Tartseva

General characteristics. Structure:

Active ingredient: 25 mg, 100 mg or 150 mg of an erlotinib (in the form of an erlotinib of a hydrochloride of 27,32 mg, 109,29 mg or 163,93 mg respectively).

Excipients: lactoses monohydrate, cellulose microcrystallic, carboxymethylstarch of sodium, sodium lauryl sulfate, magnesium stearate.

Cover: gipromelloza, hypro rod, macrogoal 400, titanium E171 dioxide; use of the ready mix Opadry White Y-5-7068 is allowed.

The first lekarsvenny drug for intake operating on a receptor of an epidermal growth factor (EGFR). Tartseva proved the efficiency in wide population of patients with widespread not small-celled cancer of a lung, having shown reliable increase in survival and decrease in severity of symptoms of a disease without by-effects inherent to himiopreparata.  

Pharmacological properties:

Pharmacodynamics. Эрлотиниб powerfully inhibits intracellular phosphorylation of a receptor of an epidermal growth factor of HER1/EGFR (HER1 = a receptor of an epidermal growth factor of the person of 1 type / EGFR = a receptor of an epidermal growth factor).

The expression of HER1/EGFR is observed on a surface of both normal, and cancer cells. On preclinical models the inhibition of EGFR phosphotyrosine slows down growth of lines of tumor cells and/or leads to their death.

Mutations of EGFR can lead to continuous activation of proliferative and anti-apoptotic alarm ways in a cell. High performance of an erlotinib concerning blocking of EGFR dependent alarm ways in the tumors bearing EGFR mutation is caused by strong linkng of an erlotinib with the ATP-connecting site of the mutated kinazny EGFR domain. At the same time the cascade of alarm reactions therefore proliferation of cells is oppressed is blocked and the internal way of cellular death is started.

Pharmacokinetics. Exposure. After intake of 150 mg of an erlotinib in an equilibrium state a median of the maximum concentration of an erlotinib (Cmax) in plasma of 1.995 ng/ml. Before reception of the following dose in 24 h a median of the minimum concentration (Cmin) of an erlotinib in plasma of 1.238 ng/ml. The area median under a curve "concentration of active ingredient - time" (AUC) in an interdose interval at achievement of equilibrium concentration makes 41.3 mkg / ч*мл.

Absorption. Эрлотиниб it is well soaked up after intake. Has a long phase of absorption, and average value of time of achievement of the maximum concentration (TCmax) in plasma makes 4 h. According to data of a research on healthy volunteers bioavailability of an erlotinib - 59%, meal can increase its bioavailability.

After absorption in blood эрлотиниб for 95% is in the connected state, first of all with proteins of a blood plasma (albumine and alfa1-an acid glycoprotein). The free fraction makes about 5%.

Distribution. The seeming volume of distribution of 232 l with distribution in tumor fabric. For the 9th day of treatment erlotiniby in a dose of 150 mg a day average concentration of an erlotinib is equal in samples of tumoral tissue of the person 1.185 ¡ú/g that makes 63% of Cmax in plasma in an equilibrium state. Concentration of the main active metabolites in fabric of a tumor 160 ¡ú/g that corresponds to 113% of Cmax in plasma in an equilibrium state. Researches on studying of distribution in fabrics marked 14C erlotinib after oral administration at bestimusny mice with a mutation on nude gene with HT5 tumoral heterograft (with use of the general autoradiografiya) showed bystry and intensive distribution in fabrics. Cmax in fabric made about 73% of concentration of an erlotinib, in fabric there is 1 h TCmax.

Metabolism. Эрлотиниб it is metabolized by isoenzymes of system of P450 cytochrome mainly with the participation of an isoenzyme of CYP3A4 and to a lesser extent CYP1A2 isoenzyme. Extrahepatic metabolism by means of CYP3A4 isoenzyme in intestines, CYP1A1 isoenzyme in lungs, CYP1B1 isoenzyme in fabric of a tumor provides metabolic clearance of an erlotinib. The researches in vitro demonstrate that 80-95% of an erlotinib are metabolized with the participation of CYP3A4 isoenzyme.

Metabolism happens in three ways: 1) O-demethylation of one of side or both chains with the subsequent oxidation to carboxylic acids; 2) oxidation of an acetylene part of a molecule with the subsequent hydrolysis to arylcarboxylic acid; 3) aromatic hydroxylation of a fenilatsetilenovy part of a molecule. The main metabolites are formed as a result of O-demethylation of one of side chains and have activity, comparable with erlotiniby in vitro in preclinical trials and on models of tumors in vivo. They are present at plasma in concentration which make <10% of concentration of an erlotinib, their pharmacokinetics is similar to pharmacokinetics of an erlotinib.

Removal. Metabolites and trace quantities of an erlotinib are removed, preferential, with bile (> 90%), kidneys remove a small amount of orally entered dose.

Clearance. At monotherapy by the drug Tartseva® average clearance of 4.47 l/h, and an average elimination half-life (T1/2) of 36.2 h. Therefore, it is expected that equilibrium concentration will be reached for 7-8 day. Considerable communication between clearance, age, body weight, a floor and race of the patient is not revealed.

The pharmacokinetics of an erlotinib depended on the following indicators: concentration of the general bilirubin, alfa1-acid glycoprotein and smoking now. Decrease in clearance of an erlotinib is noted at increase in concentration of the general bilirubin and an alfa1-acid glycoprotein, an its increase - at smokers.

Simultaneous use of gemcitabine did not influence clearance of an erlotinib.

Pharmacokinetics at special groups of patients. Special researches at children and elderly patients were not conducted.

Abnormal liver function. Эрлотиниб it is generally removed with bile. Exposure of an erlotinib is identical at patients with average extent of disturbance of hepatic function (7-9 points on a scale of Chayld-Pyyu) and at patients without abnormal liver function including patients with primary center have tumors in a liver or with metastasises in a liver.

Renal failure. Эрлотиниб and its metabolites are removed by kidneys in insignificant quantities - less than 9% of a single dose. Clinical trials at patients with a renal failure were not conducted.

Smoking. Smoking increases clearance and reduces exposure of an erlotinib. AUC0 infinity at the smoking people made 1/3 from AUC0 infinity at the non-smoking/former smokers. The observed decrease in exposure at active smokers is perhaps connected with induction of an isoenzyme of CYP1A1 in lungs and CYP1A2 isoenzyme in a liver.

At the smoking patients with not small-celled cancer of a lung the minimum equilibrium concentration made 0.65 mkg/ml that is twice lower, than at the non-smoking/former smokers (1.28 mkg/ml). At the same time the seeming clearance of an erlotinib increases by 24%.

At increase in a dose of an erlotinib from 150 mg to 300 mg (the most tolerable dose) dozozavisimy increase in exposure of an erlotinib is observed. The minimum equilibrium concentration of an erlotinib in a dose of 300 mg at smokers made 1.22 mkg/ml.

Indications to use:

Not small-celled cancer of a lung. The first line of therapy locally-spread or metastatic (IIIB-IV of a stage) not small-celled cancer of a lung with the activating mutations in EGFR gene.

Maintenance therapy of locally-spread or metastatic not small-celled cancer of lung in the absence of progressing of a disease after 4 courses of the first line of chemotherapy on the basis of platinum drugs.

Locally-spread or metastatic not small-celled cancer of a lung after failure of one or more schemes of chemotherapy.

Pancreatic cancer. The first line of therapy of a locally-spread or metastatic pancreatic cancer in a combination with gemcitabine.

Route of administration and doses:

Inside, once a day, not less than for 1 h or in 2 h after meal.

Not small-celled cancer of a lung. On 150 mg daily. At emergence of signs of progressing of a disease or development of intolerable toxicity therapy by the drug Tartseva® should be stopped.

Before an initiation of treatment at the patients with not small-celled cancer of a lung who were earlier not receiving chemotherapy it is necessary to carry out the analysis on existence of a mutation of L858R in 21 exons or deletion in the 19th exon of a gene of EGFR.

Pancreatic cancer. On 100 mg daily, it is long, in a combination with gemcitabine (see also instruction on a medical use of gemcitabine, the indication - a pancreatic cancer).

At emergence of signs of progressing of a disease therapy of the drug Tartseva® should be stopped.

If at the patient within 4-8 weeks of treatment rash does not develop, further therapy by the drug Tartseva® should be reconsidered.

Special instructions on dosing. At substrates or modulators of an isoenzyme CYP3A4 accompanying therapy change of a dose of the drug Tartseva® can be required.

If necessary the dose of the drug Tartseva® decreases by 50 mg gradually.

Abnormal liver function. In spite of the fact that patients had an identical exposure of an erlotinib with average extent of disturbance of hepatic function (7-9 points on a scale of Chayld-Pyyu) and at patients without abnormal liver function, patients need to show care at purpose of the drug Tartseva® with an abnormal liver function. Administration of drug of Tartseva® is not recommended at a heavy abnormal liver function.

At development of heavy undesirable reactions, it is necessary to consider a question of a dose decline or a break of therapy by the drug Tartseva®. Safety and efficiency at patients with a heavy abnormal liver function (activity of alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant) is more than 5 times higher than the upper bound of norm) were not studied.

Renal failure. Safety and efficiency at patients with a renal failure (concentration of creatinine in blood serum is more than 1.5 times higher than the upper bound of norm) were not studied. According to pharmacokinetic data at a slight and moderate renal failure of dose adjustment it is not required. Administration of drug of Tartseva® is not recommended at a heavy renal failure.

Children's age. Safety and efficiency of the drug Tartseva® at patients aged up to 18 years were not studied.

Smoking reduces exposure of an erlotinib by 50-60%. The most tolerable dose of the drug Tartseva® at the smoking patients with not small-celled cancer of a lung makes 300 mg.

The long-term results of efficiency and safety of use of doses are higher recommended in an initiation of treatment at the patients continuing smoking are not established.

Features of use:

Assessment of the status of mutations in EGFR gene. At assessment of the status of mutations in a gene of EGFR of the patients with locally-spread or metastatic not small-celled cancer of a lung who were earlier not receiving chemotherapy it is necessary to choose well checked and reliable methods of the analysis to avoid false negative or false positive definitions.

Smoking. The smoking patients should recommend to refuse smoking as concentration of an erlotinib in plasma at the smoking patients in comparison with non-smoking considerably decreases.

Intersticial Disease of Lungs (IDL). At the patients with not small-celled cancer of a lung, a pancreatic cancer or other widespread solid tumors receiving the drug Tartseva®, IZL-like symptoms including with a lethal outcome, were diagnosed infrequently. The general frequency of cases of the IZL-like phenomena at the patients receiving the drug Tartseva® makes 0.6%. The most frequent diagnoses at patients with suspicion on IZL-like symptoms are: pneumonitis, intersticial pneumonia, beam pneumonitis, allergic intersticial pneumonitis, intersticial disease of lungs, obliterating bronchiolitis, pneumosclerosis, acute respiratory distress syndrome, infiltration of lungs and alveolitis.

The listed IZL-like phenomena arose during the period from several days to several months after the beginning of therapy by the drug Tartseva®. The majority of cases was connected with the aggravating or promoting factors, such as the accompanying or earlier carried out chemotherapy, radiation therapy, a parenchymatous disease of lungs in the anamnesis, metastatic damage of lungs or an infection. At acute development new and/or progressing of inexplicable pulmonary symptoms (short wind, cough and fever) administration of drug of Tartseva® needs to be stopped temporarily before clarification of the reason. In case of confirmation of the diagnosis of IZL it is necessary to cancel the drug Tartseva® and to carry out necessary treatment.

Diarrhea, dehydration, electrolytic disturbances and renal failure. When developing heavy or moderate diarrhea it is necessary to appoint loperamide. In certain cases the drug Tartseva® dose decline can be required.

At heavy or steady diarrhea, nausea, anorexia or vomiting with dehydration, therapy by the drug Tartseva® has to be interrupted and carried out a regidratation. It was reported about exceptional cases of development of a hypopotassemia and a renal failure, including with a lethal outcome.

Some cases of a renal failure were caused by heavy dehydration owing to diarrhea, vomiting and/or anorexia, others - the accompanying chemotherapy. In the cases of heavy or steady diarrhea or states leading to dehydration, especially at patients in risk group (the accompanying therapy or diseases, or in the presence of other contributing factors, including advanced age), the drug Tartseva® is temporarily cancelled and carry out a parenteral regidratation. At patients with high risk of dehydration it is necessary to control blood serum electrolytes, including potassium, and function of kidneys.

Hepatitis, liver failure. During administration of drug of Tartseva® it was reported about exceptional cases of a liver failure, including cases with a lethal outcome. It is recommended to control periodically function of a liver to patients with associated diseases of a liver or receiving gepatotoksichny medicines. At development of severe damage of a liver administration of drug of Tartseva® is stopped.

Perforation of digestive tract. The patients receiving the drug Tartseva® have the increased risk of development of perforation of digestive tract which was observed infrequently, in certain cases with a lethal outcome. The patients receiving the accompanying therapy by antiangiogenic drugs, glucocorticosteroids, NPVP and/or chemotherapy on the basis of taxons or the patients having a round ulcer or a diverticular disease in the anamnesis enter into group of the increased risk.

In case of development of perforation of digestive tract therapy by the drug Tartseva® should be stopped.

Violent or exfoliative disturbances. It was reported about cases violent, followed by blistering and exfoliative disturbances, including about very exceptional cases of suspicion on development of a syndrome of Stephens Johnson / a toxic epidermal necrolysis, in certain cases with a lethal outcome. In case of development heavy violent, followed by blistering or exfoliative damages of skin, treatment by the drug Tartseva® has to be suspended or stopped.

Ophthalmologic disturbances. At use of the drug Tartseva® very exceptional cases of perforation or a keratohelcosis are registered. At treatment the drug Tartseva® observed also other ophthalmologic disturbances, including the wrong growth of eyelashes, a dry keratoconjunctivitis or a keratitis which are also risk factors of development of a perforation/keratohelcosis. Treatment by the drug Tartseva® has to be suspended or cancelled at emergence of acute ophthalmologic symptoms, such as eye pain, or deterioration in chronic ophthalmologic diseases.

During treatment by the drug Tartseva® and at least within 2 weeks after its termination it is necessary to apply reliable methods of contraception.

Utilization of the drug Tartseva® should be carried out according to local requirements.

Influence on ability to drive the car and work with mechanisms. Researches on studying of influence of drug on ability to drive the car and to work with mechanisms were not conducted. However эрлотиниб does not influence ability to concentration of attention.

Side effects:

For assessment of frequency of undesirable effects the following categories of frequency are used: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10000, <1/1000); very seldom (<1/10000), including separate cases.

From the alimentary system: very often – diarrhea, nausea, vomiting, stomatitis, abdominal pains, a meteorism, dyspepsia; often – gastrointestinal bleedings (including separate cases with a lethal outcome) some of which were connected with simultaneous use of warfarin or NPVP (non-steroidal anti-inflammatory drugs); infrequently – perforation of digestive tract, in certain cases with a lethal outcome.

From a metabolism: very often – anorexia.

From gepatobiliarny system: often – an abnormal liver function (including increase in activity of ALT, nuclear heating plant, concentration of bilirubin); seldom – a liver failure (including with a lethal outcome).

From an organ of sight: very often – conjunctivitis, a dry keratoconjunctivitis; often – a keratitis; infrequently – a growth disorder of eyelashes, including the grown eyelashes, excess growth and a thickening of eyelashes; very seldom – an ulceration or perforation of a cornea, a uveitis.

From respiratory system: very often – short wind, cough; often – nasal bleedings; infrequently – symptoms, similar to intersticial diseases of lungs, including cases with a lethal outcome.

From skin and a hypodermic fatty tissue: very often – rash (erythematic and papulo-pustular rashes which appeared or amplified under the influence of sunshine), an itch, a xeroderma, an alopecia; often – a paronychia; skin cracks, as a rule, not having serious character, in most cases associated with rash and a xeroderma, eels, akneiformny dermatitis, a folliculitis (in most cases these undesirable phenomena were frivolous, easy and moderate severity); infrequently – a hyperpegmentation, a hirsutism, changes of eyelashes/eyebrows, fragility and stratification of nails; cases of the violent, exfoliative and followed by blistering damage of skin, including very exceptional cases of suspicion on development of a syndrome of Stephens Johnson / a toxic epidermal necrolysis, in certain cases with a lethal outcome are registered.

From a nervous system: very often – a headache, a neuropathy.

From mentality: very often – a depression.

From kidneys and urinary tract: often – a renal failure; infrequently – nephrite, a proteinuria.

Others: very often – increased fatigue, heavy infections (with or without neutropenia, pneumonia, sepsis, phlegmon), fever, a fever, decrease in body weight.

Interaction with other medicines:

Эрлотиниб at the person it is metabolized by isoenzymes of system of P450 cytochrome mainly with the participation of an isoenzyme of CYP3A4 and to a lesser extent CYP1A2, and a pulmonary isoenzyme of CYP1A1. Interaction at use of an erlotinib in a combination with inhibitors or inductors of enzymes, and also drugs which are metabolized by means of these enzymes is possible.

Powerful inhibitors of an isoenzyme CYP3A4 reduce metabolism of an erlotinib and increase its concentration in plasma. The inhibition of metabolism of an isoenzyme of CYP3A4 under the influence of a ketokonazol (200 mg in 2 times a day within 5 days) led to increase in AUC of an erlotinib by 86% and Cmax by 69% in comparison with the same indicators at reception of one erlotinib. Ciprofloxacin (inhibitor of an isoenzyme of CYP3A4 and CYP1A2) increases AUC and Cmax of an erlotinib by 39% and 17%, respectively. Simultaneous use of the drug Tartseva® with powerful inhibitors of an isoenzyme of CYP3A4 or CYP3A4/CYP1A2 is made only at emergency. In case of development of toxicity it is necessary to lower a drug Tartseva® dose.

Powerful inductors of an isoenzyme CYP3A4 increase metabolism of an erlotinib and significantly reduce its concentration in plasma. Induction of metabolism with participation of an isoenzyme of CYP3A4 at a concomitant use of rifampicin (600 mg inside daily within 7 days) leads to decrease in a median of AUC of an erlotinib in a dose 150 mg for 69% in comparison with reception of one erlotinib.

After preliminary treatment by rifampicin, and also at a concomitant use of rifampicin and the drug Tartseva® the median of AUC of an erlotinib in a dose of 450 mg makes 57.5% of AUC of an erlotinib in a dose of 150 mg without preliminary therapy by rifampicin. It is whenever possible necessary to provide an alternative method of treatment without induction of activity of an isoenzyme of CYP3A4. Simultaneous use of the drug Tartseva® with powerful inductors of an isoenzyme CYP3A4, such as rifampicin, is made only at emergency, at the same time it is necessary to increase a drug Tartseva® dose to 300 mg under careful control of a profile of safety. At good tolerance at use of drug within more than 2 weeks it is possible to consider a question of increase in a dose of drug up to 450 mg, continuing to control carefully a safety profile (see the section "Special Instructions"). Higher doses in similar situations were not studied.

CYP3A4 isoenzyme substrates. The previous therapy or a concomitant use of the drug Tartseva® does not break clearance of typical substrates of an isoenzyme of CYP3A4, such as midazolam and erythromycin. Thus, considerable influence of the drug Tartseva® on clearance of other substrates of an isoenzyme of CYP3A4 is improbable. It turned out that bioavailability of midazolam at oral administration decreases by 24% that is not connected with influence on activity of an isoenzyme of CYP3A4.

Omeprazol. Solubility of an erlotinib depends from рН. At increase рН solubility of an erlotinib decreases. Thus, the drugs changing рН in upper parts of digestive tract can exert impact on solubility of an erlotinib and its bioavailability. At a concomitant use of the drug Tartseva® and an omeprazol, inhibitor of a proton pomp, AUC and Cmax of an erlotinib decreased by 46% and 61%, respectively. TCmax and an elimination half-life did not change. At a concomitant use of the drug Tartseva® and ranitidine (300 mg), H2 blocker - histamine receptors, AUC and Cmax of an erlotinib decreased by 33% and 54%, respectively.

Thus, whenever possible it is necessary to avoid the concomitant use of the drug Tartseva® and means lowering secretion of glands of a stomach. It is improbable that increase in a dose of the drug Tartseva® at a concomitant use with similar drugs can compensate decrease in its exposure. However when Tartseva® was appointed in different hours, i.e. for 2 h to or in 10 h after ranitidine reception (150 mg 2 times a day), AUC and Cmax of an erlotinib decreased only by 15% and 17%, respectively. In case of need therapy by these drugs should give preference to reception of blockers of H2 - histamine receptors, such as ranitidine, in different hours. It is necessary to take the drug Tartseva® at least for 2 h to or in 10 h after reception of a blocker of H2 - histamine receptors.

Warfarin, other derivatives of coumarin. At the patients receiving the drug Tartseva® in a combination with coumarin derivatives including warfarin, increase in the International Normalized Relation (INR) and bleeding, in some cases with a lethal outcome are registered. At the patients accepting coumarin derivatives it is necessary to control a prothrombin time or MNO regularly.

Statines. Тарцева® in a combination with statines can strengthen the myopathy caused by statines, including рабдомиолиз, observed seldom.

Smoking. It is necessary to recommend refusal of smoking at drug use as smoking, inducing isoenzymes of CYP1A1 and CYP1A2, reduces exposure of an erlotinib by 50-60%.

Gemcitabine. Considerable influence of gemcitabine on pharmacokinetics of an erlotinib and vice versa is not revealed.

Platinum drugs. Эрлотиниб increases concentration of platinum in a blood plasma. The concomitant use of an erlotinib with karboplatiny and paklitaksely leads to increase in AUC of the general platinum statistically significant, but not significant clinically for 10.6%. Increase in exposure of a karboplatin can be connected with other factors, for example a renal failure. Considerable influence of a karboplatin or a paklitaksel on pharmacokinetics of an erlotinib is not revealed.

Kapetsitabin. Kapetsitabin increases concentration of an erlotinib in a blood plasma. Use of an erlotinib in a combination with kapetsitabiny in comparison with monotherapy erlotiniby leads to statistically significant increase in AUC of an erlotinib and slight increase of Cmax of an erlotinib. Considerable influence of an erlotinib on pharmacokinetics of a kapetsitabin is not revealed.

UGT1A1 substrates. As эрлотиниб is UDF-glyukuroniltransferaza's inhibitor UGT1A1, interaction with drugs which are UGT1A1 substrates and for which the conjugation test with glucuronic acid is the main way of metabolism is possible. It is necessary to be careful at purpose of the drug Tartseva® to patients with the low level of an expression UGT1A1 or with the genetic disorders causing reduction in the rate of reaction of a glyukuronization (for example, Gilbert's syndrome) as increase in concentration of bilirubin in a blood plasma is possible.

Contraindications:

The expressed hypersensitivity to an erlotinib or to any component of drug.

Pregnancy and feeding by a breast.

Age up to 18 years (safety and efficiency were not studied).

Heavy abnormal liver function (10 and more points on a scale of Chayld-Pyyu) or kidneys.

With care. Abnormal liver function. Smoking.

Patients with rare hereditary diseases, such as intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption.

Concomitant use with powerful inductors or inhibitors of an isoenzyme CYP3A4.

Round ulcer or diverticular disease now or in the anamnesis.

Concomitant use with antiangiogenic medicines, glucocorticosteroids, non-steroidal anti-inflammatory drugs (NPVP).

The patients receiving chemotherapy which includes taxons.

Overdose:

Single dose of an erlotinib inside in a dose to 1000 mg and to 1600 mg once a week patients with oncological diseases were transferred by healthy volunteers well. However repeated reception of an erlotinib in a dose of 200 mg 2 times by healthy volunteers in several days was transferred to day badly. At reception of an erlotinib in a dose above recommended the heavy undesirable phenomena, such as diarrhea, skin rashes can be observed and increase in activity of "hepatic" transaminases is possible. In case of suspicion on overdose treatment is stopped and carry out symptomatic therapy. The antidote to an erlotinib is unknown.

Storage conditions:

Period of validity 4 years. Not to use after the period of validity specified on packaging.

At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 25 mg, 100 mg and 150 mg. On 10 tablets in the blister from PVC/Al. 3 blisters together with the application instruction place in a cardboard pack.