Erlotinib-mili-100: detailed information

INSTRUCTIONS for medical use of the medicinal product ERLOTINIB-MILI-25 ERLOTINIB-MILI-100 ERLOTINIB-MILI-150 (ERLOTINIB-MILI-25 ERLOTINIB-MILI-100 ERLOTINIB-MILI-150)

Composition:

Active substance: erlotinib;

One film-coated tablet contains erlotinib hydrochloride equivalent to erlotinib 25 mg or 100 mg or 150 mg;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, magnesium stearate, sodium lauryl sulfate;

Coating: "Opadry" White (Y-5-7068).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: white or almost white, round, biconvex film-coated tablets, with "S13" imprinted on one side and smooth on the other side;

100 mg tablets: white or almost white, round, biconvex film-coated tablets, with "S12" imprinted on one side and smooth on the other side;

150 mg tablets: white or almost white, round, biconvex film-coated tablets, with "S11" imprinted on one side and smooth on the other side.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Erlotinib.

ATC code L01E B02.

Pharmacological Properties

Pharmacodynamics

Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (epidermal growth factor receptor type 1 in humans, EGFR, also known as HER1). Erlotinib causes pronounced inhibition of intracellular phosphorylation of EGFR. EGFR is expressed on the surface of both normal and cancer cells. In preclinical models, inhibition of EGFR phosphotyrosine leads to cessation of cell growth and/or cell death. EGFR mutations may cause constitutive activation of anti-apoptotic and proliferative signaling pathways. The high efficacy of erlotinib in blocking EGFR-mediated signal transduction in such EGFR mutation-positive tumors is explained by strong binding of erlotinib to the ATP [adenosine triphosphate] binding site within the mutated EGFR kinase domain. By blocking downstream signal transmission, cell proliferation is halted and cell death is induced via natural apoptosis. In mouse models with enhanced expression of these EGFR-activating mutations, tumor regression has been observed.

Pharmacokinetics

Absorption. Maximum plasma concentration of erlotinib is reached approximately 4 hours after oral administration. Studies in healthy volunteers have estimated the absolute bioavailability of the drug to be 59%. Exposure after oral administration may be increased by food intake.

Distribution. Erlotinib has a mean apparent volume of distribution of 232 L and distributes into human tumor tissue. In a study involving 4 patients (3 with non-small cell lung cancer [NSCLC] and 1 with laryngeal cancer) who received erlotinib 150 mg daily, tumor samples obtained during surgery on day 9 of treatment contained erlotinib in tissue at a mean concentration of 1185 ng/g. This corresponds overall to a mean of 63% (range 5–161%) of the maximum plasma concentration at steady state. Primary active metabolites were present in tumor tissue at a mean concentration of 160 ng/g, corresponding overall to a mean of 113% (range 88–130%) of the maximum plasma concentration at steady state. Plasma protein binding is approximately 95%. Erlotinib binds to serum albumin and alpha-1-acid glycoprotein (AAG).

Metabolism. Erlotinib is metabolized in the liver by cytochrome P450 enzymes, primarily by CYP3A4, and to a lesser extent by CYP1A2. Extrahepatic metabolism of erlotinib occurs via CYP3A4 in the small intestine; CYP1A1 in the lungs and CYP1B1 in tumor tissue may also contribute to erlotinib metabolic clearance. Metabolism proceeds via three pathways: 1) O-demethylation of one or both side chains followed by oxidation to carboxylic acids; 2) oxidation of the acetylenic moiety followed by hydrolysis to arylcarboxylic acids; 3) aromatic hydroxylation of the phenyl-acetylene group. The primary metabolites of erlotinib, OSI-420 and OSI-413, formed by O-demethylation of one of the side chains, have activity comparable to erlotinib in preclinical in vitro assays and in vivo tumor models. These metabolites are present in plasma at concentrations less than 10% of erlotinib concentrations, and their pharmacokinetics are similar to those of erlotinib.

Elimination. Erlotinib metabolites are primarily excreted in feces (>90%), with a small amount of the orally administered dose eliminated by the kidneys (approximately 9%). Less than 2% of the orally administered dose is excreted as unchanged parent compound. Population pharmacokinetic analysis in 591 patients receiving erlotinib monotherapy showed a mean apparent clearance of 4.47 L/h and a median elimination half-life of 36.2 hours. Therefore, steady-state plasma concentrations are expected to be reached after approximately 7–8 days.

Pharmacokinetics in Special Patient Populations. Population pharmacokinetic analysis data showed no clinically significant relationships between predicted apparent clearance and patient age, body weight, sex, or ethnicity. Erlotinib pharmacokinetics correlated with serum total bilirubin levels, alpha-1-acid glycoprotein (AAG) levels, and current smoking status. Increased serum total bilirubin and AAG concentrations were associated with reduced erlotinib clearance. The clinical significance of this observation is unknown. However, in smokers, accelerated erlotinib clearance has been observed, confirmed in a pharmacokinetic study of a single 150 mg dose of erlotinib administered to nonsmokers and current smokers. The geometric mean maximum concentration (Cmax) was 1056 ng/mL in nonsmokers and 689 ng/mL in smokers, with a mean ratio of 65.2% (95% CI [confidence interval]: 44.3–95.9; p = 0.031). The geometric mean AUC0–∞ was 18726 ng·h/mL in nonsmokers and 6718 ng·h/mL in smokers, with a mean ratio of 35.9% (95% CI: 23.7–54.3; p < 0.0001). The geometric mean 24-hour concentration was 288 ng/mL in nonsmokers and 34.8 ng/mL in smokers, with a mean ratio of 12.1% (95% CI: 4.82–30.2; p = 0.0001). In a pivotal Phase III study in current smoker patients with non-small cell lung cancer, the minimum steady-state plasma concentration was 0.65 µg/mL (n = 16), which is two-fold lower than in former smokers/nonsmokers (1.28 µg/mL, n = 108). This was associated with a 24% increase in plasma clearance of erlotinib.

In a Phase I dose-escalation study involving NSCLC patients who smoked during the study, pharmacokinetic analysis at steady state demonstrated dose-proportional increases in erlotinib exposure when the erlotinib dose was increased from 150 mg to the maximum tolerated dose of 300 mg. The steady-state minimum plasma concentration after a 300 mg dose in continuing smokers in this study was 1.22 µg/mL (n = 17) (see sections "Dosage and Administration", "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Based on pharmacokinetic study results, smokers are advised to stop smoking during erlotinib treatment, as otherwise a reduction in plasma drug concentration may occur.

Population pharmacokinetic analysis data indicate that in the presence of opioids, erlotinib exposure increases by approximately 11%.

A second population pharmacokinetic analysis was conducted using erlotinib data from 204 patients with pancreatic cancer who received erlotinib in combination with gemcitabine. This analysis showed that covariates affecting erlotinib clearance in pancreatic cancer patients were practically the same as those observed in previous monotherapy pharmacokinetic analyses. No new covariate effects were identified. Concomitant administration of gemcitabine does not affect erlotinib plasma clearance.

Pediatric Patients. Specific studies in children have not been conducted.

Elderly Patients. Specific studies in elderly patients have not been conducted.

Hepatic Impairment. Erlotinib elimination occurs primarily via the liver. In patients with solid tumors and moderate hepatic impairment (7–9 points on the Child–Pugh scale), geometric mean values of AUC0–t and Cmax for erlotinib were 27000 ng·h/mL and 805 ng/mL, respectively, compared to 29300 ng·h/mL and 1090 ng/mL in patients with normal liver function, including those with primary liver cancer or liver metastases. Although Cmax was statistically significantly lower in patients with moderate hepatic impairment, this difference is not considered clinically significant. There are no data on the effect of severe hepatic dysfunction on erlotinib pharmacokinetics. In population pharmacokinetic analysis, increased serum total bilirubin concentration was associated with slower erlotinib elimination.

Renal Impairment. Erlotinib and its metabolites are excreted in urine in minimal amounts: less than 9% of a single dose is excreted in urine. In population pharmacokinetic analysis, no clinically significant correlation was observed between erlotinib clearance and creatinine clearance. There are no data in patients with creatinine clearance < 15 mL/min.

Clinical characteristics

Indications

Non-small cell lung cancer

First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations.

The medicinal product Erlotinib-Mili is also indicated for maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations and stable disease after first-line chemotherapy.

The medicinal product Erlotinib-Mili is also indicated for the treatment of locally advanced or metastatic non-small cell lung cancer following failure of at least one prior chemotherapy regimen. For patients with tumours without EGFR-activating mutations, Erlotinib-Mili is indicated when other treatment options are not suitable.

When prescribing Erlotinib-Mili, factors related to prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients with tumours lacking epidermal growth factor receptor (EGFR) as determined by immunohistochemical testing.

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing the medicinal product Erlotinib-Mili, factors related to prolonged survival should be considered.

No survival benefit has been demonstrated in patients with locally advanced pancreatic cancer.

Contraindications
Hypersensitivity to erlotinib or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other types of interactions

Interaction studies have been conducted only in adults.

Erlotinib and other CYP substrates

Erlotinib is a potent inhibitor of CYP1A1 and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a potent inhibitor of glucuronidation UGT1A1 in vitro.

The physiological significance of potent CYP1A1 inhibition is unknown due to the very limited expression of CYP1A1 in human tissues.

When erlotinib was administered with ciprofloxacin, a moderate inhibitor of CYP1A2, erlotinib exposure (AUC) increased significantly by 39%, while maximum concentration (Cmax) did not change statistically significantly. Similarly, exposure (AUC) of the active metabolite increased by 60%, and Cmax by 48%. The clinical significance of this increased exposure has not been established. Therefore, caution is required when prescribing Erlotinib-Mili with ciprofloxacin or potent CYP1A2 inhibitors (e.g., fluvoxamine). If erlotinib-related adverse reactions occur, the dose of the drug may be reduced.

Prior or concomitant administration of erlotinib did not alter the clearance of prototype CYP3A4 substrates midazolam and erythromycin. However, a reduction in oral bioavailability of midazolam by up to 24% was observed. In another clinical study, erlotinib was shown not to affect the pharmacokinetics of the CYP3A4/2C8 substrate paclitaxel when administered concomitantly. Therefore, clinically significant interactions with the clearance of other CYP3A4 substrates are unlikely.

Inhibition of glucuronidation may cause interactions with medicinal products that are substrates of UGT1A1 and are eliminated exclusively via this metabolic pathway. In patients with low UGT1A1 expression or genetically determined disorders of glucuronidation (e.g., Gilbert’s syndrome), increased serum bilirubin concentration may occur; therefore, treatment of these patients requires caution.

Erlotinib is metabolized in the liver by human hepatic cytochromes, primarily by CYP3A4 enzymes, to a lesser extent by CYP1A2. Extrahepatic metabolism involving CYP3A4 in the small intestine, CYP1A1 in the lungs, and CYP1B1 in tumour tissue may also potentially contribute to erlotinib's metabolic clearance. Interactions are possible with active substances that are metabolized by these enzymes or are their inducers or inhibitors.

Potent inhibitors of CYP3A4 activity reduce erlotinib metabolism and increase its plasma concentration. In a clinical study, concomitant administration of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in increased erlotinib exposure (by 86% in AUC and by 69% in Cmax). Erlotinib-Mili should be prescribed cautiously with potent CYP3A4 inhibitors, including azole antifungal agents (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, clarithromycin. If toxicity develops, the dose of Erlotinib-Mili should be reduced.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly reduce its plasma concentration. In a clinical study, concomitant administration of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% reduction in median AUC of erlotinib. When rifampicin was co-administered with a single 450 mg dose of erlotinib, mean erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg dose of erlotinib in the absence of rifampicin therapy. Concomitant use of Erlotinib-Mili and CYP3A4 inducers should be avoided. If a patient requires concomitant treatment with Erlotinib-Mili and a potent CYP3A4 inducer (such as rifampicin), the dose of Erlotinib-Mili may be increased up to 300 mg with careful monitoring of patient safety (including kidney and liver function and serum electrolyte levels). If well tolerated for more than 2 weeks, the dose of Erlotinib-Mili may be increased to 450 mg with careful safety monitoring. Reduced erlotinib exposure is possible when administered concomitantly with other CYP3A4 inducers (phenytoin, carbamazepine, barbiturates, preparations containing St. John’s wort). Use of these agents in combination with erlotinib requires caution. If possible, alternative medicinal products that are not potent CYP3A4 inducers should be prescribed.

Erlotinib and anticoagulants, coumarin derivatives

An increase in international normalized ratio (INR) and bleeding, including isolated cases with fatal outcome, has been reported when erlotinib was used concomitantly with coumarin derivative anticoagulants, including warfarin. In patients receiving coumarin derivative anticoagulants, prothrombin time or INR should be monitored regularly.

Erlotinib and statins

When Erlotinib-Mili is used concomitantly with statins, the risk of statin-induced myopathy, including rare cases of rhabdomyolysis, is increased.

Use of erlotinib in patients who smoke

Pharmacokinetic interaction studies in non-smokers and current smokers showed that smoking reduces AUCinf, Cmax, and plasma concentration of erlotinib at 24 hours by 2.8, 1.5, and 9 times, respectively. Therefore, smokers should be advised to stop smoking as early as possible before starting treatment with Erlotinib-Mili due to reduced erlotinib plasma concentrations if smoking continues. Based on results of the CURRENTS study, there is no evidence supporting the use of a higher erlotinib dose of 300 mg in active smokers compared to the recommended dose of 150 mg. Safety data were comparable for 300 mg and 150 mg doses; however, a significant increase in the frequency of rash, interstitial lung disease, and diarrhoea was observed in patients receiving higher erlotinib doses (see sections "Dosage and administration", "Special precautions", "Pharmacokinetics").

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant administration of Erlotinib-Mili and P-glycoprotein inhibitors (e.g., cyclosporine, verapamil) may lead to altered distribution and/or elimination of erlotinib. The consequences of such interactions, including potential toxic effects on the central nervous system, have not been established. Caution is required in such situations.

Erlotinib and medicinal products affecting pH

Erlotinib has reduced solubility at pH above 5. Medicinal products affecting pH in the upper gastrointestinal tract may influence erlotinib solubility and its bioavailability. When erlotinib was administered concomitantly with omeprazole, a proton pump inhibitor, erlotinib exposure (AUC) and maximum concentration (Cmax) decreased by 46% and 61%, respectively. Tmax and elimination half-life were not affected. When erlotinib was administered concomitantly with ranitidine (300 mg), an H2-receptor antagonist, erlotinib exposure (AUC) and maximum concentration (Cmax) decreased by 33% and 54%, respectively. It is unlikely that increasing the dose of Erlotinib-Mili when co-administered with such agents can compensate for the reduced exposure. However, when erlotinib was administered 2 hours before or 10 hours after ranitidine (150 mg twice daily), AUC and Cmax of erlotinib decreased only by 15% and 17%, respectively. The effect of antacids on erlotinib absorption has not been studied, but impaired absorption of erlotinib is possible, which may lead to reduced plasma levels of erlotinib. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is required during treatment with Erlotinib-Mili, antacids should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib-Mili. If ranitidine is prescribed, its administration should be staggered with Erlotinib-Mili: the drug should be taken at least 2 hours before or 10 hours after ranitidine.

Erlotinib and gemcitabine

In a phase Ib study, no significant effect of gemcitabine on erlotinib pharmacokinetics or of erlotinib on gemcitabine pharmacokinetics was observed.

Erlotinib and carboplatin/paclitaxel

Erlotinib increases platinum concentration in plasma. In a clinical study, concomitant administration of erlotinib with carboplatin and paclitaxel resulted in a statistically significant increase in AUC0–48 of total platinum by 10.6%. Despite statistical significance, this difference is considered not clinically relevant. In clinical practice, other concomitant factors may contribute to increased carboplatin exposure, such as impaired renal function. No significant effect of carboplatin or paclitaxel on erlotinib pharmacokinetics was observed.

Erlotinib and capecitabine

Capecitabine may increase erlotinib concentration. After administration of erlotinib in combination with capecitabine, a statistically significant increase in AUC of erlotinib and a borderline increase in Cmax were observed compared to values obtained in another study where erlotinib was administered as monotherapy. No significant effect of erlotinib on capecitabine pharmacokinetics was observed.

Erlotinib and proteasome inhibitors

Based on the mechanism of action, it can be expected that proteasome inhibitors, including bortezomib, may affect the activity of epidermal growth factor receptor (EGFR) inhibitors, including erlotinib. Some clinical data and preclinical study results support this effect, showing proteasome-mediated degradation of EGFR.

Special precautions for use

Testing for epidermal growth factor receptor (EGFR) mutations

When deciding to use Erlotinib-Mili as first-line or maintenance treatment for locally advanced or metastatic NSCLC, it is important to determine the EGFR mutation status.

According to medical practice, a validated, reliable and sensitive test with a defined limit of positivity and demonstrated utility in determining EGFR mutation status should be used, employing tumour DNA from a tissue sample or cell-free DNA (cfDNA) from a blood (plasma) sample.

If a plasma-based cfDNA test is used and results for activating mutations are negative, tissue testing is recommended, as false-negative results with plasma-based tests are possible.

Use in smokers

Smokers should be advised to stop smoking, as erlotinib plasma concentrations are reduced in smokers compared to non-smokers. The degree of reduction in erlotinib plasma concentration is likely to be clinically significant (see sections “Posology and method of administration”, “Interaction with other medicinal products and other forms of interaction”, “Pharmacokinetics”).

Interstitial lung disease

Interstitial lung disease (ILD)-like events, including fatal cases, have been infrequently observed in patients with non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours receiving erlotinib therapy. In the pivotal BR.21 study in patients with NSCLC receiving placebo or erlotinib, the incidence of ILD was 0.8% in each group. According to data from a meta-analysis of randomised controlled clinical trials in NSCLC (excluding phase I and single-arm phase II trials due to lack of control groups), the incidence of ILD-like events was 0.9% in erlotinib treatment groups and 0.4% in control groups. In the pancreatic cancer study using erlotinib in combination with gemcitabine, the incidence of ILD-like events in patients with pancreatic cancer receiving erlotinib and gemcitabine was 2.5%, compared to 0.4% in the group receiving gemcitabine and placebo. Diagnoses in patients suspected of ILD-like events included pneumonia, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infiltration and alveolitis. Symptoms occurred from several days to several months after initiation of erlotinib therapy. Provocative or predisposing factors were often present, such as concomitant or prior chemotherapy, radiotherapy, underlying parenchymal lung disease, metastatic lung involvement, or lung infection. A higher incidence of ILD (approximately 5%, with a mortality rate of 1.5%) has been observed in patients enrolled in studies conducted in Japan.

In patients with acute onset of new and/or progressive respiratory symptoms of unknown origin (dyspnoea, cough, fever), treatment with Erlotinib-Mili should be temporarily discontinued pending diagnostic evaluation. Patients receiving concomitant treatment with erlotinib and gemcitabine should be closely monitored for potential development of ILD-like toxicity. In the event of ILD development, Erlotinib-Mili should be discontinued and appropriate treatment initiated if necessary (see section “Adverse reactions”).

Diarrhoea, dehydration, electrolyte imbalance and renal failure

Diarrhoea (including very rare fatal cases) was observed in approximately 50% of patients receiving erlotinib therapy. In cases of severe or moderate diarrhoea, treatment with agents such as loperamide is required. In some cases, dose reduction may be necessary. In clinical trials, doses were reduced in 50 mg increments. Dose reductions in 25 mg steps have not been studied. Treatment with Erlotinib-Mili should be interrupted and appropriate measures taken to correct dehydration in cases of severe or persistent diarrhoea, nausea, anorexia or vomiting associated with dehydration (see section “Adverse reactions”). Hypokalaemia and renal failure (including fatal cases) have been rarely reported. Some cases were due to severe dehydration resulting from diarrhoea, vomiting and/or anorexia, while in others, interpretation was complicated by concomitant chemotherapy. In cases of more severe or persistent diarrhoea or cases leading to dehydration, particularly in patient groups with risk factors (especially with concomitant chemotherapy or other drugs, presence of symptoms or conditions, or other predisposing factors including advanced age), treatment with Erlotinib-Mili should be interrupted and appropriate measures taken, including intensive intravenous rehydration. Additionally, in patients at risk of dehydration, renal function and serum electrolyte levels, particularly potassium, should be monitored.

Hepatitis, hepatic failure

Cases of hepatic failure (including fatal cases) have been rarely reported during erlotinib therapy. Factors complicating interpretation include pre-existing liver disease and concomitant use of hepatotoxic medicinal products. Therefore, periodic monitoring of liver function is required in these patients. Erlotinib-Mili treatment should be interrupted in cases of severe liver function abnormalities (see section “Adverse reactions”). Erlotinib-Mili is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforations

Patients receiving Erlotinib-Mili are at increased risk of gastrointestinal perforation, which occurs infrequently (including isolated fatal cases). The risk of gastrointestinal perforation is increased in patients receiving concomitant anti-angiogenic agents, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or taxane-based chemotherapy, as well as in patients with a history of peptic ulcer or diverticular disease. In the event of gastrointestinal perforation, Erlotinib-Mili treatment should be permanently discontinued (see section “Adverse reactions”).

Bullous and exfoliative skin disorders

Bullous, blistering and exfoliative skin disorders have been reported, including very rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, some of which were fatal (see section “Adverse reactions”). In the event of bullous, blistering or exfoliative skin disorders, treatment with Erlotinib-Mili should be temporarily interrupted or discontinued. Patients with bullous or exfoliative skin disorders should be evaluated for skin infections and treated according to local guidelines.

Ocular disorders

Patients presenting with signs and symptoms characteristic of keratitis, such as acute onset or exacerbation of eye inflammation, lacrimation, photophobia, blurred vision, eye pain and/or eye redness, should be referred immediately for ophthalmological consultation. In cases of confirmed ulcerative keratitis, treatment with Erlotinib-Mili should be temporarily or permanently discontinued. The benefit-risk balance of continuing Erlotinib-Mili treatment should be carefully considered in patients diagnosed with keratitis. Erlotinib-Mili 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 corneal ulceration. Cases of corneal perforation or ulceration during erlotinib therapy have been very rarely observed (see section “Adverse reactions”).

Interaction with other medicinal products

Strong inducers of CYP3A4 enzymes may reduce the efficacy of erlotinib, while strong inhibitors of CYP3A4 may increase its toxicity. Concomitant use of Erlotinib-Mili with drugs of these types should be avoided (see section “Interaction with other medicinal products and other forms of interaction”).

Other forms of interaction

Erlotinib has reduced solubility at pH levels above 5. Medicinal products that alter the pH in the upper gastrointestinal tract (GIT), such as proton pump inhibitors, H2-receptor antagonists and antacids, may affect erlotinib solubility and thus its bioavailability. It is unlikely that increasing the dose of Erlotinib-Mili during concomitant use of these agents can compensate for reduced exposure. Concomitant use of Erlotinib-Mili with proton pump inhibitors should be avoided. The consequences of concomitant use of erlotinib with H2-receptor antagonists and antacids are unknown, but reduced bioavailability is possible. Therefore, concomitant use should be avoided (see section “Interaction with other medicinal products and other forms of interaction”). If antacid therapy is required during treatment with Erlotinib-Mili, these agents should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib-Mili.

Excipients with known effect

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Erlotinib-Mili.

This medicinal product contains less than 1 mmol (less than 23 mg) of sodium per tablet, i.e. essentially "sodium-free".

Disposal of unused or expired medicinal product. Environmental contamination should be minimised. The product should not be disposed of via wastewater or household waste. "Waste collection systems" should be used for disposal, if available.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of erlotinib in pregnant women. Animal studies did not reveal signs of teratogenic effects or delivery abnormalities. However, a negative effect on pregnancy cannot be excluded, as increased embryofetal lethality was observed in animal studies. The potential risk to humans is unknown. Women of childbearing potential should be advised to avoid pregnancy and to use reliable contraceptive methods during treatment with Erlotinib-Mili and for at least 2 weeks after completion of treatment. Treatment of a pregnant woman should only continue if the expected benefit to the mother outweighs the potential risk to the foetus.

Breastfeeding

It is unknown whether erlotinib is excreted in human breast milk. Studies on the effect of erlotinib on milk production or its presence in breast milk have not been conducted. Since the potential harm to breastfed infants is unknown, mothers should be advised to avoid breastfeeding during treatment with Erlotinib-Mili and for at least 2 weeks after the last dose.

Fertility

Animal studies did not reveal impairment of fertility. However, an undesirable effect on fertility cannot be excluded, as effects on reproductive parameters were observed in animal studies. The potential risk to humans is unknown.

Ability to affect driving and use of machines. Studies on the effect on the ability to drive or operate machinery have not been conducted; however, erlotinib use is not associated with cognitive impairment.

Method of Administration and Dosage

Treatment with Erlotinib-Mili should be administered by a physician experienced in anticancer therapy.

Non-small cell lung cancer

Testing for epidermal growth factor receptor (EGFR) mutations must be performed (see section "Indications").

The recommended dose of Erlotinib-Mili is 150 mg once daily, taken at least 1 hour before or 2 hours after a meal.

Pancreatic cancer

The recommended dose of Erlotinib-Mili is 100 mg once daily, taken at least 1 hour before or 2 hours after a meal; administer in combination with gemcitabine (see also the gemcitabine prescribing information for medical use, indication — pancreatic cancer).

If a patient does not develop rash within the first 4–8 weeks of treatment, continuation of therapy with Erlotinib-Mili should be reconsidered (see section "Pharmacodynamics").

If dose adjustment is required, the dose should be reduced in 50 mg decrements (see section "Special Instructions").

Dose adjustment may be necessary when co-administering substrates and modulators of CYP3A4 (see section "Interaction with Other Medicinal Products and Other Types of Interactions").

Hepatic impairment

Erlotinib is eliminated via hepatic metabolism and excreted in bile. Although erlotinib exposure was similar in patients with moderate hepatic impairment (Child-Pugh score 7–9) and those with normal hepatic function, caution should be exercised when administering Erlotinib-Mili to patients with hepatic insufficiency. If severe adverse reactions occur, the dose of Erlotinib-Mili should be reduced or treatment discontinued. The safety and efficacy of Erlotinib-Mili in patients with severe hepatic impairment (AST/SGOT [aspartate aminotransferase/serum glutamic-oxaloacetic transaminase] and ALT/SGPT [alanine aminotransferase/serum glutamic-pyruvic transaminase] > 5 × ULN [upper limit of normal]) have not been studied. Erlotinib-Mili is not recommended for patients with severe hepatic impairment (see section "Pharmacokinetics").

Renal impairment

The safety and efficacy of the drug in patients with renal impairment (serum creatinine concentration 1.5 times above ULN) have not been studied. Based on pharmacokinetic data, dose adjustment is not necessary for patients with mild to moderate renal impairment (see section "Pharmacokinetics"). Erlotinib-Mili is not recommended for patients with severe renal impairment.

Use in patients who smoke

Smoking has been shown to reduce erlotinib exposure by 50–60%. The maximum tolerated dose of Erlotinib-Mili in patients with non-small cell lung cancer who currently smoke is 300 mg. A dose of 300 mg did not demonstrate improved efficacy in second-line treatment after ineffective chemotherapy compared to the recommended dose of 150 mg in patients who continue to smoke. Safety data were comparable between the 300 mg and 150 mg doses; however, patients receiving the higher erlotinib dose experienced a significant increase in the frequency of rash, interstitial lung disease, and diarrhea. Patients who continue to smoke are advised to quit smoking (see sections "Special Instructions", "Interaction with Other Medicinal Products and Other Types of Interactions", "Pharmacokinetics").

Children. The safety and efficacy of erlotinib for the approved indications in patients under 18 years of age have not been established. Erlotinib-Mili is not recommended for use in children.

Overdose

Symptoms

Single oral doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg in cancer patients were well tolerated. Tolerability of multiple daily doses of 200 mg twice daily in healthy volunteers deteriorated only after several days of administration. According to data from these studies, severe adverse reactions may occur following overdose, including diarrhea, rash, and possibly elevated levels of hepatic aminotransferases.

Treatment

In case of suspected overdose, treatment with Erlotinib-Mili should be discontinued and symptomatic therapy initiated.

Adverse Reactions

The safety evaluation of erlotinib is based on data from more than 1500 patients who received at least one dose of erlotinib as monotherapy (150 mg), and more than 300 patients who received erlotinib at doses of 100 or 150 mg in combination with gemcitabine.

The adverse reactions listed below were recorded during clinical trials of erlotinib used either as monotherapy or in combination with chemotherapy, graded according to the NCI-CTC [National Cancer Institute Common Toxicity Criteria (USA)]. The reported adverse reactions are those occurring at a frequency of at least 10% (in the erlotinib treatment group) and more frequently (≥ 3%) in patients receiving erlotinib compared to the control group.

Adverse reactions observed in clinical trials (see below) are listed by system organ classes (MedDRA [Medical Dictionary for Regulatory Activities] classification). The criteria used to define the frequency of adverse reactions are: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Non-small cell lung cancer (erlotinib monotherapy)

First-line treatment of patients with EGFR mutations

In an open-label, randomized Phase III trial (ML20650) involving 154 patients, the safety of erlotinib in first-line treatment of patients with NSCLC and activating EGFR mutations was evaluated in 75 patients; no new adverse events were observed in these patients.

The most common adverse reactions in patients receiving erlotinib in trial ML20650 were rash and diarrhea (any grade: 80% and 57%, respectively), the majority of which were Grade 1/2 in severity and did not require intervention. Grade 3 rash and diarrhea were observed in 9% and 4% of patients, respectively. Grade 4 rash and diarrhea were not observed. Rash and diarrhea led to discontinuation of therapy in 1% of patients. Dose modification (treatment interruption or dose reduction) due to rash and diarrhea was required in 11% and 7% of patients, respectively.

Maintenance treatment

In two other double-blind, randomized, placebo-controlled Phase III trials, BO18192 (SATURN) and BO25460 (IUNO), erlotinib was used as maintenance therapy following first-line chemotherapy. These trials included a total of 1532 patients with advanced, recurrent, or metastatic NSCLC after standard first-line platinum-based chemotherapy. No new adverse events were identified.

The most common adverse reactions observed in patients receiving erlotinib in trials BO18192 and BO25460 were skin rash (BO18192: all grades – 49.2%, Grade 3 – 6%; BO25460: all grades – 39.4%, Grade 3 – 5%) and diarrhea (BO18192: all grades – 20.3%, Grade 3 – 1.8%; BO25460: all grades – 24.2%, Grade 3 – 2.5%). No cases of Grade 4 rash or diarrhea were observed in either of these trials. Rash and diarrhea led to premature discontinuation of erlotinib therapy in 1% and <1% of patients, respectively, in trial BO18192; in trial BO25460, no premature discontinuation of erlotinib due to rash or diarrhea was observed. Dose modification (treatment interruption or dose reduction) due to rash and diarrhea was required in 8.3% and 3% of patients, respectively, in trial BO18192, and in 5.6% and 2.8% of patients, respectively, in trial BO25460.

Second and further lines of treatment

In the randomized, double-blind trial BR.21 (erlotinib used in second-line therapy), the most common adverse reactions were rash (75%) and diarrhea (54%), the majority of which were Grade 1 or 2 in severity and resolved without intervention. Grade 3/4 rash and diarrhea were observed in 9% and 6% of patients with non-small cell lung cancer receiving erlotinib, respectively, and each of these reactions led to study withdrawal in 1% of patients and dose modification in 6% and 1% of patients, respectively. In trial BR.21, the median time to onset of rash was 8 days, and to onset of diarrhea was 12 days.

The rash was characterized as erythematous and papulopustular eruptions of mild to moderate severity, occurring or worsening in sun-exposed skin areas. Patients exposed to sunlight are advised to wear protective clothing and/or use sun protection products (e.g., mineral-based sunscreens).

Pancreatic cancer (concomitant use of erlotinib with gemcitabine)

The most common adverse reactions in the pivotal trial PA.3 involving patients with pancreatic cancer who received erlotinib 100 mg in combination with gemcitabine were fatigue, rash, and diarrhea. In the erlotinib plus gemcitabine group, Grade 3/4 rash and diarrhea occurred in 5% of patients. The median time to onset of rash was 10 days, and to onset of diarrhea was 15 days. Each of these events required dose reduction in 2% of patients and led to premature withdrawal from the study in up to 1% of patients receiving erlotinib in combination with gemcitabine.

The adverse reactions listed below occurred in ≥ 10% of patients in trials BR.21 (erlotinib treatment) and PA.3 (combination treatment with erlotinib and gemcitabine), and adverse reactions occurring more frequently (≥ 3%) than in the placebo group in trials BR.21 (erlotinib treatment) and PA.3 (combination treatment with erlotinib and gemcitabine).

NCI-CTC Grade

Erlotinib (BR.21)

N = 485

Erlotinib (PA.3)

N = 259

Frequency category with highest prevalence

Any grade

Preferred MedDRA Term

Infections and infestations

Infections*

< 1

Very common

Metabolism and nutrition disorders

Anorexia

Weight decreased

Very common

Eye disorders

Dry keratoconjunctivitis

Conjunctivitis

< 1

Very common

Psychiatric disorders

Depression

Very common

Nervous system disorders

Neuropathy

Headache

< 1

Very common

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

Very common

Gastrointestinal disorders

Diarrhoea**

Nausea

Vomiting

Stomatitis

Abdominal pain

Dyspepsia

Flatulence

< 1

Very common

Skin and subcutaneous tissue disorders

Rash***

Pruritus

Dry skin

Alopecia

< 1

Very common

General disorders and administration site conditions

Fatigue

Pyrexia

Chills

Very common

Severe infections, with or without neutropenia, include pneumonia, sepsis, and cellulitis.

** May lead to dehydration, hypokalemia, and renal failure.

*** Rashes include acneiform dermatitis.

Corresponds to the percentage below the threshold specified below.

Other adverse reactions, including those observed in other clinical trials, are listed below by frequency category.

System organ	Very common	Common	Uncommon	Rare	Very rare
Eye disorders		keratitis, conjunctivitis1	eyelash changes2		corneal perforation, corneal ulceration, uveitis
Respiratory, thoracic and mediastinal disorders		epistaxis	interstitial lung disease (ILD)3
Gastrointestinal disorders	diarrhea7	gastrointestinal hemorrhage4,7	gastrointestinal perforation7
Hepatobiliary disorders	abnormal liver function tests5			hepatic failure6
Skin and subcutaneous tissue disorders	rash	alopecia, dry skin1, paronychia, folliculitis, acne / acneiform dermatitis, skin fissures	hirsutism, eyebrow changes, nail brittleness and loss, mild skin reactions such as hyperpigmentation	palmar-plantar erythrodysesthesia syndrome	Stevens-Johnson syndrome / toxic epidermal necrolysis7
Renal and urinary disorders		renal failure1	nephritis1, proteinuria1

1 In clinical study PA.3.

2 In particular, trichomegaly, excessive growth, and thickening of eyelashes.

3 Including fatal cases in patients who received erlotinib for the treatment of NSCLC or other common solid tumours (see section "Dosage and administration"). More frequently observed in patients in Japan (see section "Dosage and administration").

4 In clinical studies; in some cases associated with concomitant use of warfarin and in some cases with concomitant use of NSAIDs (see section "Interaction with other medicinal products and other forms of interaction").

5 In particular, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. This adverse reaction was very common in clinical study PA.3 and common in clinical study BR.21. Most cases were of mild or moderate severity, transient in nature, or associated with liver metastases.

6 Including fatal cases. Contributing factors complicating interpretation included underlying liver disease or concomitant use of hepatotoxic medicinal products (see section "Dosage and administration").

7 Including fatal cases (see section "Dosage and administration").

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 film-coated tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Shilpa Medika Limited / Shilpa Medicare Limited.

Manufacturer's address and location of its business operations.

Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India / Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahabubnagar, Telangana, 509301, India.

Marketing Authorization Holder.

Mili Healthcare Limited / Mili Healthcare Limited.

Address of the Marketing Authorization Holder.

Second Floor Office Suite, 4 Chartfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, Great Britain / Second Floor Office Suite, 4 Chartfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, Great Britain.