Active ingredients: Erlotinib
Tarceva 25 mg film-coated tablets
Tarceva 100 mg film-coated tablets
Tarceva 150 mg film-coated tablets
Why is Tarceva used? What is it for?
Tarceva contains the active substance erlotinib. Tarceva is a medicine used to treat cancer and works by blocking the activity of a protein called epidermal growth factor receptor (EGFR), which is involved in the growth and spread of cancer cells.
Tarceva is indicated for adults. This medicine may be prescribed to you if you have advanced non-small cell lung cancer. It can be prescribed to you as an initial therapy or as a therapy if the disease remains mostly unchanged after the initial chemotherapy, as long as the cancer cells have specific EGFR mutations. It can also be prescribed if previous chemotherapy has failed to stop the cancer. illness.
This medicine may also be prescribed to you in combination with another treatment called gemcitabine if you have metastatic pancreatic cancer.
Contraindications When Tarceva should not be used
Do not take Tarceva
- if you are allergic to erlotinib or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before you take Tarceva
Warnings and Precautions:
- if you are taking other medicines that may increase or decrease the amount of erlotinib in your blood or affect its effectiveness (for example, antifungals such as ketoconazole, protease inhibitors, erythromycin, clarithromycin, phenytoin, carbamazepine, barbiturates , rifampicin, ciprofloxacin, omeprazole, ranitidine, St. John's wort or proteasome inhibitors), ask your doctor. In some cases, these medicines may reduce the effectiveness or increase the side effects of Tarceva, and if so, your doctor may need to adjust your therapy. Your doctor may arrange for you not to take these medicines while you are being treated with Tarceva.
- if you take anticoagulants (medicines that help prevent thrombosis or blood clotting e.g. warfarin), Tarceva may increase the propensity to bleed. Talk to your doctor, who will need to monitor you by prescribing some blood tests periodically.
- if you take statins (medicines to lower blood cholesterol), Tarceva may increase the risk of statin-related muscle problems, which in rare cases can lead to severe muscle breakdown (rhabdomyolysis) resulting in kidney damage. Talk to your doctor.
- if you use contact lenses and / or have ever had eye problems such as severe dry eyes, inflammation of the front of the eye (cornea) or ulcers that have involved the front of the eye, talk to your doctor. See also in "Other medicines and Tarceva".
You must inform your doctor:
- if you have "sudden difficulty in breathing associated with cough or fever, as your doctor may need to prescribe other medicines and stop taking Tarceva;
- if you have diarrhea, as your doctor may need to prescribe antidiarrheals (e.g. loperamide);
- immediately if you have severe or persistent diarrhea, nausea, loss of appetite or vomiting, as your doctor may need to stop your Tarceva therapy and you need treatment in hospital.
- if you have severe abdominal pain, severe skin reactions such as blistering or peeling. Your doctor may find it necessary to interrupt or stop treatment.
- if you develop acute red or worsening eye redness accompanied by pain, increased lacrimation, blurred vision and / or sensitivity to light, talk to your doctor or nurse immediately, as you may need urgent treatment (see Possible side effects).
- if you are also taking a statin and experience unexplained muscle pain, tenderness, weakness or cramps. The doctor may find it necessary to interrupt or suspend treatment.
See also section 4 "Possible side effects".
Diseases of the liver and kidneys
It is not known whether the effects of Tarceva change if the liver or kidneys do not function normally. If you have severe liver or kidney disease, treatment with this medicine is not recommended.
Glucuronation disorder such as Gilbert's syndrome
If you have a glucuronidation disorder, such as Gilbert's syndrome, your doctor should treat you with caution.
Smoke
If you take Tarceva, you should stop smoking, as smoking can reduce the amount of the medicine in your blood.
Children and adolescents
Tarceva has not been studied in patients under 18 years of age. Treatment with this medicine is not recommended in children and adolescents.
Interactions Which drugs or foods can change the effect of Tarceva
Other medicines and Tarceva
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Tarceva with food and drink
Do not take Tarceva with food. See also section 3 "How to take Tarceva"
Warnings It is important to know that:
Pregnancy and breastfeeding
Avoid becoming pregnant while on Tarceva therapy. If you think pregnancy may occur, use adequate contraception during therapy and for at least 2 weeks after taking the last tablet. If pregnancy occurs while taking Tarceva, tell your doctor immediately who will decide whether to continue. treatment. Do not breast-feed while taking Tarceva. If you are pregnant, think you may be pregnant or are planning to become pregnant, or if you are breast-feeding ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
No studies have been performed on the possible effects of Tarceva on the ability to drive and use machines, but treatment is very unlikely to alter this ability.
Hypersensitivity
Tarceva contains a sugar called lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Tarceva.
Dose, Method and Time of Administration How to use Tarceva: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The tablet should be taken at least one hour before or two hours after food.
The usual dose is one Tarceva 150mg tablet a day if you have non-small cell lung cancer.The usual dose is one Tarceva 100mg tablet a day if you have metastatic pancreatic cancer. Tarceva is given in combination with gemcitabine.
Your doctor may change the dose by 50mg at a time. For the different dosage regimens Tarceva is available in strengths of 25mg, 100mg or 150mg.
Overdose What to do if you have taken too much Tarceva
If you take more Tarceva than you should
Contact your doctor or pharmacist immediately. It may be that the side effects get worse and your doctor will make you stop taking it.
If you forget to take Tarceva
If you miss one or more doses of Tarceva, contact your doctor or pharmacist as soon as possible. Do not take a double dose to make up for a forgotten dose.
If you stop taking Tarceva
It is important to keep taking Tarceva every day, for as long as your doctor prescribes it.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Tarceva
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the side effects listed below, please contact your doctor as soon as possible. In some cases the doctor may need to reduce the dose of Tarceva or stop therapy.
- Diarrhea and vomiting (very common, may affect more than 1 in 10 patients). Persistent and severe diarrhea can lead to decreased blood potassium and kidney failure, especially if you are being treated with other chemotherapy drugs at the same time. In case of more severe or persistent diarrhea, contact your doctor immediately who may decide to treat you in hospital.
- Eye irritation due to conjunctivitis / keratoconjunctivitis (very common, may affect more than 1 in 10 patients) and keratitis (common, may affect up to 1 in 10 patients).
- A form of lung inflammation called interstitial lung disease (uncommon in European patients, common in Japanese patients: may affect up to 1 in 100 patients in Europe and up to 1 in 10 in Japan). This disease can also be linked to the natural progression of your medical condition and can be fatal in some cases. If you experience symptoms such as "sudden difficulty in breathing associated with cough or fever, contact your doctor immediately, as you may have this disease. Your doctor may decide to permanently stop Tarceva therapy."
- Cases of gastrointestinal perforation have been observed (uncommon, may affect up to 1 in 100 patients). Tell your doctor if you experience severe pain in your abdomen. Also, tell your doctor if you have ever had a peptic ulcer or diverticular disease, as this may increase the risk of perforation.
- In rare cases, liver failure has been observed (rare, may affect up to 1 in 1000 patients). If your blood tests indicate serious changes in liver function, your doctor may decide to discontinue therapy.
Very common side effects (may affect more than 1 in 10 patients):
- Skin rash that may develop or worsen in sun-exposed areas. If you are exposed to the sun, it may be advisable to use protective clothing and / or sunscreens (eg. Based on mineral substances)
- Infection
- Loss of appetite, weight loss
- Depression
- Headache, changes in skin sensation or numbness in the extremities
- Difficulty in breathing, cough
- Nausea
- Mouth irritations
- Stomach pain, indigestion and flatulence
- Changes in blood tests related to liver function
- Itchy, dry skin and hair loss
- Tiredness, fever, chills
Common side effects (may affect up to 1 in 10 patients):
- Nose bleeding
- Bleeding from the stomach or intestines
- Inflammatory reactions around the nails
- Hair follicle infection
- Acne
- Split skin (skin fissures)
- Reduced kidney function (when given outside of the approved indications in combination with chemotherapy)
Uncommon side effects (may affect up to 1 in 100 people)
- alterations of the eyelashes
- excessive hair on the face and body with a male pattern distribution
- alterations of the eyebrows
- brittle and peeling nails
Rare side effects (may affect up to 1 in 1000 patients):
- redness or pain in the palms or soles of the feet (palmar-plantar erythrodysaesthesia syndrome)
Very rare side effects (may affect up to 1 in 10,000 patients)
- Cases of corneal ulceration or perforation
- Severe skin reactions such as blistering or peeling (indicative of Stevens-Johnson syndrome)
- Inflammation of the colored part of the eye
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton after EXP / EXP. The expiry date refers to the last day of the month.
This medicinal product does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Tarceva contains:
- The active substance in Tarceva is erlotinib. Each film-coated tablet contains 25 mg, 100 mg or 150 mg of erlotinib (as erlotinib hydrochloride), depending on the strength.
- The other ingredients are: Tablet core: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate type A, sodium laurilsulfate, magnesium stearate (see also section 2 for lactose monohydrate). Tablet coating: hypromellose, hydroxypropylcellulose, titanium dioxide, macrogol.
What Tarceva looks like and contents of the pack:
Tarceva 25mg is supplied as a white to yellowish, round film-coated tablet with "T 25" engraved on one side and is available in packs of 30 tablets.
Tarceva 100mg is supplied as a white to yellowish, round film-coated tablet with "T 100" engraved on one side and is available in packs of 30 tablets.
Tarceva 150mg is supplied as a white to yellowish, round film-coated tablet with "T 150" engraved on one side and is available in pack sizes of 30 tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TARCEVA 150 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 150 mg of erlotinib (as erlotinib hydrochloride).
Excipients with known effect: each film-coated tablet contains 103.82 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
White to yellowish, round, biconvex tablets, engraved with "T 150" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Non-Small Cell Lung Carcinoma ( Non-Small Cell Lung Cancer , NSCLC):
Tarceva is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations.
Tarceva is also indicated as a switch maintenance treatment in patients with locally advanced or metastatic NSCLC with activating EGFR mutations and stable disease after first-line chemotherapy.
Tarceva is also indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one previous chemotherapy regimen.
When prescribing Tarceva, factors associated with increased survival should be considered.
Treatment did not demonstrate survival benefits or other clinically relevant effects in patients with Epidermal Growth Factor Receptor (EGFR) -IHC negative tumors (see section 5.1).
Pancreatic cancer:
Tarceva in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer.
When prescribing Tarceva, factors associated with increased survival should be considered (see sections 4.2 and 5.1).
No survival advantage has been shown for patients with locally advanced disease.
04.2 Posology and method of administration
Treatment with Tarceva should be supervised by a physician experienced in the use of antineoplastic therapies.
Patients with Non-Small Cell Lung Carcinoma:
EGFR mutation testing should be performed prior to initiating Tarceva therapy in chemo-naïve patients with advanced or metastatic NSCLC.
The recommended daily dose of Tarceva is 150 mg taken at least one hour before or two hours after food.
Patients with pancreatic cancer:
The recommended daily dose of Tarceva is 100 mg to be taken at least one hour before or two hours after food, in combination with gemcitabine (see the Summary of Product Characteristics for gemcitabine in the indication of pancreatic cancer).
In patients who do not develop a skin rash in the first 4-8 weeks of therapy, it should be re-evaluated whether to continue treatment with Tarceva (see section 5.1).
If the dose needs to be changed, it should be reduced by 50 mg each time (see section 4.4).
Tarceva is available in strengths of 25 mg, 100 mg and 150 mg.
The concomitant use of CYP3A4 substrates and modulators may require a modification of the posology (see section 4.5).
Patients with hepatic insufficiency: Elimination of erlotinib occurs through hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderate hepatic impairment (Child-Pugh score of 7-9) and in patients with adequate hepatic function, caution should be exercised when administering Tarceva to patients with hepatic impairment. If serious adverse reactions occur, a dose reduction or discontinuation of Tarceva treatment should be considered. The safety and efficacy of erlotinib have not been studied in patients with severe hepatic dysfunction (AST / SGOT and ALT / SGPT> 5 x ULN). Tarceva is not recommended for use in patients with severe hepatic dysfunction (see section 5.2. ).
Patients with renal insufficiency: The safety and efficacy of erlotinib have not been studied in patients with renal insufficiency (serum creatinine> 1.5 times the upper limit of normal). Based on pharmacokinetic data, in patients with mild or moderate renal insufficiency it is not necessary change the posology (see section 5.2). The use of Tarceva in patients with severe renal insufficiency is not recommended.
Pediatric population: The safety and efficacy of erlotinib in patients less than 18 years of age have not been established. The use of Tarceva in pediatric patients is not recommended.
Smokers: Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of Tarceva in NSCLC patients who smoke cigarettes was 300 mg. Long-term efficacy and safety higher than the initial recommended dose have not been determined in patients who continue to smoke (see sections 4.5 and 5.2). Therefore, smokers should be advised to stop smoking because plasma concentrations of erlotinib in smokers are lower than in non-smokers.
04.3 Contraindications
Hypersensitivity to erlotinib or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Assessment of EGFR mutation status:
To assess a patient's EGFR mutation status it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
Smokers
Smokers should be advised to stop smoking because plasma concentrations of erlotinib are lower in smokers than in non-smokers. The degree of reduction could be clinically significant (see section 4.5).
Pulmonary interstitial disease (ILD)
Uncommonly, cases of ILD-like events, sometimes fatal, have been reported in patients taking Tarceva for the treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumors. . In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was identical in the placebo group and in the Tarceva group. In the pancreatic cancer study in association with gemcitabine, the incidence of ILD-like events was was 2.5% in the Tarceva and gemcitabine group compared to 0.4% in the placebo and gemcitabine group. The overall incidence in Tarceva-treated patients across all studies (including uncontrolled and those with concomitant chemotherapy) is approximately 0.6%, compared with 0.2% in placebo-treated patients. Among the reported diagnoses in patients suspected of having ILD-like events have appeared pneumonia, radiation pneumonia, hypersensitivity pneumonitis, interstitial pneumonia, pulmonary interstitial disease, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, alveolitis and "pulmonary infiltration. Symptoms appeared within days to several months after initiation of Tarceva therapy. Confusing or concurrent factors such as concomitant or previous chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastases or lung infections A higher incidence of ILD (about 5% with a mortality rate of 1.5%) was observed among the population of Japanese origin.
In patients with acute new and / or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, Tarceva should be discontinued pending diagnostic evaluation. Patients treated concomitantly with erlotinib and gemcitabine should be closely monitored for the possibility of developing ILD-like toxicity. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment initiated as needed (see section 4.8).
Diarrhea, dehydration, electrolyte imbalance and kidney failure
Approximately 50% of patients treated with Tarceva experienced diarrhea (including very rare cases with a fatal outcome); moderate or severe diarrhea should be treated, for example with loperamide. In some cases it may be necessary to reduce the dose. In clinical studies, doses were reduced by 50 mg steps. Dose reductions of 25 mg at a time have not been studied. In the event of severe or persistent diarrhea, nausea, anorexia or vomiting associated with dehydration, administration of Tarceva should be discontinued and appropriate measures taken to treat the dehydration (see section 4.8). Rare cases of hypokalaemia and renal failure (including fatal cases) have been reported. Some cases were secondary to severe dehydration caused by diarrhea, vomiting and / or anorexia, while others were due to concomitant chemotherapy.In cases of more severe or persistent diarrhea, or leading to dehydration, particularly in groups of patients with aggravating risk factors (particularly in conjunction with chemotherapy treatment and other medications, symptoms or diseases or other predisposing conditions, including age advanced) administration of Tarceva should be discontinued and appropriate measures taken for intensive intravenous rehydration of the patient.In addition, renal function and serum electrolytes, including potassium, should be monitored in patients at risk of dehydration.
Hepatitis, liver failure
Rare cases of hepatic failure (including fatal cases) have been reported during treatment with Tarceva. Pre-existing liver disease or co-administration of hepatotoxic drugs were considered confounding factors. In such patients, a periodic examination of liver function should therefore be considered. Tarceva administration should be discontinued if liver function abnormalities are severe (see section 4.8). The use of Tarceva is not recommended in patients with severe hepatic dysfunction.
Gastrointestinal perforation
Patients taking Tarceva are at increased risk of developing gastrointestinal perforation, which is observed uncommonly (including some fatal cases). The risk is higher in patients taking concomitant antiangiogenic agents, corticosteroids, NSAIDs, and / or taxane-based chemotherapy, or with a history of peptic ulcer or diverticular disease. Treatment with Tarceva should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).
Bullous, exfoliative skin disorders
Bullous, vesicular and exfoliative skin disorders have been reported, including very rare cases indicative of Stevens-Johnson syndrome / toxic epidermal necrolysis, which in some cases were fatal (see section 4.8). Treatment with Tarceva should be discontinued or discontinued if the patient develops severe bullous, vesicular or exfoliative disorders. Patients with bullous and exfoliative skin changes should be evaluated for skin infections and treated according to local guidelines.
Ocular pathologies
Patients presenting with signs or symptoms suggestive of keratitis such as acute eye inflammation or worsening of the eye, lacrimation, photophobia, blurred vision, eye pain and / or red eye, should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with Tarceva should be discontinued or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Tarceva should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. The use of contact lenses is also a risk factor for keratitis and ulceration. Very rare cases of corneal perforation or ulceration have been reported during use of Tarceva (see section 4.8).
Interactions with other medicines
Potent CYP3A4 inducers may reduce the efficacy of erlotinib while potent CYP3A4 inhibitors may lead to increased toxicity. Concomitant treatment with this type of substance should be avoided (see section 4.5).
Other forms of interaction
Erlotinib is characterized by a decrease in solubility at pH values above 5. Medicines that alter the pH of the upper gastrointestinal (GI) tract, such as proton pump inhibitors, H2 antagonists, and antacids, can affect the solubility of erlotinib and therefore its bioavailability. Increasing the dose of Tarceva, when given concomitantly with these medicines, may not compensate for the reduction in exposure. The combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown, however, it is likely that there is reduced bioavailability. Concomitant administration of these should therefore be avoided. combinations (see section 4.5). If antacids are considered necessary during Tarceva therapy, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva.
The tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Erlotinib and other CYP substrates
Erlotinib is a potent inhibitor of CYP1A1 and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation in vitro by the UGT1A1.
Due to the very reduced expression of CYP1A1 in human tissues, the physiological relevance of the strong inhibition of CYP1A1 is unknown.
When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the exposure to erlotinib [AUC] was significantly increased by 39%, while no statistically significant change in Cmax was observed. exposure to the active metabolite increased approximately 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when administering ciprofloxacin or potent CYP1A2 inhibitors (eg eg fluvoxamine) in combination with erlotinib If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.
Pre-treatment or co-administration of Tarceva did not alter the clearance of CYP3A4 prototypical substrates, such as midazolam and erythromycin, but appeared to reduce the oral bioavailability of midazolam by up to 24%. In another clinical study, erlotinib did not change the pharmacokinetics of the concomitantly administered paclitaxel substrate of CYP3A4 / 2C8. Therefore, significant interactions with the clearance of other CYP3A4 substrates are unlikely.
Inhibition of glucuronidation may cause interactions with medicinal products which are substrates of UGT1A1 and which are cleared exclusively through this route. Patients with reduced levels of UGT1A1 expression or with genetic alterations of glucuronidation (eg Gilbert's disease) may have increased serum bilirubin concentrations and should be treated with caution.
In humans, erlotinib is metabolised in the liver by hepatic cytochromes, mainly by CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism, mediated by CYP3A4 in the intestine, CYP1A1 in the lung and CYP1B1 in tumor tissue, also provides a potential contribution to metabolic clearance of erlotinib. There are possible interactions with the active ingredients that are metabolized by these enzymes or that act on them as inhibitors or inducers.
Potent inhibitors of CYP3A4 activity reduce the metabolism of erlotinib and increase plasma concentrations of erlotinib. In a clinical study, the concomitant use of erlotinib and ketoconazole (200 mg oral twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase in erlotinib exposure (86% of AUC and 69% of Cmax). Therefore, caution should be exercised when administering erlotinib in combination with a potent CYP3A4 inhibitor, such as azole antifungals (eg ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin or clarithromycin. dose of erlotinib, especially in the presence of toxicity.
Potent inducers of CYP3A4 activity increase the metabolism of erlotinib and significantly reduce plasma concentrations of erlotinib. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg / day orally for 7 days), a potent inducer of the CYP3A4, resulted in a 69% reduction in median erlotinib AUC. Co-administration of rifampicin and a single 450 mg dose of Tarceva resulted in a mean erlotinib exposure (AUC) of 57.5% compared to that obtained after administration of a single 150 mg dose of Tarceva, in the absence of treatment with rifampicin. Co-administration of Tarceva with inducers of CYP3A4 should therefore be avoided. For patients requiring concomitant treatment with Tarceva and a potent CYP3A4 inducer, such as rifampicin, a dose increase to 300 mg should be considered, while their safety (including renal and hepatic function and serum electrolytes) is closely monitored and, if well tolerated for more than 2 weeks, a further dose increase to 450 mg with close safety monitoring may be considered. A reduction in exposure may also occur with other inducers such as phenytoin, carbamazepine, barbiturates or St. John's wort (Hypericum perforatum). Caution should be exercised when these active substances are combined with erlotinib. Whenever possible, alternative treatments without potent inductive CYP3A4 activity should be considered.
Erlotinib and coumarin-derived anticoagulants
Cases of interactions with coumarin-derived anticoagulants, including warfarin, resulting in increased INR (International Normalized Ratio) and bleeding events, which in some cases were fatal, have been reported in patients receiving Tarceva. taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.
Erlotinib and statins
The combination of Tarceva and a statin may increase the risk of statin induced myopathy, including rhabdomyolysis, which has been rarely observed.
Erlotinib and smokers
The results of a pharmacokinetic interaction study showed a significant reduction of 2.8 after administration of Tarceva; 1.5 and 9 times the AUCinf, Cmax and 24-hour plasma concentration, respectively, in smokers compared to non-smokers (see section 5.2). Therefore, patients who still smoke should be encouraged to stop smoking as soon as possible. , prior to initiation of Tarceva therapy, otherwise the plasma concentrations of erlotinib are reduced. The clinical effect of reduced exposure has not been definitively established but may be clinically significant.
Erlotinib and P-glycoprotein inhibitors
Erlotinib is a substrate of P-glycoprotein, the carrier of the active ingredient. Co-administration of P-glycoprotein inhibitors, e.g. cyclosporine and verapamil, could lead to altered distribution and / or elimination of erlotinib. The consequences of this interaction for, for example, CNS toxicity have not been established. One should proceed with caution in such situations.
Erlotinib and medicines that alter the pH
Erlotinib is characterized by a decrease in solubility at pH values above 5. Medicinal products that alter the pH of the upper gastrointestinal (GI) tract may alter the solubility of erlotinib and consequently its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased erlotinib exposure [AUC] and peak concentration [Cmax] by 46% and 61%, respectively. No change was detected. of Tmax or half-life. Concomitant administration of Tarceva with 300 mg ranitidine, an H2 receptor antagonist, reduced erlotinib exposure [AUC] and peak concentrations [Cmax] by 33% and 54%, respectively. Increase the dose of Tarceva when administered concomitantly with these drugs may not compensate for the reduction in exposure. However, when Tarceva was administered in a staggered manner, 2 hours before or 10 hours after 150 mg ranitidine bid, erlotinib exposure [AUC] and peak concentrations [Cmax ] fell by only 15% and 17%, respectively. The effect of antacids on the absorption of erlotinib has not been investigated but the absorption may be impaired, resulting in lower plasma levels. In summary, the combination of erlotinib with proton pump inhibitors should be avoided. If antacids are considered necessary during Tarceva therapy, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva. If ranitidine is considered, they should be administered the two drugs in a staggered way: Tarceva should be taken at least 2 hours before or 10 hours after ranitidine administration.
Erlotinib and Gemcitabine
In a phase Ib study, no significant effects of gemcitabine on the pharmacokinetics of erlotinib were observed, nor any significant effects of erlotinib on the pharmacokinetics of gemcitabine.
Erlotinib and Carboplatin / Paclitaxel
Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel resulted in an increase in total platinum AUC0-48 of 10.6%. Although this increase is statistically significant, the magnitude of this difference is not considered clinically relevant. In clinical practice there may be other co-factors that lead to increased exposure to carboplatin, such as renal failure. No effects have been observed. of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.
Erlotinib and Capecitabine
Capecitabine can increase erlotinib concentrations. When erlotinib was co-administered with capecitabine there was a statistically significant increase in erlotinib AUC and a minor increase in Cmax when compared to values observed in another study in which erlotinib was administered alone. There are no significant effects of erlotinib on the pharmacokinetics of capecitabine.
Erlotinib and proteasome inhibitors
In relation to the mechanism of action, proteasome inhibitors including bortezomib may affect the activity of EGFR inhibitors including erlotinib. This influence is supported by a limited availability of clinical and preclinical data highlighting the degradation of EGFR via the proteasome.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data on the use of erlotinib in pregnant women. Animal studies have shown no teratogenicity or abnormal births. However, an adverse effect on pregnancy cannot be excluded as studies in rats and rabbits have shown a increased embryo / fetal lethality (see section 5.3) The potential risk for humans is unknown.
Women of childbearing age
Women of childbearing potential should be advised to avoid pregnancy while being treated with Tarceva. Appropriate methods of contraception should be used during treatment and for at least 2 weeks after the end of treatment. In pregnant women, treatment should only be continued in cases where the potential benefit to the mother outweighs the risk to the fetus.
Feeding time
It is unknown whether erlotinib is excreted in human milk. Due to the potential harm to the newborn, mothers should be advised not to breastfeed during treatment with Tarceva.
Fertility
Animal studies have not shown impaired fertility. However, a negative effect on fertility cannot be excluded as animal studies have shown effects on reproductive parameters (see section 5.3). The potential risk for humans is unknown.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed; however erlotinib is not associated with impaired mental abilities.
04.8 Undesirable effects
Non-small cell lung cancer (Tarceva given alone):
In a randomized double-blind study (BR.21; Tarceva given as second-line therapy), the most commonly reported adverse drug reactions were rash (75%) and diarrhea (54%), in most cases of intensity equal to grade 1/2 and manageable without any intervention. Grade 3/4 rash and diarrhea occurred in 9% and 6% of patients treated with Tarceva, respectively, and both resulted in discontinuation of the study for 1% of patients. dosage in 6% and 1% of patients, respectively. In study BR.21, the median time to onset of rash was 8 days and the median time to onset of diarrhea was 12 days.
In general, the rash manifests itself as a "mild to moderate erythematous and papular-pustular eruption, which may arise or worsen in areas exposed to the sun. For patients who expose themselves to the sun, it may be advisable to use protective clothing" and / or sunscreens (e.g. based on mineral substances).
Table 1 summarizes, by NCI-CTC grade (National Cancer Institute Common Toxicity Criteria), the adverse reactions that occurred with greater frequency (≥3%) among patients treated with Tarceva compared to the placebo group in the pivotal study BR.21 and in at least 10% of patients in the Tarceva group.
The following terms are used to classify undesirable effects by frequency: very common (≥1 / 10); common (≥1 / 100,
Within each frequency group, adverse reactions are presented in order of decreasing severity.
Table 1: Very common adverse reactions in study BR.21
* Severe infections, with or without neutropenia, including pneumonia, sepsis and cellulitis.
** Can lead to dehydration, hypokalaemia and renal failure.
*** The rash included cases of acneiform dermatitis.
In 2 other randomized, double-blind, placebo-controlled phase III studies BO18192, (SATURN) and BO25460 (IUNO); Tarceva was given as maintenance therapy after first-line chemotherapy. These studies were conducted in a total of 1532 patients with advanced, relapsed or metastatic NSCLC after standard first-line platinum-based chemotherapy, no new safety reports were identified.
The most frequently observed adverse reactions in Tarceva-treated patients in studies BO18192 and BO25460 were rash and diarrhea (see Table 2). No Grade 4 rash or diarrhea was observed in either study. Rash and diarrhea caused Tarceva to be discontinued in 1% and 1%, respectively
Table 2: Most frequent adverse reactions in studies BO18192 (SATURN) and BO25460 (IUNO)
* Safety Assessment Group
In an open-label Phase III ML 20650 study in 154 patients, the safety of Tarceva for first-line treatment of patients with NSCLC and EGFR activating mutations was evaluated in 75 patients; no new related reports were identified. safety in these patients.
The most frequently observed adverse reactions in Tarceva-treated patients in ML 20650 were rash and diarrhea (any grade, 80% and 57% respectively), mostly Grade 1/2 intensity and manageable. Grade 3 rash and diarrhea occurred in 9% and 4% of patients, respectively. No case of grade 4 rash or diarrhea was observed. Rash and diarrhea both caused Tarceva to be discontinued in 1 % of patients. Dose modifications (interruptions or reductions) due to rash and diarrhea were necessary in 11% and 7% of patients, respectively.
Pancreatic cancer (Tarceva administered concomitantly with gemcitabine):
The most common adverse reactions in the pivotal study PA.3 in pancreatic cancer patients treated with Tarceva 100 mg and gemcitabine were fatigue, rash and diarrhea. In the Tarceva plus gemcitabine arm, rash and grade 3/4 diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. days. Rash and diarrhea each resulted in dose reductions in 2% of patients and resulted in study discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.
In the pivotal study PA.3, adverse reactions that occurred more frequently (≥3%) in patients treated with Tarceva 100 mg plus gemcitabine than in the placebo plus gemcitabine group and in at least 10% of patients in the Tarceva group 100 mg plus gemcitabine are summarized in Table 3 based on the National Cancer Institute's Common Toxicity Criteria (NCI-CTC).
The following terms are used to classify undesirable effects by frequency: very common (≥1 / 10); common (≥1 / 100,
Within each frequency group, adverse reactions are presented in order of decreasing severity.
Table 3: Very common adverse reactions in study PA.3 (100 mg cohort)
* Severe infections, with or without neutropenia, including pneumonia, sepsis and cellulitis.
** Can lead to dehydration, hypokalaemia and renal failure.
*** The rash included cases of acneiform dermatitis.
Other remarks:
The safety assessment of Tarceva is based on data from more than 1500 patients treated with at least one 150 mg dose of Tarceva alone and more than 300 patients treated with Tarceva 100 or 150 mg in combination with gemcitabine.
The following adverse reactions have been observed in patients treated with Tarceva monotherapy and in patients treated with Tarceva concomitantly with chemotherapy.
Very common adverse reactions from studies BR 21 and PA 3 are reported in Tables 1 and 3, other adverse reactions including those from other studies are summarized in Table 4.
Within each frequency group, adverse reactions are presented in order of decreasing severity.
Table 4: Adverse reactions by frequency category
1 In study PA.3.
2 Including eyelashes that grow inside, excessive growth and thickening of the eyelashes.
3 Including fatal cases, in patients taking Tarceva for the treatment of NSCLC or other advanced solid tumors (see section 4.4). A higher incidence was observed in patients of Japanese descent.
4 In clinical studies, some cases have been associated with co-administration of warfarin (see section 4.5) and sometimes with co-administration of NSAIDs.
5 Including increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin). These were most often mild or moderate in nature, transient in nature or associated with liver metastases.
6 Including fatal cases. Pre-existing liver disease or co-administration of hepatotoxic drugs were considered confounding factors (see section 4.4).
7 Including fatal cases (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms
Single oral doses of Tarceva up to 1000 mg of erlotinib in healthy subjects and up to 1600 mg in cancer patients have been tolerated. Repeated doses of 200 mg twice daily in healthy subjects were poorly tolerated after a few days of administration. Based on the data from these studies, it is possible that serious adverse reactions such as diarrhea, rash and possibly increased hepatic aminotransferase activity may occur with doses higher than recommended.
Management
If overdose is suspected, administration of Tarceva should be discontinued and symptomatic treatment initiated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: protein kinase inhibitor antineoplastic drug.
ATC code: L01XE03.
Mechanism of action
Erlotinib is an epidermal growth factor receptor / human epidermal growth factor receptor type I (EGFR, also known as HER1) tyrosine kinase inhibitor. Erlotinib is a potent inhibitor of EGFR intracellular phosphorylation. EGFR is expressed on the cell surface of normal and tumor cells. In non-clinical models, inhibition of EGFR's phosphotyrosine causes cell stasis and / or death.
EGFR mutations may result in "constitutive activation of the anti-apoptotic and proliferative signaling pathways. The potent efficacy of erlotinib in blocking EGFR-mediated signal transduction in these EGFR mutation-positive tumors is attributed to the close link between erlotinib at the ATP binding site in the mutated kinase domain of EGFR. Due to blockade of the downstream transduction signal, cell proliferation is arrested and cell death is induced via the intrinsic apoptotic pathway. Tumor regression is observed. in mouse models with marked expression of these activating EGFR mutations.
Clinical efficacy
• First-line therapy of non-small cell lung cancer (NSCLC) in patients with activating EGFR mutations (Tarceva administered alone):
The efficacy of Tarceva in first-line patients with activating EGFR mutations in NSCLC was demonstrated in a randomized, open-label phase III study (ML20650, EURTAC). This study was conducted in Caucasian patients with metastatic or locally advanced NSCLC (stage IIIB and IV) who had not previously received chemotherapy or any systemic antineoplastic therapy for their disease and who had mutations in the tyrosine kinase domain of EGFR (exon deletion). 19 or exon 21 mutation) Patients were randomized 1: 1 to receive Tarceva 150 mg daily or up to 4 cycles of a platinum-based brace chemotherapy.
The primary endpoint was investigator-assessed PFS.
The efficacy results are summarized in Table 5.
Table 5: Efficacy results of Tarceva versus chemotherapy in study ML20650 (EURTAC)
CR = complete response; RP = partial response.
* A 58% reduction in the risk of disease progression or death was observed.
** The overall agreement rate between the investigator's and the IRC's assessment of PFS was 70%.
*** A "high cross-over rate" was observed with 82% of patients in the chemotherapy arm receiving subsequent therapy with an EGFR-associated tyrosine kinase inhibitor and all but 2 patients were treated with Tarceva.
- Maintenance therapy of NSCLC after first-line chemotherapy (Tarceva given as monotherapy):
The efficacy and safety of Tarceva as maintenance therapy after first-line chemotherapy for NSCLC were investigated in a randomized, double-blind, placebo-controlled study (BO18192, SATURN). This study involved 889 patients with Locally advanced NSCLC that did not progress after 4 cycles of two-agent, platinum-based chemotherapy. Patients were randomized 1: 1 to treatment with Tarceva 150 mg or placebo orally once daily until progression. L "The main endpoint of the study included progression-free survival (PFS) in all patients. The demographic and disease characteristics at entry were well balanced between the two treatment arms. Patients with ECOG PS> 1, significant hepatic or renal comorbidities were not included in the study.
In this study, the entire population showed a benefit for the PFS primary endpoint (HR = 0.71p
67% of placebo-treated patients in the EGFR mutation positive subgroup received EGFR-TKI inhibitors in second or subsequent lines of treatment.
Study BO25460 (IUNO) was conducted in 643 patients with advanced NSCLC without activating EGFR mutations (exon 19 deletion or exon 21 L858R mutation) and who had not shown disease progression after four courses of platinum-based chemotherapy.
The aim of the study was to compare the overall survival of erlotinib given as a first line of maintenance versus erlotinib given at the time of disease progression. The study did not meet the primary endpoint. OS of Tarceva in maintenance was not superior to that of Tarceva given as second-line treatment in patients whose tumor did not have an activating EGFR mutation (HR = 1.02, 95% CI, 0.85-1 , 22, p = 0.82). The secondary endpoint of progression-free survival (PFS) did not differ between Tarceva and placebo on maintenance treatment (HR = 0.94, 95% CI, 0.80- 1.11; p = 0.48).
Based on data from study BO25460 (IUNO), the use of Tarceva is not recommended as first-line maintenance treatment in patients without an activating EGFR mutation.
- Treatment of NSCLC after failure of at least one previous line of chemotherapy (Tarceva administered alone):
The efficacy and safety of Tarceva as second / third line therapy was demonstrated in a randomized, double-blind, placebo-controlled study (BR.21) in 731 patients with locally advanced or metastatic NSCLC after failure of at least a chemotherapy regimen. Patients were randomized 2: 1 to treatment with Tarceva 150 mg or placebo orally once daily. Study endpoints included overall survival, progression-free survival (PFS), response, duration of response, time to worsening of lung cancer-related symptoms (cough, dyspnoea and pain) and safety. The primary endpoint was survival.
Demographic characteristics were well balanced between the two treatment groups. About two-thirds of the patients were male, about one-third had an ECOG performance status (PS) at admission of 2 and 9% an ECOG PS at admission of 3. 93% and 92% of all patients, respectively. of the Tarceva group and the placebo group had previously been treated with a platinum-based regimen and 36% and 37% of all patients, respectively, had previously been treated with taxanes.
The adjusted hazard ratio (HR) for deaths in the Tarceva group versus the placebo group was 0.73 (95% CI: 0.60-0.87) (p = 0.001). 31.2% and 21.5% of patients in the Tarceva and placebo groups, respectively, were alive at 12 months. Median overall survival was 6.7 months in the Tarceva group (95% CI: 5.5-7.8 months) compared to 4.7 months in the placebo group (95% CI: 4.1-6, 3 months).
The effect on overall survival was investigated in different patient subgroups.The effect of Tarceva on overall survival was similar in patients with a baseline performance status (ECOG) of 2-3 (HR = 0.77, 95% CI 0.6-1.0) or 0-1 (HR = 0.73, 95% CI 0.6-0.9), in male (HR = 0.76, 95% CI 0.6-0.9) or female (HR = 0 , 80, 95% CI 0.6-1.1), in patients less than 65 years of age (HR = 0.75, 95% CI 0.6-0.9) or in older patients (HR = 0.79, 95% CI 0.6-1.0), in patients treated with a previous regimen (HR = 0.76, 95% CI 0.6-1.0) or with more than one prior regimen (HR = 0.75, 95% CI 0.6-1.0), in Caucasian (HR = 0.79, 95% CI 0.6-1.0) or Asian (HR = 0, 61, 95% CI 0.4-1.0), in patients with adenocarcinoma (HR = 0.71, 95% CI 0.6-0.9) or squamous cell carcinoma (HR = 0.67, CI at 95% 0.5-0.9), but not in patients with other histology (HR 1.04, 95% CI 0.7-1.5), in patients with stage IV disease at diagnosis (HR = 0 , 92, 95% CI 0.7-1.2) or stage
In 45% of patients with known EGFR expression status, the hazard ratio was 0.68 (95% CI 0.49-0.94) for patients with EGFR-positive tumors and 0 , 93 (95% CI 0.63-1.36) for patients with EGFR-negative tumors (defined by IHC, using the EGFR pharmDx kit, as EGFR negative those with less than 10% tumor cell labeling) . In the remaining 55% of patients with unknown EGFR expression status, the hazard ratio was 0.77 (95% CI 0.61-0.98).
Median PFS was 9.7 weeks in the Tarceva group (95% CI, 8.4-12.4 weeks) compared to 8.0 weeks in the placebo group (95% CI, 7.9-8.1 weeks). ).
In the Tarceva group, the RECIST objective response rate was 8.9% (95% CI, 6.4-12.0). The first 330 patients were centrally assessed (response rate 6, 2%); 401 patients were investigator assessed (response rate 11.2%).
The median duration of response was 34.3 weeks, with a minimum of 9.7 and a maximum of 57.6+ weeks. 44.0% of patients achieved complete, partial response or disease stabilization in the Tarceva group, compared with 27.5% of patients in the placebo group (p = 0.004).
A survival benefit with Tarceva was also seen in patients who did not achieve an objective tumor response (RECIST criteria). This was evidenced by a hazard ratio for death of 0.82 (95% CI, 0.68-0.99) among patients who achieved disease stabilization or progression as the best response.
Tarceva induced symptomatic benefits by significantly prolonging the time to worsening of cough, dyspnoea and pain compared to placebo.
- Pancreatic cancer (Tarceva co-administered with gemcitabine in study PA.3):
The efficacy and safety of Tarceva in combination with gemcitabine as first-line treatment were evaluated in a randomized, double-blind, placebo-controlled study in patients with locally advanced, unresectable or metastatic pancreatic cancer. were randomized to treatment with Tarceva or placebo once daily on a continuous basis and iv gemcitabine (1000 mg / m2, cycle 1 - days 1, 8, 15, 22, 29, 36 and 43 of an 8-week cycle; 2 and subsequent cycles - days 1, 8, and 15 of a 4-week cycle [approved dosage and schedule for pancreatic cancer, see gemcitabine SmPC]). Tarceva or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Patient demographic and disease characteristics at entry were similar for the 2 treatment groups, Tarceva 100 mg plus gemcitabine or placebo plus gemcitabine, except for a slightly higher proportion of women in the erlotinib / gemcitabine arm compared to the placebo / gemcitabine arm. :
Survival was assessed in the intent-to-treat population based on follow-up survival data. The results are described in the following table (the results for the groups of patients with metastatic and locally advanced disease are derived from an exploratory subgroup analysis).
Patients with a favorable clinical status at baseline (low pain intensity, good QoL and good PS) could benefit more from Tarceva, as shown by a "post-hoc analysis. The benefit is derived mainly from the presence of a low level of pain intensity.
In a post-hoc analysis, Tarceva-treated patients who developed a rash had a longer overall survival compared to patients who did not develop a rash (median OS 7.2 months versus 5 months, HR : 0.61).
90% of patients taking Tarceva developed a rash within the first 44 days. Median time to rash onset was 10 days.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Tarceva in all subsets of the pediatric population for indications in non-small cell lung cancer and pancreatic cancer (see section 4.2 for information on "pediatric use).
05.2 "Pharmacokinetic properties
AbsorptionPeak plasma concentrations of erlotinib are achieved approximately 4 hours after oral administration. A study in normal healthy volunteers provided an estimated absolute bioavailability of 59%. Food may increase exposure after an oral dose.
Distribution: erlotinib has a mean apparent volume of distribution of 232 l and is distributed in human tumor tissue. In a study carried out on 4 patients (3 with non-small cell lung cancer (NSCLC) and 1 with laryngeal cancer), treated with 150 mg per day of Tarceva orally, the samples obtained by surgical excision of the tumor on the 9th day of treatment showed erlotinib concentrations within the tumor on average of 1.185 ng / g of tissue, corresponding overall to a mean of 63% (range: 5-161%) of the peak plasma concentration observed at steady state. The major metabolites active substances were present in the tumor at concentrations on average of 160 ng / g of tissue, corresponding overall to a mean of 113% (range: 88-130%) of the peak plasma concentration observed at steady state. Plasma protein binding is about 95%. Erlotinib binds to serum albumin and alpha-1 acid glycoprotein (AAG).
Biotransformation: In humans, erlotinib is metabolised in the liver by hepatic cytochromes, mainly by CYP3A4 and to a lesser extent by CYP1A2. CYP3A4-mediated extrahepatic metabolism in the intestine, CYP1A1 in the lung and 1B1 in tumor tissue provides a potential contribution to clearance metabolic rate of erlotinib.
Three main metabolic pathways have been identified: 1) O-demethylation of one or both side chains, followed by oxidation to carboxylic acids; 2) oxidation of the acetylenic fraction followed by hydrolysis to arylcarboxylic acid; and 3) the aromatic hydroxylation of the phenylacetylene fraction. The major erlotinib metabolites OSI-420 and OSI-413, produced by O-demethylation of one of the side chains, showed similar potency to erlotinib in non-clinical analyzes. in vitro and in tumor models in vivo. They are present in plasma at levels less than 10% of those of erlotinib and exhibit similar pharmacokinetics to erlotinib.
Elimination: erlotinib is mainly excreted metabolised via faeces (> 90%) while renal elimination accounts for only a small fraction (approximately 9%) of the amount administered orally. Less than 2% of the dose administered orally is excreted unchanged. One Population pharmacokinetic analysis of 591 patients treated with Tarceva monotherapy shows a mean apparent clearance of 4.47 l / h with a median half-life of 36.2 hours. Therefore, steady-state plasma concentration can be expected to be reached. in about 7 or 8 days.
Pharmacokinetics in special populations:
Based on the population pharmacokinetic analysis, no clinically significant correlations were observed between the apparent expected clearance and the patient's age, body weight, gender or ethnicity. Patient-related factors that showed a correlation with pharmacokinetics of erlotinib were total bilirubin, "AAG and" being a smoker. Increased serum total bilirubin and AAG concentrations were associated with decreased erlotinib clearance. The clinical relevance of these differences is unclear. However, the rate of erlotinib clearance was increased in smokers.
This was confirmed by a pharmacokinetic study in healthy non-smokers and cigarette smokers who received a single 150 mg oral dose of erlotinb. The geometric mean of Cmax was 1056 ng / ml in nonsmokers and 689 ng / ml in smokers with a mean ratio of smokers to nonsmokers of 65.2% (95% CI: 44.3 - 95.9 ; p = 0.031). The geometric mean of 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
In the pivotal phase III NSCLC study, smokers achieved a steady-state plasma concentration of erlotinib of 0.65 μg / mL (n = 16), approximately 2-fold lower than former smokers or patients who had never smoked (1.28 mcg / ml, n = 108). This effect was accompanied by a 24% increase in the apparent plasma clearance of erlotinib. In a phase I dose escalation study in smoking NSCLC patients, steady-state pharmacokinetic analyzes indicated a dose-proportional increase in erlotinib exposure by increasing the dose of Tarceva from 150 mg to the maximum tolerated dose of 300. In this study, the steady-state plasma concentration at the 300 mg dose in smokers was 1.22 μg / mL (n = 17).
Based on the results of pharmacokinetic studies, current smokers should be advised to stop smoking while taking Tarceva, as otherwise plasma concentrations may be reduced.
Based on population pharmacokinetic analysis, the presence of an opioid appears to increase exposure by approximately 11%.
A second population pharmacokinetic analysis was conducted, including erlotinib data from 204 pancreatic cancer patients treated with erlotinib and gemcitabine. This analysis demonstrated that covariants affecting erlotinib clearance in study patients on pancreatic cancer were very similar to those observed in the previous pharmacokinetic analysis of monotherapy. No new covariate effects were identified. Co-administration of gemcitabine had no effect on the plasma clearance of erlotinib.
Pediatric population: No specific studies have been conducted on pediatric patients
Elderly patients: No specific studies have been conducted in elderly patients.
Hepatic insufficiency: clearance of erlotinib is predominantly hepatic. In patients with solid tumors and moderate hepatic impairment (Child-Pugh score of 7-9) the geometric mean AUC0-t and Cmax of erlotinib were 27,000 ng • h / ml and 805 ng / ml, while they were 29300 ng • h / ml and 1090 ng / ml in patients with adequate hepatic function, including those with primary liver cancer or liver metastases. Although Cmax was statistically significantly lower in patients with insufficiency moderate hepatic function, this difference is not considered clinically relevant. There is no data on the effect of severe hepatic dysfunction on erlotinib pharmacokinetics. In the population pharmacokinetic analysis, an increase in serum total bilirubin concentrations is associated with a slowing of erlotinib clearance.
Kidney failure: Renal excretion of erlotinib and its metabolites is not significant, as less than 9% of a single dose is excreted in the urine. Clinically significant correlations between erlotinib clearance and creatinine clearance, but there are no data available for patients with creatinine clearance
05.3 Preclinical safety data
Among the effects observed after chronic administration in at least one animal species or a study, there are those on the cornea (atrophy, ulceration), on the skin (follicular degeneration and inflammation, redness and alopecia), on the ovary (atrophy), on the liver ( hepatic necrosis), on the kidney (renal papillary necrosis and tubular dilatation) and on the gastrointestinal tract (delayed gastric emptying and diarrhea). There was a reduction in red blood cell parameters and an increase in white blood cells, especially neutrophils. an increase in ALT, AST and bilirubin was associated and these data emerged for exposures well below the clinically relevant ones.
Based on the mechanism of action, erlotinib is potentially teratogenic. Data from reproductive toxicity studies in rats and rabbits at doses close to the maximum tolerated dose and / or maternally toxic doses indicated reproductive toxicity (embryotoxicity in the rat). , embryonic resorption and fetotoxicity in rabbits) and development (reduced growth and survival of pups in rats), but showed no teratogenicity or impairment of fertility. These results were observed for clinically relevant exposures.
Conventional genotoxicity studies of erlotinib have failed. 2-year carcinogenicity studies conducted in rats and mice with erlotinib up to concentrations in excess of the therapeutic concentrations used in humans (up to 2-fold and 10-fold, respectively, based on Cmax and / or AUC) were negative.
In rats, a mild phototoxic skin reaction was observed after UV irradiation.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Lactose monohydrate
Microcrystalline cellulose (E460)
Sodium starch glycolate type A
Sodium lauryl sulfate
Magnesium stearate (E470 b)
Tablet coating:
Hydroxypropylcellulose (E463)
Titanium dioxide (E171)
Macrogol
Hypromellose (E464)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC blister sealed with aluminum foil containing 30 tablets.
06.6 Instructions for use and handling
No special instructions for disposal.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/05/311/003
036871034
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19 September 2005
Date of last renewal: 19 September 2010
10.0 DATE OF REVISION OF THE TEXT
January 2016
