Universal reference book for medicines
Product name: TARLENIB (TARLENIB)

Active substance: erlotinib

Type: Antitumor drug.
Protein tyrosine kinase inhibitor
Manufacturer: JODAS EXPOIM (Russia) manufactured by NOVALEK PHARMACEITICAL (India)
Composition, form of production and packaging
The tablets covered with a film membrane
white or white with a yellowish shade of color, round, biconcave.

1 tab.

erlotinib hydrochloride 27.32 mg,

which corresponds to the content of erlotinib 25 mg

[PRING] lactose monohydrate - 54 mg, microcrystalline cellulose - 15 mg, sodium carboxymethyl starch type A - 0.7 mg, sodium lauryl sulfate - 2 mg, magnesium stearate - 1 mg.

Composition of the film coat: hypromellose - 2 mg, giprolose - 2 mg, titanium dioxide (E171) - 0.6 mg;
Macrogol 4000 - 0.4 mg.
10 pieces.
- Strips (3) - packs of cardboard.
30 pcs.
- polyethylene bottles (1) - cardboard packs.
The tablets covered with a film membrane white or white with a yellowish shade of color, round, biconcave.

1 tab.

erlotinib hydrochloride 54.65 mg,

which corresponds to the content of erlotinib 50 mg

[PRING] lactose monohydrate - 54.65 mg, microcrystalline cellulose - 67.5 mg, sodium carboxymethyl starch type A - 1.4 mg, sodium lauryl sulfate - 3.5 mg, magnesium stearate - 1.5 mg.

The composition of the film shell: hypromellose - 2.75 mg, giprolose - 2.85 mg, titanium dioxide (E171) - 1.19 mg;
macrogol 4000 - 0.72 mg.
10 pieces.
- Strips (3) - packs of cardboard.
30 pcs.
- polyethylene bottles (1) - cardboard packs.
The tablets covered with a film membrane white or white with a yellowish shade of color, round, biconcave.

1 tab.

erlotinib hydrochloride 109.29 mg,

which corresponds to the content of erlotinib 100 mg

[PRING] lactose monohydrate - 135 mg, microcrystalline cellulose - 43 mg, sodium carboxymethyl starch type A - 2.8 mg, sodium lauryl sulfate - 7 mg, magnesium stearate - 3 mg.

Composition of the film coat: hypromellose - 5.49 mg, giprolose - 5.7 mg, titanium dioxide (E171) - 2.38 mg;
Macrogol 4000 - 1.43 mg.
10 pieces.
- Strips (3) - packs of cardboard.
30 pcs.
- polyethylene bottles (1) - cardboard packs.
The tablets covered with a film membrane white or white with a yellowish shade of color, round, biconcave.

1 tab.

erlotinib hydrochloride 163.93 mg,

which corresponds to the content of erlotinib 150 mg

[PRING] lactose monohydrate - 135 mg, microcrystalline cellulose - 66 mg, sodium carboxymethyl starch type A - 4.2 mg, sodium lauryl sulfate - 11 mg, magnesium stearate - 5 mg.

Composition of the film coat: hypromellose - 8 mg, giprolose - 8.4 mg, titanium dioxide (E171) - 4 mg;
Macrogol 4000 - 2 mg.
10 pieces.
- Strips (3) - packs of cardboard.
30 pcs.
- polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

Erlotinib is a potent tyrosine kinase inhibitor of the epilemal growth factor receptor HER1 / EGFR (HER1 is an epidermal growth factor 1 human type receptor / EGFR is an epidermal growth factor receptor).
The tyrosine kinase is responsible for the process of intracellular phosphorylation of HER1 / EGFR. Expression of HER1 / EGFR is observed on the surface of both normal and cancer cells. 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

Suction

Erlotinib is well absorbed after ingestion.
T max in plasma 4 hours Bioavailability of erlotinib - 59%, eating can increase its bioavailability.
Distribution .

With max, erlotinib in plasma is 1.995 ng / ml.
C ss is achieved by 7-8 days. Before taking the next dose, the mean C min of erlotinib in plasma is 1.238 ng / ml. AUC in the inter-dose interval upon reaching the equilibrium concentration is 41.3 μg * h / ml. Apparent V d 232 l with distribution in the tumor tissue. In tumor tissue samples (lung cancer, laryngeal cancer) on the 9th day of treatment, 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. With MAXin the tissue is about 73% of the concentration of the drug in the plasma, T max in the tissue -1 hour.
The connection with plasma proteins (albumin and alpha-1 acidic glycoprotein) is 95%.

Metabolism .

Erlotinib is metabolized in the liver with the participation of the CYP3A4 isoenzyme and, to a lesser extent, the CYP1A2 isoenzyme.
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.
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 by subsequent hydrolysis to an arylcarboxylic acid;

3) aromatic hydroxylation of the phenyl-acetylene 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.
They are present in plasma at concentrations that are <10% erlotinib concentrations, their pharmacokinetics similar to the pharmacokinetics of erlotinib.
Excretion

The average ground clearance is 4.47 l / h.
There was no connection between the clearance, age, body weight, sex and race of the patient. Mean T 1/2 - 36.2 hours Metabolites and trace amounts of erlotinib are excreted mainly by the intestine (> 90%). A small amount of the administered dose is excreted by the kidneys.
The decrease in clearance of erlotinib was noted with an increase in the concentration of total bilirubin and alpha-1 acid glycoprotein, and its increase in smokers.
The simultaneous use of gemcitabine does not affect the clearance of erlotinib.
Special patient groups

Patients with renal insufficiency

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.
Patients with hepatic impairment

Erlotinib is mainly excreted through the liver.
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.
Smoking

Smoking increases clearance and reduces the exposure of erlotinib, possibly due to the induction of the CYP1A1 isoenzyme in the lungs and the isoenzyme CYP1A2 in the liver.
AUC, calculated from the moment of taking the drug and up to infinity (AUC o-infinity ) Smoking people is 1/3 of AUC o-infinity . For non-smokers / ex-smokers. In smokers with non-small cell lung cancer, the minimum equilibrium concentration is 0.65 μg / ml, which is 2 times lower than that of 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), the pharmacokinetic analysis in the equilibrium state showed a dose-dependent increase in the exposure of the drug.
The minimum equilibrium concentration of erlotinib at a dose of 300 mg in smokers is 1.22 μg / ml.
Elderly age

Special studies in elderly patients were not conducted.

Children

Special studies in children were not conducted.

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.
Supportive therapy for locally disseminated 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

Inside, 1 time / day, not less than 1 hour or 2 hours after food intake.

Non-small cell lung cancer

For 150 mg daily, long.
If there is evidence of disease progression or development of intolerable toxicity, erlotinib therapy should be discontinued. 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 mutation of L858R in 21 exons or division in the 19 exop of the EGFR gene.
Pancreas cancer

For 100 mg daily, long-term in combination with gemcitabine (see also the instruction on medical use of gemcitabine, the indication of pancreatic cancer).

If there is evidence of progression of the disease, erlotinib therapy should be discontinued.
If the patient does not develop a rash within 4-8 weeks of treatment, further therapy with erlotinib should be reviewed.
Special patient groups

With concomitant therapy with substrates or modulators of the CYP3A4 isoenzyme, a dose adjustment of erlotinib may be required.
In this case, it is recommended to reduce the dose gradually by 50 mg.
Patients with impaired renal function

According to pharmacokinetic data, with a mild to moderate degree of renal failure, no dose adjustment is required.
The use of erlotinib is not recommended for severe renal dysfunction.
Patients with impaired hepatic function

Erlotinib is excreted by hepatic metabolism and biliary excretion.
Despite the fact that erlotinib exposure was the same in patients with an average degree of impaired hepatic function (7-9 on the Child-Pugh scale) and in patients without impaired liver function, caution should be exercised in appointing erlotinib to patients with impaired hepatic function.
In the development of severe adverse reactions, consideration should be given to reducing the dose or interrupting therapy with erlotinib.
The use of erlotinib is not recommended for severe liver dysfunction.
Childhood

Safety and efficacy in patients under the age of 18 years have not been studied.

Smoking patients

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

The incidence of adverse events is determined according to the WHO classification: very often> 1/10 (> 10%), often> 1/100 to <1/10, infrequently from> 1/1000 to <1/100, rarely> 1/10000 up to <1/1000, very rarely from <1/10000, including individual messages.

Monotherapy for non-small-volume lung cancer

The most frequent adverse events, regardless of the connection with taking erlotinib: rash (75%) and diarrhea (54%).
most of which (1 and 2 degrees of severity) and did not require medical intervention. Rash and diarrhea of ​​3/4 severity were observed in 9% and 6% of patients with non-small cell lung cancer (1% of patients had to stop treatment, and correction of the dose of erlotinib in 6% and 1% of patients, respectively). The median time to the onset of rash is 8 days, before the onset of diarrhea - 12 days.
Very common side effects

From the gastrointestinal tract: anorexia, diarrhea, nausea, vomiting, stomatitis, abdominal pain.

From the side of the organ of vision: conjunctivitis, dry keratoconjunctivitis.

From the respiratory system: cough, shortness of breath.

From the skin and its appendages: rash, dry skin, itching.

Other: increased fatigue, severe infections (with neutropenia or without it, pneumonia, sepsis, phlegmon).

With pancreatic cancer in combination with gemcitabine

The most common adverse events with treatment with erlotinib at a dose of 100 mg in combination with gemcitabine.
regardless of the connection with the drug: increased fatigue, rash and diarrhea. Rash and diarrhea of ​​3/4 severity were observed in 5% of patients, each of these events required discontinuation of therapy in 1% of patients and correction of the dose of erlotinib in 2% of patients. The average time to the onset of the rash is 10 days, before the onset of diarrhea -15 days.
The combination of erlotinib in a dose of 100 mg and gemcitabine increases the incidence of adverse reactions, including rash, which may often necessitate dose adjustment or discontinuation of therapy.

Very common side effects

From the side. ZhKT: diarrhea, stomatitis, dyspepsia, flatulence.

From the respiratory system: cough;

From the nervous system and mental sphere: headache, neuropathy, depression.

From the skin and its appendages: rash, alopecia.

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

Side effects with erlotinib therapy at a dose of 150 mg in monotherapy, as well as in the therapy of a combination of erlotinib in a dose of 100-150 mg with gemcitabine

Very common side effects are presented above (see side effects with monotherapy of non-small cell lung cancer and pancreatic cancer in combination with gemcitabine)

From the gastrointestinal tract: gastrointestinal bleeding, some of which were associated with the simultaneous use of warfarin or non-steroidal anti-inflammatory drugs (NSAIDs);
Perforation of the gastrointestinal tract in some cases with a fatal outcome.
On the part of the hepatobiliary system: often (very often with pancreatic cancer) - violations of the liver (including increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), concentration

bilirubin), mainly transient, mild or moderate severity, or associated with metastases in the liver;
rarely - hepatitis, hepatic insufficiency (including fatal outcome), predisposing factors of which were a history of liver disease or concomitant hegthrotoxic therapy.
From the side of the organ of vision: often - keratitis, conjunctivitis (occurs in pancreatic cancer);
very rarely - ulceration or perforation of the cornea, uveitis.
On the part of the respiratory system: infrequently (with the therapy of non-small cell lung cancer and other common solid tumors) - symptoms similar to interstitial lung diseases (ISC-like symptoms), including cases with fatal outcome.

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 a paronychia; skin cracks, usually not serious, most associated with rash and dry skin, acne, acneiform dermatitis, folliculitis (in most cases, these adverse events were not serious, mild and moderate severity); infrequently - hyperpigmentation, hirsutism, changes in eyelashes / eyebrows, fragility and bundle of nails; cases of bullous, exfoliative and accompanied by formation of blisters of skin lesions, including very rare cases of suspected development of Stevens-Johnson syndrome / toxic epidermal necrolysis, in some cases fatal, syndrome of palmar-plantar erythrodysesthesia.
From the urinary system: nephritis, proteinuria.

Other: often - epistaxis;
rarely - dehydration, hypokalemia and renal failure (including fatal outcome).
Postmarketing surveillance

Infrequent changes in hair and nails are rarely observed, such as hirsutism, changes in the eyelashes / eyebrows, paronychia.
fragility and bundle of nails.
CONTRAINDICATIONS

- hypersensitivity to erlotinib or to any component of the drug;

- Pregnancy and lactation;

- children's age till 18 years;

- a violation of the liver and kidneys of severe severity.

Carefully

- impaired liver function;

- lactose intolerance, lactase deficiency, glucose-galactose insufficiency;

- Smoking;

- simultaneous administration with powerful inducers or inhibitors of the isoenzyme CYP3A4, P-glycoprotein inhibitors;

- Peptic ulcer or diverticular disease at present or in anamnesis;

- simultaneous reception with anti-angiogenic drugs, GCS, NSAIDs, gaxans.
warfarin;
- interstitial lung diseases, the appearance of acute ophthalmologic symptoms.

APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with mild to moderate renal impairment do not need dose adjustment.

The use of the drug for patients with impaired renal function is severely contraindicated.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution apply the drug to patients with impaired liver function.

The use of the drug in patients with impaired hepatic function is contraindicated.

APPLICATION FOR CHILDREN

The use of the drug for children and adolescents under the age of 18 is contraindicated.

SPECIAL INSTRUCTIONS

Interstitial lung disease (PID)

In patients with non-small cell lung cancer, pancreatic cancer, or other common solid tumors receiving erlotinib, ILE-like symptoms, incl.
with a fatal outcome, were not diagnosed infrequently. In patients with non-small cell lung cancer receiving placebo or erlotinib, the incidence of severe ILE-like symptoms was 0.8% in each group. The incidence of ILD-like symptoms in patients with pancreatic cancer treated with erlotinib and gemcitabine was 2.5% compared with 0.4% in the group treated with placebo and gemcitabine. The overall incidence of ILD-like symptoms in the patients treated with erlotinib, including use in combination with chemotherapy, is 0.6%.
Pneumonitis, interstitial pneumonitis, radiation pneumonitis, allergic interstitial pneumonitis, interstitial lung disease, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltration and alveolitis are the most common diagnoses in patients with ILD-like symptoms.
These events occurred in the period from a few days up to several months after initiation of therapy with erlotinib. Most of the cases were associated with receiving concomitant chemotherapy or previously conducted, radiation therapy, parenchymal lung disease, a history of lung metastases or infection. With the development of new and / or progression of pulmonary symptoms (dyspnea, cough, and fever) receiving erlotinib need to temporarily stop to determine the cause. In the case of confirmation of the diagnosis of ILD is necessary to cancel erlotinib and spend the necessary treatment.
Diarrhea, dehydration, electrolyte disturbances and renal failure
In the event of severe or moderate diarrhea, you must assign loperamide. In some cases, you may need to decrease the dose of erlotinib. In severe or resistant diarrhea, nausea, anorexia, vomiting or dehydration, erlotinib therapy should be interrupted and held rehydration. In rare cases may develop 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 the most severe or resistant cases of diarrhea or conditions leading to dehydration, particularly in at-risk patients (advanced age, concomitant therapy or disease) erlotinib temporarily cancel and spend parenteral rehydration.In patients with a high risk of dehydration should monitor serum electrolytes, including potassium and renal function.
Hepatitis, liver failure, including fatal cases rarely occurred during reception erlotinib. In patients with underlying hepatic disease or receiving hepatotoxic drugs recommended to monitor liver function. With the development of advanced liver disease receiving erlotinib stopped.
During treatment with erlotinib, at least for 2 weeks after its closure to be applied reliable methods of contraception.
Assessment of mutation status of EGFR gene.When assessing the status of mutations in the EGFR gene of patients with locally advanced or metastatic non-small cell lung cancer, not previously treated with chemotherapy, you must choose a well-tested and reliable analytical methods to avoid false negative or false positive determinations.
Smoking. Smoking patients should be advised to stop smoking, because Erlotinib plasma concentrations in smokers compared to non-smokers significantly reduced.
Perforation of the gastrointestinal tract.Patients receiving the drug Tarlenib have an increased risk of developing gastrointestinal perforation, which was observed infrequently, in some cases fatal. The risk group includes patients receiving concomitant therapy aitiangiogennymi drugs, 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 Tarlenib should be discontinued.
Bullous or exfoliative violations.Reported cases of bullous, blistering and accompanied eksfolnativnyh 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 Tarlenib drug must be suspended or terminated.
Ophthalmic disorders.In applying erlotinib registered very rare cases of perforation or ulceration of the cornea. When erlotinib was observed and other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis, which are also risk factors for perforation / ulceration of the cornea. Treatment with Tarlenib should be suspended or revoked when a sharp ophthalmic symptoms, such as pain in the eye, or ophthalmic worsening of chronic diseases.
The effect on the ability of control of vehicles and mechanisms
Investigations on the influence of the drug on the ability to drive and operate the mechanisms have not been conducted. However, erlotinib does not affect the ability to concentrate.
OVERDOSE

Single doses of erlotinib inwardly to 1000 mg in healthy volunteers, and 1 to 1600 mg once a week to patients with cancer are well tolerated. However reception erlotinib 2 times / day at a dose of 200 mg in a few days is poorly tolerated.
When receiving erlotinib at a dose higher than the recommended, may experience severe adverse events include diarrhea, skin rash and possibly increased activity of "liver" transaminases. In the case of suspected overdose treatment is suspended and symptomatic therapy. Antidote to erlotinib is not known.
DRUG INTERACTION

Erlotinib metabolized isoenzymes system in humans mainly cytochrome P450 isoenzyme CYP3A4 involving a lesser extent CYP1A2, and pulmonary isoenzyme CYP1A1.
Possible interaction when used in combination with erlotinib inhibitors or inducers of isozymes, as well as drugs that are metabolized by these isoenzymes.
Potent inhibitors of CYP3A4 isoenzyme reduce erlotinib metabolism and increase its concentration in plasma. Inhibition of CYP3A4 metabolism isoenzyme under the action of ketoconazole (200 mg orally 2 times / day for 5 days) resulted in an increase in AUC of erlotinib 86% and C maxby 69% compared to the same parameters when receiving one erlotinib. Ciprofloxacin (isozymes CYP3A4 inhibitor and a CYP1A2) increases the AUC and C max erlotinib at 39% and 17%, respectively. Concomitant use with erlotinib potent inhibitors isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, protease inhibitors, erythromycin, clarithromycin) or CYP3A4 / CYP1A2 performed only when absolutely necessary. In the case of toxicity is necessary to reduce the dose of erlotinib.
Strong inducers of CYP3A4increase erlotinib metabolism and significantly reduce its concentration in plasma. The induction of metabolism involving CYP3A4 isozyme while 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. and while receiving rifampicin and erlotinib median AUC erlotinib 450 mg of 57.5% of the AUC of erlotinib at 150 mg without preliminary therapy with rifampicin. Concomitant use of erlotinib potent inducers of CYP3A4 isoenzyme, such as rifampicin, only when absolutely necessary, and the need to increase the dose of erlotinib to 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 (see. Section "Special instructions"). Higher doses in similar situations have not been studied. Reducing the concentration of erlotinib possible and while the use of other inducers of CYP3A4, such as phenytoin, carbamazepine, barbiturates or drugs Hypericum perforatum. Caution must be exercised while the use CYP3A4 inducers and erlotinib. Wherever possible to provide an alternative method of treatment without a powerful induction of isoenzyme CYP3A4.section "Special instructions"). Higher doses in similar situations have not been studied. Reducing the concentration of erlotinib possible and while the use of other inducers of CYP3A4, such as phenytoin, carbamazepine, barbiturates or drugs Hypericum perforatum. Caution must be exercised while the use CYP3A4 inducers and erlotinib. Wherever possible to provide an alternative method of treatment without a powerful induction of isoenzyme CYP3A4.section "Special instructions"). Higher doses in similar situations have not been studied. Reducing the concentration of erlotinib possible and while the use of other inducers of CYP3A4, such as phenytoin, carbamazepine, barbiturates or drugs Hypericum perforatum. Caution must be exercised while the use CYP3A4 inducers and erlotinib. Wherever possible to provide an alternative method of treatment without a powerful induction of isoenzyme CYP3A4.Caution must be exercised while the use CYP3A4 inducers and erlotinib. Wherever possible to provide an alternative method of treatment without a powerful induction of isoenzyme CYP3A4.Caution must be exercised while the use CYP3A4 inducers and erlotinib. Wherever possible to provide an alternative method of treatment without a powerful induction of isoenzyme CYP3A4.
Substrates of CYP3A4 isoenzyme. Previous therapy or concomitant use of erlotinib clearance does not violate the typical substrates of CYP3A4 isoenzyme, such as midazolam and erythromycin. Thus, a significant effect on the clearance of other erlotinib isoenzyme CYP3A4 substrates improbable. 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.
Formulations changing pH. Solubility erlotinib depends on pH. At higher pH> 5 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 erlotinib and omeprazole, a proton pump inhibitor. AUC and C maxerlotinib were reduced by 46% and 61% respectively. T max and T 1/2 are not changed. When simultaneous administration of erlotinib and ranitidine (300 mg), blockers of H 2 histamine receptors, AUC and C max erlotinib decreased by 33% and 54% respectively. Thus, should be avoided simultaneous ingestion Tarlenib and means reducing the secretion of gastric glands. It is unlikely that increased doses of the drug at Tarlenib concomitantly with such drugs can compensate for the decrease its exposure. However, in cases when erlotinib 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 reception blockers H 2 - histamine receptors, such as ranitidine, at different times. Tarlenib should take the drug for at least 2 hours before or 10 hours after receiving blocker H2 histamine receptors.
Warfarin and other coumarin derivatives. In patients treated with erlotinib 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.Erlotinib 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.
Carboplatin / paclitaxel.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%. Increased exposure of carboplatin may be associated with 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 Tarlenib patients with low expression of UGT1A1 or with genetic disorders which cause a decrease glucuronidation rate of reaction (e.g., Gilbert's syndrome) as possible to increase the concentration of bilirubin in the blood plasma.
Erlotinib and proteasome inhibitors.According to the mechanism of action of proteasome inhibitors (e.g., bortezomib) can be expected to influence the effect of EGFR inhibitors, including erlotinib. This reaction is confirmed by the limited number of clinical and preclinical studies showing EGFR degradation by proteasomes.
Erlotinib and inhibitors of P-glycoprotein. Erlotinib is a substrate of the active substance transporter P-glycoprotein (P-gp). The simultaneous use of erlotinib and inhibitors of P-gp (such as cyclosporin and verapamil), may change the distribution and / or elimination of erlotinib. Insufficient explored this drug interactions and toxicity interactions in the CNS, and therefore, caution should be exercised while the use of erlotinib and inhibitors of P-gp.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The preparation should be stored in a dry place, protected from light and the reach of children at a temperature not higher than 25 ° C.
Shelf life - 4 years.
The drug should not be used after the expiration date printed on the package!

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