Erlotoks

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

Composition:

Active substance: erlotinib;

One film-coated tablet contains erlotinib 25 mg in the form of erlotinib hydrochloride 27.30 mg; erlotinib 100 mg in the form of erlotinib hydrochloride 109.30 mg; or erlotinib 150 mg in the form of erlotinib hydrochloride 163.90 mg;

Excipients: microcrystalline cellulose, anhydrous lactose, sodium starch glycolate (type A), sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate; film coating Opadry White 20A580000 (hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), sodium lauryl sulfate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: film-coated tablets, white to almost white, round, biconvex, with engraving «E» and «25» on one side and no engraving on the other side;

100 mg tablets: film-coated tablets, white to almost white, round, biconvex, with engraving «E» and «100» on one side and no engraving on the other side;

150 mg tablets: film-coated tablets, white to almost white, round, biconvex, with engraving «E» and «150» on one side and no engraving on the other side.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Erlotinib. ATC code L01X E03.

Pharmacological Properties.

Pharmacodynamics.

Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor type 1 (HER1). Erlotinib causes pronounced inhibition of intracellular phosphorylation of EGFR. EGFR is expressed on the surface of both healthy and cancer cells. In preclinical models, inhibition of EGFR phosphotyrosine leads to arrest of cell growth and cell death.

EGFR-activating mutations may lead to persistent 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 within the mutated kinase domain of EGFR. 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 tissues. In a study involving 4 patients (3 with non-small cell lung cancer [NSCLC] and 1 with laryngeal cancer) who received Erlotoks at a dose of 150 mg daily, tumor samples obtained during surgery on day 9 contained erlotinib in tissue at a mean concentration of 1185 ng/g. 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 tumor tissue at a mean concentration of 160 ng/g, corresponding to an overall mean of 113% (range: 88–130%) of the steady-state maximum stable plasma concentration. Plasma protein binding is approximately 95%. Erlotinib binds to serum albumin and α1-acid glycoprotein (AAG).

Metabolism.

Erlotinib is metabolized in the liver by the cytochrome P450 system, primarily via CYP3A4 enzymes, and to a lesser extent by 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 erlotinib metabolic clearance. Metabolism occurs via three pathways: 1) O-demethylation of one or both side chains followed by oxidation to carboxylic acids; 2) oxidation of the acetylenic portion of the molecule 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 side chain, 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 primarily excreted in feces (>90%), with a small amount of the orally administered dose eliminated via kidneys (approximately 9%). Less than 2% of the orally administered dose is excreted as unchanged parent compound. Population pharmacokinetic analysis in 591 patients receiving Erlotoks as 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 concentration is expected to be reached after approximately 7–8 days.

Pharmacokinetics in Special Patient Populations.

Population pharmacokinetic analysis revealed no clinically significant relationships between predicted apparent clearance and patient age, body weight, gender, or ethnicity. Erlotinib pharmacokinetics were influenced by serum total bilirubin concentration, α1-acid glycoprotein (AAG) levels, and current smoking status. Erlotinib clearance was reduced with increased concentrations of total bilirubin and AAG. The clinical significance of this observation is unknown. However, accelerated erlotinib clearance was observed in smokers, confirmed in a pharmacokinetic study of single-dose erlotinib 150 mg in nonsmokers and current smokers. The geometric mean maximum concentration was 1056 ng/mL in nonsmokers 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 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 phase III pivotal study in NSCLC patients who smoked, 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, steady-state pharmacokinetic analysis showed dose-proportional increases in erlotinib exposure after increasing the Erlotoks dose from 150 mg to the maximum tolerated dose of 300 mg. The steady-state minimum plasma concentration after 300 mg dosing in continuing smokers in this study was 1.22 µg/mL (n=17).

Based on pharmacokinetic study results, patients who smoke are advised to quit smoking during Erlotoks treatment, as otherwise a reduction in plasma drug concentration may occur.

According to population pharmacokinetic analysis, erlotinib exposure increased by approximately 11% in the presence of opioid medications.

A second population pharmacokinetic analysis was conducted using 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 the plasma clearance of erlotinib.

Children.

No specific studies have been conducted in pediatric patients.

Elderly Patients.

No specific studies have been conducted in elderly patients.

Hepatic Impairment.

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

Renal Impairment.

Erlotinib and its metabolites are excreted in minimal amounts via the kidneys—less than 9% of a single dose is excreted in urine. In the population pharmacokinetic analysis, no clinically significant association 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.

Erlotek is also indicated for transition to maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations and stable disease after first-line chemotherapy.

Treatment of locally advanced or metastatic non-small cell lung cancer after failure of one or more chemotherapy regimens.

When prescribing Erlotek, factors associated with prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients whose tumors lack epidermal growth factor receptor (EGFR) as determined by immunohistochemical testing.

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing Erlotek, 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 component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies were conducted only in adults.

Erlotinib and other CYP substrates

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

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

Concomitant administration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP1A2, increased erlotinib exposure (AUC) by 39%, while maximum concentration (Cmax) did not change significantly. Similarly, exposure (AUC) of active metabolites increased by 60% and 48% for AUC and Cmax, respectively. The clinical significance of this increased exposure has not been established. Therefore, caution is required when prescribing Erlotek with ciprofloxacin or potent inhibitors of CYP1A2 (e.g., fluvoxamine). If adverse reactions related to erlotinib occur, the dose of the medicinal product may be reduced.

Prior or concomitant treatment with Erlotek did not alter the clearance of prototype substrates of CYP3A4 – 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 affecting 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. Patients with low expression levels of UGT1A1 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 primarily by hepatic cytochromes, predominantly CYP3A4, and to a lesser extent CYP1A2. Extrahepatic metabolism involving 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 an increase in erlotinib exposure (by 86% in AUC and by 69% in Cmax). Caution is required when prescribing Erlotek with potent CYP3A4 inhibitors, including azole antifungal agents (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, and clarithromycin. In case of toxicity development, the dose of Erlotek 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 Erlotek, the average erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg dose of Erlotek without rifampicin therapy. Concomitant use of Erlotek and CYP3A4 inducers should be avoided. For patients requiring concomitant treatment with Erlotek and a potent CYP3A4 inducer (such as rifampicin), dose escalation of Erlotek to 300 mg should be considered with careful monitoring of the patient’s condition (including renal and hepatic function and serum electrolyte levels). If well tolerated for more than 2 weeks, the dose of Erlotek 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 agents with erlotinib requires caution. Where possible, alternative medicinal products that are not potent CYP3A4 inducers should be prescribed.

Erlotinib and anticoagulants, coumarin derivatives

Increased international normalized ratio (INR) and bleeding events, including isolated cases with fatal outcomes, have been reported with concomitant use of Erlotek and coumarin-derived anticoagulants, including warfarin. Patients receiving coumarin-derived anticoagulants should have their prothrombin time or INR monitored regularly.

Erlotinib and statins

When Erlotek is used concomitantly with statins, the risk of statin-induced myopathy, including rhabdomyolysis (rare), may increase.

Erlotinib and smoking patients

Pharmacokinetic study 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 stop smoking as early as possible before starting treatment with Erlotek due to reduced plasma concentrations of erlotinib with continued smoking. The clinical consequences of reduced erlotinib exposure have not been formally studied but are likely to be clinically significant.

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant administration of Erlotek and P-glycoprotein inhibitors (e.g., cyclosporine and verapamil) may alter the distribution and/or elimination of erlotinib. The consequences of such interactions, particularly for the CNS, such as toxic effects, 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 Erlotek 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 altered. When Erlotek was administered concomitantly with ranitidine (300 mg), an H2-receptor antagonist, erlotinib exposure (AUC) and maximum concentration (Cmax) decreased by 33% and 54%, respectively. Increasing the dose of Erlotek when co-administered with such agents is unlikely to compensate for the reduced exposure. However, when Erlotek 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. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is necessary during Erlotek treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotek. If ranitidine is prescribed, its administration should be staggered relative to Erlotek: 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%, but this was not clinically significant. 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 cause increased erlotinib concentrations. After erlotinib administration in combination with capecitabine, a statistically significant increase in AUC of erlotinib and a marginal increase in Cmax 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, it can be expected that proteasome inhibitors, including bortezomib, may 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 interaction.

Special precautions for use.

Testing for epidermal growth factor receptor mutations

When testing for epidermal growth factor receptor mutations, it is important to use a well-validated and reliable method to avoid false-negative and false-positive results.

Use in patients who smoke

Smokers should be advised to stop smoking, as erlotinib plasma concentrations are reduced in smokers compared to non-smokers. The extent of reduction in erlotinib plasma concentration is likely to be clinically significant (see section "Interaction with other medicinal products and other forms of interaction").

Interstitial lung disease

Cases of interstitial lung disease (ILD)-like events, including fatal ILD, have been infrequently observed in patients with non-small cell lung cancer, pancreatic cancer, or other advanced solid tumors receiving Erlocip. In the pivotal BR.21 study in patients with non-small cell lung cancer receiving placebo or Erlocip, the incidence of ILD was 0.8% in each group. The incidence of ILD-like events in patients with pancreatic cancer receiving Erlocip and gemcitabine was 2.5% compared to 0.4% in the group receiving gemcitabine and placebo. The overall incidence of events in patients receiving Erlocip, including in uncontrolled studies and studies with concomitant chemotherapy, is 0.6% compared to 0.2% in patients receiving placebo. ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infiltration, and alveolitis, occurring from several days to several months after initiation of Erlocip therapy. Frequently, factors associated with concomitant or prior chemotherapy, radiotherapy, underlying parenchymal lung disease, metastatic lung involvement, or infection were present. A higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) has been observed in patients of Japanese origin.

Upon development of new and/or progressive respiratory symptoms of unknown origin (dyspnea, cough, and fever), administration of Erlocip should be temporarily discontinued until the cause is determined. Patients receiving concomitant erlotinib and gemcitabine should be closely monitored for the potential development of ILD-like toxicity. If ILD develops, Erlocip should be discontinued and appropriate treatment initiated (see section "Undesirable effects").

Diarrhea, dehydration, electrolyte imbalance, and renal failure

Diarrhea (including very rare cases with fatal outcome) was observed in approximately 50% of patients receiving Erlocip. In cases of severe or moderate diarrhea, treatment with, for example, loperamide should be initiated. In some cases, dose reduction of the medicinal product may be necessary. In clinical trials, the dose was reduced in 50 mg steps. Dose reductions in 25 mg steps have not been studied. In cases of severe or persistent diarrhea, nausea, anorexia, or vomiting associated with dehydration, the use of Erlocip should be suspended and appropriate measures taken to correct dehydration (see section "Undesirable effects"). Rare cases of hypokalemia and renal failure (including fatal outcomes) have been reported. In some cases, dehydration was 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, especially in patient groups with predisposing risk factors (concomitant use of other drugs, presence of symptoms or diseases, or other susceptibility factors, including advanced age), treatment with Erlocip should be interrupted and appropriate measures taken for intensive intravenous rehydration. In patients at risk of dehydration, renal function and serum electrolyte levels, including potassium, should also be monitored.

Hepatitis, hepatic failure

Rare cases of hepatic failure (including fatal outcomes) have been reported during treatment with Erlocip. 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. Treatment with Erlocip should be suspended in case of marked changes in liver function (see section "Undesirable effects"). Erlocip is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforation

Patients taking Erlocip are at increased risk of gastrointestinal perforation, which occurs infrequently (including isolated cases with fatal outcome). 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, treatment with Erlocip should be permanently discontinued (see section "Undesirable effects").

Bullous and exfoliative skin disorders

Bullous, vesicular, and exfoliative skin disorders, including very rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, some of which were fatal, have been observed during treatment with Erlocip (see section "Undesirable effects"). In case of bullous, vesicular, or exfoliative skin disorders, treatment with Erlocip should be temporarily discontinued or stopped. Patients with bullous and exfoliative skin disorders should be evaluated for skin infections and treated according to local treatment guidelines.

Ocular disorders

Patients presenting signs and symptoms typical of keratitis, such as acute onset or worsening of ocular inflammation, lacrimation, photophobia, blurred vision, eye pain, and/or redness, should be referred immediately for ophthalmologic evaluation. Upon confirmation of ulcerative keratitis, treatment with Erlocip should be temporarily or permanently discontinued. The benefit-risk balance of continuing Erlocip treatment should be carefully considered in patients diagnosed with keratitis. Erlocip should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eyes. Contact lens use is also a risk factor for keratitis and corneal ulceration. Very rare cases of corneal perforation or ulceration have been reported during Erlocip treatment (see section "Undesirable effects").

Interaction with other medicinal products

Strong inducers of CYP3A4 enzymes may reduce the efficacy of erlotinib, whereas strong inhibitors of CYP3A4 may lead to increased toxicity. Concomitant use of Erlocip with medicinal products 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 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, consequently, its bioavailability. It is unlikely that increasing the dose of Erlocip when co-administered with these agents can compensate for the reduced exposure. Concomitant use of Erlocip with proton pump inhibitors should be avoided. The consequences of concomitant use of erlotinib with H2-receptor antagonists and antacids are unknown, but a reduction in 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 Erlocip treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlocip.

The tablets contain lactose and therefore should not be administered to patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Disposal of unused medicine and expired products. Environmental contamination should be minimized. The medicine should not be disposed of via wastewater or household waste. Disposal should be carried out using a "waste collection system" if available.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data on the use of erlotinib in pregnant women. Animal studies have demonstrated no signs of teratogenic effects or delivery abnormalities. However, a negative impact 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 avoid pregnancy and use reliable contraceptive methods during treatment with Erlocip and for at least 2 weeks after completion of treatment. Treatment of a pregnant woman should continue only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether erlotinib is excreted in human breast milk. Women receiving Erlocip are advised to discontinue breastfeeding.

Fertility

Animal studies indicate no impairment of fertility. However, undesirable effects 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 reaction speed when driving or operating machinery.

Studies on the influence on the ability to drive or operate machinery have not been conducted; however, the effect of erlotinib is not expected to impair mental function.

Method of Administration and Dosage

Treatment with Erlotoks should be administered by a physician experienced in anticancer therapy.

Non-small cell lung cancer

Prior to initiating treatment with Erlotoks, patients with advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy must be tested for epidermal growth factor receptor (EGFR) mutations.

The recommended dose of Erlotoks is 150 mg once daily, taken 1 hour before or 2 hours after a meal.

Pancreatic cancer

The recommended dose of Erlotoks is 100 mg once daily, taken 1 hour before or 2 hours after a meal, 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, consideration should be given to continuing therapy with Erlotoks (see section "Pharmacodynamics").

If dose adjustment is required, the dose should be reduced stepwise by 50 mg (see section "Special instructions for use"). Dose adjustments may be necessary when Erlotoks is used concomitantly with CYP3A4 substrates and modulators (see section "Interaction with other medicinal products and other forms of interactions").

Liver function impairment

Erlotinib is eliminated via hepatic metabolism and excreted in bile. Although erlotinib exposure was approximately similar in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared to those with normal liver function, caution should be exercised when administering Erlotoks to patients with hepatic insufficiency. In the event of severe adverse reactions, the dose of Erlotoks should be reduced or treatment discontinued. The safety and efficacy of Erlotoks 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; therefore, Erlotoks is not recommended for use in such patients (see section "Pharmacokinetics").

Renal function impairment

The safety and efficacy of Erlotoks in patients with renal impairment (serum creatinine concentration 1.5 times above the upper limit of normal [ULN]) have not been studied. Based on pharmacokinetic data, dose adjustment is not recommended for patients with mild to moderate renal impairment (see section "Pharmacokinetics"). Erlotoks is not recommended for use in patients with severe renal impairment.

Use in smokers

Smoking reduces erlotinib exposure by 50–60%. The maximum tolerated dose of Erlotoks in patients with non-small cell lung cancer who smoke is 300 mg. The efficacy and long-term safety of doses exceeding the recommended initial dose have not been established in patients who continue to smoke (see sections "Interaction with other medicinal products and other forms of interactions" and "Pharmacokinetics"). Therefore, patients who continue to smoke are advised to quit, as plasma concentrations of erlotinib are lower in smokers compared to non-smokers.

Children

The safety and efficacy of erlotinib in patients under 18 years of age have not been established. Erlotoks is not recommended for use in children.

Overdose

Symptoms

Single oral doses of Erlotoks 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 these studies, overdose may lead to severe adverse reactions such as diarrhea, rash, and possibly elevated liver transaminase levels.

Treatment

In case of suspected overdose, treatment should be discontinued and symptomatic therapy initiated.

Adverse reactions

Monotherapy in non-small cell lung cancer

In the randomized, double-blind BR.21 study (Erlotax administered as second-line therapy), the most common adverse reactions were rash (75%) and diarrhea (54%), most of which were of grade 1 or 2 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 Erlotax, respectively. Each of these reactions led to discontinuation in 1% of patients and required dose adjustment in 6% and 1% of patients, respectively. In the BR.21 study, the median time to onset of rash was 8 days and to onset of diarrhea was 12 days.

In most cases, the rash presented as erythematous or papulopustular lesions of mild to moderate severity, occurring or worsening in sun-exposed areas of the skin. Patients who are exposed to sunlight are advised to wear protective clothing and/or use sun protection (e.g., mineral-based sunscreen).

Adverse reactions occurring more frequently (≥3%) in patients treated with Erlotax compared to those receiving placebo in the pivotal BR.21 study and in at least 10% of patients in the Erlotax group are listed below by severity grade according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC).

The following frequency categories are used to classify adverse reactions: 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), including isolated case reports.

Within each category, adverse reactions are listed in decreasing order of severity.

Infections and infestations: very common – severe infections (with or without neutropenia, pneumonia, sepsis, cellulitis).

Metabolism and nutrition disorders: very common – anorexia.

Eye disorders: very common – conjunctivitis, dry keratoconjunctivitis.

Respiratory, thoracic and mediastinal disorders: very common – dyspnea, cough.

Gastrointestinal disorders: very common – diarrhea (may lead to dehydration, hypokalemia, renal failure), nausea, vomiting, stomatitis, abdominal pain.

Skin and subcutaneous tissue disorders: very common – rash (including acneiform dermatitis), pruritus, dry skin.

General disorders: very common – fatigue.

In two other double-blind, randomized, placebo-controlled phase III studies, BO18192 (SATURN) and BO25460 (IUNO), Erlotax was administered as maintenance therapy following first-line chemotherapy. These studies included a total of 1,532 patients with advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) after standard platinum-based first-line chemotherapy. No new safety signals were identified.

The most common adverse reactions observed in patients treated with Erlotax in studies BO18192 and BO25460 were rash and diarrhea (see table below). No cases of grade 4 rash or diarrhea were observed in either study. Rash and diarrhea led to premature discontinuation of Erlotax in 1% and <1% of patients, respectively, in study BO18192; in study BO25460, no premature discontinuations due to rash or diarrhea were reported. Dose modifications (treatment interruption or dose reduction) due to rash and diarrhea were 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.

Most common adverse reactions observed in studies BO18192 (SATURN) and BO25460 (IUNO)

Table 1

	BO18192 (SATURN)*		BO25460 (IUNO)*
	Erlotek n=433	Placebo n=445	Erlotek n=322	Placebo n=319
	%	%	%	%
Rash, all grades of severity	49.2	5.8	39.4	10.0
Grade 3 severity	6.0	0	5.0	1.6
Diarrhea, all grades of severity	20.3	4.5	24.2	4.4
Grade 3 severity	1.8	0	2.5	0.3

*Safety analysis population

In an open-label, randomized Phase III study (ML20650) involving 154 patients, the safety of Erlotax was evaluated in 75 patients receiving Erlotax as first-line treatment for non-small cell lung cancer with epidermal growth factor receptor (EGFR) activating mutations. No new safety signals were observed in these patients.

The most common adverse reactions were rash and diarrhea (of any grade, 80% and 57%, respectively), most of which were Grade 1 and 2 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 modifications (treatment interruption or dose reduction) due to rash and diarrhea were required in 11% and 7% of patients, respectively.

Pancreatic cancer (concomitant use of Erlotax with gemcitabine)

In the pivotal PA.3 study involving patients with pancreatic cancer who received Erlotax 100 mg in combination with gemcitabine, the most common adverse reactions were fatigue, rash, and diarrhea. In the Erlotax 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 required dose reduction in 2% of patients and led to premature discontinuation from the study in up to 1% of patients.

In the pivotal PA.3 study, adverse reactions occurred more frequently (≥ 3%) in patients receiving Erlotax 100 mg in combination with gemcitabine compared to those receiving placebo with gemcitabine, and in at least 10% of patients in the Erlotax 100 mg plus gemcitabine group. These adverse reactions are listed below by severity grades as defined by the National Cancer Institute’s Common Toxicity Criteria (NCI-CTC).

The following frequency categories are used: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated reports.

Within each category, adverse reactions are listed in decreasing order of severity.

Infections and infestations: very common – severe infections (with or without neutropenia, pneumonia, sepsis, cellulitis).

Metabolism and nutrition disorders: very common – weight loss.

Psychiatric disorders: very common – depression.

Nervous system disorders: very common – headache, neuropathy.

Respiratory, thoracic and mediastinal disorders: very common – cough.

Gastrointestinal disorders: very common – diarrhea (may lead to dehydration, hypokalemia, renal failure), stomatitis, dyspepsia, flatulence.

Skin and subcutaneous tissue disorders: very common – rash (including acneiform dermatitis), alopecia.

General disorders and administration site conditions: very common – fatigue, chills, pyrexia.

Other observations

The safety of Erlotax was evaluated based on data from over 1200 patients who received at least one dose of Erlotax 150 mg as monotherapy, and more than 300 patients who received Erlotax in combination with gemcitabine.

The following adverse reactions were observed in patients treated with Erlotax either as monotherapy or in combination with chemotherapy.

Within each category, adverse reactions are listed in decreasing order of severity.

Eye disorders: common – keratitis (see section "Special warnings and precautions for use"), conjunctivitis1; uncommon – eyelash changes, including trichomegaly, excessive growth, and eyelash thickening; very rare – corneal perforation, corneal ulceration, uveitis.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; serious interstitial lung disease (ILD), including fatal ILD in patients with non-small cell lung cancer or other advanced solid tumors treated with Erlotax (see section "Special warnings and precautions for use").

Gastrointestinal disorders: very common – diarrhea (including fatal cases (see section "Special warnings and precautions for use")); common – gastrointestinal hemorrhage (some associated with concomitant warfarin use, others with NSAIDs, including isolated fatal cases (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use")); uncommon – gastrointestinal perforation, including isolated fatal cases (see section "Special warnings and precautions for use").

Hepatobiliary disorders: very common – liver function test abnormalities (including increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin), mostly mild or moderate in severity, transient, or related to liver metastases; rare – hepatic failure (including fatal cases). Contributing factors included underlying liver disease or concomitant use of hepatotoxic medicinal products (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders: common – alopecia, dry skin1, paronychia, folliculitis, acne/acneiform dermatitis, skin fissures; uncommon – hirsutism, eyebrow changes, brittle nails and nail loss, mild skin reactions such as hyperpigmentation; rare – palmar-plantar erythrodysesthesia syndrome; very rare – Stevens-Johnson syndrome/toxic epidermal necrolysis (including fatal cases (see section "Special warnings and precautions for use")).

Renal and urinary disorders: common – renal failure1; uncommon – nephritis1, proteinuria1.

1 In clinical study PA.3.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach of children. No special storage conditions are required.

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

RELIANCE LIFE SCIENCES PRIVATE LIMITED (PLANT 6)

RELIANCE LIFE SCIENCES PRIVATE LIMITED (PLANT 6)

Manufacturer’s address and place of business.

DHIRUBHAI AMBANI LIFE SCIENCES CENTRE (DALS), THANE, BELAPUR ROAD, RABALE, NAVI MUMBAI, 400701, India

DHIRUBHAI AMBANI LIFE SCIENCES CENTRE (DALS), THANE, BELAPUR ROAD, RABALE, NAVI MUMBAI, IN-400701, India

Marketing authorization holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of marketing authorization holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom