Egrotib 25, 100 & 150 25 mg, 100 mg, 150 mg Tablet

Non-Small Cell Lung Cancer (NSCLC)
EGROTIB is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer with EGFR activating mutation after failure of at least one prior chemotherapy regimen. EGROTIB was not effective after platinum-based therapy that included gemcitabine. EGROTIB 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.
Bronchial Adenocarcinoma
EGROTIB 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 ECOG performance status of 0 u2013 1. When prescribing EGROTIB, 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.
Pancreatic Cancer
EGROTIB in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Posology
EGROTIB 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 EGROTIB 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 EGROTIB 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 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 EGROTIB to patients with hepatic impairment (see section 5.2). EGROTIB should not be used in patients with severe hepatic dysfunction (AST/SGOT and ALT/SGPT > 5 x ULN). Dose reduction or interruption of EGROTIB 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 EGROTIB has not been studied in patients with renal impairment (see section 5.2). EGROTIB 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 EGROTIB 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.
Pediatric use: The safety and efficacy of EGROTIB has not been established in patients under the age of 18 years.
Method of administration
Oral use.

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

Interstitial Lung Disease: Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving 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 was (0,8 %) the same in both the placebo and the erlotinib groups. In the 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. 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 erlotinib therapy. 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, EGROTIB therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with EGROTIB and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, EGROTIB 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 and moderate or severe diarrhoea should be treated, e.g. with loperamide. In some cases dose reduction may be necessary. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, EGROTIB 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 reports of renal failure 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 patients with aggravating risk factors (concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), EGROTIB 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. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medicines. Therefore, in such patients, periodic liver function testing should be considered. EGROTIB dosing should be interrupted if changes in liver function are severe. EGROTIB is not recommended for use in patients with severe hepatic dysfunction.
Gastrointestinal Perforation: Patients receiving EGROTIB are at increased risk of developing gastrointestinal perforation (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. EGROTIB should be permanently discontinued in patients who develop gastrointestinal perforation.
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. EGROTIB 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 sun screen (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 erlotinib. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with erlotinib treatment which are also risk factors for corneal perforation/ulceration. EGROTIB therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain. 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 EGROTIB should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. EGROTIB should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
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 sections 4.2, 4.5 and 5.2).

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 medicines 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 (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of EGROTIB when co-administered with such medicines 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. Therefore, concomitant administration of these combinations should be avoided (see section 4.5). If the use of antacids is considered necessary during treatment with EGROTIB, they should be taken at least 4 hours before or 2 hours after the daily dose of EGROTIB.

Women of childbearing potential/Contraception in males and females
Women of childbearing potential must be advised to avoid pregnancy while on EGROTIB. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Women who are pregnant and/or breastfeeding should not receive EGROTIB.
Pregnancy
There are no studies in pregnant and/or breastfeeding women using EGROTIB. 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 is excreted in human milk. No studies have been conducted to assess the impact of EGROTIB on milk production or its presence in breast milk. As the potential harm to the nursing infant is unknown, mothers should be advised against breastfeeding while receiving EGROTIB 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, EGROTIB is not associated with impairment of mental ability.

Tabulated list of adverse reactions
System Organ Class
Frequent
Less frequent
Infections and infestations
Infection
1
Metabolism and nutrition disorders
Anorexia, decreased weight
Psychiatric disorders
Depression
Nervous system disorders
Headache, neuropathy
Eye disorders
Keratitis, keratoconjunctivitis sicca, conjunctivitis
Eyelash changes (including in-growing eyelashes, excessive growth and thickening of the eyelashes), corneal ulcerations and perforations
2, uveitis
Respiratory, thoracic and mediastinal disorders
Epistaxis, dyspnoea, cough
Serious interstitial lung disease (ILD), including fatalities
Gastrointestinal disorders
Diarrhoea
3, nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence.
Gastrointestinal bleeding
4, including fatalities.
perforations, including fatalities
Hepato-biliary disorders
Liver function test abnormalities
5 (including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin)
Cases of hepatic failure (including fatalities)
6
Skin and subcutaneous tissue disorders
Alopecia, paronychia, dry skin, skin fissures, pruritus, rash
7 (all grades).
Acne, dermatitis acneiform and folliculitis
8. Hirsutism, eyebrow changes and brittle and loose nails. Mild skin reactions such as hyperpigmentation.
Bullous, blistering and exfoliative skin conditions including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which may be fatal.
General disorders and administration site conditions
Fatigue, pyrexia, rigors
1 Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis.
2 Corneal ulcerations and perforations have been reported very rarely in patients receiving erlotinib as a complication of mucocutaneous inflammation.
3 Can lead to dehydration, hypokalaemia and renal failure.
4 Some cases have been associated with concomitant warfarin administration (see section 4.5) and some with concomitant NSAID administration.
5 These were mainly mild or moderate in severity, transient in nature or associated with liver metastases.
6 Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).
7 In general, rash manifests as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in sun exposed areas.
8 Acne, dermatitis acneiform and folliculitis, as mild to moderate and non-serious.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Single oral doses of erlotinib up to 1 000 mg in healthy subjects, and up to 1 600 mg (given as a single dose once weekly) 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 events such as diarrhoea, rash and possibly liver transaminase elevation may occur above the recommended dose. In case of suspected overdose EGROTIB should be withheld and symptomatic treatment initiated.