Modification Pulmonary (Patients who have not received recent definitive platinum-based chemoradiation therapy) Any Grade Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO. Pulmonary (Patients who have received recent definitive platinum-based chemoradiation therapy) s for Combination Therapy When TAGRISSO is administered in combination with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate. For TAGRISSO dose modification instructions, see Table 3.

Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information. Drug Interactions Strong CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers with TAGRISSO. If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer.

Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS section reflect exposure to TAGRISSO in 1813 patients with EGFR mutation-positive NSCLC who received TAGRISSO monotherapy at the recommended dose of 80 mg orally once daily until disease progression or unacceptable toxicity in four randomized, controlled trials, two single arm trials {NCT02094261}, and one dose-finding study, AURA1 (n=173). In this pooled safety population, the most common adverse reactions in ≥20% of 1813 patients who received TAGRISSO monotherapy were diarrhea ( %).

In addition to the 1813 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to TAGRISSO monotherapy (80 mg orally once daily until disease progression or unacceptable toxicity) following definitive platinum-based chemoradiation therapy (n=143) in the LAURA study. The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, 143 patients with EGFR mutation-positive locally advanced, unresectable (stage III) NSCLC, and 833 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in five randomized, controlled trials. The data also reflect exposure to TAGRISSO at the recommended dose of 80 mg daily given in combination with pemetrexed and platinum-based chemotherapy in 276 patients with EGFR mutation-positive locally advanced or metastatic NSCLC in one randomized controlled trial.

Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies. Adjuvant Treatment of EGFR Mutation-Positive NSCLC - Monotherapy The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.

Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO.

Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%). Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 4. QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec. Table 5.

Laboratory Abnormalities Worsening from Baseline in ≥ Laboratory abnormalities in ADAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (10%). Locally Advanced, Unresectable (Stage III) EGFR Mutation Positive NSCLC The safety of TAGRISSO was evaluated in LAURA, a double blind, randomized (2:1), placebo controlled study conducted in 216 patients with EGFR exon 19 deletions or exon 21 L858R mutation positive, locally advanced, unresectable (stage III) NSCLC, who had not progressed during or following definitive platinum based chemoradiation therapy. Among patients who received TAGRISSO, 81% were exposed for 6 months or longer and 74% were exposed for one year or longer.

Fatal adverse reactions occurred in 1.4% of patients who received TAGRISSO due to pneumonia (0.7%) and ILD/pneumonitis (0.7%). Permanent discontinuation of TAGRISSO due to an adverse reaction occurred in 13% of patients. The adverse reactions resulting in permanent discontinuation of TAGRISSO in > 1 patient were ILD/pneumonitis (7%) and pneumonia (1.4%).

Dosage interruptions of TAGRISSO due to an adverse reaction occurred in 56% of patients. Dose reductions of TAGRISSO due to an adverse reaction occurred in 8% of patients. The most common adverse reactions, including laboratory abnormalities worsening from baseline, were lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19.

Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in LAURA. Table 6. Table 7.

Laboratory Abnormalities Worsening from Baseline in ≥ A clinically relevant laboratory abnormality in LAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (19%). Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer - Monotherapy The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active‑controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months.

The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%). Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.

Table 8. Table 9. Laboratory Abnormalities Worsening from Baseline in ≥ is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO and EGFR comparator.

A clinically relevant laboratory abnormality in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%). Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy The safety of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was evaluated in FLAURA2, a multicenter international open-label, randomized (1:1), active-controlled trial conducted in 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was 22.3 months and the median duration of exposure to TAGRISSO monotherapy was 19.3 months.

Adverse reactions leading to dose reduction of TAGRISSO occurred in 10% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy. The most frequently reported adverse reactions leading to dose reduction of TAGRISSO in the combination arm in ≥1% of patients were diarrhea (1.1%) and rash (1.1%). The most common adverse reactions, including laboratory abnormalities worsening from baseline, were leukopenia, thrombocytopenia, neutropenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, increased blood creatinine.

Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2. Table 10. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2 NCI CTCAE v5.0 Clinically relevant adverse reactions in FLAURA2 in <10% of patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy were alopecia (9%), epistaxis (7%), palmar-plantar erythrodysesthesia syndrome (5%), interstitial lung disease ( %).

Table 11. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2 NCI CTCAE v5.0 Findings based on test results presented as CTCAE grade shifts. 0M Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment.

A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients.

No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO.

Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. Table 12. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3 NCI CTCAE v4.0.

Table 13. Laboratory Abnormalities Worsening from Baseline in ≥ Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%). Other Clinical Trials Experience The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. o Skin and subcutaneous tissue: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans o Blood and lymphatic system disorders: Aplastic anemia.

Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Co-administering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone. Decreased osimertinib exposure may lead to reduced efficacy. Avoid co-administering TAGRISSO with strong CYP3A inducers.

Increase the TAGRISSO dosage when co-administering with a strong CYP3A4 inducer if concurrent use is unavoidable. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

Effect of Osimertinib on Other Drugs Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone. Increased BCRP or P-gp substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO.

Drugs That Prolong the QTc Interval

The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring.

Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death.

When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.

Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established.