Erlotinib

Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR, also known as HER1) tyrosine kinase. EGFR is found on the surface of normal cells and cancer cells. Activating mutations in the EGFR kinase domain can keep proliferation and anti-apoptotic signalling switched on, and erlotinib is particularly effective against these EGFR-mutation-positive tumours.

Mechanism of Action

• EGFR inhibition: erlotinib potently inhibits the intracellular phosphorylation of EGFR. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.
• Mutated EGFR: its effectiveness in EGFR-mutation-positive tumours is attributed to tight binding to the ATP-binding site of the mutated kinase domain. Blocking the downstream signalling stops cell proliferation and induces cell death through the intrinsic apoptotic pathway. Tumour regression was seen in mouse models with enforced expression of EGFR activating mutations.

Pharmacokinetics

• Absorption: peak plasma levels are reached about 4 hours after an oral dose. Absolute bioavailability is about 59%, and food increases exposure (towards almost 100%), which is why the tablets are taken at least one hour before or two hours after a meal. Solubility falls at pH above 5.
• Distribution: apparent volume of distribution 232 L; erlotinib distributes into tumour tissue. Plasma protein binding is about 95%, to albumin and alpha-1 acid glycoprotein.
• Metabolism: hepatic, mainly by CYP3A4 and to a lesser extent CYP1A2. Extrahepatic metabolism by CYP3A4 in the intestine, CYP1A1 in the lung and CYP1B1 in tumour tissue may also contribute. The main metabolites, OSI-420 and OSI-413 (formed by O-demethylation), are about as potent as erlotinib in non-clinical models and are present at below 10% of the erlotinib level.
• Elimination: excreted mainly as metabolites in the faeces (more than 90%); renal elimination accounts for about 9% of an oral dose, and less than 2% is excreted as unchanged drug. In a population analysis of 591 patients the mean apparent clearance was 4.47 L/hour and the median half-life 36.2 hours.
• Smokers: cigarette smoking reduces erlotinib exposure by 50–60%.
• Special populations: exposure was similar in moderate hepatic impairment (Child-Pugh 7–9) to that with adequate liver function; no dose adjustment appears necessary in mild or moderate renal impairment.

• NSCLC, first line: locally advanced or metastatic non-small cell lung cancer with EGFR activating mutations.
• NSCLC, switch maintenance: locally advanced or metastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy.
• NSCLC after chemotherapy: locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. In patients with tumours without EGFR activating mutations, it is indicated when other treatment options are not considered suitable.
• Pancreatic cancer: in combination with gemcitabine for metastatic pancreatic cancer. No survival advantage could be shown for patients with locally advanced disease.
• Prescribing notes: factors associated with prolonged survival should be taken into account. No survival benefit or other clinically relevant effect has been shown in NSCLC patients with EGFR-IHC-negative tumours.
• EGFR mutation testing: for NSCLC it is performed in accordance with the approved indications (see Special Instructions).

• Hypersensitivity to erlotinib or to any of the excipients.

Safety data come from more than 1,500 patients treated with at least one 150 mg dose of erlotinib alone and more than 300 patients given 100 or 150 mg together with gemcitabine. Rash and diarrhoea are the most frequent reactions in lung cancer studies, mostly grade 1 or 2 and manageable without intervention; in the pancreatic cancer study the most common were fatigue, rash and diarrhoea. In the first-line study in EGFR-mutation-positive NSCLC, rash occurred in 80% of patients (grade 3 in 9%) and diarrhoea in 57% (grade 3 in 4%). The median time to onset was 8–10 days for rash and 12–15 days for diarrhoea.

Very common (≥1/10): infection; anorexia, weight decreased; depression; neuropathy, headache; keratoconjunctivitis sicca; dyspnoea, cough; diarrhoea, nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence; liver function test abnormalities; rash, pruritus; fatigue, pyrexia, rigors.

Common (≥1/100 to <1/10): keratitis, conjunctivitis; epistaxis; gastrointestinal bleeding; alopecia, dry skin, paronychia, folliculitis, acne or acneiform dermatitis, skin fissures; renal insufficiency.

Uncommon (≥1/1,000 to <1/100): eyelash changes; interstitial lung disease; gastrointestinal perforation; hirsutism, eyebrow changes, brittle and loose nails, mild skin reactions such as hyperpigmentation; nephritis, proteinuria.

Rare (≥1/10,000 to <1/1,000): pneumatosis intestinalis; hepatic failure, hepatitis; palmar-plantar erythrodysaesthesia syndrome.

Very rare (<1/10,000): corneal perforation, corneal ulceration, uveitis; Stevens-Johnson syndrome and toxic epidermal necrolysis.

Not known: acute hepatitis.

Rash is mostly a mild or moderate erythematous, papulopustular eruption that may appear or worsen in sun-exposed areas; protective clothing or sunscreen may be advisable. Interstitial lung disease, hepatic failure, gastrointestinal bleeding or perforation and Stevens-Johnson syndrome or toxic epidermal necrolysis have included fatal cases.

• Strong CYP3A4 inhibitors (azole antifungals such as ketoconazole, itraconazole and voriconazole; protease inhibitors; erythromycin; clarithromycin): ketoconazole raised erlotinib exposure by 86% (AUC) and 69% (Cmax). Use with caution and reduce the erlotinib dose if necessary, particularly if toxicity occurs.
• Potent CYP3A4 inducers: rifampicin lowered the median erlotinib AUC by 69%. Avoid the combination. If a potent inducer such as rifampicin is required, the SmPC says an increase to 300 mg should be considered with close safety monitoring (including renal and liver function and serum electrolytes) and, if well tolerated for more than 2 weeks, a further increase to 450 mg. Phenytoin, carbamazepine, barbiturates and St John’s wort (Hypericum perforatum) may also reduce exposure; alternatives without potent inducing activity should be considered.
• CYP1A2 inhibitors: ciprofloxacin raised erlotinib AUC by 39%. Use caution with ciprofloxacin or potent CYP1A2 inhibitors such as fluvoxamine, and reduce the dose if reactions occur.
• Smoking: lowers exposure (AUC 2.8-fold, Cmax 1.5-fold lower than in non-smokers). A 300 mg dose gave no added benefit in active smokers, so smokers are encouraged to stop.
• Acid-lowering medicines: omeprazole reduced erlotinib AUC by 46% and Cmax by 61%; ranitidine 300 mg reduced them by 33% and 54%. Avoid proton pump inhibitors. If antacids are needed, take them at least 4 hours before or 2 hours after erlotinib. If ranitidine is used, take erlotinib at least 2 hours before or 10 hours after it. Raising the erlotinib dose does not compensate.
• Coumarin anticoagulants (warfarin): raised INR and bleeding events, some fatal, have been reported; prothrombin time or INR should be monitored regularly.
• Statins: the combination may increase the risk of statin-induced myopathy, including rhabdomyolysis (observed rarely).
• P-glycoprotein inhibitors (for example ciclosporin, verapamil): may change the distribution or elimination of erlotinib; use caution.
• UGT1A1 substrates: erlotinib strongly inhibits UGT1A1-mediated glucuronidation in vitro, so substrates cleared exclusively by this pathway may interact. Patients with low UGT1A1 expression or Gilbert’s disease may have raised bilirubin. Erlotinib is also a potent inhibitor of CYP1A1 and a moderate inhibitor of CYP3A4 and CYP2C8 in vitro; it did not change the clearance of midazolam, erythromycin or paclitaxel.
• Other anticancer medicines: gemcitabine and erlotinib did not change each other’s pharmacokinetics; erlotinib raised platinum levels by about 11% with carboplatin and paclitaxel (not clinically relevant); capecitabine may increase erlotinib concentrations; proteasome inhibitors such as bortezomib may be expected to influence the effect of EGFR inhibitors.
• Food: take on an empty stomach (at least one hour before or two hours after food). Grapefruit inhibits CYP3A4 and St John’s wort induces it, so both call for caution.

Treatment should be supervised by a physician experienced in the use of anti-cancer therapies. In NSCLC, EGFR mutation testing is performed in accordance with the approved indications. The tablets are taken once daily at least one hour before or two hours after food.

Recommended Dose

• NSCLC: 150 mg once daily.
• Pancreatic cancer: 100 mg once daily, in combination with gemcitabine (see the gemcitabine SmPC for the pancreatic cancer dose). If rash has not developed within the first 4–8 weeks, continuing treatment should be re-assessed.
• Strengths: 25 mg, 100 mg and 150 mg tablets.

Dose Adjustments

• When a reduction is needed, the dose is lowered in 50 mg steps. Steps of 25 mg have not been investigated.
• Concomitant CYP3A4 substrates and modulators may require a dose adjustment (see Drug Interactions).
• Smokers: smoking lowers exposure by 50–60%. The maximum tolerated dose in NSCLC patients who smoked was 300 mg, but it showed no better efficacy than 150 mg in second-line treatment, with a numerical increase in rash, interstitial lung disease and diarrhoea. Current smokers should be advised to stop smoking.

Special Populations

• Hepatic impairment: exposure was similar in moderate impairment (Child-Pugh 7–9) but caution is needed; consider dose reduction or interruption if severe reactions occur. Not studied in severe hepatic dysfunction (AST and ALT above 5 times the upper limit of normal), and use is not recommended.
• Renal impairment: not studied when serum creatinine exceeds 1.5 times the upper limit of normal. No adjustment appears necessary in mild or moderate impairment; use is not recommended in severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established, and use is not recommended.

EGFR Mutation Status

When Tarceva is considered for first-line or maintenance treatment of locally advanced or metastatic NSCLC, the patient’s EGFR mutation status must be determined. The SmPC calls for a validated, robust, reliable and sensitive test with a prespecified positivity threshold, using either tumour DNA from a tissue sample or circulating free DNA (cfDNA) from a blood (plasma) sample, performed according to local medical practice. If a plasma-based test is negative for activating mutations, a tissue test should be performed wherever possible, because plasma tests can give false-negative results.

Smoking

Current smokers should be advised to stop smoking, because their plasma erlotinib concentrations are lower and the difference is likely to be clinically significant.

Interstitial Lung Disease

Interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients with NSCLC, pancreatic cancer or other advanced solid tumours: 0.9% with erlotinib versus 0.4% in control arms in a meta-analysis of NSCLC trials, 2.5% versus 0.4% in the pancreatic cancer study with gemcitabine, and about 5% (mortality 1.5%) in studies in Japan. Treatment is interrupted pending evaluation in anyone with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, and discontinued if ILD is diagnosed.

Diarrhoea, Dehydration, Electrolyte Imbalance and Renal Failure

Diarrhoea (very rarely fatal) occurs in about 50% of patients; moderate or severe diarrhoea should be treated, for example with loperamide, and dose reduction may be needed. In severe or persistent diarrhoea, nausea, anorexia or vomiting with dehydration, treatment is interrupted and dehydration treated, with intravenous rehydration in more severe cases. Hypokalaemia and renal failure (including fatalities) have been reported rarely, so renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.

Hepatotoxicity

Serious drug-induced liver injury, including hepatitis, acute hepatitis and hepatic failure (with fatalities), has been reported. Pre-existing liver disease and concomitant hepatotoxic medicines are risk factors. Liver function is tested periodically, more often if there is hepatic impairment or biliary obstruction, and symptoms suggesting liver injury are evaluated promptly. Dosing is interrupted if changes in liver function are severe, and use is not recommended in severe hepatic dysfunction.

Gastrointestinal Perforation

Gastrointestinal perforation is uncommon but sometimes fatal. The risk is higher with anti-angiogenic agents, corticosteroids, NSAIDs or taxane-based chemotherapy, and with a history of peptic ulceration or diverticular disease. Treatment is permanently discontinued if perforation occurs.

Bullous and Exfoliative Skin Disorders

Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, some fatal. Treatment is interrupted or discontinued if they are severe, and skin infection is tested for and treated.

Ocular Disorders

Patients with signs or symptoms suggesting keratitis (acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain or red eye) should be referred promptly to an ophthalmologist. If ulcerative keratitis is confirmed, treatment is interrupted or discontinued; if keratitis is diagnosed, the benefits and risks of continuing are weighed carefully. Caution is needed with a history of keratitis, ulcerative keratitis or severe dry eye, and contact lens use is also a risk factor. Corneal perforation or ulceration has been reported very rarely.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data. Animal studies showed no teratogenicity or abnormal parturition but did show increased embryo-foetal lethality in rats and rabbits; the risk to humans is unknown. In pregnant women, treatment should continue only if the benefit to the mother outweighs the risk to the foetus.
• Contraception: women of childbearing potential should avoid pregnancy during treatment and use adequate contraception during therapy and for at least 2 weeks after completing it.
• Breastfeeding: it is not known whether erlotinib passes into human milk, so mothers are advised against breastfeeding during treatment and for at least 2 weeks after the final dose.
• Fertility: animal studies showed no impaired fertility, but an adverse effect cannot be excluded; the risk to humans is unknown.

Lactose and Sodium

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially sodium-free.

Effect on Driving

No studies on the ability to drive and use machines have been performed; erlotinib is not associated with impairment of mental ability.

Tarceva tablets need no special storage conditions. They are supplied in PVC blisters sealed with aluminium foil, 30 tablets per pack.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), with treatment supervised by a physician experienced in the use of anti-cancer therapies. Erlotinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.