Tarceva

St. John's wort is a potent CYP3A4 inducer. Co-administration with erlotinib can lead to increased erlotinib metabolism and decreased erlotinib plasma concentrations (see Drug-Drug Interactions).

Smokers should be advised to stop smoking as cigarette smoking, which is known to induce CYP1A1 and CYP1A2, has been shown to reduce erlotinib exposure by 50-60% (see Dosage and Administration, Dosing Considerations).

Grapefruit juice has CYP3A4 inhibitory activity, therefore ingestion of grapefruit juice while on TARCEVA therapy may lead to decreased erlotinib metabolism and increased erlotinib plasma concentrations (see Drug-Drug Interactions).

Comprehensive testing of drug-drug interactions with TARCEVA (erlotinib) has not been done.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg po BID for 5 days) resulted in increased exposure to erlotinib (86% in median erlotinib exposure [AUC]) and a 69% increase in C_max when compared to erlotinib alone. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration (C_max) increased by 39% and 17%, respectively. Therefore caution should be used when administering TARCEVA with potent CYP3A4 or combined CYP3A4/CYP1A2 inhibitors. These include, but are not limited to, calcium channel blockers (eg. diltiazem, verapamil); antifungals (eg. ketoconazole, fluconazole, itraconazole, voriconazole); macrolide antibiotics (eg. erythromycin, clarithromycin); fluoroquinalone antibiotics (eg. ciprofloxacin, norfloxacin); some HIV antivirals (eg. ritonavir, indinavir); and grapefruit juice. In these situations, the dose of TARCEVA should be reduced if toxicity is observed (see Dosage and Administration).

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. Induction of CYP3A4 metabolism by rifampicin (600 mg po QD for 7 days) resulted in a 69% decrease in the median erlotinib AUC, following a 150 mg dose of TARCEVA, as compared to TARCEVA alone. In a separate study, pre-treatment and co-administration of rifampicin with a single 450 mg dose of TARCEVA reduced the mean erlotinib exposure [AUC] to 57.5% of what was observed at a single 150 mg TARCEVA dose in the absence of rifampicin treatment. On the other hand, systemic exposure of the active metabolites (OSI-413 and OSI-420) of TARCEVA was largely unaffected by rifampicin treatment. As a result, the active metabolites consist of 18% of the total erlotinib exposure following the concomitant administration compared to only 5% when TARCEVA was given alone. Alternative treatments lacking potent CYP3A4 inducing activity should be considered when possible.

Other CYP3A4 inducers include, but are not limited to, barbiturates (eg. phenobarbital); anticonvulsants (eg. carbamazepine, phenytoin); glucocorticoids; pioglitazone; St. John's wort, and some HIV antivirals (eg. efavirenz, nevirapine). Alternate treatments lacking potent CYP3A4 inducing activity should be considered when possible.

Pre-treatment or co-administration of TARCEVA did not alter the clearance of the prototypical CYP3A4 substrates midazolam and erythromycin. Significant interactions with the clearance of other CYP3A4 substrates are therefore unlikely. Oral availability of midazolam did appear to decrease by up to 24%, which was however not attributed to effects on CYP3A4 activity.

The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [C_max] by 46% and 61%, respectively. There was no change to T_max or half-life. Therefore, drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for this loss of exposure.

International Normalized Ratio (INR) elevations and bleeding events including gastrointestinal bleeding (see Warnings and Precautions and Adverse Reactions) have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin derivative anticoagulants should be monitored regularly for any changes in prothrombin time or INR.

Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1. Potential interactions may occur with drugs which are metabolized by, or are inhibitors or inducers of, these enzymes.

No meaningful differences in safety or pharmacokinetics were observed between younger and older patients, therefore, no dosing adjustment is necessary (see Indications and Clinical Use).

Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure following a single 150 mg was similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function, ten of the fifteen patients with hepatic impairment died during treatment or within 30 days of the last dose of TARCEVA. A reduced dose should be considered for patients with moderate hepatic impairment. Hepatic function should be closely monitored in patients with pre-existing liver disease, hepatic impairment and/or taking concomitant hepatotoxic medications. TARCEVA dosing should be interrupted or discontinued if significant changes in liver function tests are observed. The use of TARCEVA in patients with severe hepatic dysfunction including total bilirubin of >3×ULN and/or transaminases of >5×ULN is not recommended (see Warnings and Precautions, Special Populations, Patients with Hepatic Impairment).

Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of TARCEVA in NSCLC patients who concurrently smoked cigarettes was 300 mg. Efficacy and long term safety of a dose higher than the recommended 150 mg has not been established in patients who continue to smoke cigarettes (see Drug Interactions, Drug-Lifestyle Interactions).

The safety and efficacy of TARCEVA has not been studied in patients with renal impairment.

When dose reduction is necessary, it is recommended to reduce in 50 mg steps.

Diarrhea can mostly be managed by loperamide. Patients with severe diarrhea that are unresponsive to loperamide or associated with dehydration may require a dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require a dose reduction or temporary interruption of therapy (see Warnings and Precautions).

In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment initiated as necessary (see Warnings and Precautions).

In patients being concomitantly treated with a potent CYP3A4 inhibitor such as, but not limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, troleandomycin, or atanazavir, a dose reduction should be considered in the presence of severe adverse events (see Drug Interactions).

A double-dose should not be administered to make up for forgotten individual doses.

Keratitis has been reported commonly in clinical trials of TARCEVA. Corneal ulcerations may occur. Corneal ulcerations have been reported very rarely in patients receiving TARCEVA as a complication of mucocutaneous inflammation.

The primary safety population was defined as the 856 patients treated with at least one 150 mg dose of TARCEVA monotherapy during Phase II and Phase III studies in NSCLC (A248-1007, BR.21) and other Phase I through II studies in populations other than NSCLC. This population also takes into consideration the 242 patients who received placebo in study BR.21. The following common and uncommon adverse reactions have been observed in patients who received TARCEVA monotherapy in the primary safety population.

The following terms are used to rank the undesirable effects by frequency: 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 reports.

Liver function test abnormalities (including elevated alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) have been observed commonly. These were mainly mild or moderate in severity, transient in nature or associated with liver metastases]. Grade 2 (>2.5-5.0×ULN) ALT elevations occurred in 4% and <1% of TARCEVA and placebo treated patients, respectively. Grade 3 (<5.0-20.0×ULN) elevations were not observed in TARCEVA treated patients. Fatal cases of hepatic failure including hepatorenal syndrome have been reported during use of TARCEVA. Confounding factors in some cases have included pre-existing liver disease, hepatic impairment and/or concomitant hepatotoxic medications (see Warnings and Precautions).

headaches and dizziness.

There have been uncommon reports of serious interstitial lung disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC and other advanced solid tumors (see Warnings and Precautions).

hair and nail changes, dermatitis acneiform, erythema, hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails.

Adverse Events Occurring More Frequently (≥3%) in the TARCEVA Group Than in the Placebo Group and in ≥10% of Patients in the TARCEVA Group in Study BR.21

Cases of gastrointestinal bleeding have been commonly reported in clinical studies, some associated with concomitant warfarin administration (see also Drug Interactions) and some with concomitant NSAID administration.

There have been no specific studies in elderly patients. Of the total number of patients participating in the phase III study, BR.21 (n=731), 62% were less than 65 years of age and 38% of patients were aged 65 years or older. The survival benefit was maintained across both age groups. No meaningful differences in safety or pharmacokinetics were observed between younger and older patients. Therefore, no dosage adjustments are recommended in elderly patients.

The safety and efficacy of TARCEVA in the pediatric population has not been established.

Each white to yellowish, round, biconvex, film-coated tablet with “Tarceva 100” and logo printed in grey on one side, contains: erlotinib HCl corresponding to 100 mg of erlotinib. Nonmedicinal ingredients: tablet core: lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate; tablet coat: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. PVC blisters sealed with aluminum foil of 10 tablets, cartons of 3.

Each white to yellowish, round, biconvex, film-coated tablet, with “Tarceva 25” and logo printed in brownish yellow on one side, contains: erlotinib HCl corresponding to 25 mg of erlotinib. Nonmedicinal ingredients: tablet core: lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate; tablet coat: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. PVC blisters sealed with aluminum foil of 10 tablets, cartons of 3.

Each white to yellowish, round, biconvex, film-coated tablet with “Tarceva 150” and logo printed in brown on one side, contains: erlotinib HCl corresponding to 150 mg of erlotinib. Nonmedicinal ingredients: tablet core: lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate; tablet coat: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. PVC blisters sealed with aluminum foil of 10 tablets, cartons of 3.

Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2 and the pulmonary isoform CYP1A1. Potential interactions may occur with drugs which are metabolized by, or are inhibitors or inducers of, these enzymes (see Drug Interactions).

Cases of ILD-like events, including fatalities, have been reported uncommonly in patients receiving TARCEVA for treatment of NSCLC or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of serious ILD-like events was 0.8% in both the TARCEVA and placebo arms. The overall incidence in TARCEVA treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) is approximately 0.6%. Some examples of reported diagnoses in patients suspected of having ILD-like events include pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome, lung infiltration and alveolitis. Symptoms started from 5 days to more than 9 months (median 47 days) after initiating TARCEVA. Most of the cases were associated with confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.

In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment initiated as necessary (see Adverse Reactions and Dosage and Administration).

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

In pivotal trial BR.21, over three quarters of patients developed a rash. Nine percent (9%) of patients had severe rash, and 6% required dose reduction. Median time to onset of rash was 8 days.

International Normalized Ratio (INR) elevations and bleeding events including gastrointestinal bleeding have been reported in clinical studies, some associated with concomitant warfarin administration (see Adverse Reactions). Patients taking warfarin or other coumarin derivative anticoagulants should be monitored regularly for any changes in prothrombin time or INR (see Drug Interactions).

Pivotal trial BR.21 excluded patients with CNS metastases that were symptomatic, and those with asymptomatic metastases but not on a stable dose of corticosteroids for at least 4 weeks prior to randomization. Therefore, the safety of TARCEVA in this patient population is unknown.

TARCEVA is eliminated by hepatic metabolism and biliary excretion. A pharmacokinetic study was conducted in patients with advanced solid tumours comparing patients with moderate hepatic impairment (Child-Pugh score 7-9) and patients with adequate hepatic function. Ten of the fifteen patients with moderate hepatic impairment died during TARCEVA treatment or within 30 days of the last dose. Five of the 10 patients died within the first month after initiating TARCEVA treatment. Six of the 10 patients who died had baseline total bilirubin >3×ULN suggesting severe hepatic impairment. Patients with hepatic impairment should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or discontinued if significant changes in liver function are observed. The use of TARCEVA in patients with severe hepatic impairment is not recommended (see Warnings and Precautions, Hepatotoxicity and Adverse Reactions).

In pivotal trial BR.21, adequate hepatic function was defined as total bilirubin <1.5×ULN and ALT/SGPT <2×ULN, unless clearly attributable to liver metastases, in which cases <5×ULN was allowed. Approximately 20% of patients on BR.21 had liver metastases. Asymptomatic increases in liver transaminases have been observed in TARCEVA treated patients; therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) should be considered. Dose reduction or interruption of TARCEVA should be considered if significant changes in liver function are observed (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings).

Diarrhea has occurred in patients on TARCEVA and moderate or severe diarrhea should be treated with loperamide. In some cases, dose reduction may be necessary. In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting associated with dehydration, TARCEVA therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see Dosage and Administration).

There have been rare reports of hypokalaemia and renal failure (including fatalities) mainly in patients receiving concomitant chemotherapy but also in a few patients receiving TARCEVA as monotherapy. Some reports of renal failure were secondary to severe dehydration due to diarrhea, vomiting and/or anorexia while others were confounded by concomitant use of chemotherapy. In more severe or persistent cases of diarrhea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (known renal disease, concurrent vomiting, concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at high risk of dehydration.

Gastrointestinal bleeding was seen in 2% of patients receiving TARCEVA therapy on study BR.21 in NSCLC. No cases were reported on the placebo arm. Confounding factors include concomitant NSAID use and history of ulcer disease. In patients who develop gastrointestinal bleeding while receiving TARCEVA, the drug should be discontinued (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Gastrointestinal Disorders).

Asymptomatic increases in liver transaminases have been observed in patients receiving TARCEVA. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) should be considered. Dose reduction or interruption of TARCEVA therapy should be considered if liver function changes are severe (see Adverse Reactions).

There are no adequate or well-controlled studies in pregnant women using TARCEVA. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Women of childbearing potential must be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus. If TARCEVA is used during pregnancy, the patient must be informed of the potential hazard to the fetus or potential risk for loss of the pregnancy.

It is not known whether erlotinib is excreted in human milk. Because of the potential harm to the infant, mothers should be advised against breast-feeding while receiving TARCEVA.

Fatal cases of hepatic failure including hepatorenal syndrome have been reported during use of TARCEVA. Confounding factors in some patients have included pre-existing liver disease, impaired hepatic function and/or concomitant hepatotoxic medications. Close monitoring of liver function testing should be considered in these patients. TARCEVA dosing should be interrupted or discontinued if significant changes in liver function are observed. TARCEVA treatment is not recommended in patients with severe hepatic impairment including those with total bilirubin of >3×ULN and/or transaminases of >5×ULN. (See Warnings and Precautions, Special Populations, Patients with Hepatic Impairment and Adverse Reactions.)

A population pharmacokinetic analysis in 591 patients receiving single agent TARCEVA shows a mean apparent clearance of 4.47 L/hour with a median half-life of 36.2 hours. Therefore, the time to reach steady state plasma concentration would be expected to occur in approximately 7-8 days. No significant relationships between predicted apparent clearance and patient age, body weight, gender, and ethnicity were observed.

Serum total bilirubin, AAG concentrations and smoking are major confounding factors for erlotinib clearance. Increased serum concentration of total bilirubin or AAG was associated with reduced erlotinib clearance and an increase in systemic exposure. Smokers had a 24% higher rate of erlotinib clearance.

Erlotinib has a mean apparent volume of distribution of 232 L and distributes into tumor tissue of humans. In a study of 4 patients (3 with non-small cell lung cancer [NSCLC], and 1 with laryngeal cancer) receiving 150 mg daily oral doses of TARCEVA, tumor samples from surgical excisions on Day 9 of treatment revealed tumor concentrations of erlotinib that averaged 1185 ng/g of tissue. This corresponded to an overall average of 63% of the steady state observed peak plasma concentrations. The primary active metabolites were present in tumors at concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113% of the observed steady state peak plasma concentrations. Tissue distribution studies using whole body autoradiography following oral administration with [¹⁴C] labeled erlotinib in athymic nude mice with HN5 tumor xenografts have shown rapid and extensive tissue distribution with maximum concentrations of radiolabeled drug (approximately 73% of that in plasma) observed at 1 hour. Higher radioactivity exposure (4-8 fold as measured in other peripheral tissues) was observed in kidney and liver in these studies.

Following a 150 mg oral dose of TARCEVA, at steady state, the median time to reach maximum plasma concentrations is approximately 4.0 hours with median maximum plasma concentrations achieved of 1995 ng/mL. Prior to the next dose at 24 hours, the median minimum plasma concentrations are 1238 ng/mL. Median AUC achieved during the dosing interval at steady state are 41 300 ng·h/mL.

Oral erlotinib is well absorbed and has an extended absorption phase, with mean peak plasma levels occurring at 4 hours after oral dosing. A study in normal healthy volunteers provided an estimate of bioavailability of 59%. The exposure after an oral dose may be increased by food.

Following absorption, erlotinib is highly bound in blood, with approximately 95% bound to blood components, primarily to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein [AAG]), with a free fraction of approximately 5%.

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib potently inhibits the intracellular phosphorylation of HER1/EGFR. HER1/EGFR is expressed on the cell surface of normal cells and cancer cells. Specificity of erlotinib inhibition on other tyrosine kinase receptors of the ErbB family has not been characterized.

A pharmacokinetic study in nonsmoking and currently cigarette smoking healthy subjects has shown that cigarette smoking leads to increased clearance of, and decreased exposure to, erlotinib. The AUC_0-infinity in smokers was about 1/3 of that in never/former smokers (n=16 in each of smoker and never/former smoker arms). This reduced exposure in current smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver.

In the pivotal Phase III NSCLC trial, current smokers achieved erlotinib steady state trough plasma concentration of 0.65 µg/mL (n=16) which was approximately 2-fold less than the former smokers or patients who had never smoked (1.28 µg/mL, n=108). This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance.

In a phase I dose escalation study in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in erlotinib exposure when the TARCEVA dose was increased from 150 mg to 300 mg (see Drug Interactions, Drug-Lifestyle Interactions).

Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1. In vitro studies indicate approximately 80-95% of erlotinib metabolism is by the CYP3A4 enzyme. There are three main metabolic pathways identified: 1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety. The primary metabolites of erlotinib produced by O-demethylation of either side chain are present in plasma at levels that are <10% of erlotinib and display similar pharmacokinetics as erlotinib. The metabolites and trace amounts of erlotinib are excreted predominantly via the feces (>90%), with renal elimination accounting for only a small amount of an oral dose.

Erlotinib is mainly cleared by the liver. A pharmacokinetic study was conducted in patients with advance solid tumors comparing patients with moderate hepatic impairment (Child-Pugh score 7-9) and those with adequate hepatic function. Erlotinib exposure following a single 150 mg dose was similar in patients with moderate hepatic impairment and those with adequate hepatic function whereas the steady-state pharmacokinetic parameters following TARCEVA daily dosing were not measured. Safety and pharmacokinetics of TARCEVA in patients with severe hepatic impairment is unknown (see Warnings and Precautions and Dosage and Administration, Dosing Considerations).

Erlotinib and its metabolites are not significantly excreted by the kidneys, as less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.