IRESSA Film-coated tablets Ref.[9032] Active ingredients: Gefitinib

When considering the use of IRESSA as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used.

Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations (see section 5.1).

Interstitial lung disease (ILD)

Interstitial lung disease (ILD) which may be acute in onset, has been observed in 1.3% of patients receiving gefitinib, and some cases have been fatal (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and the patient should be promptly investigated. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately.

In a Japanese pharmacoepidemiological case control study in 3,159 patients with NSCLC receiving gefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received IRESSA or chemotherapy) were identified: smoking, poor performance status (PS ≥2), CT scan evidence of reduced normal lung (≤50%), recent diagnosis of NSCLC (<6 months), pre-existing ILD, older age (≥55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on IRESSA or chemotherapy was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤50%), pre-existing ILD, older age (≥65 years old), and extensive areas adherent to pleura (≥50%).

Hepatotoxicity and liver impairment

Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis (see section 4.8). There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe.

Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations of gefitinib (see section 5.2).

Interactions with other medicinal products

CYP3A4 inducers may increase metabolism of gefitinib and decrease gefitinib plasma concentrations. Therefore, concomitant administration of CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or herbal preparations containing St John’s wort/Hypericum perforatum) may reduce efficacy of the treatment and should be avoided (see section 4.5).

In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4 inhibitor might lead to increased plasma levels of gefitinib. At initiation of treatment with a CYP3A4 inhibitor, patients should be closely monitored for gefitinib adverse reactions (see section 4.5).

International normalised ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin together with gefitinib (see section 4.5). Patients taking warfarin and gefitinib concomitantly should be monitored regularly for changes in prothrombin time (PT) or INR.

Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pump inhibitors and h₂-antagonists may reduce bioavailability and plasma concentrations of gefitinib and, therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of gefitinib may have a similar effect (see sections 4.5 and 5.2).

Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine.

Lactose

IRESSA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

IRESSA contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free.'

Further precautions for use

Patients should be advised to seek medical advice immediately if they experience severe or persistent diarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptoms should be managed as clinically indicated (see section 4.8).

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.

If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do not resolve, or if symptoms recur on reintroduction of gefitinib, permanent discontinuation should be considered.

In a phase I/II trial studying the use of gefitinib and radiation in paediatric patients, with newly diagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of Central Nervous System (CNS) haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established.

Gastrointestinal perforation has been reported in patients taking gefitinib. In most cases this is associated with other known risk factors, including concomitant medications such as steroids or NSAIDS, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation.

The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6.

Active substances that may increase gefitinib plasma concentrations

In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding.

Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions.

There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold (see section 5.2). If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions.

Active substances that may reduce gefitinib plasma concentrations

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John’s wort/Hypericum perforatum) should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% (see section 4.4).

Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib. Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥5 resulted in a reduced mean gefitinib AUC by 47% in healthy volunteers (see section 4.4 and 5.2).

Active substances that may have their plasma concentrations altered by gefitinib

In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial in patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6 substrate should be considered especially for products with a narrow therapeutic window.

Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding is unknown.

Other potential interactions

INR elevations and/or bleeding events have been reported in some patients concomitantly taking warfarin (see section 4.4).

Women of childbearing potential

Women of childbearing potential must be advised not to get pregnant during therapy.

Pregnancy

There are no data from the use of gefitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IRESSA should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether gefitinib is secreted in human milk. Gefitinib and metabolites of gefitinib accumulated in milk of lactating rats (see section 5.3). Gefitinib is contraindicated during breast-feeding and therefore breast-feeding must be discontinued while receiving gefitinib therapy (see section 4.3).

During treatment with gefitinib, asthenia has been reported. Therefore, patients who experience this symptom should be cautious when driving or using machines.

Summary of the safety profile

In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients), the most frequently reported adverse drug reactions (ADRs), occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR.

Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.

Tabulated list of adverse reactions

The safety profile presented in Table 1 is based on the gefitinib clinical development programme and postmarketed experience. Adverse reactions have been assigned to the frequency categories in Table 1 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients).

Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse reactions:

Metabolism and nutrition disorders

Very common: Anorexia mild or moderate (CTC grade 1 or 2)

Eye disorders

Common: Conjunctivitis, blepharitis, and dry eye*, mainly mild (CTC grade 1)

Uncommon: Corneal erosion, reversible and sometimes in association with aberrant eyelash growth, Keratitis (0.12%)

Vascular disorders

Common: Haemorrhage, such as epistaxis and haematuria

Respiratory, thoracic and mediastinal disorders

Common: Interstitial lung disease (1.3%), often severe (CTC grade 3 -4). Cases with fatal outcomes have been reported

Gastrointestinal disorders

Very common: Diarrhoea, mainly mild or moderate (CTC grade 1 or 2), Vomiting, mainly mild or moderate (CTC grade 1 or 2), Nausea, mainly mild (CTC grade 1), Stomatitis, predominantly mild in nature (CTC grade 1)

Common: Dehydration, secondary to diarrhoea, nausea, vomiting or anorexia, Dry mouth*, predominantly mild (CTC grade 1)

Uncommon: Pancreatitis, Gastrointestinal perforation

Hepatobiliary disorders

__Very common Elevations in alanine aminotransferase, mainly mild to moderate

Common: Elevations in aspartate aminotransferase, mainly mild to moderate, Elevations in total bilirubin, mainly mild to moderate

Uncommon: Hepatitis**

Skin and subcutaneous tissue disorders

Very common: Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, including skin fissures, on an erythematous base

Common: Nail disorder, Alopecia, Allergic reactions (1.1%), including angioedema and urticaria

Rare: Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme, Cutaneous vasculitis

Renal and urinary disorders

Common: Asymptomatic laboratory elevations in blood creatinine, Proteinuria, Cystitis

Rare: Haemorrhagic cystitis

General disorders and administration site conditions

Very common: Asthenia, predominantly mild (CTC grade 1)

Common: Pyrexia

The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with a change from baseline of 2 or more CTC grades in the relevant laboratory parameters.

* This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen with gefitinib.
** This includes isolated reports of hepatic failure which in some cases led to fatal outcomes.

Interstitial lung disease (ILD)

In the INTEREST trial, the incidence of ILD type events was 1.4% (10) patients in the gefitinib group versus 1.1% (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in a patient receiving gefitinib.

In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1% in both treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo was approximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.

In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%. The proportion of ILD-type events with a fatal outcome was 38.6%.

In a phase III open-label clinical trial (IPASS) in 1217 patients comparing IRESSA to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the IRESSA treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.