Erlotinib krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERLONAT KRKA (Erlotinib KRKA)

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, hydroxypropylcellulose, sodium lauryl sulfate, sodium starch glycolate (type A), calcium silicate, magnesium stearate;

Film coating: coating mixture: hypromellose, titanium dioxide (E 171), talc, propylene glycol; iron oxide red (E 172) – only for 100 mg tablets; iron oxide yellow (E 172) – only for 25 mg and 100 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: pale yellow, round, slightly biconvex, film-coated tablets with beveled edges and engraved "25" on one side of the tablet.

100 mg tablets: pale orange-pink, round, slightly biconvex, film-coated tablets with beveled edges and engraved "100" on one side of the tablet.

150 mg tablets: white or almost white, round, biconvex, film-coated tablets with beveled edges and engraved "150" on one side of the tablet.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR). Erlotinib. ATC code L01E B02.

Pharmacological Properties

Pharmacodynamics

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

EGFR-activating 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 tumors harboring such EGFR mutations is explained by the strong binding of erlotinib to the ATP-binding site within the mutated EGFR kinase domain. By blocking downstream signal transmission, cell proliferation is inhibited 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

The maximum plasma concentration (Cmax) 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%. Oral exposure 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 Erlotinib KRKA at a dose of 150 mg daily, tumor samples obtained on day 9 of surgery 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. The 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 alpha-1-acid glycoprotein (AAG).

Metabolism

Erlotinib is metabolized in the liver by hepatic 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 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 phenylacetylene 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 primarily eliminated via feces (>90%), with a small amount of the orally administered dose excreted 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 KRKA as monotherapy showed a mean apparent clearance of 4.47 L/hour 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 did not reveal clinically significant relationships between predicted apparent clearance and patient age, body weight, gender, or ethnicity. Erlotinib pharmacokinetics were influenced by serum total bilirubin concentration, AAG levels, and current smoking status. Reduced erlotinib clearance was observed with increased total bilirubin and AAG concentrations. The clinical significance of this observation is unknown. However, accelerated clearance of erlotinib was observed in smokers, as confirmed in a pharmacokinetic study administering a single 150 mg dose of erlotinib to nonsmokers and current smokers. The geometric mean maximum concentration was 1056 ng/mL in nonsmokers and 689 ng/mL in smokers, with a geometric 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 geometric mean ratio of 35.9% (95% CI: 23.7–54.3; p<0.0001). The geometric mean concentration (C24h) was 288 ng/mL in nonsmokers and 34.8 ng/mL in smokers, with a geometric mean ratio of 12.1% (95% CI: 4.82–30.2; p=0.0001).

In a phase III baseline study of 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 or nonsmokers (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 involving NSCLC patients who smoked during the study, steady-state pharmacokinetic analysis showed dose-proportional increases in erlotinib exposure when the dose of Erlotinib KRKA 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 "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use", "Dosage and Administration").

Based on the results of pharmacokinetic studies, smokers are advised to stop smoking during treatment with Erlotinib KRKA, as continued smoking may reduce plasma drug concentrations.

Population pharmacokinetic analysis data indicate that concomitant use of opioid medications increases erlotinib exposure by approximately 11%.

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 the covariates affecting erlotinib clearance in patients with pancreatic cancer were essentially the same as those identified in previous monotherapy pharmacokinetic analyses. No new covariate effects were identified. Concomitant administration of gemcitabine does not affect the plasma clearance of erlotinib.

Pediatric Patients

No specific studies have been conducted in pediatric patients.

Elderly Patients

No specific studies have been conducted in elderly patients.

Hepatic Impairment

Erlotinib is primarily eliminated via the liver. In patients with solid tumors and moderate hepatic impairment (Child-Pugh score of 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 the pharmacokinetics of erlotinib. In 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 population pharmacokinetic analysis, no clinically significant relationship was observed between erlotinib clearance and creatinine clearance. There are no data available for 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 KRKA 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 KRKA is also indicated for treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. In patients with tumors lacking EGFR-activating mutations, Erlotinib KRKA is indicated when other treatment options are not suitable.

When prescribing Erlotinib KRKA, factors associated with prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients with tumors lacking epidermal growth factor receptor (EGFR) as determined by immunohistochemical analysis (see section "Pharmacodynamics").

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing Erlotinib KRKA, factors associated with prolonged survival should be considered (see sections "Dosage and administration" and "Pharmacodynamics").

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 have been conducted only in adults.

Erlotinib and other CYP substrates

Erlotinib is a potent inhibitor of CYP1A1 and a moderately potent 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.

Concomitant administration of erlotinib with ciprofloxacin, a moderately potent CYP1A2 inhibitor, increased erlotinib exposure (AUC) by 39%, while Cmax did not change significantly. Similarly, AUC of active metabolites 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 KRKA 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 treatment with Erlotinib KRKA did not alter the clearance of prototype CYP3A4 substrates midazolam and erythromycin. However, a 24% reduction in oral bioavailability of midazolam 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 affecting clearance of other CYP3A4 substrates are unlikely.

Inhibition of glucuronidation may lead to interactions with medicinal products that are UGT1A1 substrates and are eliminated exclusively via this metabolic pathway. Increased serum bilirubin concentrations may occur in patients with low UGT1A1 expression or genetically determined disorders of glucuronidation (e.g., Gilbert's syndrome); therefore, treatment of such patients requires caution.

Erlotinib is metabolized in the liver by hepatic cytochromes, primarily CYP3A4 enzymes, 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's metabolic clearance. Potential interactions may occur with active substances metabolized by these enzymes or acting as 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 (AUC by 86% and Cmax by 69%). Caution is required when prescribing Erlotinib KRKA with potent CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, clarithromycin. If toxicity develops, the dose of Erlotinib KRKA 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 erlotinib AUC. When rifampicin was co-administered with a single 450 mg dose of Erlotinib KRKA, mean erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg dose of Erlotinib KRKA in the absence of rifampicin therapy. Concomitant use of Erlotinib KRKA and CYP3A4 inducers should be avoided. For patients requiring concomitant treatment with Erlotinib KRKA and a potent CYP3A4 inducer (such as rifampicin), dose escalation of Erlotinib KRKA to 300 mg should be considered with careful monitoring of the patient's condition (including renal and hepatic function and serum electrolyte levels). If the drug is well tolerated for more than 2 weeks, the dose may be increased to 450 mg with careful monitoring of safety. 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

Increased international normalized ratio (INR) and bleeding, including isolated cases with fatal outcome, have been reported with concomitant use of Erlotinib KRKA and coumarin-derived anticoagulants, including warfarin. Patients receiving coumarin-derived anticoagulants should have 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 KRKA is used concomitantly with statins.

Erlotinib and smoking patients

Pharmacokinetic studies in non-smokers and current smokers showed that smoking reduces AUCinf, Cmax, and 24-hour plasma concentration of erlotinib by 2.8-, 1.5-, and 9-fold, respectively. Therefore, smokers should be encouraged to quit smoking as early as possible before starting treatment with Erlotinib KRKA due to reduced plasma concentrations of erlotinib with continued smoking. Based on data from the CURRENTS study, no evidence of benefit was found for a higher erlotinib dose of 300 mg compared to the recommended dose of 150 mg in active smokers. Safety data were comparable between 300 mg and 150 mg doses, although 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", "Dosage and administration").

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant use of Erlotinib KRKA and P-glycoprotein inhibitors (e.g., cyclosporine, verapamil) may alter the distribution and/or elimination of erlotinib. The consequences of such interactions, particularly regarding the central nervous system (e.g., toxic effects), have not been established. Caution is required in such situations.

Erlotinib and medicinal products affecting pH

Erlotinib has reduced solubility at pH values above 5. Medicinal products affecting pH in the upper gastrointestinal tract may influence erlotinib solubility and bioavailability. Concomitant administration of Erlotinib KRKA with omeprazole, a proton pump inhibitor, reduced erlotinib AUC and Cmax by 46% and 61%, respectively. Tmax and elimination half-life were unchanged. When Erlotinib KRKA was administered concomitantly with ranitidine (300 mg), an H2-receptor antagonist, erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Increasing the dose of Erlotinib KRKA is unlikely to compensate for the reduced exposure when co-administered with such agents. However, when Erlotinib KRKA was administered 2 hours before or 10 hours after ranitidine (150 mg twice daily), erlotinib AUC and Cmax 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, potentially leading to reduced plasma levels. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is necessary during Erlotinib KRKA treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib KRKA. If ranitidine is prescribed, its administration should be staggered with Erlotinib KRKA: 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 10.6% increase in AUC0-48 of total platinum, 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 lead to increased erlotinib concentrations. After administration of erlotinib in combination with capecitabine, statistically significant increases in erlotinib AUC and marginal increases in Cmax were observed compared to values from another study where erlotinib was used as monotherapy. No significant effect of erlotinib on capecitabine pharmacokinetics was observed.

Erlotinib and proteasome inhibitors

Based on mechanism of action, proteasome inhibitors, including bortezomib, may affect the activity of epidermal growth factor receptor (EGFR) inhibitors, including erlotinib. Limited clinical data and preclinical study results suggesting proteasome-mediated degradation of EGFR support such an interaction.

Special precautions for use.

Testing for epidermal growth factor receptor mutations

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

A well-validated, reliable, and sensitive test with a predefined positivity threshold for determining EGFR mutation status, using either tumour DNA obtained from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed in accordance with local medical practice.

If a plasma-based cfDNA test is used and the result is negative for activating mutations, tissue testing should be performed if possible, as false-negative results may occur with plasma-based tests.

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 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”).

Interstitial lung disease

Cases of interstitial lung disease (ILD)-like events, including fatal cases, have been infrequently observed in patients with NSCLC, pancreatic cancer, or other advanced solid tumours receiving Erlotinib KRKA. In the pivotal BR.21 study in NSCLC patients receiving placebo or Erlotinib KRKA, the incidence of ILD was 0.8% in each group. The incidence of ILD-like events in pancreatic cancer patients receiving Erlotinib KRKA and gemcitabine was 2.5% compared to 0.4% in the group receiving gemcitabine and placebo. The overall incidence of ILD-like events in patients receiving Erlotinib KRKA, including in uncontrolled studies and studies with concomitant chemotherapy, is 0.6% compared to 0.2% in placebo recipients. 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, which occurred from several days to several months after initiation of Erlotinib KRKA therapy. Often, factors associated with concomitant or prior chemotherapy, radiotherapy, pre-existing parenchymal lung disease, metastatic lung involvement, or infection were present. A higher incidence of ILD (approximately 5%) with a mortality rate of 1.5% was observed among Japanese patients.

Upon development of new and/or worsening pulmonary symptoms of unknown origin (dyspnoea, cough, fever), treatment with Erlotinib KRKA should be temporarily discontinued until the cause is determined. Patients receiving concomitant erlotinib and gemcitabine should be closely monitored for potential development of ILD-like toxicity. If ILD develops, Erlotinib KRKA should be discontinued and appropriate treatment initiated (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 KRKA. In cases of severe or moderate diarrhoea, treatment with, for example, loperamide should be initiated. In some cases, dose reduction of the medicinal product may be necessary. In clinical trials, doses were reduced in 50 mg steps. Dose reductions in 25 mg steps have not been studied. Erlotinib KRKA should be temporarily discontinued 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 more severe or persistent cases of diarrhoea 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 Erlotinib KRKA 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.

Hepatotoxicity

Serious cases of drug-induced liver injury (DILI), including hepatitis, acute hepatitis, and hepatic failure (including fatal cases), have been reported during erlotinib use. Risk factors may include pre-existing liver disease or concomitant use of hepatotoxic drugs. Periodic monitoring of liver function is recommended during erlotinib treatment. The frequency of liver function monitoring should be increased in patients with pre-existing hepatic insufficiency or biliary obstruction. Patients reporting symptoms suggestive of liver injury should undergo immediate clinical evaluation and measurement of liver function parameters. Treatment with Erlotinib KRKA should be temporarily discontinued in the presence of marked abnormalities in liver function (see section “Adverse reactions”). Erlotinib KRKA is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforation

Patients receiving Erlotinib KRKA are at increased risk of gastrointestinal perforation, which occurs infrequently (including isolated fatal cases). Increased risk of gastrointestinal perforation has been observed 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. Erlotinib KRKA treatment should be permanently discontinued if gastrointestinal perforation occurs (see section “Adverse reactions”).

Bullous and exfoliative skin disorders

Bullous, blistering, and exfoliative skin disorders, including very rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, some of which were fatal, have been observed during Erlotinib KRKA treatment (see section “Adverse reactions”). Treatment with Erlotinib KRKA should be temporarily discontinued or permanently stopped in the event of bullous, blistering, or exfoliative skin disorders. 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 eye redness, should be immediately referred for ophthalmologic consultation. Erlotinib KRKA treatment should be temporarily or permanently discontinued in the event of confirmed ulcerative keratitis. The benefit-risk balance of continuing Erlotinib KRKA treatment should be carefully considered in patients diagnosed with keratitis. Erlotinib KRKA 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 Erlotinib KRKA 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 Erlotinib KRKA 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 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, consequently, its bioavailability. It is unlikely that increasing the dose of Erlotinib KRKA during concomitant use of these medicinal products will compensate for the reduced exposure. Concomitant use of Erlotinib KRKA 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 Erlotinib KRKA treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib KRKA.

Erlotinib KRKA contains lactose and therefore should not be administered to patients with rare hereditary problems such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Disposal of unused or expired medicinal product.
Environmental contamination should be minimised. The medicinal product should not be disposed of via wastewater or household waste. “Take-back” or 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 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

Women of childbearing potential are advised to avoid pregnancy and use reliable contraception during treatment with Erlotinib KRKA 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.

Lactation

It is unknown whether erlotinib is excreted in human breast milk. No studies have been conducted to evaluate the effect of erlotinib on milk production or the presence of erlotinib in breast milk. As the potential harm to the breastfed infant is unknown, breastfeeding should be avoided during treatment with Erlotinib KRKA and for at least two 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.

Effects on ability to drive and use machines.

Studies on the influence 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 KRKA should be initiated and supervised by a physician experienced in anticancer therapy.

Non-small cell lung cancer

Testing for epidermal growth factor receptor (EGFR) mutations should be performed according to approved indications (see section "Indications").

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

Pancreatic cancer

The recommended dose of Erlotinib KRKA is 100 mg once daily, taken at least 1 hour before or 2 hours after a meal, in combination with gemcitabine (see also the gemcitabine package leaflet, indication – pancreatic cancer).

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

If dose adjustment is required, the dose should be reduced in steps of 50 mg (see section "Special precautions for use").

Erlotinib KRKA is available in 25 mg, 100 mg, and 150 mg strengths.

When co-administering substrates and modulators of CYP3A4, dose adjustment may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic 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 class 7–9 points) compared to those with normal liver function, caution should be exercised when administering Erlotinib KRKA to patients with hepatic insufficiency. If severe adverse reactions occur, the dose should be reduced or treatment discontinued. The safety and efficacy of Erlotinib KRKA 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, Erlotinib KRKA is not recommended for such patients (see section "Pharmacokinetics").

Renal impairment

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

Use in smokers

Smoking reduces erlotinib exposure by 50–60%. The maximum tolerated dose of Erlotinib KRKA 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 chemotherapy failure compared to the recommended 150 mg dose 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 (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").

Children

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

Overdose

Symptoms

Single oral doses of Erlotinib KRKA 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 worsened only after several days of administration. According to data from these studies, severe adverse reactions such as diarrhea, rash, and possibly elevated liver transaminase levels may occur following overdose.

Treatment

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

Adverse Reactions

Summary of Safety Profile

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

Monotherapy in NSCLC

First-line treatment of patients with EGFR mutations

In an open-label, randomized Phase III study (ML20650) involving 154 patients, the safety of erlotinib was evaluated in 75 patients receiving first-line treatment for NSCLC with activating epidermal growth factor receptor (EGFR) mutations.

The most common adverse reactions were rash and diarrhea, most of which were Grade I and II in severity and did not require drug discontinuation. Complete information on the grade and frequency of rash and diarrhea across all clinical studies is available in the section “Description of selected adverse reactions” below.

Maintenance therapy

In two other double-blind, randomized, placebo-controlled Phase III studies, BO18192 (SATURN) and BO25460 (IUNO), Erlotinib KRKA was administered as maintenance therapy following first-line chemotherapy. These studies 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 treated with Erlotinib KRKA in studies BO18192 and BO25460 were rash and diarrhea.

Second-line and subsequent treatment

In the randomized, double-blind study BR.21 (Erlotinib KRKA administered as second-line therapy), the most common adverse reactions were rash and diarrhea, most of which were Grade I and II in severity and resolved without intervention. Median time to onset of rash was 8 days, and to onset of diarrhea was 12 days.

Pancreatic cancer (erlotinib in combination with gemcitabine)

In the pivotal study PA.3 involving patients with pancreatic cancer who received erlotinib 100 mg in combination with gemcitabine, the most common adverse reactions were fatigue, rash, and diarrhea. Median time to onset of rash was 10 days, and to onset of diarrhea was 15 days, respectively.

Summary table of adverse reactions

The frequency of adverse reactions reported during clinical trials and post-marketing experience with erlotinib, used alone or in combination with chemotherapy, is summarized in Table 1. Adverse drug reactions are listed by MedDRA system organ classes. The following frequency criteria are used: 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); not known (cannot be estimated from available data).

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

Table 1.

Summary of adverse reactions during clinical trials and post-marketing experience by frequency

Infections and infestations
Very common	infections*
Metabolism and nutrition disorders
Very common	anorexia, weight decreased
Psychiatric disorders
Very common	depression
Nervous system disorders
Very common	neuropathy, headache
Eye disorders
Very common	dry keratoconjunctivitis
Common	keratitis, conjunctivitis
Uncommon	eyelash changes*
Very rare	corneal perforation, corneal ulceration, uveitis
Respiratory, thoracic and mediastinal disorders
Very common	dyspnea, cough
Common	epistaxis
Uncommon	interstitial lung disease (ILD)*
Gastrointestinal disorders
Very common	diarrhea*, nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence
Common	gastrointestinal hemorrhage*
Uncommon	gastrointestinal perforation*
Rare	intestinal pneumatosis
Hepatobiliary disorders
Very common	abnormal liver function tests*
Rare	hepatic failure*, hepatitis
Not known	acute hepatitis
Skin and subcutaneous tissue disorders
Very common	rash*, pruritus
Common	alopecia, dry skin, paronychia, folliculitis, acne/acneiform dermatitis, skin fissures
Uncommon	hirsutism, eyebrow changes, brittle nails and nail loss, mild skin reactions such as hyperpigmentation
Rare	palmoplantar erythrodysesthesia syndrome
Very rare	Stevens-Johnson syndrome/toxic epidermal necrolysis*
Renal and urinary disorders
Common	renal failure
Uncommon	nephritis, proteinuria
General disorders
Very common	fatigue, pyrexia, chills

*For additional information, see the section "Description of selected adverse reactions" below.

Description of selected adverse reactions

Rash

Rash, including acneiform dermatitis. Generally, rash presents as mild or moderate erythematous and papulopustular eruptions, which may appear or worsen in sun-exposed areas. Patients should be advised to wear protective clothing and/or use sunscreen (e.g., mineral-based sunscreen) when exposed to sunlight.

Diarrhea

Diarrhea may lead to dehydration, hypokalemia, and renal failure, including fatal cases (see section "Special precautions for use").

Table 2.

Summary of the frequency and severity of rash and diarrhea observed in each clinical study

Study	Indication	Rash (%)					Diarrhea (%)
		Frequency			Actions taken		Frequency			Actions taken
		Any	3	4	Discon.1	Mod.2	Any	3	4	Discon.1	Mod.2
ML20650	NSCLC	80	9	0	1	11	57	4	0	1	7
BO18192	NSCLC	49.2	6.0	0	1	8.3	20.3	1.8	0	<1	3
BO25460	NSCLC	39.4	5.0	0	0	5.6	24.2	2.5	0	0	2.8
BR.21	NSCLC	75	9		1	6	54	6		1	1
PA.3	Pancreatic cancer	-	5		1	2	-	5		1	2

1. Discontinuation.

2. Dosage modification.

Infections

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

Changes in eyelashes

Changes include eyelash in-growth, excessive growth, and thickening of eyelashes.

Interstitial lung disease (ILD)

Including ILD with fatal outcomes in patients who received erlotinib for the treatment of NSCLC or other progressive solid tumors (see section "Special precautions"). A higher incidence was observed in patients in Japan (see section "Special precautions").

Gastrointestinal bleeding

Including fatal outcomes (see section "Special precautions"). In clinical studies, some cases were associated with concomitant use of warfarin, and others with concomitant use of NSAIDs (see section "Interaction with other medicinal products and other forms of interaction"). Gastrointestinal perforations also included fatal outcomes (see section "Special precautions").

Abnormal liver function tests

Abnormalities included increased alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin. Cases were mostly mild or moderate in severity, transient, or associated with liver metastases.

Hepatic failure

Including fatal cases. Risk factors may include underlying liver disease or concomitant use of hepatotoxic drugs (see section "Special precautions").

Stevens-Johnson syndrome / toxic epidermal necrolysis

Including fatal cases (see section "Special precautions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical 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. 3 years.

Storage conditions.

Store in the original packaging to protect from moisture. No special temperature conditions are required for storage of this medicinal product. Keep out of reach and sight of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

KRKA-FARMA d.o.o. / KRKA-FARMA d.o.o.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

V. Holjevca 20/E, 10450 Jastrebarsko, Croatia / V. Holjevca 20/E, 10450 Jastrebarsko, Croatia.