Erlero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERLERO (ERLERO)

Composition:

Active substance: erlotinib;

One film-coated tablet contains 25 mg, 100 mg, or 150 mg of erlotinib in the form of erlotinib hydrochloride;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); magnesium stearate; sodium lauryl sulfate;

Film coating: Opadry White 20B580000 (hypromellose, hydroxypropyl cellulose, titanium dioxide (E 171), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: white, round, biconvex, film-coated tablets, marked with "H" on one side and "28" on the other;

100 mg tablets: white, round, biconvex, film-coated tablets, marked with "H" on one side and "21" on the other;

150 mg tablets: white, round, biconvex, film-coated tablets, marked with "H" on one side and "22" on the other.

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

ATC code L01E B02.

Pharmacological properties.

Pharmacodynamics.

Erlotinib is an inhibitor of tyrosine kinase of the epidermal growth factor receptor/human epidermal growth factor receptor type 1 (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 growth arrest and/or cell death. EGFR mutations may lead to 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 the strong binding of erlotinib to the ATP-binding site in the mutated kinase domain of EGFR. By blocking downstream signal transduction, 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 (Cmax) of erlotinib is reached approximately 4 hours after oral administration. Studies in healthy volunteers have estimated the absolute bioavailability of erlotinib 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 patients with non-small cell lung cancer [NSCLC] and 1 patient 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 of tissue. This corresponds to an overall mean of 63% (range 5–161%) of the maximum plasma concentration at steady state. Primary active metabolites were present in the tumor at a mean concentration of 160 ng/g of tissue, corresponding to an overall mean of 113% (range 88–130%) of the maximum plasma concentration at steady state. Protein binding to plasma proteins 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 via CYP3A4, and to a lesser extent via CYP1A2. Extrahepatic metabolism of erlotinib occurs via CYP3A4 in the small intestine, and CYP1A1 in the lungs and CYP1B1 in tumor tissue may also contribute to the metabolic clearance of erlotinib. 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, exhibit 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 excreted predominantly in feces (>90%), with a small amount of the orally administered dose eliminated via 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 as monotherapy showed a mean apparent clearance of 4.47 L/hour and a median elimination half-life of 36.2 hours. Therefore, the time to reach steady-state plasma concentration is expected to be approximately 7–8 days.

Pharmacokinetics in special patient populations

Population pharmacokinetic analysis revealed no clinically significant relationships between predicted apparent clearance and age, body weight, gender, or ethnicity. Pharmacokinetics of erlotinib correlated with serum total bilirubin concentration, alpha-1-acid glycoprotein (AAG) levels, and current smoking status. Increased serum total bilirubin and AAG concentrations were associated with decreased erlotinib clearance. The clinical significance of this observation is unknown. However, in smokers, accelerated clearance of erlotinib has been demonstrated, as confirmed in a pharmacokinetic study of a single 150 mg dose of erlotinib administered to non-smokers and current smokers. The geometric mean Cmax was 1056 ng/mL in non-smokers and 689 ng/mL in smokers, with a mean ratio of 65.2% (95% CI: 44.3–95.9; p=0.031). The geometric mean AUC0-inf was 18726 ng•h/mL in non-smokers 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 non-smokers and 34.8 ng/mL in smokers, with a mean ratio of 12.1% (95% CI: 4.82–30.2; p=0.0001). In the pivotal phase III study, current smokers with NSCLC had a minimum steady-state plasma concentration of 0.65 µg/mL (n=16), which was half that observed in former smokers/non-smokers (1.28 µg/mL, n=108). This was accompanied by a 24% increase in plasma clearance of erlotinib.

In a phase I dose-escalation study in NSCLC patients who smoked during the study, steady-state pharmacokinetic analysis showed dose-proportional increases in erlotinib exposure when the dose was increased from 150 mg to the maximum tolerated dose of 300 mg. The steady-state minimum plasma concentration after 300 mg in continuing smokers in this study was 1.22 µg/mL (n=17) (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", and "Dosage and administration").

Based on pharmacokinetic study results, patients who smoke are advised to stop smoking during treatment with Erlero, as otherwise a reduction in plasma concentration of erlotinib may occur.

According to population pharmacokinetic analysis, concomitant use of opioids increased erlotinib exposure by approximately 11%.

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

Children

Specific studies in children have not been conducted.

Elderly patients

Specific studies in elderly patients have not been conducted.

Hepatic impairment

Erlotinib clearance occurs primarily via the liver. In patients with solid tumors and moderate hepatic impairment (Child-Pugh score 7–9 points), geometric mean values of AUC0-t and Cmax of 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 the pharmacokinetics of erlotinib. In population pharmacokinetic analysis, increased serum total bilirubin concentration was associated with slower elimination of erlotinib.

Renal impairment

Erlotinib and its metabolites are excreted in small amounts via the kidneys—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 (NSCLC)

First-line treatment of patients with locally advanced or metastatic NSCLC harboring EGFR-activating mutations.

Erlotinib is also indicated for maintenance treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations who have stable disease after first-line chemotherapy.

Erlotinib is also indicated for treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Erlotinib is indicated in patients with tumors lacking EGFR-activating mutations when other treatment options are not suitable.

When prescribing Erlotinib, factors associated with prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients with tumors negative for epidermal growth factor receptor (EGFR) by immunohistochemical analysis.

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing Erlotinib, factors associated with 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 excipient of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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 UGT1A1 glucuronidation in vitro.

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

When erlotinib was administered with ciprofloxacin, a moderate inhibitor of CYP1A2, erlotinib exposure (AUC) significantly increased by 39%, while Cmax did not change statistically significantly. Similarly, 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 with ciprofloxacin or with potent CYP1A2 inhibitors (e.g., fluvoxamine). If adverse reactions related to erlotinib occur, the dose of the drug may be reduced.

Prior or concomitant treatment with 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 co-administered. Therefore, clinically significant interactions with the clearance of other CYP3A4 substrates are unlikely.

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

Erlotinib is metabolized in the liver by human hepatic cytochromes, primarily CYP3A4 enzymes, and to a lesser extent CYP1A2. Extrahepatic metabolism by CYP3A4 in the small intestine, CYP1A1 in the lungs, and CYP1B1 in tumor tissue may also contribute to erlotinib metabolic clearance. Potential 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). Caution is required when prescribing Erlotinib with potent CYP3A4 inhibitors, including azole antifungal agents (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, and clarithromycin. If toxicity develops, the dose of Erlotinib 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, led to a 69% reduction in median AUC of erlotinib. When rifampicin was co-administered with a single 450 mg dose of Erlotinib, the mean AUC of erlotinib was 57.5% of that observed after a single 150 mg dose of erlotinib in the absence of rifampicin therapy. Concomitant use of Erlotinib and CYP3A4 inducers should be avoided. For patients requiring concomitant treatment with Erlotinib and a potent CYP3A4 inducer (such as rifampicin), consideration should be given to increasing the dose of Erlotinib to 300 mg with careful monitoring of the patient’s safety (including renal and hepatic function and serum electrolyte levels). If well tolerated for more than 2 weeks, the dose of Erlotinib may be increased to 450 mg with careful safety monitoring. Reduced erlotinib exposure is possible when co-administered with other CYP3A4 inducers (phenytoin, carbamazepine, barbiturates, St. John’s wort-containing products). Concomitant use of these medicinal products with erlotinib requires caution. Where 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 fatal cases, has been reported with concomitant use of erlotinib and coumarin-derived anticoagulants, including warfarin. Patients receiving coumarin-derived anticoagulants should have their prothrombin time or INR monitored regularly.

Erlotinib and statins

The risk of statin-induced myopathy, including rare cases of rhabdomyolysis, may be increased when erlotinib is used concomitantly with statins.

Erlotinib and smoking patients

Pharmacokinetic interaction results 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-fold, respectively. Therefore, smokers should be advised to quit smoking as early as possible before starting treatment with Erlotinib due to reduced plasma concentrations of erlotinib with continued smoking. Based on results from the CURRENTS study, there is no evidence supporting the use of a higher erlotinib dose of 300 mg compared to the recommended 150 mg dose in active smokers. Safety data were comparable between 300 mg and 150 mg doses; however, a significant increase in the frequency of rash, interstitial lung disease, and diarrhea was observed in patients receiving higher erlotinib doses (see sections “Pharmacokinetics”, “Special warnings and precautions for use”, and “Dosage and administration”).

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant administration of Erlotinib and P-glycoprotein inhibitors (e.g., cyclosporine and verapamil) may alter the 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 bioavailability. When erlotinib was co-administered with omeprazole, a proton pump inhibitor, AUC and Cmax of erlotinib decreased by 46% and 61%, respectively. Tmax and elimination half-life were unchanged. When erlotinib was co-administered with ranitidine (300 mg), an H2-receptor antagonist, AUC and Cmax of erlotinib decreased by 33% and 54%, respectively. Increasing the dose of Erlotinib when co-administered with such agents is unlikely to 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 by only 15% and 17%, respectively. The effect of antacids on erlotinib absorption has not been studied, but impaired absorption of erlotinib is possible, potentially leading to reduced plasma levels of erlotinib. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is required during Erlotinib treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib. If ranitidine is prescribed, its administration should be staggered with Erlotinib: 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 led to a statistically significant increase in AUC0-48 of total platinum by 10.6%. Despite statistical significance, this difference is considered not to have clinical relevance. 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 and a borderline increase in Cmax of erlotinib were observed compared to values obtained in another study where erlotinib was used as monotherapy. No significant effect of erlotinib on capecitabine pharmacokinetics was observed.

Erlotinib and proteasome inhibitors

Based on the mechanism of action, proteasome inhibitors, including bortezomib, are expected to affect the activity of epidermal growth factor receptor (EGFR) inhibitors, including erlotinib. Limited clinical data and preclinical study results, showing proteasome-mediated degradation of EGFR, support this potential effect.

Special precautions for use.

Testing for epidermal growth factor receptor (EGFR) mutations

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

According to local medical practice, a validated, reliable, and sensitive test with a defined positivity threshold and demonstrated utility in determining EGFR mutation status should be used, based on tumor DNA from tissue samples or circulating free DNA (cfDNA) from blood plasma samples.

If a plasma-based cfDNA test is used and results for activating mutations are negative, tissue testing should be performed if possible, due to the possibility of false-negative results with plasma-based testing.

Use in patients who smoke

Smokers should be advised to quit 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 "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage").

Interstitial lung disease

Cases of interstitial lung disease (ILD)-like events, including fatal outcomes, have been infrequently observed in patients with NSCLC, pancreatic cancer, or other advanced solid tumors receiving erlotinib. In the pivotal BR.21 study in NSCLC patients receiving placebo or erlotinib, the incidence of ILD was 0.8% in each group. According to a meta-analysis of randomized 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 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 patients receiving gemcitabine and placebo. Reported diagnoses in patients with suspected ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, 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. Often, concomitant or predisposing factors were present, such as concurrent 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%) was observed in patients enrolled in studies conducted in Japan.

In patients presenting with acute onset of new and/or progressive unexplained pulmonary symptoms (dyspnea, cough, fever), treatment with Erlero should be temporarily discontinued pending diagnostic evaluation. Patients receiving concomitant erlotinib and gemcitabine therapy should be closely monitored for the potential development of ILD-like toxicity. If ILD develops, Erlero should be discontinued and appropriate treatment initiated, if necessary (see section "Adverse reactions").

Diarrhea, dehydration, electrolyte imbalance, and renal failure

Diarrhea (including very rare fatal cases) was observed in approximately 50% of patients receiving erlotinib treatment. In cases of severe or moderate diarrhea, symptomatic treatment such as loperamide should be initiated. In some cases, dose reduction may be necessary. In clinical trials, dose reductions were performed in 50 mg steps. Dose reductions in 25 mg increments have not been studied. In cases of severe or persistent diarrhea, nausea, anorexia, or vomiting associated with dehydration, treatment with Erlero should be interrupted and appropriate measures taken to correct dehydration (see section "Adverse reactions"). Rare cases of hypokalemia and renal failure (including fatal outcomes) have been reported. Some cases were attributed to severe dehydration due to diarrhea, vomiting, and/or anorexia, while in others, interpretation was complicated by concomitant chemotherapy. In more severe or persistent cases of diarrhea or cases leading to dehydration, particularly in patient groups with risk factors (especially with concomitant chemotherapy or other medications, presence of symptoms or conditions, or other predisposing factors including advanced age), treatment with Erlero should be interrupted and appropriate measures taken, including intensive intravenous rehydration. Additionally, in patients at risk of dehydration, renal function and serum electrolyte levels, including potassium, should be monitored.

Hepatitis, hepatic failure

Rare cases of hepatic failure (including fatal outcomes) have been reported during erlotinib treatment. Contributing factors complicating interpretation include pre-existing liver disease and concomitant use of hepatotoxic medicinal products. Therefore, periodic monitoring of liver function is recommended in these patients. Treatment with Erlero should be interrupted in the presence of severe hepatic function abnormalities (see section "Adverse reactions"). Erlero is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforation

Patients receiving Erlero 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, Erlero 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 Erlero should be temporarily discontinued or permanently stopped. Patients with bullous and exfoliative skin disorders should be evaluated for skin infections and treated according to local treatment guidelines.

Eye disorders

Patients presenting with signs and symptoms characteristic of keratitis, such as acute onset or worsening of ocular inflammation, lacrimation, photophobia, blurred vision, eye pain, and/or eye redness, should be referred immediately for ophthalmologic consultation. In cases of confirmed ulcerative keratitis, treatment with Erlero should be temporarily or permanently discontinued. The benefit-risk ratio of continuing Erlero treatment should be carefully considered in patients diagnosed with keratitis. Erlero 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. Very rare cases of corneal perforation or ulceration have been observed during Erlero treatment (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 lead to increased toxicity. Concomitant use of Erlero with these types of medicinal products 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 Erlero during concomitant use of these medicinal products would compensate for reduced exposure. Concomitant use of Erlero 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 Erlero treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlero.

Excipients

Lactose. This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Sodium. One tablet of this medicinal product contains less than 1 mmol of sodium (23 mg), thus the product is considered "sodium-free".

Disposal of unused or expired medicinal product. Environmental contamination should be minimized. The medicinal product should not be disposed of via wastewater or household waste. When available, a dedicated waste collection system should be used.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data on the use of erlotinib in pregnant women. Animal studies have shown no evidence 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 contraception during treatment with Erlero and for at least 2 weeks after completion of treatment. Treatment during pregnancy should continue only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

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

Fertility

Animal studies indicate no impairment of fertility. However, an adverse 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 influence the ability to drive and use 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 Erlecco 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 Erlecco is 150 mg once daily, taken at least 1 hour before or 2 hours after eating.

Pancreatic cancer

The recommended dose of Erlecco is 100 mg once daily, taken at least 1 hour before or 2 hours after eating, in combination with gemcitabine (see also the gemcitabine prescribing information, indication – pancreatic cancer).

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

If dose adjustment is required, the dose should be reduced in 50 mg decrements (see section "Special Instructions"). Erlecco is available in 25 mg, 100 mg, and 150 mg strengths. When coadministering substrates and modulators of CYP3A4, dose adjustment may be necessary (see section "Interaction with other medicinal products and other forms 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 (7–9 points on the Child–Pugh scale) and those with normal liver function, caution should be exercised when administering Erlecco to patients with hepatic insufficiency. If severe adverse reactions occur, the dose of Erlecco should be reduced or treatment discontinued. The safety and efficacy of Erlecco in patients with severe hepatic impairment (AST/SGOT [aspartate aminotransferase/serum glutamic oxaloacetic transaminase] and ALT/SGPT [alanine aminotransferase/serum glutamic pyruvic transaminase] > 5 × upper limit of normal [ULN]) have not been studied. Erlecco is not recommended for patients with severe hepatic dysfunction (see section "Pharmacokinetics").

Renal impairment

The safety and efficacy of Erlecco 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 required for patients with mild to moderate renal impairment (see section "Pharmacokinetics"). Erlecco is not recommended for patients with severe renal impairment.

Use in smokers

Smoking has been shown to reduce erlotinib exposure by 50–60%. The maximum tolerated dose of Erlecco in patients with NSCLC who smoke is 300 mg. For the 300 mg dose, no improved efficacy has been demonstrated in second-line treatment after failure of chemotherapy compared to the recommended 150 mg dose in patients who continue to smoke. Safety profiles 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 (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interactions", and "Special Instructions").

Children

The safety and efficacy of erlotinib in patients under 18 years of age for the approved indications have not been established. Erlecco 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 tolerated. Tolerability of multiple daily doses of 200 mg twice daily in healthy volunteers worsened only after several days of administration. According to data from these studies, severe adverse reactions such as diarrhea, rash, and possibly elevated liver aminotransferase levels may occur following overdose.

Treatment

In case of suspected overdose, Erlecco treatment 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 from more than 300 patients who received erlotinib at a dose of 100 mg or 150 mg in combination with gemcitabine.

Adverse reactions observed in clinical trials (see below) are listed by MedDRA system organ class. 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 presented in order of decreasing severity.

NSCLC (erlotinib monotherapy)

First-line treatment in patients with EGFR mutations

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

The most common adverse reactions in patients receiving erlotinib in the ML20650 trial were rash and diarrhea (any grade: 80% and 57%, respectively), most 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 administered 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 safety signals were identified.

The most common adverse reactions observed in patients receiving erlotinib in trials BO18192 and BO25460 were 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 Grade 4 rash or diarrhea events were observed in either study. Rash and diarrhea led to premature discontinuation of erlotinib in 1% and <1% of patients, respectively, in study BO18192; in study 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 study BO18192, and in 5.6% and 2.8% of patients, respectively, in study 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 NSCLC patients receiving erlotinib, respectively, and each of these reactions led to study withdrawal in 1% of patients and dose adjustments in 6% and 1% of patients, respectively. In the BR.21 trial, the median time to onset of rash was 8 days, and to onset of diarrhea was 12 days.

Rash typically presented 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 (e.g., mineral-based sunscreens).

Pancreatic cancer (concomitant use of erlotinib with gemcitabine)

The most common adverse reactions in the pivotal PA.3 trial 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 study withdrawal in up to 1% of patients receiving erlotinib in combination with gemcitabine.

Below are listed adverse reactions occurring in ≥10% of patients in trials BR.21 (erlotinib monotherapy) and PA.3 (combination therapy erlotinib plus gemcitabine), and adverse reactions occurring more frequently (≥3%) than in the placebo group in trials BR.21 (erlotinib monotherapy) and PA.3 (combination therapy erlotinib plus gemcitabine).

NCI-CTC Grade	Erlotinib (BR.21) n=485			Erlotinib (PA.3) n=259			Frequency category with highest prevalence
	Any grade	3	4	Any grade	3	4
Preferred MedDRA Term	%	%	%	%	%	%
Infections and infestations Infections*	24	4	0	31	3	<1	very common
Metabolism and nutrition disorders Anorexia Weight decreased	52 -	8 -	1 -	- 39	- 2	- 0	very common very common
Eye disorders Dry eye keratoconjunctivitis Conjunctivitis	12 12	0 <1	0 0	- -	- -	- -	very common very common
Psychiatric disorders Depression	-	-	-	19	2	0	very common
Nervous system disorders Neuropathy Headache	- -	- -	- -	13 15	1 <1	<1 0	very common very common
Respiratory, thoracic and mediastinal disorders Dyspnoea Cough	41 33	17 4	11 0	- 16	- 0	- 0	very common very common
Gastrointestinal disorders Diarrhoea** Nausea Vomiting Stomatitis Abdominal pain Dyspepsia Flatulence	54 33 23 17 11 - -	6 3 2 <1 2 - -	<1 0 <1 0 <1 - -	48 - - 22 - 17 13	5 - - <1 - <1 0	<1 - - 0 - 0 0	very common very common very common very common very common very common very common
Skin and subcutaneous tissue disorders Rash*** Pruritus Dry skin Alopecia	75 13 12 -	8 <1 0 -	<1 0 0 -	69 - - 14	5 - - 0	0 - - 0	very common very common very common very common
General disorders and administration site conditions Fatigue Pyrexia Chills	52 - -	14 - -	4 - -	73 36 12	14 3 0	2 0 0	very common very common very common

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

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

*** Rash includes acneiform dermatitis.

• Corresponds to the percentage below the indicated threshold.

The following are other adverse reactions, including those observed in other clinical studies, by frequency category

System organ class	Very common (≥1/10)	Common (from ≥1/100 to <1/10)	Uncommon (from ≥1/1000 to <1/100)	Rare (from ≥1/10 000 to <1/1000)	Very rare (<1/10 000)
Eye disorders		keratitis conjunctivitis1	changes of eyelashes2		corneal perforation, corneal ulceration, uveitis
Respiratory, thoracic and mediastinal disorders		nosebleed	interstitial lung disease (ILD)3
Gastrointestinal disorders	diarrhea7	gastrointestinal hemorrhage4,7	GIT 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, changes of eyebrows, nail brittleness and loss; mild skin reactions such as hyperpigmentation	palmoplantar erythrodysesthesia syndrome	Stevens-Johnson syndrome/ toxic epidermal necrolysis7
Renal and urinary disorders		renal failure1	nephritis1, proteinuria1

1 In clinical study PA.3.

2 Including eyelash growth, excessive growth, and thickening of eyelashes.

3 Including fatal cases in patients receiving erlotinib for the treatment of NSCLC or other common solid tumours (see section "Special precautions for use"). Observed more frequently in patients in Japan (see section "Special precautions for use").

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

6 Including fatal cases. Factors complicating interpretation included underlying liver disease or concomitant use of hepatotoxic medicinal products (see section "Special precautions for use").

7 Including fatal cases (see section "Special precautions for use").

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit-V, Block-VB, TSIIC Formulation SEZ, Sy. No. 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India / Unit-V, Block-VB, TSIIC Formulation SEZ, Sy. No. 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.