Erlotinib 150 Mg/25 mg/100 mg Tablets

Non-Small Cell Lung Cancer (NSCLC): ADCO ERLOTINIB is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutation after failure of at least one prior chemotherapy regimen. ADCO ERLOTINIB was not effective after platinum-based therapy that included gemcitabine. ADCO ERLOTINIB monotherapy is indicated for the maintenance treatment of patients having received first-line platinum-based (other than gemcitabine + cisplatin) doublets chemotherapy for locally advanced or metastatic NSCLC. No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with EGFR-negative tumours. See section 5.1

Bronchial Adenocarcinoma ADCO ERLOTINIB is indicated for the first-line treatment of patients with locally advanced or metastatic (stage 4) bronchial adenocarcinoma whose tumours have demonstrated EGFR activating mutations and who have never smoked and had Eastern Cooperative Oncology Group (ECOG) performance status of 0 u2013 1. When prescribing ADCO ERLOTINIB, factors associated with prolonged survival should be taken into account. No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with EGFR-negative tumours. See section 5.1

Pancreatic Cancer ADCO ERLOTINIB in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

ADCO ERLOTINIB treatment should be supervised by a medical practitioner experienced in the use of anticancer therapies. Concomitant use of CYP3A4 substrates and modulators may require dose adjustment. See section 4.5. Where dose adjustment is necessary, reduce in 50 mg steps.

Posology Non-Small Cell Lung Cancer and Bronchial Adenocarcinoma EGFR mutation testing should be performed prior to initiation of ADCO ERLOTINIB therapy in chemo-naive patients with advanced or metastatic NSCLC and bronchial adenocarcinoma. The recommended dose is 150 mg daily taken at least 1 hour before or two hours after the ingestion of food. Where dose adjustment is necessary, reduce in 50 mg steps.

Pancreatic Cancer The recommended daily dose of ADCO ERLOTINIB is 100 mg taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine (see gemcitabine professional information for pancreatic cancer indication).

Special populations Hepatic impairment Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh score 7 u2013 9) compared with patients with adequate hepatic function, caution should be used when administering ADCO ERLOTINIB to patients with hepatic impairment. See section 5.2. ADCO ERLOTINIB should not be used in patients with severe hepatic dysfunction (AST and ALT > 5 x ULN). Dose reduction or interruption of ADCO ERLOTINIB should be considered if severe adverse reactions occur. Safety and efficacy have not been studied in patients with severe hepatic dysfunction.

Renal impairment The safety and efficacy of ADCO ERLOTINIB has not been studied in patients with renal impairment. See section 5.2. ADCO ERLOTINIB should not be used in patients with severe renal impairment.

Smokers Cigarette smoking has been shown to reduce erlotinib exposure by 50 - 60 %. The maximum tolerated dose of ADCO ERLOTINIB in NSCLC and bronchial adenocarcinoma patients who currently smoke cigarettes was 300 mg. The 300 mg dose did not show improved efficacy in second line treatment after failure of chemotherapy compared to the recommended 150 mg dose in patients who continue to smoke cigarettes.

Paediatric use The safety and efficacy of ADCO ERLOTINIB has not been established in patients under the age of 18 years.

• Hypersensitivity to the erlotinib or to any of the excipients listed in section 6.1.

Interstitial Lung Disease Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving erlotinib, as contained in ADCO ERLOTINIB, for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD-like events (0,8 %) was the same in both the placebo and erlotinib groups. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2,5 % in the erlotinib, as contained in ADCO ERLOTINIB, plus gemcitabine group versus 0,4 % in the placebo plus gemcitabine-treated group. The overall incidence in erlotinib-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) is approximately 0,6 %.

Some examples of reported diagnoses in patients suspected of having ILD -like events, included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome, alveolitis and lung infiltration. These ILD-like events started from a few days to several months after initiating therapy with erlotinib, as contained in ADCO ERLOTINIB. Most of the cases were associated with confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease or pulmonary infections. In patients who develop acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnoea, cough and fever, ADCO ERLOTINIB therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, ADCO ERLOTINIB should be discontinued and appropriate treatment administered as necessary. See section 4.8.

Diarrhoea, dehydration, electrolyte imbalance and renal failure Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50 % of patients on erlotinib as contained in ADCO ERLOTINIB and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, ADCO ERLOTINIB therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see section 4.8).

There have been reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (especially concomitant chemotherapy and other medications, symptoms or diseases or other predisposing conditions including advanced age), ADCO ERLOTINIB therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.

Hepatitis, hepatic failure Cases of hepatic failure (including fatalities) have been reported during use of erlotinib, as contained in ADCO ERLOTINIB. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. ADCO ERLOTINIB dosing should be interrupted if changes in liver function are severe (see section 4.8). ADCO ERLOTINIB is not recommended for use in patients with severe hepatic dysfunction.

Gastrointestinal perforation Patients receiving ADCO ERLOTINIB are at increased risk of developing gastrointestinal perforation (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic medicines, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. ADCO ERLOTINIB should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).

Bullous and exfoliative skin disorders Bullous, blistering and exfoliative skin conditions have been reported, including cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal (see section 4.8). ADCO ERLOTINIB treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should be tested for skin infection and treated according to local management guidelines. For patients who are exposed to sun, protective clothing, and/or use of sunscreen (e.g. mineral-containing) may be advisable.

Ocular disorders Cases of corneal perforation or ulceration, uveitis, iridocyclitis and iritis have been reported during use of ADCO ERLOTINIB. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with ADCO ERLOTINIB treatment which are also risk factors for corneal perforation/ulceration. ADCO ERLOTINIB therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain.

Smokers Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant (see section 4.5). Efficacy in smoking or previous or past-smoking patients has not been established.

Ischaemic Central Nervous System Vascular Condition Associated with Tyrosine Kinase Inhibitors (TKI) Cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs (see section 4.8). Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events. Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events.

Assessment of EGFR mutation status When considering the use of ADCO ERLOTINIB as a first line or maintenance treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation status of a patient is determined. A validated, robust, reliable and sensitive test with a prespecified positivity threshold and demonstrated utility for the determination of EGFR mutation status, using either tumor DNA derived from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed according to local medical practice. If a plasma-based cfDNA test is used and the result is negative for activating mutations, perform a tissue test wherever possible due to the potential for false negative results from a plasma-based test.

Potential inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4 may lead to increased toxicity. Concomitant treatment with these types of agents should be avoided (see section 4.5).

Other forms of interactions: Erlotinib is characterised by a decrease in solubility above 5. Medicines that alter pH of the upper gastrointestinal tract (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of ADCO ERLOTINIB when co-administered with such agents is not likely to compensate for the loss of exposure. Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Concomitant administration of these combinations should therefore be avoided (see section 4.5). If the use of antacids is considered necessary during treatment with ADCO ERLOTINIB, they should be taken at least 4 hours before or 2 hours after the daily dose of ADCO ERLOTINIB.

Women of childbearing potential Women of childbearing potential must be advised to avoid pregnancy while on ADCO ERLOTINIB. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.

Pregnancy There are no adequate data for the use of ADCO ERLOTINIB in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Breastfeeding It is not known whether erlotinib is excreted in human milk. No data is available regarding the impact of ADCO ERLOTINIB on milk production. Because of the potential harm to the infant, mothers should be advised against breastfeeding while receiving ADCO ERLOTINIB and for at least 2 weeks after the final dose.

Fertility Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility cannot be excluded as animal studies have shown effects on reproductive parameters. The potential risk for humans is unknown.

No studies on the effects on the ability to drive and use machines have been performed; however erlotinib is not associated with impairment of mental ability. Ocular disorders have been observed with ADCO ERLOTINIB treatment, affecting a a personu2019s ability to safely drive and use machines (see section 4.4, 4.8).

Summary of the safety profile ADCO ERLOTINIB monotherapy The most frequently reported side effects were rash and diarrhoea. In general, rash manifests as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in sun exposed areas. For patients who are exposed to sun, protective clothing, and/or use of sun screen (e.g. mineral-containing) may be advisable. Skin fissures, mostly non-serious, were reported, most were associated with rash and dry skin.

Table 1: Tabulated summary of adverse effects:

SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Infections and infestations Frequent Infection Metabolism and nutrition disorders Frequent Anorexia Decrease in weight Psychiatric disorders Frequent Depression Nervous system disorders Frequent Neuropathy Eye disorders Frequent Cojunctivitis Keratoconjunctivitis sicca Keratitis Less frequent Eyelash changes (including in-growing eyelashes, excessive growth and thickening of the eyelashes) Corneal perforations Corneal ulcerations Uveitis Vascular disorders Frequent Cerebrovascular Accident Less frequent Transient Ischaemic Attack Cerebral Infarction Ischaemic stroke Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea Cough Epistaxis Less frequent Interstitial lung disease (ILD) (including fatalities in patients with NSCLC and other advanced solid tumours) Gastrointestinal disorders Frequent Diarrhoea (including fatalities) Nausea Vomiting Stomatitis Abdominal pain Dyspepsia Flatulence Gastrointestinal bleeding (including fatalities) Less frequent Gastrointestinal perforations (including fatalities) Hepato biliary disorders Frequent Liver function test abnormalities (including increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) Less frequent Hepatic failure (including fatalities) Skin and subcutaneous tissue disorders Frequent Rash (mild to moderate) Pruritis Dry skin Alopecia Paronychia Folliculitis (mild to moderate and non-serious) Acne/Dermatitis acneiform Skin fissures Less frequent Hirsutism Eyebrow changes Brittle and loose nails Hyperpigmentation Palmar plantar erythrodysaesthesia syndrome Stevens-Johnson syndrome / Toxic epidermal necrolysis (including fatalities) Renal and urinary disorders Frequent Renal insufficiency Less frequent Nephritis Proteinuria General disorders and administration site conditions Frequent Fatigue Pyrexia Rigors

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the eReporting link at https://primaryreporting.who-umc.org/Reporting/Reporter?OrganizationID=ZA

Symptoms Single oral doses of ADCO ERLOTINIB up to 1000 mg in healthy subjects, and up to 1600 mg in cancer patients have been tolerated. Repeated twice daily doses of 200 mg in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, severe adverse reactions such as diarrhoea, rash and possibly increased liver transaminases may occur above the recommended dose.

Management In case of suspected overdose, ADCO ERLOTINIB should be withheld and symptomatic treatment initiated.