Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
APPROVED PROFESSIONAL INFORMATION FOR BILURA 25, 100 & 150  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
BILURA 25 (film coated tablets)  
BILURA 100 (film coated tablets)  
BILURA 150 (film coated tablets)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
BILURA 25: Each film coated tablet contains 25 mg erlotinib hydrochloride.  
BILURA 100: Each film coated tablet contains 100 mg erlotinib hydrochloride.  
BILURA 150: Each film coated tablet contains 150 mg erlotinib hydrochloride.  
Contains sugar (lactose monohydrate)  
BILURA 25: Contains 17,850 mg lactose monohydrate.  
BILURA 100: Contains 71,400 mg lactose monohydrate.  
BILURA 150: Contains 107,100 mg lactose monohydrate.  
For full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
PRODUCT NAME] 25: White coloured, round biconvex film coated tablets debossed with ‘H’ on one side  
and '28' on the other side.  
BILURA 100: White coloured, round biconvex film coated tablets debossed with ‘H’ on one side and '21' on  
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the other side.  
PRODUCT NAME] 150: White coloured, round biconvex film coated tablets debossed with ‘H’ on one side  
and '22' on the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
Non-Small Cell Lung Cancer (NSCLC)  
BILURA is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung  
cancer after failure of at least one prior chemotherapy regimen. BILURA was not effective after platinum-  
based therapy that included gemcitabine.  
BILURA 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  
BILURA is indicated for the first-line treatment of patients with locally advanced or metastatic (stage 4)  
bronchial adenocarcinoma whose tumours have demonstrated Epidermal Growth Factor Receptor (EGFR)  
activating mutations and who have never smoked and had ECOG performance status of 0 - 1.  
When prescribing BILURA, 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  
BILURA in combination with gemcitabine is indicated for the first-line treatment of patients with locally  
advanced, unresectable or metastatic pancreatic cancer.  
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4.2 Posology and method of administration  
BILURA 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 BILURA 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 BILURA is 100 mg taken at least one hour before or two hours after the  
ingestion of food, in combination with gemcitabine (see gemcitabine package insert for pancreatic cancer  
indication).  
Special populations  
Hepatic impairment  
BILURA is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in  
patients with moderately impaired hepatic function (Child-Pugh score 7 - 9) compared with patients with  
adequate hepatic function, caution should be used when administering BILURA to patients with hepatic  
impairment (see section 5.2). BILURA should not be used in patients with severe hepatic dysfunction  
(AST/SGOT and ALT/SGPT > 5 x ULN). Dose reduction or interruption of BILURA should be considered if  
severe adverse reactions occur. Safety and efficacy have not been studied in patients with severe hepatic  
dysfunction.  
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Renal impairment  
The safety and efficacy of BILURA has not been studied in patients with renal impairment (see section 5.2).  
BILURA should not be used in patients with severe renal impairment.  
Paediatric use  
The safety and efficacy of BILURA has not been studied in patients under the age of 18 years.  
Smokers  
Cigarette smoking has been shown to reduce erlotinib exposure by 50 – 60 %. The maximum tolerated dose  
of BILURA in NSCLC and bronchial adenocarcinoma patients who currently smoke cigarettes was 300 mg.  
Efficacy and long-term safety of a dose higher than the recommended starting doses have not been  
established in patients who continue to smoke cigarettes.  
Method of administration  
BILURA is taken at least 1 hour before or two hours after the ingestion of food.  
BILURA is a coated tablet, should not be chewed as it may make them to taste very unpleasant. BILURA  
should not be broken because the coating is intended to ensure a prolonged release.  
4.3 Contraindications  
•
•
Hypersensitivity to erlotinib or any of the excipients listed in section 6.1.  
Pregnancy (see section 4.6).  
4.4 Special warnings and precautions for use  
Interstitial Lung Disease: Cases of interstitial lung disease (lLD)-like events, including fatalities, have been  
reported uncommonly in patients receiving BILURA for treatment of non-small cell lung cancer (NSCLC),  
pancreatic cancer or other advanced solid tumours.  
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In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2,5 %  
in the BILURA plus gemcitabine group versus 0,4 % in the placebo plus gemcitabine-treated group. The  
overall incidence in BILURA-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 BILURA 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 a  
dyspnoea, cough and fever, BILURA therapy should be interrupted pending diagnostic evaluation. If ILD is  
diagnosed, BILURA should be discontinued and appropriate treatment administered as necessary (see  
section 4.8).  
Diarrhoea, Dehydration, Electrolyte Imbalance and Renal Failure: Diarrhoea has occurred in  
approximately 50 % of patients on BILURA 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, BILURA 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 medicines,  
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symptoms or diseases or other predisposing conditions including advanced age), BILURA 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  
BILURA. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic  
medicines. Therefore, in such patients, periodic liver function testing should be considered.  
BILURA dosing should be interrupted if changes in liver function are severe. BILURA is not recommended  
for use in patients with severe hepatic dysfunction.  
Gastrointestinal Perforation: Patients receiving BILURA are at increased risk of developing  
gastrointestinal perforation (including some cases with a fatal outcome). Patients receiving concomitant anti-  
angiogenic medicines, corticosteroids, NSAlDs, and/or taxane based chemotherapy, or who have prior  
history of peptic ulceration or diverticular disease are at increased risk. BILURA 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 Steven-Johnson syndrome/toxic epidermal necrolysis, which in some cases  
were fatal (see section 4.8). BILURA treatment should be interrupted or discontinued if the patient develops  
severe bullous, blistering or exfoliating conditions. 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 BILURA. Other ocular disorders including abnormal eyelash growth,  
keratoconjunctivitis sicca or keratitis have been observed with BILURA treatment which are also risk factors  
for corneal perforation/ulceration. BILURA therapy should be interrupted or discontinued if patients present  
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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 sections 4.2, 4.5 and 5.2).  
Interactions with other medicines: BILURA has a potential for clinically significant interactions with other  
medicines. Potent 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).  
ln order to improve traceability of biological medicines, BILURA should be clearly recorded in the patient file.  
Substitution by any other biological medicinal product requires the consent of the prescribing doctor, and the  
substitute product name to be recorded in the files. Information as set forth in this package insert only  
applies to BILURA.  
Assessment of EGFR mutation status: EGFR mutation testing should be performed prior to initiation of  
BILURA therapy in chemo-naïve patients with advanced or metastatic NSCLC and bronchial  
adenocarcinoma. 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.  
Other forms of interactions: Erlotinib is characterised by a decrease in solubility at pH above 5. Medicines  
that alter the pH of the upper Gastro-lntestinal (GI) tract, like proton pump inhibitors, H2 antagonists and  
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antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of BILURA  
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 BILURA, they should be taken at least 4 hours before or 2  
hours after the daily dose of BILURA.  
When considering the use of BILURA 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.  
Lactose warning:  
BILURA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase  
deficiency or glucose-galactose malabsorption should not take this medicine.  
4.5 Interaction with other medicines and other forms of interaction  
Interaction studies have only been performed in adults.  
Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a  
strong inhibitor of glucuronidation by UGT1A1 in vitro. The physiological relevance of the strong inhibition of  
CYP1A1 is unknown due to the very limited expression of CYP1A1 in human tissues.  
When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure  
[AUC] increased significantly by 39 %, while no statistically significant change in Cmax was found. Similarly,  
the exposure to the active metabolite increased by about 60 % and 48 % for AUC and Cmax, respectively.  
The clinical relevance of this increase has not been established. Caution should be exercised when  
ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse events  
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related to erlotinib are observed, the dose of erlotinib may be reduced.  
Pre-treatment or co-administration of BILURA did not alter the clearance of the prototypical CYP3A4  
substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by  
up to 24 %. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the concomitantly  
administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance of other CYP3A4  
substrates are therefore unlikely.  
The inhibition of glucuronidation may cause interactions with medicines which are substrates of UGT1A1 and  
exclusively cleared by this pathway. Patients with low expression levels of UGT1A1 or genetic  
glucuronidation disorders (e.g. Gilbert's disease) may exhibit increased serum concentrations of bilirubin and  
must be treated with caution.  
Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser  
extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in  
tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may  
occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.  
Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma  
concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice  
daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86 % of AUC and  
69 % of Cmax). Therefore, caution should be used when erlotinib is combined with a potent CYP3A4 inhibitor  
or combined CYP3A4/CYP1A2 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole,  
voriconazole), protease inhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be  
reduced, particularly if toxicity is observed.  
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma  
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concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily  
for 7 days), a potent CYP3A4 inducer, resulted in a 69 % decrease in the median erlotinib AUC, following a  
150 mg dose of BILURA, as compared to BILURA alone. Pre-treatment and co-administration of rifampicin  
with a single 450 mg dose of BILURA resulted in a mean erlotinib exposure (AUC) of 57,5 % of that after a  
single 150 mg BILURA dose in the absence of rifampicin treatment. Co-administration of BILURA with  
CYP3A4 inducers should therefore be avoided. Alternative treatments lacking potent CYP3A4 inducing  
activity should be considered when possible. For patients who require concomitant treatment with BILURA  
and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while  
their safety (including renal and liver functions and serum electrolytes) is closely monitored, and if well  
tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety  
monitoring. Higher doses have not been studied in this setting.  
Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St.  
John’s Wort (hypericum perforatum). Caution should be observed when these active substances are  
combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered  
when possible.  
Interactions with warfarin, leading to increased International Normalised Ratio (INR) and bleeding events,  
which in some cases were fatal have been reported in patients receiving BILURA. Patients taking warfarin  
should be monitored regularly for changes in prothrombin time or INR.  
The combination of BILURA and a statin may increase the potential for statin-induced myopathy, including  
rhabdomyolysis, which was observed rarely.  
Results of a pharmacokinetic interaction study indicated a significant 2,8-, 1,5- and 9-fold reduced AUCinf,  
Cmax and plasma concentration at 24 hours, respectively, after administration of BILURA in smokers as  
compared to non-smokers (see section 5.2).  
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Efficacy in smoking patients has not been established.  
Smokers should be advised to stop smoking, as cigarette smoking, which is known to induce CYP1A1 and  
CYP1A2, has been shown to reduce erlotinib exposure by 50 - 60 %.  
Erlotinib is a substrate for the P-glycoprotein (Pgp) active substance transporter. Concomitant administration  
of inhibitors of Pgp, e.g. ciclosporin and verapamil, may lead to altered distribution and/or altered elimination  
of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been established. Caution  
should be exercised in such situations.  
Erlotinib is characterised by a decrease in solubility at pH above 5.  
Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib  
exposure [AUC] and maximum concentration [Cmax] by 46 % and 61 %, respectively. There was no change  
to Tmax or half-life. Therefore, medicines that alter the pH of the upper GI tract may alter the solubility of  
erlotinib and hence its bioavailability. Increasing the dose of BILURA when co-administered with such  
medicines is not likely to compensate for this loss of exposure. The effect of antacids and H2 antagonists on  
the absorption of erlotinib have not been investigated but absorption may be impaired, leading to lower  
plasma levels. 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. If the  
use of antacids is considered necessary during treatment with BILURA, they should be taken at least 4  
hours before or 2 hours after the daily dose of BILURA.  
If the use of ranitidine is considered, it should be used in a staggered manner, i.e. erlotinib must be taken at  
least 2 hours before or 10 hours after the ranitidine dosing. The ranitidine dose should be divided into 2  
equal doses per day.  
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In a Phase Ib study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor  
were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.  
Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with  
carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10,6 %. Although statistically  
significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice,  
there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There  
were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.  
Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with  
capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in Cmax  
when compared with values observed in another study in which erlotinib was given as single medicine.  
There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.  
Erlotinib and proteasome inhibitors  
Due to the working mechanism, proteasome inhibitors including bortezomib may be expected to influence  
the effect of EGFR inhibitors including erlotinib.  
4.6 Fertility, pregnancy and lactation  
Women of childbearing potential/Contraception in males and females  
Women of childbearing potential must be advised to avoid pregnancy while on BILURA. 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 BILURA.  
Pregnancy  
There are no studies in pregnant and/or breastfeeding women using BILURA. Studies in animals have  
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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 BILURA 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 BILURA 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.  
4.7 Effects on ability to drive and use machines  
No studies on the effects on the ability to drive and use machines have been performed, however, BILURA  
is not associated with impairment of mental ability.  
4.8 Undesirable effects  
a) Summary of the safety profile  
BILURA monotherapy: Rash (75 %) and diarrhoea (54 %) were the most frequent side effects regardless of  
causality. Most were Grade 1/2 in severity and manageable without intervention. Grade 3/4 rash and  
diarrhoea occurred in 9 % and 6 %, respectively in BILURA-treated patients and each resulted in study  
discontinuation in 1 % of patients. Dose reduction for rash and diarrhoea was needed in 6 and 1 % of  
patients, respectively. The median time to onset of rash was 8 days and the median time to onset of  
diarrhoea was 12 days.  
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BILURA in combination with chemotherapy for pancreatic carcinoma: The most common side effects in  
pancreatic cancer patients receiving BILURA 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In  
the BILURA plus gemcitabine arm, Grade 3/4 rash and diarrhoea were each reported in 5 % of patients. The  
median time to onset of rash and diarrhoea was 10 days and 15 days, respectively. Rash and diarrhoea  
each resulted in dose reductions in 2 % of patients, and resulted in study discontinuation in up to 1 % of  
patients receiving BILURA plus gemcitabine.  
The BILURA 150 mg plus gemcitabine cohort (23 patients) was  
associated with a higher rate of certain class-specific side effects including rash and required more frequent  
dose reduction or interruption.  
b) Tabulated list of adverse reactions  
BILURA monotherapy:  
Infections and Infestations  
Frequent: Infections with or without neutropenia, pneumonia, sepsis, cellulitis.  
Metabolism and nutrition disorders  
Frequent: Anorexia.  
Frequency unknown: Hypokalaemia  
Eye disorders  
Frequent: Keratoconjunctivitis sicca, conjunctivitis.  
Respiratory, thoracic and mediastinal disorders  
Frequent: Dyspnoea, cough.  
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Gastrointestinal disorders  
Frequent: Diarrhoea, nausea, vomiting, stomatitis, abdominal pain.  
Skin and subcutaneous tissue disorders  
Frequent: Rash, pruritus, dry skin.  
General disorders and administrative site conditions  
Frequent: Fatigue.  
BILURA in combination with chemotherapy for pancreatic carcinoma:  
Infections and Infestations  
Frequent: Infections such as pneumonia, sepsis, cellulitis.  
Metabolism and nutrition disorders  
Frequent: Weight decreased.  
Psychiatric disorders  
Frequent: Depression.  
Nervous system disorders  
Frequent: Neuropathy, headache.  
Respiratory, thoracic and mediastinal disorders  
Frequent: Cough.  
Gastrointestinal disorders  
Frequent: Diarrhoea, stomatitis, dyspepsia, flatulence.  
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Skin and subcutaneous tissue disorders  
Frequent: Rash, alopecia.  
General disorders and administrative site conditions  
Frequent: Fatigue, pyrexia, rigors.  
Other Observations:  
The following undesirable effects have been observed in patients who received erlotinib as a single  
medicine and patients who received erlotinib concurrently with chemotherapy:  
Eye disorders  
Frequent: Keratitis, conjunctivitis.  
Less frequent: Eyelash changes (including in-growing eyelashes, excessive growth and thickening of the  
eyelashes, Corneal ulcerations and perforations have been reported very rarely. Cases of uveitis have been  
reported.  
Respiratory, thoracic and mediastinal disorders  
Frequent: Epistaxis.  
Less frequent: Serious interstitial lung disease (ILD), including fatalities.  
Gastrointestinal disorders  
Frequent: Gastrointestinal bleeding, including fatalities.  
Less frequent: Gastrointestinal perforations, including fatalities.  
Hepato-biliary disorders  
Less frequent: Cases of hepatic failure (including fatalities) have been reported. Confounding factors have  
included pre-existing liver disease or concomitant hepatotoxic medicines (see section 4.4).  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
Skin and subcutaneous tissue disorders  
Frequent: Alopecia, paronychia, dry skin, rash, as mild to moderate, acne, dermatitis acneiform and folliculitis,  
as mild to moderate and non-serious.  
Less frequent: 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.  
Investigations  
Frequent: Liver function test abnormalities (including increased alanine aminotransferase [ALT], aspartate  
aminotransferase [AST], bilirubin). These were mainly mild or moderate in severity, transient in nature or  
associated with liver metastases.  
c) Description of selected adverse reactions  
BILURA monotherapy: Rash and diarrhoea were the most frequent side effects regardless of causality.  
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.  
BILURA in combination with chemotherapy for pancreatic carcinoma: The most common adverse  
effects in pancreatic cancer patients receiving BILURA plus gemcitabine were fatigue, rash and diarrhoea.  
d) Paediatric population  
There have been no specific studies in paediatric patients.  
e) Other special population  
Elderly patients  
Initial K.B  
May 2022  
Page 17 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
There have been no specific studies in elderly patients.  
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. Health care providers are asked to  
report any suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”, found  
online under SAHPRA’s publications: https://www.sahpra.org.za/publications/Index/8 or to the Holder of  
certificate of registration through the mail: pvg.cdma@heterogroups.com.  
Post marketing experience  
Not Applicable  
4.9 Overdose  
Overdosage: Single oral doses of 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. Severe adverse events such as diarrhoea, rash and possibly liver transaminase  
elevation may occur above the recommended dose.  
Treatment: In case of suspected overdose BILURA should be withheld and symptomatic treatment  
initiated.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Category and Class: A 26 Cytostatic agents.  
Mechanism of Action: Erlotinib inhibits the intracellular phosphorylation of HER 1 / EGFR (epidermal  
growth factor receptor type l, also known as HER 1). HER 1 / EGFR is expressed on cell surface of normal  
cells and cancer cells. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or  
death.  
Initial K.B  
May 2022  
Page 18 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
5.2 Pharmacokinetic properties  
Absorption  
Oral erlotinib is absorbed after oral administration and has an extended absorption phase, with mean peak  
plasma levels occurring at approximately 4 hours after oral dosing. Oral bioavailability is approximately 59 %  
compared to IV administration. The exposure after an oral dose may be increased by food. Following  
absorption, erlotinib is highly bound in blood, with approximately 95 % bound to blood components, primarily  
to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein [AAG]), with a free fraction of approximately  
5 % at the recommended dose. Following a 150 mg oral dose of erlotinib, at steady state, the median time to  
reach maximum plasma concentrations is approximately 4,0 hours with median maximum plasma  
concentrations achieved of 1,995 ng/mℓ. Prior to the next dose at 24 hours, the median minimum plasma  
concentrations are 1,238 ng/mℓ. Median AUC achieved during the dosing interval at steady state are 41,300  
μg*hr/mℓ.  
Distribution  
Erlotinib has a mean apparent volume of distribution of 232 ℓ. Erlotinib distributes into tumour tissue of  
humans. In a study of 4 patients (3 with non-small cell lung cancer [N SCLC], and 1 with laryngeal cancer)  
receiving 150 mg daily oral doses of erlotinib, tumour samples from surgical excisions on Day 9 of treatment  
revealed tumour concentrations of erlotinib that varied widely but averaged 1,185 ng/g of tissue.  
This corresponded to an overall average of 63 % of the steady state observed peak plasma concentrations.  
The primary active metabolites were present in tumours at concentrations averaging 160 ng/g tissue, which  
corresponded to an overall average of 113 % of the observed steady state peak plasma concentrations.  
Plasma protein binding is approximately 95 %. Erlotinib binds to serum albumin and alpha-1 acid  
glycoprotein (AAG).  
Biotransformation  
Initial K.B  
May 2022  
Page 19 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
Erlotinib is metabolised in humans by hepatic cytochrome P450 enzymes, primarily CYP3A4, and to a lesser  
extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in the intestine, CYP1A1 in lung and CYP1B1 in  
tumour tissue potentially contribute to the metabolic clearance of erlotinib. In vitro studies indicate  
approximately 80 - 95 % of erlotinib metabolism is by the CYP3A4 enzyme. There are three main metabolic  
pathways identified:  
1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids;  
2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and  
3) aromatic hydroxylation of the phenyl-acetylene moiety.  
The primary metabolites of erlotinib produced by O-demethylation of either side chain have comparable  
potency to erlotinib in preclinical in vitro assays and in vivo tumour models. They are present at levels that  
are less than 10 % of erlotinib and display similar pharmacokinetics as erlotinib.  
Elimination  
The metabolites and trace amounts of erlotinib are excreted predominantly via the faeces (more than 90 %),  
with renal elimination accounting for only a small amount of an oral dose.  
A population pharmacokinetic analysis in 591 patients receiving single agent BILURA show a mean  
apparent clearance of 4,47 ℓ/hour with a median half-life of 36,2 hours. Therefore, the time to reach steady  
state plasma concentration would be expected to occur in approximately 7 - 8 days. No significant  
relationships between predicted apparent clearance and patient age, body weight, gender, and ethnicity  
were observed.  
Patient factors, which correlate with erlotinib pharmacokinetics, are serum total bilirubin, AAG concentrations  
and current smoking. Increased serum concentrations of total bilirubin and AAG concentrations were  
associated with a slower rate of erlotinib clearance; however. Smokers had a higher rate of erlotinib  
clearance.  
Initial K.B  
May 2022  
Page 20 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204  
pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstrated that  
covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those seen  
in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co  
administration of gemcitabine had no effect on erlotinib plasma clearance.  
Pharmacokinetics in special populations  
There have been no specific studies in paediatric or elderly patients.  
Hepatic impairment: Erlotinib is mainly cleared by the liver. Erlotinib exposure was similar in patients with  
moderately impaired hepatic function (Child-Pugh score 7 - 9) compared with patients with adequate hepatic  
function including patients with primary liver cancer or hepatic metastases.  
Renal impairment: Erlotinib and its metabolite are not significantly excreted by the kidneys, as less than 9  
% of a single dose is excreted in the urine. No data are available in patients with compromised renal function  
(creatinine clearance < 15 mL/min).  
Smokers: A pharmacokinetic study in nonsmoking and currently cigarette smoking healthy subjects has  
shown that cigarette smoking leads to increased clearance of, and decreased exposure to, erlotinib. The  
AUC0-infinity in smokers was about 1/3 of that in never/former smokers. This reduced exposure in current  
smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver (see sections 4.2, 4.4  
and 4.5).  
Clinical studies confirmed that current smokers achieved erlotinib steady state trough plasma concentration  
approximately 2-fold less than the former smokers or patients who had never smoked. This effect was  
accompanied by a 24 % increase in apparent erlotinib plasma clearance.  
A dose escalation study indicated a dose proportional increase in erlotinib exposure when the BILURA dose  
Initial K.B  
May 2022  
Page 21 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
was increased from 150 mg to the maximum tolerated dose of 300 mg.  
Steady-state trough plasma concentrations at a 300 mg dose in current smokers in this study was 1,22  
μg/mℓ (n = 17).  
Environmental Risk Assessment  
Erlotinib is a well-established active ingredient used in pharmaceutical preparations for human use. Given  
the anticipated pattern of use and disposal of the product, the environmental exposure of the active  
substance and metabolites are expected to be very limited. The use of erlotinib Tablets 25 mg, 100 mg and  
250 mg is not considered warranting any environmental concerns or requiring any special product labelling.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
•
•
Lactose monohydrate  
Magnesium stearate  
Microcrystalline cellulose  
Sodium lauryl sulphate  
Sodium starch glycolate  
Opadry White 20B580000 (contains hypromellose/HPMC, hydroxypropyl cellulose, macrogol/PEG  
and titanium dioxide).  
6.2 Incompatibilities  
Not applicable  
6.3 Shelf life  
24 months  
6.4 Special precautions for storage  
Initial K.B  
May 2022  
Page 22 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
•
•
•
Store at or below 25 °C. Protect from light and moisture.  
Keep the tablets in the original container until required for use.  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
HDPE bottles:  
Round, white opaque HDPE bottle with 4 g silica gel sachet and purified cotton space filler enclosed with a  
white opaque polypropylene, ribbed, child resistant plastic cap with pulp liners.  
Pack size: 30 film coated tablets per bottle.  
Blister strips:  
Blister strips of plain silver PVC/Aluminium/OPA forming foil and plain silver Aluminium lidding foil, containing  
10 film coated tablets per blister.  
Pack sizes: 10 film coated tablets per blister. 10 x 6 blisters packed in a box.  
10 film coated tablets per blister. 10 x 3 blisters packed in a box.  
HDPE bottle and blister packs are enclosed in an outer carton box.  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Initial K.B  
May 2022  
Page 23 of 24  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: BILURA 25, 100 & 150  
Dosage form and strength: Film coated tablets and 25 mg, 100 mg and 150 mg  
Waterfall Corporate Campus,  
Building 2, First Floor,  
74 Waterfall Drive,  
Midrand, 2066,  
Tel: 012 644 1220.  
8 REGISTRATION NUMBER(S)  
BILURA 25: 52/26/0558.555  
BILURA 100: 52/26/0559.556  
BILURA 150: 52/26/0560.557  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
16 February 2021  
10 DATE OF REVISION OF THE TEXT  
19 May 2022  
Initial K.B  
May 2022  
Page 24 of 24