Erlotinib Zydus 25/100/150 25 mg, 100 mg, 150 mg Tablets

Non - small cell lung cancer (NSCLC) ERLOTINIB ZYDUS 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. ERLOTINIB ZYDUS was not ef fective after platinum - based therapy that included gemcitabine. ERLOTINIB ZYDUS monotherapy is indicated for the maintenance treatment of patients having received first line platinum - based (other than gemcitabine + cisplatin) doublets chemotherapy for loc ally 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 ERLOTINIB ZYDUS 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 (EC OG) performance status of 0 u2013 1. When prescribing ERLOTINIB ZYDUS , 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 ERLOTINIB ZYDUS in combination with gemcitabine is indicated for the first - line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Posology ERLOTINIB ZYDUS 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.

Non - small cell lung cancer and bronchial adenocarcinoma EGFR mutation testing should be performed prior to initiation of ERLOTINIB ZYDUS therapy in chemo - nau00efve 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 ERL OTINIB ZYDUS 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).

Hepatic impairment Erlotinib is eliminated by hepa tic 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 ER LOTINIB ZYDUS to patients with hepatic impairment (see section 5.2). ERLOTINIB ZYDUS should not be used in patients with severe hepatic dysfunction (AST/SGOT and ALT/SGPT > 5 x ULN). Dose reduction or interruption of ERLOTINIB ZYDUS 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 ERLOTINIB ZYDUS has not been studied in patients with renal impairment (see section 5.2). E RLOTINIB ZYDUS should not be used in patients with severe renal impairment.

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

Smokers Cigarette smoking has been shown to reduce erlotinib exposure by 50 u2013 60 %. The maximum tolerated dose of ERLOTINIB ZYDUS 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.

Method of administration Oral.

Severe hypersensitivity to erlotinib or to any of the excipients listed in section 6.1.

Assessment of EGFR mutation status When considering the use of ERLOTINIB ZYDUS as a first line or maintenance treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutat ion 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 tumour DNA derived from a tissue sample o r 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.

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 likel y to be clinically significant (see sections 4.2, 4.5 and 5.2).

Interstitial lung disease (ILD) Cases of ILD - like events, including fatalities, have been reported less frequently in patients receiving ERLOTINIB ZYDUS for treatment of NSCLC, pancreatic can cer or other advanced solid tumours. A pivotal study BR.21 in NSCLC revealed that the incidence of ILD (0,8 %) was the same in both the placebo and erlotinib groups. In a meta - analysis of NSCLC randomised controlled clinical trials, the incidence of ILD - li ke events was 0,9 % in erlotinib compared to 0,4 % in patients in the control arms. In a pancreatic cancer study in combination with gemcitabine, the incidence of ILD - like events was 2,5 % in the erlotinib plus gemcitabine group versus 0,4 % in the placebo plus gemcitabine treated group. Reported diagnoses in patients suspected of having ILD - like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, inters titial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating erlotinib therapy. Confounding or contri buting factors such as concomitant or prior chemotherapy, prior radiotherapy, pre - existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, ERLOTINIB ZYDUS therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with ERLOTINIB ZYDUS and gemcitabine should be monitored carefully for the possibility to deve lop ILD - like toxicity. If ILD is diagnosed, ERLOTINIB ZYDUS should be discontinued and appropriate treatment initiated as necessary (see section 4.8).

Diarrhoea, dehydration, electrolyte imbalance and renal failure Diarrhoea (including very rare cases wit h a fatal outcome) has occurred in approximately 50 % of patients on erlotinib and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the event of severe or persistent diarrhoea, nausea, a norexia, or vomiting associated with dehydration, ERLOTINIB ZYDUS 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 fata lities). Some reports 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 (concomitant chemotherapy and other medicines, symptoms or diseases or other predisposing conditions including advanced age), ERLOTINIB ZYDUS 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 fat alities) have been reported during use of erlotinib . Confounding factors have included pre - existing liver disease or concomitant hepatotoxic medicines. Therefore, in such patients, periodic liver function testing should be considered. ERLOTINIB ZYDUS dosin g should be interrupted if changes in liver function are severe (see section 4.8). ERLOTINIB ZYDUS is not recommended for use in patients with severe hepatic dysfunction.

Gastrointestinal perforation Patients receiving ERLOTINIB ZYDUS 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. ERLOTINIB ZYDUS should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).

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

Ocular disorders Cases of corneal perforation or ulceration, uveitis, iridocyclitis and iritis have been reported during use of erlotinib (see section 4.8). Other ocular disorders including abnorma l eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with erlotinib treatment which are also risk factors for corneal perforation/ulceration. ERLOTINIB ZYDUS should be used with caution in patients with a history of keratitis, ulcer ative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. ERLOTINIB ZYDUS therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain or when a diagnosis of ulcerative keratitis is confirmed.

Potent inducers of CYP3A4 may reduce the efficacy of ERLOTINIB ZYDUS whereas potent inhibitors of CYP3A4 may lead to increased toxicity. Concomitant treatment with these types of medicines should be avoided (see section 4.5) Other forms of interactions Erlotinib is characterised by a decrease i n solubility at pH above 5. Medicines that alter the pH of the upper gastrointestinal (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of ERLOTINIB ZYDUS and hence its bioavailability. Increasing the dose of ER LOTINIB ZYDUS when co - administered with such medicines is not likely to compensate for the loss of exposure. Combination of ERLOTINIB ZYDUS with proton pump inhibitors should be avoided (see section 4.5). The effects of concomitant administration of ERLOTI NIB ZYDUS with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided (see section 4.5). If the use of antacids are considered necessary during trea tment with ERLOTINIB ZYDUS , they should be taken at least 4 hours before or 2 hours after the daily dose of ERLOTINIB ZYDUS . ERLOTINIB ZYDUS contains sugar ERLOTINIB ZYDUS contains lactose monohydrate. Patients with the rare hereditary condition of galact ose intolerance, total lactase deficiency or glucose - galactose malabsorption should not take ERLOTINIB ZYDUS .

Women of childbearing potential Women of childbearing potential must be advised to avoid pregnancy while on ERLOTINIB ZYDUS . Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy with ERLOTINIB ZYDUS . Women who are pregnant and/or breastfeeding should not receive ERLOTINIB ZYDUS .

Pregnancy There are no studies in pregn ant and/or breastfeeding women using ERLOTINIB ZYDUS . Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy cannot be excluded as rat and rabbit studies have shown increased embryo/ foetal lethality. The potential risk for humans is unknown.

Breastfeeding It is not known whether ERLOTINIB ZYDUS is excreted in human milk. No studies have been conducted to assess the impact of ERLOTINIB ZYDUS on milk production or its presence in breast milk. As the potential for harm to the nursing infant is unknown, mothers should be advised against breastfeedin g while receiving ERLOTINIB ZYDUS 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. ERLOTINIB ZYDUS is not associated with impairment of mental ability. Caution is advised before driving a vehicle or operating machinery until the effects of ERLOTINIB ZYDUS are known.

Summary of the safety profile The safety evaluation of erlotinib is based on the data from patients treated with at least one dose of erlotinib monotherapy and patients who received erlotinib in combination with gemcit abine. The most frequent side effects seen in patients treated with erlotinib in clinical studies were rash and diarrhoea. Both rash and diarrhoea resulted in discontinuation of erlotinib in up to 1 % of patients. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in some of the patients. 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 sunscreen (e.g. mineral containing) may be advisable. Skin fissures, mostly non - serious, were reported, most were associated with rash and dry skin. Erlotinib plus gemcitabine was associated with a highe r rate of certain class - specific side effects including rash and required more frequent dose reduction or interruption.

List of adverse reactions Infections and infestations Frequent: infection 1 Metabolism and endocrine disorders Frequent: anorexia, decreased weight Psychiatric disorders Frequent: depression Nervous system disorders Frequent: neuropathy, headache Eye disorders Frequent: keratoconjunctivitis sicca, conjuctivitis, keratitis Less frequent: eyelash changes 2 , corneal perfo rations and corneal ulcerations (have been reported as a complication of mucocutaneous inflammation, uveitis Respiratory, thoracic and mediastinal disorders Frequent: dyspnoea , cough, epistaxis Less frequent: interstitial lung disease (ILD) 3 Gastrointestinal disorders Frequent: diarrhoea 7,8 , nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence, gastrointestinal bleeding 4,7 Less frequent: gastrointestinal perforations 7 Hepatobiliary disorders Frequent: liver function test ab normalities 5 Less frequent: hepatic failure 6 Skin and subcutateous tissue disorders Frequent: rash, pruritis, alopecia, dry skin, paronychia, folliculitis, acne/dermatitis acneiform, skin fissures Less frequent: hirsutism, eyebrow changes, brittle and loose nails, mild skin reactions such as hyperpigmentation, palmar plantar erythrodysaesthesia syndrome, Stevens - Johnson syndrome/toxic epidermal necrolysis 7 Musculoskeletal and connective tissue disorders Frequent: rigors Renal and urinary disorders Frequent: renal insufficiency Less frequent: nephritis, proteinuria General disorders and administration site conditions Frequent: fatigue, pyrexia 1 Severe infections, with or without neutropenia, have included pneumonia, sepsis and cellulitis. 2 Including in - growing eyelashes, excessive growth and thickening of the eyelashes. 3 Including fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid tumours (see section 4.4). 4 In clinical studies, some cases have been associated with concomitant warfarin administration and some with concomitant nonsteroidal anti - inflammatory drug (NSAID) administration (see section 4.5). 5 Including increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin. Cases were mainly mild to moderate in severity, transient in nature or associated with liver metastases. 6 Including fatalities. Confounding factors includ ed pre - existing liver disease or concomitant hepatotoxic medications (see section 4.4). 7 Including fatalities (see section 4.4) 8 Can lead to dehydration, hypokalaemia and renal failure.

Symptoms Single oral doses of ERLOTINIB ZYDUS up to 1 000 mg in healthy subjects, and up to 1 600 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 adv erse reactions such as diarrhoea, rash and possibly increased activity of liver aminotransferases may occur above the recommended dose.

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