SANDOZ GEFITINIB

2 Recommended Dose and Dosage Adjustment The recommended daily dose of Sandoz Gefitinib (gefitinib) is one 250 mg tablet with or without food. Higher doses do not produce a better response and lead to increased toxicity. No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity or renal function.

However, data are limited in patients with severe renal impairment (creatinine clearance ≤ 20 ml/min (see 10 CLINICAL PHARMACOLOGY – Pharmacokinetics – Special Populations and Conditions) and caution is advised in these patients. For patients unable to tolerate treatment after a therapy interruption for toxicity, Sandoz Gefitinib should be discontinued and another treatment option should be considered.

Dosage Adjustment due to Toxicity Poorly tolerated diarrhea Patients with poorly tolerated diarrhea (sometimes associated with dehydration) may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose once toxicity has resolved.

Skin adverse drug reactions Patients with skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose once toxicity has resolved.

Eye Symptoms Patients who develop eye symptoms should be evaluated and managed, including interruption of therapy with Sandoz Gefitinib. Reinstatement of the 250 mg/day Sandoz Gefitinib dose should be considered when symptoms and eye changes have resolved.

Respiratory symptoms If patients present with acute onset or worsening of respiratory symptoms such as dyspnea, cough and fever, gefitinib should be interrupted and prompt investigation initiated. If Interstitial Lung Disease (ILD) is confirmed, Sandoz Gefitinib should be discontinued and the patient treated appropriately (see 7 WARNINGS AND PRECAUTIONS - Respiratory and 8 ADVERSE REACTIONS sections).

1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment due to cirrhosis was observed in a phase I hepatic impairment study (see 7 WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic and 10 CLINICAL PHARMACOLOGY sections).

This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib. No dose adjustments are recommended for patients with moderate to severe hepatic impairment (Child Pugh B or C) however, these patients should be closely monitored.

sections). 1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment due to cirrhosis was observed in a phase I hepatic impairment study (see 7 WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic and 10 CLINICAL PHARMACOLOGY sections).

This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib. No dose adjustments are recommended for patients with moderate to severe hepatic impairment (Child Pugh B or C) however, these patients should be closely monitored.

No dose adjustments are recommended for patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases. These patients should be closely monitored for adverse events. In patients with impaired liver function secondary to liver metastases, gefitinib exposure was similar for patients with moderate hepatic dysfunction compared to normal hepatic function.

Data from four patients with severe hepatic dysfunction due to liver metastases suggested that steady state exposures in these patients are also similar to those in patients with normal hepatic function. 5 times upper limit of normal (ULN) with no demonstrable liver metastases or greater than 5 times ULN in the presence of liver metastases were excluded due to potential hepatic concerns associated with the carboplatin/paclitaxel doublet.

Consequently, the IPASS study does not contribute any data in this patient population. 4 Administration Sandoz Gefitinib is for oral use only. 5 Missed Dose If a dose of Sandoz Gefitinib is missed, it should be taken as soon as the patient remembers, as long as it is at least 12 hours before the next dose is due.

If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose. 5 OVERDOSAGE A limited number of patients were treated with daily doses of up to 1000 mg in phase I clinical trials.

– Monitoring and Laboratory Tests) This indication was based on progression-free survival (PFS). After 78% of trial patients had died, no statistically significant difference in overall survival (OS) was demonstrated with first line gefitinib compared to the first line chemotherapy doublet in patients with EGFR mutation positive tumours in the IPASS study (see 14 CLINICAL TRIALS).

1 Special Populations). 1 Special Populations). 2 CONTRAINDICATIONS Sandoz Gefitinib is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING). 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions  Sandoz Gefitinib (gefitinib) should be administered under the supervision of a qualified health professional who is experienced in the treatment and management of patients with cancer.

 Sandoz Gefitinib should not be used in patients with EGFR mutation negative tumours (see 7 WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests; and 14 CLINICAL TRIALS).  Sandoz Gefitinib has not been studied in patients with severe renal impairment (see 10 CLINICAL PHARMACOLOGY – Special Populations and Conditions).

 Isolated cases of hepatic failure and fulminant hepatitis, including fatalities, have been Sandoz Gefitinib Page 5 of 41 reported with Sandoz Gefitinib use (see 7 WARNINGS AND PRECAUTIONS – Hepatotoxicity). 2 Recommended Dose and Dosage Adjustment The recommended daily dose of Sandoz Gefitinib (gefitinib) is one 250 mg tablet with or without food.

Higher doses do not produce a better response and lead to increased toxicity. No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity or renal function. However, data are limited in patients with severe renal impairment (creatinine clearance ≤ 20 ml/min (see 10 CLINICAL PHARMACOLOGY – Pharmacokinetics – Special Populations and Conditions) and caution is advised in these patients.

Sandoz Gefitinib is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).