Universal reference book for medicines
Product name: TARTSEVA ® (TARCEVA ® )

Active substance: erlotinib

Type: Antitumor drug.
Protein tyrosine kinase inhibitor
Manufacturer: F.Hoffmann-La Roche (Switzerland) manufactured by Kremers Urban Pharmaceuticals (USA)
Composition, form of production and packaging
Tablets covered with a film coating of
white or white with a yellowish hue, round, biconvex, on one side of the tablet the inscription "TARCEVA 25" is orange and the original logo;
dimensions: diameter 6.3-6.7 mm, thickness 3.0-3.6 mm.
1 tab.

erlotinib hydrochloride 27.32 mg,

which corresponds to the content of erlotinib 25 mg

[PRING] lactose monohydrate - 27.43 mg, microcrystalline cellulose - 35 mg, sodium carboxymethyl starch - 8 mg, sodium lauryl sulfate - 1 mg, magnesium stearate - 1.25 mg.

Sheath composition: 3-5 mg (hypromellose, giprolose, macrogol 400, titanium dioxide (E171));
it is allowed to use the finished mixture Opadry White Y-5-7068.
Composition of yellow ink for inscription on the tablet: shellac, modified in ethanol denatured (methylated alcohol) 74 EP, iron pigment oxide yellow (E172), butanol, isopropanol, propylene glycol, purified water, ethanol denatured (methylated alcohol) 74 OP;
It is allowed to use ready-made Opacode Yellow S-1-22970 inks.
10 pieces.
- blisters from PVC / Al (3) - packs cardboard.
Tablets coated with a white or white film cover with a yellowish hue, round, biconvex, on one side of the tablet the inscription "TARCEVA 100" is gray and the original logo;
Dimensions: diameter 8.7-9.1 mm, thickness 4.4-5.4 mm.
1 tab.

erlotinib hydrochloride 109.29 mg,

which corresponds to the content of erlotinib 100 mg

[PRING] lactose monohydrate - 69.21 mg, microcrystalline cellulose - 88.5 mg, sodium carboxymethyl starch - 24 mg, sodium lauryl sulfate - 3 mg, magnesium stearate - 6 mg.

Sheath composition: 9-15 mg (hypromellose, giprolose, macrogol 400, titanium dioxide (E171));
it is allowed to use the finished mixture Opadry White Y-5-7068.
The composition of the gray ink for inscription on the tablet: shellac, modified in ethanol denatured (methylated alcohol) 74 OP, titanium dioxide (E171), iron dye oxide black (E172), iron dye oxide yellow (E172), butanol, isopropanol, propylene glycol, purified water, ethanol denatured (methylated alcohol) 74 EP, ammonia solution concentrated;
It is allowed to use ready-made Opacode Gray S-1-27645 inks.
10 pieces.
- blisters from PVC / Al (3) - packs cardboard.
The tablets covered with a film membrane white or white with a yellowish shade of color, round, biconcave, on one side of the tablet the inscription "TARCEVA 150" is brown and the original logo;
dimensions: diameter 10.3-10.7 mm, thickness 4.9-5.9 mm.
1 tab.

erlotinib hydrochloride 163.93 mg,

which corresponds to the content of erlotinib 150 mg

[PRING] lactose monohydrate - 103.82 mg, microcrystalline cellulose - 132.75 mg, sodium carboxymethyl starch - 36 mg, sodium lauryl sulfate - 4.5 mg, magnesium stearate - 9 mg.

Sheath composition: 13.5-22.5 mg (hypromellose, giprolose, macrogol 400, titanium dioxide (E171));
it is allowed to use the finished mixture Opadry White Y-5-7068.
Composition of brown ink for tablet inscription: shellac, modified in ethanol denatured (methylated alcohol) 74 EP, iron dye red oxide (E172), butanol, isopropanol, propylene glycol, purified water, ethanol denatured (methylated alcohol) 74 EP, ammonia solution concentrated;
It is allowed to use ready-made Opacode Brown ink S-1-26604.
10 pieces.
- blisters from PVC / Al (3) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2013.

PHARMACHOLOGIC EFFECT

Erlotinib potently inhibits intracellular phosphorylation of the epidermal growth factor receptor HER1 / EGFR (HER1 = epidermal growth factor receptor of type 1 human / EGFR = epidermal growth factor receptor).
Expression of HER1 / EGFR is observed on the surface of both normal and cancer cells. In preclinical models, inhibition of phosphotyrosine EGFR inhibits the growth of tumor cell lines and / or leads to their death.
EGFR mutations can lead to a constant activation of proliferative and anti-apoptotic signaling pathways in the cell.
The high efficacy of erlotinib in blocking EGFR-dependent signaling pathways in tumors bearing the EGFR mutation is due to the strong binding of erlotinib to the ATP-binding site of the mutated kinase domain of EGFR. At the same time, the cascade of signaling reactions is blocked, as a result of which cell proliferation is inhibited and the internal pathway of cell death starts.
PHARMACOKINETICS

Exposition

After oral administration of 150 mg erlotinib in equilibrium, the median C max erlotinib in plasma is 1.995 ng / ml.
Before taking the next dose at 24 hours, the median C min of erlotinib in plasma was 1.238 ng / ml. Median AUC in the inter-dose interval when the equilibrium concentration reaches 41.3 μg / h? ml.
Suction

Erlotinib is well absorbed after ingestion.
Has a long-term absorption phase, and the mean TC max in plasma is 4 hours. According to the study on healthy volunteers, the bioavailability of erlotinib is 59%, eating can increase its bioavailability.
After absorption in the blood, erlotinib is 95% bound, primarily with plasma proteins (albumin and alpha-acid glycoprotein).
The free fraction is approximately 5%.
Distribution

Apparent V d - 232 l with distribution in the tumor tissue.
In the samples of human tumor tissue on the 9th day of treatment with erlotinib at a dose of 150 mg / day, the average concentration of erlotinib is 1.185 ng / g, which is 63% of C max in the plasma in equilibrium. The concentration of the main active metabolites in the tumor tissue is 160 ng / g, which corresponds to 113% C max in the plasma in the equilibrium state. Studies on the distribution in tissues of 14 C labeled erlotinib after oral administration in athymic mice with a nude gene mutation with HT5 tumor xenograft (using common autoradiography) demonstrated a rapid and intensive distribution in tissues. C max in the tissue was about 73% erlotinib concentration, TC max in the tissue - 1 hour.
Metabolism

Erlotinib is metabolized by isoenzymes of the cytochrome P450 system, mainly with the participation of the CYP3A4 isoenzyme and, to a lesser extent, CYP1A2.

Extrahepatic metabolism via the CYP3A4 isoenzyme in the intestine, the CYP1A1 isoenzyme in the lungs, the CYP1B1 isoenzyme in the tumor tissue provides the metabolic clearance of erlotinib.
In vitro studies indicate that 80-95% of erlotinib is metabolized with the participation of the CYP3A4 isoenzyme.
Metabolism occurs in three ways: 1) O-demethylation of one of the side or both chains followed by oxidation to carboxylic acids;
2) oxidation of the acetylene moiety of the molecule followed by hydrolysis to arylcarboxylic acid; 3) aromatic hydroxylation of the phenyl-cetylene moiety of the molecule. The main metabolites are formed as a result of O-demethylation of one of the side chains and have activity comparable to erlotinib in preclinical studies in vitro and in tumor models in vivo.They are present in plasma at concentrations that are <10% erlotinib concentrations, their pharmacokinetics similar to the pharmacokinetics of erlotinib.
Excretion

Metabolites and trace amounts of erlotinib are excreted mainly with bile (> 90%), a small amount of orally administered dose is excreted by the kidneys.

Clearance

In monotherapy with Tarceva ®, the average clearance is 4.47 l / h, and the average T 1/2 is 36.2 hours. Therefore, it is expected that C ss will be reached on day 7-8.
A significant relationship between the clearance, age, body weight, sex and race of the patient was not revealed.
The pharmacokinetics of erlotinib depended on the following indices: the concentration of total bilirubin, alpha-1-acid glycoprotein and smoking at the present time.The decrease in clearance of erlotinib was noted with an increase in the concentration of total bilirubin and alpha1-acid glycoprotein, and its increase in smokers.

The simultaneous use of gemcitabine did not affect the clearance of erlotinib.

Pharmacokinetics in specific patient groups

Special studies in children and elderly patients have not been conducted.

Impaired liver function

Erlotinib is mainly excreted with bile.
Exposure of erlotinib is the same in patients with an average degree of impaired hepatic function (7-9 points on the Child-Pugh scale) and in patients without impaired liver function, incl. and in patients with a primary tumor focus in the liver or with metastases to the liver.
Impaired renal function

Erlotinib and its metabolites are excreted by the kidneys in small amounts - less than 9% of a single dose.
Clinical studies in patients with impaired renal function were not performed.
Smoking

Smoking increases clearance and reduces the exposure of erlotinib.
AUC 0-infinity in smokers was 1/3 of AUC 0-infinity in non-smokers / ex-smokers. The observed decrease in exposure in active smokers is probably due to the induction of the CYP1A1 isoenzyme in the lungs and the isoenzyme CYP1A2 in the liver.
In smokers with non-small cell lung cancer, C ss min was 0.65 μg / ml, which is 2 times lower than for non-smokers / ex-smokers (1.28 μg / ml).
At the same time, the apparent clearance of erlotinib increases by 24%.
With an increase in the dose of erlotinib from 150 mg to 300 mg (the maximum tolerated dose), a dose-dependent increase in erlotinib exposure is observed.
C ss min oferlotinib at a dose of 300 mg in smokers was 1.22 μg / ml.
INDICATIONS

Non-small cell lung cancer

- the first line of therapy for locally advanced or metastatic (IIIB-IV stage) non-small cell lung cancer with activating mutations in the EGFR gene;

- maintenance therapy of locally advanced or metastatic non-small cell lung cancer in the absence of disease progression after 4 courses of the first line of chemotherapy on the basis of platinum preparations;

- locally advanced or metastatic non-small cell lung cancer after failure of one or more chemotherapy regimens.

Pancreas cancer

- the first line of therapy for locally advanced or metastatic pancreatic cancer in combination with gemcitabine.

DOSING MODE

The drug is taken orally, 1 time / day, not less than 1 hour before or 2 hours after ingestion.

Non-small cell lung cancer

Assign 150 mg daily.
If signs of disease progression or development of intolerable toxicity appear, therapy with Tarceva ® should be discontinued.
Pancreas cancer

Assign 100 mg daily, long-term, in combination with gemcitabine (see also the instruction for medical use of gemcitabine, indication - pancreatic cancer).
If signs of disease progression appear, therapy with Tarceva ® should be discontinued. If the patient does not develop a rash within 4-8 weeks of treatment, further therapy with Tarceva ® should be reviewed.
Special instructions for dosing

With concomitant therapy with substrates or modulators of the CYP3A4 isoenzyme, a dose change of the Tarceva ® preparation may be required.
If necessary, the dose of Tarceva ® is reduced by 50 mg gradually.
Impaired liver function

Despite the fact that the exposure of erlotinib was the same in patients with an average degree of impaired hepatic function (7-9 on the Child-Pugh scale) and in patients without a violation of liver function , caution should be exercised when administering Tarcev® to patients with impaired hepatic function .
The administration of Tarceva ® is not recommended for severe liver dysfunction .
In the development of severe adverse reactions, consideration should be given to reducing the dose or interrupting therapy with Tarceva ® .
Safety and efficacy inpatients with severe impairment of liver function (ALT and AST activity more than 5 times higher than UGN) have not been studied.
Impaired renal function

Safety and efficacy in patients with impaired renal function (serum creatinine concentration more than 1.5 times higher than ULN) have not been studied.According to pharmacokinetic data, with a mild and moderate renal failure, dose adjustment is not required.
Taking Tarzeva ® is not recommended for severe kidney dysfunction .
Childhood

The safety and efficacy of Tarceva ® in patients under the age of 18 years have not been studied.

Smoking

Smoking
reduces the exposure of erlotinib by 50-60%. The maximum tolerated dose of Tarceva ® in smoking patients with non-small cell lung cancer is 300 mg. Long-term results of efficacy and safety of doses above those recommended at the beginning of treatment in patients who continue smoking are not established.
SIDE EFFECT

To estimate the frequency of unwanted effects, the following frequency categories are used: very often (? 1/10);
often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000), including individual cases.
From the digestive system: very often - diarrhea, nausea, vomiting, stomatitis, abdominal pain, flatulence, indigestion;
often - gastrointestinal bleeding (including isolated cases with a fatal outcome), some of which were associated with simultaneous use of warfarin or NSAIDs; infrequent - perforation of the gastrointestinal tract, in some cases with a fatal outcome.
From the metabolism: very often - anorexia.

From the hepatobiliary system: often - a violation of the liver (including increased activity of ALT, AST, bilirubin concentrations);
rarely - hepatic insufficiency (including fatal outcome).
From the side of the organ of vision: very often - conjunctivitis, dry keratoconjunctivitis;
often - keratitis; infrequent - a violation of the growth of eyelashes (including ingrown eyelashes, excessive growth and thickening of the eyelashes); very rarely - corneal ulceration or perforation.
From the respiratory system: very often - cough, shortness of breath;
often - nosebleeds; infrequently - symptoms similar to interstitial lung diseases, including fatal cases.
From the skin and subcutaneous fat: very often - a rash (erythematous and papulo-pustular eruptions that appeared or intensified under the influence of sunlight), itching, dry skin, alopecia;
often paronychia; skin cracks, usually not serious, most associated with skin rash and dry skin; infrequently - hyperpigmentation, hirsutism, changes in eyelashes / eyebrows, fragility and bundle of nails; cases of bullous, exfoliative and accompanied by the formation of blisters of skin lesions, including very rare cases of suspected development of the Stevens-Johnson syndrome / toxic epidermal necrolysis, in some cases fatal.
From the nervous system: very often - headache, neuropathy.

From the side of the psyche : very often - depression.

Other: very often - fatigue, severe infections (with or without neutropenia, pneumonia, sepsis, phlegmon), fever, chills, weight loss.

CONTRAINDICATIONS

- severe violation of liver function (10 or more points on the Child-Pugh scale);

- severe renal dysfunction;

- Pregnancy;

- the period of breastfeeding;

- age under 18 years (safety and efficacy not studied);

- marked hypersensitivity to erlotinib or to any component of the drug.

Caution should be given to the drug for smoking patients;
at violations of liver function; patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption; simultaneously with the use of powerful inducers or inhibitors of the isoenzyme CYP3A4; with peptic ulcer or diverticular disease at present or in anamnesis; simultaneously with anti-angiogenic drugs, GCS, NSAIDs; patients who receive chemotherapy, which includes taxanes.
PREGNANCY AND LACTATION

The use of Tarceva ® is contraindicated in pregnancy and lactation.

During treatment with Tartzev ® and at least 2 weeks after its end, reliable contraceptive methods should be used.

APPLICATION FOR FUNCTIONS OF THE LIVER

The safety and efficacy of Tarceva in patients with impaired renal function have not been studied.
According to pharmacokinetic data, correction of the dose is not required for renal insufficiency of mild and moderate severity . Taking Tarceva is not recommended for severe kidney dysfunction .
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution should prescribe the drug in violation of liver function.

APPLICATION FOR CHILDREN

Safety and efficacy of Tarceva in children and adolescents under the age of 18 years have not been studied.

SPECIAL INSTRUCTIONS

Before starting treatment in patients with non-small cell lung cancer who had not previously received chemotherapy, an analysis should be performed for the presence of a L858R mutation in 21 exons or a deletion in the 19 exon of the EGFR gene.

Interstitial lung disease (PID)

In patients with non-small cell lung cancer, pancreatic cancer, or other common solid tumors who received the Tarceva ® preparation, IZL-like symptoms, incl.
with a lethal outcome, were diagnosed infrequently. The total incidence of CLL-like events in patients treated with Tarceva ® is 0.6%. The most frequent diagnoses in patients with suspected ILE-like symptoms are: pneumonitis, interstitial pneumonia, radiation pneumonitis, allergic interstitial pneumonitis, interstitial lung disease, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltration and alveolitis.
The listed ILE-like phenomena occurred in the period from several days to several months after the initiation of Tartzev ® therapy.
Most of the cases were related to aggravating or contributing factors such as concomitant or previously pursued by chemotherapy, radiation therapy, parenchymal lung disease history, metastatic lung disease or infection. In acute development of new and / or progressive unexplained pulmonary symptoms (dyspnea, cough, and fever) the drug Tarceva ® is necessary to temporarily stop to determine the cause. In the case of confirmation of the diagnosis of ILD is necessary to stop the drug Tarceva ® and carry out the necessary treatment.
Diarrhea, dehydration, electrolyte disturbances and renal failure
If you have severe or moderate diarrhea, you must assign loperamide. In some cases, you may need to decrease the dose of the drug Tarceva® .
In severe or resistant diarrhea, nausea, anorexia, or vomiting with dehydration therapy Tarceva ® should be discontinued and held rehydration. It reported rare cases of hypokalemia and renal failure, including fatal.
Some cases of renal failure have been caused by severe dehydration due to diarrhea, vomiting and / or anorexia, while others - concomitant chemotherapy. In cases of severe diarrhea or stable or conditions that lead to dehydration, especially in patients at risk (concomitant therapy or disease or the presence of other predisposing factors, including advanced age), Tarceva ®temporarily cancel and spend parenteral rehydration. In patients with a high risk of dehydration should monitor serum electrolytes, including potassium and renal function.
Hepatitis, hepatic insufficiency
During the drug Tarceva ® reported rare cases of liver failure, including cases fatal. It is recommended to periodically monitor liver function of patients with underlying hepatic disease or receiving hepatotoxic drugs. With the development of severe liver injury reception drug Tarceva ® stopped.
Gastrointestinal perforation
Patients receiving Tarceva ®Have an increased risk of developing gastrointestinal perforation, observed infrequently, in some cases fatal. The risk group includes patients receiving concomitant therapy with anti-angiogenic agents, corticosteroids, NSAIDs and / or taxane based chemotherapy, or patients with a history of peptic ulcer or diverticular disease.
In the case of gastrointestinal perforation therapy with Tarceva ® should be discontinued.
Bullous or exfoliative violations
Reported cases of bullous accompanied by blistering and exfoliative violations, including a very rare cases of suspected Syndrome development of Stevens-Johnson / toxic epidermal necrolysis, in some cases fatal. In case of severe bullous accompanied by blistering or exfoliative skin lesions, treatment with Tarceva ® must be suspended or terminated.
Ophthalmic disorders
Using the drug Tarceva ® registered very rare cases of perforation or ulceration of the cornea. In drug treatment, Tarceva ®observed and other ophthalmological disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis, which are also risk factors for perforation / ulceration of the cornea. Treatment with Tarceva ® should be suspended or revoked when a sharp ophthalmic symptoms, such as pain in the eye, or ophthalmic worsening of chronic diseases.
Disposal preparation
recycle Tarceva ® should be performed in accordance with local requirements.
Impact on the ability to drive vehicles and manage mechanisms

Studies on the effect of the drug on the ability to drive and operate machinery have not been conducted. However, erlotinib does not affect the ability to concentrate.
OVERDOSE

A single dose of erlotinib inwardly to 1000 mg in healthy volunteers, and 1 to 1600 mg once a week to patients with cancer were well tolerated. However, the re-appointment of erlotinib at a dose of 200 mg 2 times / day in healthy volunteers after a few days is not well tolerated.
When receiving erlotinib at a dose recommended above may occur severe adverse events such as diarrhea, skin rash and possibly increase in liver transaminases.
In the case of suspected overdose treatment is suspended and symptomatic therapy. Antidote to erlotinib unknown.
DRUG INTERACTION

Erlotinib metabolized isoenzymes system in humans mainly cytochrome P450 isoenzyme CYP3A4 involving a lesser extent CYP1A2, CYP1A1 isoenzyme and pulmonary. Possible interaction when used in combination with erlotinib inhibitors or inducers of enzymes, and drugs which are metabolized by these enzymes.
Strong inhibitors of CYP3A4 isoenzyme reduce erlotinib metabolism and increase its concentration in plasma. Inhibition of metabolism of the CYP3A4 isoenzyme under the effect of ketoconazole (200 mg orally 2 times / day for 5 days) resulted in an increase in AUC of erlotinib 86% and C max by 69% compared to the same parameters when receiving one erlotinib. ciprofloxacin(an inhibitor of isozyme CYP3A4 and CYP1A2) increases the AUC and C max erlotinib at 39% and 17% respectively. Simultaneous use of the drug Tarceva ® with potent inhibitors of CYP3A4 isozyme or CYP3A4 / CYP1A2 performed only when absolutely necessary. In the case of toxicity is necessary to reduce the dose of drug Tarceva ® .
Powerful isoenzyme CYP3A4 inducers increase erlotinib metabolism and significantly reduce its concentration in plasma. The induction of metabolism involving CYP3A4 isozyme while receiving rifampicin (600 mg orally daily for 7 days) leads to a decrease in median AUC erlotinib 150 mg of 69% compared with the reception of erlotinib.
After preliminary treatment with rifampicin, but also while receiving rifampicin and Tarceva ® median AUC erlotinib 450 mg of 57.5% of the AUC of erlotinib at 150 mg without preliminary therapy with rifampicin. If possible, it is necessary to provide an alternative method of treatment without induction of CYP3A4 isoenzyme activity. Simultaneous use of the drug Tarceva ® with potent inducers of CYP3A4 isoenzyme, such as rifampicin, only when absolutely necessary, thus it is necessary to increase the dose of the drug Tarceva ®300 mg under close supervision of the safety profile. With good endurance when using the drug for more than 2 weeks, you can consider increasing the dose to 450 mg, while continuing to closely monitor the safety profile. Higher doses in similar situations have not been studied.
Substrates of CYP3A4 isoenzyme. Prior therapy or simultaneous reception drug Tarceva ® does not violate clearance typical substrates isoenzyme CYP3A4, such asmidazolam and erythromycin . Thus, a significant effect of the drug Tarceva ®on the clearance of other substrates of CYP3A4 is unlikely. It was found that the bioavailability of midazolam after oral administration is reduced by 24%, which is not connected with the influence on the activity of the isoenzyme CYP3A4.
Omeprazole. Erlotinib solubility is pH dependent. At higher pH erlotinib solubility decreases. Thus, drugs that alter the pH in the upper gastrointestinal tract, can affect the solubility and bioavailability of erlotinib. When simultaneous administration of the drug Tarceva ® and Omeprazole, a proton pump inhibitor, AUC and Cmax erlotinib were reduced by 46% and 61% respectively. TA max and T 1/2 is not changed. When simultaneous administration of the drug Tarceva ®and ranitidine (300 mg), blocker histamine H 2 -receptors, AUC and C max erlotinib were reduced by 33% and 54% respectively.
Thus, should be avoided simultaneous ingestion Tarceva ® and means reducing the secretion of gastric glands. It is unlikely that the increase in the drug dose Tarceva® while taking with such drugs can compensate for a decrease in its exposure. However, in cases when the Tarceva ® was administered at different times, ie, for 2 h before or 10 h after administration of ranitidine (150 mg, 2 times / day), AUC and C maxerlotinib were reduced by only 15% and 17% respectively. If necessary, treatment with these preparations should be favored receiving histamine H 2 receptor antagonists such as ranitidine, at different times. It is to be Tarceva ® at least 2 hours before or 10 hours after receiving blocker histamine H 2 -receptors.
Warfarin and other coumarin derivatives. Patients treated with the drug Tarceva ® in combination with the coumarin derivatives including warfarin were elevated INR bleeding and, in some cases, fatal. In patients taking coumarin derivatives, should regularly monitor the prothrombin time or INR.
Statins.Tarceva ® in combination with statins may enhance myopathy caused by statins, including rhabdomyolysis, rarely observed.
Smoking. Should be advised to stop smoking when using the drug, since smoking induce isozymes CYP1A1 and CYP1A2, the erlotinib exposure reduces by 50-60%.
Gemcitabine. Revealed no significant effect on the pharmacokinetics of gemcitabine, erlotinib, and vice versa.
Platinum drugs.Erlotinib increases platinum concentrations in the blood plasma. Simultaneous treatment with erlotinib with carboplatin and paclitaxel resulted in a statistically significant but not clinically significant increase of total platinum AUC by 10.6%. Increasing carboplatin exposure may be due to other factors such as impaired renal function. Revealed no significant effect of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.
Capecitabine. Capecitabine erlotinib increases the concentration in blood plasma. Erlotinib in combination with capecitabine monotherapy compared with erlotinib resulted in a statistically significant increase in AUC and erlotinib slight increase in C max erlotinib. Revealed no significant effect of erlotinib on the pharmacokinetics of capecitabine.
Substrates of UGT1A1. Since the inhibitor is erlotinib UDP-glucuronyl UGT1A1, possible interactions with drugs that are substrates of UGT1A1, and for which the conjugation reaction with glucuronic acid metabolism is the main route. Care should be taken when administering the drug Tarceva ® patients with low expression of UGT1A1 or with genetic disorders which cause a decrease glucuronidation rate of reaction (e.g., Gilbert syndrome) as possible to increase the concentration of bilirubin in the blood plasma.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug is stored in reach of children at a temperature not higher than 30 ° C.
Shelf life - 4 years. Do not use after the expiration date printed on the package.
Claims consumers sent to the Representative of F. Hoffmann-La Roche Ltd .: 107031, Russia, Moscow, Pipe area, d. 2 tel. (495) 229-29-99, fax (495) 229-79-99.
In the case of packaging UAB "ORTAT" customer complaints sent to the following address: 157092, Russia, Kostroma, Susanin district, with.. Northern, md-n Kharitonovo bodies. / Fax (4942) 650-806.
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