Tarceva, 100 mg, film-coated tablets, 30 pcs.

Description of the dosage form

Tablets 25 mg: round, biconvex, film-coated, white or white with a yellowish tint; on the surface of the tablet there is the inscription “TARCEVA 25” in orange and a logo.

Tablets 100 mg: round, biconvex, film-coated, white or white with a yellowish tint; on the surface of the tablet there is the inscription “TARCEVA 100” in gray and a logo.

Tablets 150 mg: round, biconvex, film-coated, white or white with a yellowish tint; on the surface of the tablet there is the inscription “TARCEVA 150” in brown and a logo.

Pharmacokinetics

Suction

Erlotinib is well absorbed after oral administration. The time to reach Tmax in plasma is 4 hours. The bioavailability of erlotinib is 59%; food intake may increase its bioavailability.

Distribution

Cmax in plasma is 1.995 ng/ml. Equilibrium concentration is achieved on the 7th–8th day. Before taking the next dose, the average plasma Cmin of erlotinib was 1.238 ng/ml. AUC in the interdose interval when equilibrium concentration is reached is 41.3 mcg·h/ml.

The apparent volume of distribution is 232 L with distribution into 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 Cmax in plasma at steady state. The concentration of the main active metabolites in tumor tissue is 160 ng/g, which corresponds to 113% Cmax in plasma at steady state. Cmax in tissue is about 73% of the drug concentration in plasma, Tmax in tissue is 1 hour.

Plasma protein binding (albumin and alpha-1 acid glycoprotein) - 95%.

Metabolism

Erlotinib is metabolized by liver enzymes of the cytochrome P450 system, mainly with the participation of the CYP3A4 enzyme, and to a lesser extent, CYP1A2. Extrahepatic metabolism via the CYP3A4 isoform in the intestine, the CYP1A1 isoform in the lungs, and the CYP1B1 isoform in tumor tissue provides metabolic clearance of erlotinib. In vitro, 80–95% of erlotinib is metabolized by CYP3A4. Metabolism occurs in three ways:

1) O-dimethylation of one of the side chains or both, followed by oxidation to carboxylic acids;

2) oxidation of the acetylene part of the molecule followed by hydrolysis to arylcarboxylic acid;

3) aromatic hydroxylation of the phenyl-acetylene part of the molecule.

The main metabolites are formed as a result of O-dimethylation of one of the side chains and have activity comparable to erlotinib. They are present in plasma at concentrations that are <10% of erlotinib concentrations and have pharmacokinetics similar to those of erlotinib.

Removal

Average ground clearance - 4.47 l/h. There was no relationship between clearance, age, body weight, gender and race of the patient. Average T1/2 is 36.2 hours. Metabolites and trace amounts of erlotinib are excreted mainly in the feces (>90%), a small amount of the administered dose is excreted by the kidneys.

A decrease in the clearance of erlotinib was noted with an increase in the concentration of total bilirubin and alpha-1 acid glycoprotein, and its increase was observed in smokers.

Pharmacokinetics in special groups of patients

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

Liver dysfunction. Erlotinib is primarily excreted in bile. Erlotinib exposure is the same in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale) and in patients without hepatic impairment, incl. and in patients with a primary tumor site in the liver or with liver metastases.

Renal dysfunction. Erlotinib and its metabolites are excreted by the kidneys in small amounts - less than 9% of a single dose. Clinical studies have not been conducted in patients with impaired renal function.

Smoking increases the clearance and decreases the exposure of erlotinib, possibly due to the induction of the CYP1A1 isoform in the lungs and CYP1A2 in the liver. AUC0-infinity in smokers is 1/3 of AUC0-infinity in non-smokers/ex-smokers. In smoking patients with non-small cell lung cancer, Cmin is 0.65 mcg/ml, which is 2 times lower than in non-smokers/ex-smokers (1.28 mcg/ml). At the same time, the apparent clearance of erlotinib increases by 24%.

As the dose of erlotinib was increased from 150 to 300 mg (maximum tolerated dose), steady-state pharmacokinetic analysis showed a dose-dependent increase in drug exposure. The Cmin of erlotinib at a dose of 300 mg in smokers is 1.22 mcg/ml.

Pharmacological properties of the drug Tarceva

Pharmacodynamics: Erlotinib is a potent inhibitor of the tyrosine kinase of the epidermal growth factor receptors HER1/EGFR (HER1 - human epidermal growth factor receptor type I / EGFR - epidermal growth factor receptor). Tyrosine kinase is responsible for the process of intracellular phosphorylation of HER1/EGFR. HER1/EGFR is expressed on the surface of both normal and cancer cells. Inhibition of EGFR phosphotyrosine inhibits the growth of tumor cell lines and/or causes their death. Pharmacokinetics Absorption Erlotinib is well absorbed after oral administration. The maximum concentration in blood plasma is achieved 4 hours after administration. Bioavailability in healthy volunteers is 59%. Concomitant food intake may increase the bioavailability of erlotinib. Distribution The maximum concentration in blood plasma is 1.995 ng/ml. Equilibrium concentration is achieved on the 8th day. Before the next dose, the mean trough plasma concentration of erlotinib was 1.238 ng/mL. The AUC value in the interdose interval when equilibrium concentration is reached is 41.3 ng / h/ml. In tumor tissue samples on day 9 of treatment, the average erlotinib concentration was 1.185 ng/g tissue, which is 63% of the maximum plasma concentration at steady state. The concentration of the main active metabolites in tumor tissue is 160 ng/g, which corresponds to 113% of the maximum concentration in blood plasma at steady state. 1 hour after oral administration of erlotinib, the maximum concentration of the drug in blood plasma is about 73%. The degree of binding to blood plasma proteins (albumin and alpha-1 acid glycoprotein) is 95%. Metabolism Erlotinib is metabolized in the liver with the participation of CYP3A4 enzymes, to a lesser extent - CYP1A2 and the pulmonary isoform CYP1A1. In vitro, 80–95% of erlotinib is metabolized by CYP3A4. Metabolism occurs in three ways: O-dimethylation of one of the side chains or both chains with further oxidation to carboxylic acids; oxidation of the acetylene part of the molecule with further hydrolysis to arylcarboxylic acid; and aromatic hydroxylation of the phenyl-acetylene part of the molecule. The main metabolites are formed as a result of O-dimethylation of one of the side chains and have activity comparable to erlotinib. They are present in plasma at concentrations ≤10% of erlotinib concentrations and have pharmacokinetics similar to those of erlotinib. Excretion Average clearance - 4.47 l/h. There was no connection between the indicator and creatinine clearance, age, body weight, gender and race of the patient. The average half-life is 36.2 hours. Metabolites and trace amounts of erlotinib are excreted primarily in feces (90%) and in small amounts in urine. A decrease in the clearance of erlotinib was noted with an increase in the concentration of total bilirubin and alpha-1 acid glycoprotein, and its increase was observed in smokers. Pharmacokinetics in special populations No specific studies have been conducted in children and elderly patients. Hepatic impairment Erlotinib is primarily excreted in the bile, however, there are currently no data on the effect of liver metastases and/or hepatic impairment on the pharmacokinetics of erlotinib. Impaired renal function Erlotinib and its metabolites are excreted by the kidneys in small quantities - less than 9% of a single dose. Clinical studies have not been conducted in patients with impaired renal function.

Side effects

Side effects were distributed by frequency as follows: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated cases.

Monotherapy for non-small cell lung cancer

The most common adverse events, regardless of relationship with the drug: rash (75%) and diarrhea (54%), most of which are grade 1 and 2 and do not require medical intervention. Grade 3–4 rash and diarrhea were observed in 9 and 6% of patients with non-small cell lung cancer, each of which required discontinuation of therapy in 1% of patients and dose adjustment of erlotinib in 6 and 1% of patients, respectively. The average period of time before the onset of a rash is 8 days, and the average time until the onset of diarrhea is 12 days.

The most common side effects:

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

From the organs 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 or without neutropenia, pneumonia, sepsis, cellulitis).

In combination with gemcitabine for pancreatic cancer

The most common adverse events during treatment with Tarceva 100 mg in combination with gemcitabine, regardless of drug-related: fatigue, rash and diarrhea. Rash and diarrhea of ​​grade 3–4 severity were observed in 5% of patients, each of these events required discontinuation of therapy in 1% of patients and dose adjustment of erlotinib in 2% of patients. The average period of time before the onset of a rash is 10 days, and before the onset of diarrhea is 15 days.

When Tarceva 150 mg was combined with gemcitabine, the incidence of class-specific adverse reactions, including rash, increased, and dose adjustment or discontinuation of therapy was required more often.

The most common side effects:

From the gastrointestinal tract: 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, fatigue, chills, severe infections (with or without neutropenia, pneumonia, sepsis, cellulitis), weight loss.

Side effects in patients receiving Tarceva 150 mg as monotherapy and Tarceva 100 or 150 mg in combination with gemcitabine: very common side effects are presented above (see “Side effects during monotherapy for non-small cell lung cancer and for pancreatic cancer in combination with gemcitabine ").

From the gastrointestinal tract: often - gastrointestinal bleeding, some of which were associated with the simultaneous use of warfarin or NSAIDs.

From the hepatobiliary system: often (very often with pancreatic cancer) - liver dysfunction (including increased ALT, AST, bilirubin), mostly transient, mild or moderate in severity or associated with liver metastases; rarely - hepatitis, liver failure (including fatal), the predisposing factors of which were a history of liver disease or concomitant hepatotoxic therapy.

From the organs of vision: often - keratitis, conjunctivitis (occurs in pancreatic cancer); very rarely - ulceration of the cornea (as a complication of mucocutaneous inflammation).

From the respiratory system: infrequently (in the treatment of non-small cell lung cancer and other common solid tumors) - symptoms similar to interstitial lung diseases (ILD-like symptoms), including cases with a fatal outcome.

From the skin and its appendages: often - dry skin (with pancreatic cancer), alopecia (with non-small cell lung cancer). Minor changes in hair and nails are also observed: often - paronychia; uncommon - hirsutism, changes in eyelashes/eyebrows, brittleness and splitting of nails.

Other: often - nosebleeds; rarely - dehydration, hypokalemia and renal failure (including fatal outcomes).

Post-marketing surveillance

Minor changes in hair and nails such as hirsutism, changes in eyelashes/eyebrows, paronychia, brittleness and splitting of nails are infrequently observed.

Tartseva for non-small cell lung cancer

According to Russian statistics, 59 thousand people fell ill in 2004. In the morbidity structure, lung cancer accounts for 22% in men and 4% in women, with an increasing trend. The main problem remains late detection - about 70% of patients at the time of diagnosis have stages III–IV. In addition, even after radical operations, more than half of patients experience either local recurrence or distant metastases. Almost all patients with non-small cell lung cancer (NSCLC) require drug therapy at various stages of treatment. As numerous studies have shown, combination platinum-containing chemotherapy can increase life expectancy, improve control of disease symptoms and quality of life in patients with NSCLC. To date, the achievements of modern chemotherapy have reached a certain peak without a tendency to further increase. The main problem with chemotherapy is still toxicity, especially in assessing the general condition of the patient and his quality of life when using most cytotoxic drugs. The main directions for further research of cytotoxic drugs are: increasing efficiency, reducing toxicity, maximizing the quality of life, as well as using the latest advances in pharmacogenomics in creating new drugs and creating therapeutic “hybrids” with the ability to achieve maximum cytoreduction, followed by long-term administration of targeted drugs. A unique area of ​​drug treatment is the development of targeted or targeted drugs. Their introduction radically changes not only the methodology for clinical drug studies, but also the entire chemotherapy strategy. They act on their own target, the expression of which in one way or another affects tumor growth. Many of them are aimed at achieving stabilization of the tumor process, transferring it to a chronic state. A new approach in the development of drugs has become the study of tyrosine kinase domains of various receptors, which are one of the key links in the transduction of signals from surface receptors to the tumor cell nucleus. Thus, through a long scientific search, molecules were discovered that block the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), resulting in a sharp decrease in cell proliferation at the G1 stage, cell invasion and angiogenesis; as well as activation of apoptosis; increased sensitivity to radiation therapy; decreased resistance to chemotherapeutic agents. Accordingly, a new therapeutic direction has emerged, the main mechanism of which is to turn off a point link from the cascade of the signaling pathway that supports the life support of a tumor cell, the effectiveness of which has been proven in various biological models of the tumor process and has been successfully introduced into clinical practice. One such drug is Tarceva (erlotinib) [7]. Its mechanism of action is direct reversible inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase and reduction of autophosphorylation in intact tumor cells. EGFR expression is increased in many solid epithelial tumors. OSI Pharmaceuticals Inc. is jointly developing and studying the drug. (USA), Genentech Inc. and F.Hoffmann-La Roche Ltd. (Switzerland). Tarceva is available in tablets of 25, 100 and 150 mg for oral use. Preclinical studies revealed significant antitumor activity of Tarceva in 7 different xenograft models of human NSCLC, as well as head and neck, breast, and colon cancer. In Phase I clinical trials, patients with a variety of solid tumors resistant to standard chemotherapy were treated with Tarceva, while side effects and maximum tolerated doses of Tarceva were determined. The most common complications, diarrhea and skin rash, were dose- and regimen-dependent. In addition, mucositis, hyperbilirubinemia, and headache rarely occurred, but their manifestations were minor and were not related to doses and treatment regimens. For further use, a dose of Tarceva 150 mg daily was recommended. Further attempts were made to create drug combinations with targeted drugs. There are preliminary results from phase I studies in which Tarceva was used in combination with docetaxel, paclitaxel/carboplatin, gemcitabine/cisplatin, Xeloda/docetaxel, Xeloda/oxaliplatin and the FOLFOX4 regimen. The combination of Tarceva and docetaxel showed antitumor activity in patients with solid tumors who had previously received chemotherapy. In all of these studies, no significant pharmacokinetic interactions between the drugs were identified, and tolerability was satisfactory. In phase II studies, Tarceva demonstrated antitumor activity in NSCLC and other solid tumors in the second and third line. Moreover, the objective effects, stabilization, and patient survival recorded in all studies were comparable to the results of the use of some cytotoxic drugs in monotherapy. Tarceva was well tolerated; grade 3 and 4 toxicity when administered at a dose of 150 mg per day was observed in only 6% of patients. A correlation was found between the frequency, severity of skin manifestations and the immediate effectiveness of treatment and survival. The results of second-line treatment with docetaxel, pemetrexed and Tarceva for NSCLC were similar (Table 1). In two large phase III placebo-controlled studies, Tarceva was studied in combination with standard platinum-containing chemotherapy in previously untreated stage IIIB–IV NSCLC. In the TRIBUTE study (USA), Tarceva was used in combination with carboplatin and paclitaxel. In another study (TALENT), Tarceva was administered in combination with cisplatin and gemcitabine. However, no advantage was shown in overall effectiveness, survival, or time to progression compared to standard chemotherapy alone. A statistically significant improvement in survival was obtained in the BR.21 study using Tarceva alone in stage IIIB–IV NSCLC. The study included patients who had previously received one or two lines of standard chemotherapy and were randomized into two groups. In the first group, patients were treated with Tarceva at a dose of 150 mg daily; in the second group, patients received placebo. A total of 731 patients were included in the study. This study showed a significant, clinically significant increase in survival in the group of patients treated with Tarceva compared with placebo (median overall survival was 6.67 and 4.7 months, respectively). The data are shown in Table 3. In the group of patients receiving Tarceva, there was a significant improvement in the general condition of the patients, associated with a decrease in cough, shortness of breath, and pain. In addition, 4 complete tumor regressions and 34 partial regressions were recorded in this group. It was also shown that the effectiveness of Tarceva was higher in patients with EGFR mutations, with an increase in the content of the EGFR protein and/or an increase in the number of copies in the genome of the EGFR gene. These differences were significant with an increase in the number of gene copies determined by FISH. In addition, EGFR mutations were predictive of better survival, regardless of treatment. A variety of dermatological manifestations have been reported in patients treated with Tarceva [6]. In phase II studies, rash was reported in approximately 70% to 80% of patients receiving Tarceva as monotherapy. A similar incidence of rash was observed when Tarceva was combined with chemotherapy drugs such as gemcitabine, paclitaxel, cisplatin, and carboplatin. Morphological manifestations of the rash included: acne, acne-like dermatitis, exfoliative dermatitis, eczema, erythema, eyelid redness, exanthema, folliculitis, macular rash, pustular rash, scaly rash, blistering rash, seborrheic dermatitis, skin desquamation. In most patients, the rash was mild to moderate and well tolerated. In most cases, no dose reduction or discontinuation of the drug was required. The pathogenesis of the rash may be related to the mechanism of action of Tarceva. Antihistamines, corticosteroids, oral antibiotics, and topical medications have been used to treat the rash. Based on data from the BR.21 study in the United States, on November 18, 2004, Tarceva was approved and authorized for use as monotherapy in patients with stage IIIB–IV NSCLC resistant to standard I–II line chemotherapy. A very interesting approach was the combination of Tarceva with bevacizumab. The combination of anti-HER1/EGFR and anti-VEGF therapy is justified by the following factors [3]: • these receptors are expressed on most solid tumor cells, • VEGF is involved in the formation of resistance to anti-HER1/EGFR therapy, • this combination has an additive effect in experimental study on xenograft models of human tumors. A clinical study of the effectiveness of the combination of Tarceva with bevacizumab was conducted. A phase I/II study evaluating the anti-VEGF monoclonal antibody bevacizumab and Tarceva in patients with recurrent NSCLC showed a partial effect in 20% of cases, stabilization in 65% of patients, which ensured control of the tumor process in 85% of cases, with a median survival of 7 months, and one-year progression-free survival is 38%. The most frequently noted side effects were: rash - 85%, diarrhea - 65%, hematuria - 32% and infectious complications - 29%, in most cases 1-2 degrees of severity. These are quite promising results, even despite the small number of patients in the study (n=40). A phase III trial of Tarceva with or without bevacizumab in patients with refractory NSCLC is planned. In addition to the results of the BR.21 study, the effectiveness of Tarceva alone in the form of confirmed full or partial effects was noted in patients with breast, ovarian, head and neck cancer, and some central nervous system tumors. A trial is currently underway in Canada studying Tarceva in pancreatic cancer in combination with gemcitabine. There are promising preliminary results in improved survival and good tolerability. Final data will be published. Thus, the results of phase III studies confirmed the good tolerability and minimal toxicity of Tarceva. Rash and diarrhea are the most common side effects, but they are usually mild to moderate. When using Tarceva, a significant improvement in the quality of life of patients was noted when compared with standard chemotherapy regimens, both in terms of physical and functional status, and in prolonging the period before the onset of deterioration of clinical symptoms. The data are shown in Table 4. Tarceva alone (150 mg daily) and in combination with other targeted drugs opens up new opportunities in the treatment of patients with locally advanced and metastatic NSCLC resistant to standard first-line chemotherapy. Active study of Tartseva in various directions continues.

References 1. Hanna N et al J Clin Oncol 2004;22:1589–1597 2. Shepherd FA, et al. N Engl J Med 2005;353:123–32 3. Herbst RS, et al. J Clin Oncol 2005;23:2544–55 4. Shepherd F, et al. J Clin Oncol 2000;18:2095–103 5. Fossella F, et al. J Clin Oncol 2000;18:2354–62 6. P?rez–Soler R, et al. Lung Cancer 2003;41(Suppl. 2): S246 (Abs. P–611) 7. Wood ER, et al. Cancer Res 2004;64:6652–59 8. Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I): 625s (Abs. 7018); 9. OSI and Roche data on file

Interaction

Interaction is possible when erlotinib is used in combination with enzyme inhibitors or inducers (CYP3A4, CYP1A2, CYP1A1), as well as drugs that are metabolized by these enzymes.

CYP3A4 inhibitors reduce the metabolism of erlotinib and increase its plasma concentration. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg orally 2 times daily for 5 days) leads to an increase in erlotinib AUC by 86% and Cmax by 69%. Ciprofloxacin (an inhibitor of CYP3A4 and CYP1A2) increased the AUC and Cmax of Tarceva by 39 and 17%, respectively. Caution should be exercised when using Tarceva in combination with inhibitors of CYP3A4 or CYP3A4/CYP1A2. If toxicity develops, the dose of Tarceva should be reduced.

Inducers of CYP3A4 increase the metabolism of erlotinib and significantly reduce its plasma concentration. Induction of metabolism involving CYP3A4 during concomitant administration of rifampicin (600 mg orally 4 times daily for 7 days) leads to a 69% reduction in the median AUC of erlotinib at a dose of 150 mg. Following pretreatment with rifampicin and when coadministered with rifampicin and Tarceva, the median AUC of erlotinib 450 mg was 57.5% of the AUC of erlotinib 150 mg without pretreatment with rifampicin. If possible, an alternative treatment without inducing CYP3A4 activity should be considered.

If concomitant use of potential CYP3A4 inducers, such as rifampicin, is necessary, the dose of Tarceva should be increased to 300 mg under close monitoring of the safety profile. If well tolerated, after 2 weeks you can consider increasing the dose of the drug to 450 mg, while continuing to carefully monitor the safety profile. Higher doses have not been studied.

Precursors of CYP3A4 substrates. Prior therapy or concomitant use of Tarceva does not impair the clearance of precursor CYP3A4 substrates such as midazolam and erythromycin. Therefore, a significant effect of Tarceva on the clearance of other CYP3A4 substrates is unlikely. The bioavailability of midazolam when taken orally is reduced by 24%, which is not associated with an effect on CYP3A4 activity.

Omeprazole. Erlotinib solubility is pH dependent. As the pH increases, the solubility of erlotinib decreases. When coadministered with Tarceva and omeprazole, a proton pump inhibitor, the AUC and Cmax of Tarceva are reduced by 46 and 61%, respectively. Tmax and T1/2 do not change. Therefore, drugs that alter upper gastrointestinal pH may affect erlotinib solubility and bioavailability. It is unlikely that increasing the dose of Tarceva when taken concomitantly with similar drugs can compensate for the decrease in its exposure.

Warfarin, other coumarin derivatives. Increased INR and bleeding, including gastrointestinal bleeding, have been observed, some of which have been associated with concomitant administration of warfarin. In patients taking warfarin or other coumarin derivatives, PT or INR should be regularly monitored.

Gemcitabine. No interaction detected.

Smoking. Smoking cessation should be recommended because smoking, by inducing the enzymes CYP1A1 and CYP1A2, reduces erlotinib exposure by 50–60%.

Tarceva oral tablets

Instructions for medical use of the drug

Description of pharmacological action

Erlotinib is a potent inhibitor of the HER1/EGFR epidermal growth factor receptor tyrosine kinase (HER1 = human epidermal growth factor receptor type 1/EGFR = epidermal growth factor receptor). Tyrosine kinase is responsible for the process of intracellular phosphorylation of HER1/EGFR. HER1/EGFR expression is observed on the surface of both normal and cancer cells. Inhibition of EGFR phosphotyrosine inhibits the growth of tumor cell lines and/or leads to their death.

Indications for use

- locally advanced or metastatic non-small cell lung cancer after failure of one or more chemotherapy regimens; - first line of treatment for locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine.

Release form

tablets, coated with spit coating 100 mg; blister 10, cardboard pack 3; tablets, coated with spit coating 150 mg; blister 10, cardboard pack 3; tablets, spit-coated 25 mg; blister 10, cardboard pack 3; Warehouse Tablets, coated 1 tablet. erlotinib 25 mg for erlotinib hydrochloride 27.32 mg erlotinib 100 mg for erlotinib hydrochloride 109.29 mg erlotinib 150 mg for erlotinib hydrochloride 163.93 mg additional ingredients: lactose monohydrate; MCC; sodium starch glycolate; sodium lauryl sulfate; magnesium stearate coating: Opadry white (Y-5-7068) (hypromelose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide (E 171)) in a blister 10 pcs.; There are 3 blisters in a cardboard package.

Pharmacodynamics

Erlotinib is a potent tyrosine kinase inhibitor of epidermal growth factor receptors HER1 / EGFR (HER1 = human epidermal growth factor receptor type 1 / EGFR = epidermal growth factor receptor). Tyrosine kinase is responsible for the process of intracellular phosphorylation of HER1 / EGFR. HER1/EGFR expression occurs on the surface of both normal and cancer cells. Inhibition of phosphotyrosine EGFR inhibits the growth of plump cells and/or leads to their death.

Pharmacokinetics

Soaking Erlotinib will soak well after taking it halfway. The reach time Tmax in plasma is 4 years. The bioavailability of erlotinib is 59%; taking other drugs may increase its bioavailability. Rozpodil Cmax in plasma - 1.995 ng/ml. An equal concentration is achieved on the 7-8th day. Before taking the initial dose, the average Cmin of erlotinib in plasma is 1.238 ng/ml. AUC in the interdose interval when a stable concentration level is reached is 41.3 mcg year / ml. The volume of the section is 232 liters with a section of fluffy fabric. In tumors of swollen tissue (cancer of the leg, laryngeal cancer) on the 9th day of treatment, the average concentration of erlotinib was 1.185 ng/g, which was 63% of Cmax in plasma at the same level. The concentration of the main active metabolites in the tissue of the puffy tissue is 160 ng/g, which indicates 113% Cmax in plasma at normal levels. Cmax in tissue is close to 73% of the concentration of the drug in plasma, Tmax in tissue is 1 year. Binding to plasma proteins (albumin and alpha-1 acid glycoprotein) - 95%. Metabolism Erlotinib is metabolized by liver enzymes of the cytochrome P450 system, the main one, including the enzyme CYP3A4, and to a lesser extent, CYP1A2. Post-hepatic metabolism via the CYP3A4 isoform in the intestine, the CYP1A1 isoform in the lungs, and the CYP1B1 isoform in the tissue of the tumor will ensure the metabolic clearance of erlotinib. In vitro, 80-95% of erlotinib is metabolized by CYP3A4. Metabolism occurs in three ways: 1) O-dimethylation of one or both lancinates with further oxidation to carboxylic acids; 2) oxidation of the acetylene part of the molecule with subsequent hydrolysis to arylcarboxylic acid; 3) aromatic hydroxylation of the phenyl-acetylene part of the molecule. The main metabolites are created as a result of O-demethylation of one of the wild lancets and exhibit activity similar to erlotinib. Odors are present in plasma in concentrations such as the average clearance - 4.47 l/year. No relationship was found between clearance, age, body weight, body size and race of the patient. Average T1/2 – 36.2 years. Metabolites and trace amounts of erlotinib are excreted mainly in feces (> 90%), and only a small part of the administered dose is excreted. A decrease in the clearance of erlotinib was observed with increased concentrations of bilirubin and alpha-1 acid glycoprotein, and this increase was observed in chickens. Pharmacokinetics in special groups of patients No special studies have been conducted in children or adult patients. Impaired liver function Erlotinib is mainly eliminated directly. The exposure of erlotinib is, however, the same in patients with moderate impairment of liver function (7-9 points on the Child-Pugh scale) and in patients without impairment of liver function, incl. and in patients with primary swelling in the liver or with metastases to the liver. Impaired function of drugs Erlotinib and its metabolites are eliminated by drugs in small amounts - less than 9% of a single dose. Clinical studies have not been carried out on patients with impaired function. Chicken increases clearance and reduces exposure of erlotinib, possibly inducing the CYP1A1 isoform in the lungs and CYP1A2 in the liver. AUC0-infinity in chickens becomes 1/3 of AUC0-infinity in non-smoking/excessive chickens. In patients with non-smoking lung cancer, Cmin is 0.65 mcg/ml, which is 2 times lower than in non-smokers/excessive chickens (1.28 mcg/ml). In this case, the clearance of erlotinib increases by 24%. With an increased dose of erlotinib from 150 to 300 mg (maximum tolerated dose), pharmacokinetic analysis consistently showed a correspondingly increased exposure to the drug. The Cmin of erlotinib at a dose of 300 mg in chickens becomes 1.22 mcg/ml.

Contraindications for use

— hypersensitivity to erlotinib or any component of the drug is observed; - Vaginism and breastfeeding. With caution: - impaired liver function; - century to 18 rocks.

Side effects

Side effects were divided according to frequency by occurrence: very often (≥1/10); often (≥1 / 100, Monotherapy for non-clinical lung cancer The majority of side effects are independent of the drug: visip (75%) and diarrhea (54%), most of them 1st and 2nd stage severity and not Visip and diarrhea of ​​the 3-4th stage of severity were observed in 9 and 6% of patients with non-lichen cancer of the lungs, skin diseases of these lesions required administration of therapy in 1% of patients and dose correction erlotinib in 6 and 1% of patients with HIV/AIDS. period from 1 hour to visipus - 8 days, to the onset of diarrhea - 12 days.The most common side effects are: On the side of the intestinal tract: anorexia, diarrhea, boredom, vomiting, stomatitis, abdominal pain i. On the side of the organs: con' Junctivitis, keratoconjunctivitis sicca. On the side of the respiratory system: cough, shortness of breath. On the side of the skin and appendages: flaking, dry skin, itching. Others: increased fatigue, important infection ii (with or without neutropenia, pneumonia, sepsis, phlegmon). In combination with gemcitabine for substellar cancer, the greatest number of side effects during Tarceva therapy at a dose of 100 mg in combination with gemcitabine, regardless of the association with the drug: increased and nausea, visiping and diarrhea. Visip and diarrhea of ​​the 3-4th degree of severity were prevented in 5% of patients, skin problems required treatment in 1% of patients and dose correction of erlotinib in 2% of patients. The average period before the onset of vomiting is 10 days, before the onset of diarrhea is 15 days. When combining Tarceva at a dose of 150 mg with gemcitabine, the incidence of class-specific adverse reactions, including viscera, increased, and dose adjustment or treatment was required more frequently. The most common side effects are: On the side of the intestinal tract: diarrhea, stomatitis, dyspepsia, flatulence. On the side of the respiratory system: cough. On the side of the nervous system and psyche: headache, neuropathy, depression. On the side of the skin and appendages: sagging, alopecia. Others: shortness of breath, fatigue, chills, severe infections (or without neutropenia, pneumonia, sepsis, phlegmon), decreased body weight. Side effects in patients treated with Tarceva 150 mg in the form of monotherapy and Tarceva 100 or 150 mg in combination with gemcitabine: side effects are often more common (div. “Both no effect in monotherapy of non-ligamentous cancer of the legs and in cancer of the substellar fossa in combination with gemcitabine"). On the side of the scutulo-intestinal tract: often - scutulo-intestinal bleeding, which is associated with overnight treatment with warfarin or NSAIDs. On the side of the liver: inodes (even often in subgaleal cancer) - impaired liver function (including elevations of ALT, AST, bilirubin), mostly mild or moderate stage of severity or associated with metastases ami in the liver; rarely - hepatitis, liver failure (including with a fatal result), favorable factors such as a history of liver disease or concomitant hepatotoxicity therapy. On the side of the organs of the eye: often - keratitis, conjunctivitis (increases with cancer of the substellar phallus); very rarely - a rash of the cornea (as a result of the formation of mucocutaneous inflammation). On the side of the respiratory system: not often (in the treatment of non-lichen cancer of the leg and other enlarged solid tumors) - symptoms similar to interstitial diseases of the leg (ILD-like symptoms), including episodes with a fatal result . On the side of the skin and appendages: often - dry skin (with substellar cancer), alopecia (with non-cellulite lung cancer). Also beware of non-serious changes in hair and nails: often - paronychia; infrequently - hirsutism, hair loss, brittleness and fraying of nails. Otherwise: often - nosebleeds; rarely - dehydration, hypokalemia and nitric deficiency (including fatal results). Post-Marketing Warnings Serious changes in hair and nails such as hirsutism, hair loss, paronychia, brittleness and fraying of nails are infrequently observed.

Directions for use and doses

Every day, 1 time per dose, no less than a year or two years after taking it. Non-clinical cancer of the leg For 150 mg daily, trivalo. Pancreatic cancer For 100 mg daily, trivalo, in combination with gemcitabine. When a sign of progression of illness appears, Tarceva therapy should be administered. Special dosing instructions When concomitant therapy with substrates or CYP3A4 modulators, it may be necessary to change the dose of Tarceva. If correction is necessary, it is recommended to change the dose by 50 mg increments. Impaired liver function Erlotinib is eliminated through hepatic metabolism and biliary excretion. Regardless, exposure to erlotinib was observed in patients with moderate impairment of liver function (7-9 points on the Child-Pugh scale) and in patients without impairment of liver function. However, it is necessary to exercise caution if Tartseva is diagnosed with impaired liver function. If severe adverse reactions develop, consider reducing the dose or interrupting Tarcev therapy. Safety and effectiveness were not assessed in patients with severely impaired liver function. Impaired function did not depend at all on the safety and effectiveness of patients with impaired function. Children's age Safety and effectiveness of Tarceva in patients under 18 years of age was not observed. Chicken reduces exposure to erlotinib by 50-60%. The maximum tolerated dose of Tarceva in patients treated with non-inflammatory cell carcinoma is 300 mg. The results on the effectiveness and safety of stagnant doses above the recommended dose in patients who continue to chew chicken have not been established.

Overdose

Single doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg once a day in patients with cancer are well tolerated. However, repeated use of erlotinib 2 times a day at a dose of 200 mg is not tolerated after several days. Symptoms: When taking erlotinib at a dose higher than recommended, you may experience severe symptoms such as diarrhea, skin rashes and possible elevation of liver transaminases. Treatment: symptomatic therapy, Tartsev treatment is prescribed.

Interactions with other drugs

Interactions are possible when erlotinib is administered in combination with inhibitors or enzyme inducers (CYP3A4, CYP1A2, CYP1A1), as well as drugs that are metabolized by these enzymes. CYP3A4 inhibitors reduce the metabolism of erlotinib and increase its concentration in plasma. Inhibition of CYP3A4 metabolism with ketoconazole (200 mg twice daily for 5 days) results in an increase in erlotinib AUC by 86% and Cmax by 69%. Ciprofloxacin (inhibitor of CYP3A4 and CYP1A2) increased the AUC and Cmax of Tarceva by 39 and 17% similar. It is necessary to exercise caution when taking Tarceva in combination with CYP3A4 or CYP3A4 / CYP1A2 inhibitors. If toxicity develops, it is necessary to reduce the dose of Tarceva. Inducers of CYP3A4 increase the metabolism of erlotinib and significantly reduce its concentration in plasma. Induction of metabolism via CYP3A4 with one-hour administration of rifampicin (600 mg 4 times daily for 7 days) results in a reduction in the median AUC of erlotinib at a dose of 150 mg by 69%. After upfront treatment with rifampicin, as well as after one-hour administration of rifampicin and Tarceva, the median AUC of erlotinib at a dose of 450 mg becomes 57.5% of the AUC of erlotinib at a dose of 150 mg without upfront treatment with rifampicin ohm If possible, an alternative method of administration without inducing CYP3A4 activity should be considered. If there is a need to take potent CYP3A4 inducers such as rifampicin overnight, the dose of Tarceva should be increased to 300 mg under close monitoring of the safety profile. If tolerance is achieved, after 2 days you can consider increasing the dose of the drug to 450 mg, while continuing to carefully monitor the safety profile. It was not possible to stagnate at higher doses. Precursors of CYP3A4 substrates. Upfront therapy or overnight administration of Tarceva does not impair the clearance of CYP3A4 precursor substrates such as midazolam and erythromycin. Thus, the significant impact of Tarceva on the clearance of other CYP3A4 substrates is low. The bioavailability of midazolam after oral administration is reduced by 24%, which is not associated with an increase in CYP3A4 activity. Omeprazole The sensitivity of erlotinib should be kept at pH level. When the pH is elevated, the toxicity of erlotinib decreases. With one-hour administration of Tarceva and omeprazole, a proton pump inhibitor, AUC and Cmax of Tarceva decreased by 46 and 61% similar. Tmax and T1 / 2 do not change. Thus, drugs that change the pH in the upper parts of the scolio-intestinal tract may affect the sensitivity of erlotinib and its bioavailability. It is unlikely that a higher dose of Tarceva when taken simultaneously with similar drugs may compensate for the decrease in exposure. Warfarin, other derivatives of coumarin. Increased INR and bleeding, including bowel bleeding, have been observed, which have been associated with immediate administration of warfarin. In patients taking warfarin or other related coumarins, it is necessary to regularly monitor PT and INR. Gemcitabine No interaction was detected. Chicken residue is recommended to be used as chicken scraps, by inducing the enzymes CYP1A1 and CYP1A2, reducing exposure to erlotinib by 50-60%. Overdosing Single doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg once a day in patients with cancer are well tolerated. However, repeated use of erlotinib 2 times a day at a dose of 200 mg is not tolerated after several days. Symptoms: When taking erlotinib at a dose higher than recommended, you may experience severe symptoms such as diarrhea, skin rashes and possible elevation of liver transaminases. Treatment: symptomatic therapy, Tartsev treatment is prescribed.

Special instructions for use

Interstitial disease of the lungs (ILD). In patients with non-cellulite cancer of the leg, carcinoma of the subglottis, or other wide-solid swellings, which were treated by Tartseva, ILD-like symptoms, incl. with a fatal result, was diagnosed infrequently. In patients with breast cancer treated with placebo or Tarceva, the incidence of serious ILD-like symptoms was 0.8% in the skin group. The incidence of ILD-like symptoms in patients with substellar cancer treated with Tarceva and gemcitabine was 2.5% compared with 0.4% in the group treated with gemcitabine and placebo. The overall incidence of ILD-like symptoms in patients treated with Tarceva, including those in combination with chemotherapy, is 0.6%. Pneumonia, interstitial pneumonia, promenal pneumonitis, allergic interstitial pneumonitis, interstitial pulmonary disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltration and alveolitis are the most common diagnoses in patients with ILD-like symptoms. Overdoses occurred for several days to several months after starting Tarcev therapy. Most of the seizures were associated with the use of concomitant or previously conducted chemotherapy, metabolic therapy, a history of parenchymal diseases of the lungs, metastatic diseases of the lungs or infection. When new or progressive symptoms develop (shortness, cough and fever), Tarceva treatment must be promptly administered until the cause is identified. Once the diagnosis of ILD is confirmed, it is necessary to remove Tartseva and carry out the necessary treatment. Diarrhea, dehydration, electrolyte disturbances and nitric deficiency. For severe or fatal diarrhea, loperamide should be taken. In certain cases of illness, a reduced dose of Tarcevi may be needed. For severe or persistent diarrhea, boredom, anorexia, or vomiting due to diarrhea, Tarceva therapy should be interrupted and rehydration performed. In some cases, there may be development of hypokalemia and nitric deficiency, incl. with a fatal result. Some episodes of nicotine deficiency are caused by significant dehydration as a result of diarrhea, vomiting and/or anorexia, and others - concomitant chemotherapy. In the most important or persistent episodes of diarrhea or pain that lead to dehydration, especially in patients in the rizika group (advanced age, concomitant therapy or illness), Tartseva is immediately changed and carried out parenteral rehydration. In patients with a high risk of dehydration, blood serum electrolytes, including potassium, and nitric function should be monitored. Hepatitis, liver failure, including seizures with fatal results, rarely occurred when taking Tarcevi. In patients with concomitant liver disease or taking hepatotoxic drugs, it is recommended to monitor liver function. When a severe liver infection develops, take Tarcevi. At the end of the Tartseva bath, at least for 2 days after completion, establish reliable methods of contraception. Tarceva is not recommended for patients with rare respiratory conditions, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption. Injection of the drug into a car and work with mechanisms. No further investigations were carried out on the injection of the drug into a car and work with mechanisms. However, erlotinib does not reach the target concentration.

Storage conditions

At a temperature not exceeding 30 ° C.

Best before date

36 months

ATX classification:

L Antineoplastic drugs and immunomodulators

L01 Antineoplastic drugs

L01X Other antineoplastic drugs

L01XX Other antineoplastic drugs

L01XX34 Erlotinib

Directions for use and doses

Orally, 1 time per day, no less than an hour or two hours after a meal.

Non-small cell lung cancer

150 mg daily, long-term.

Pancreas cancer

100 mg daily, long-term, in combination with gemcitabine.

If signs of disease progression appear, Tarceva therapy should be discontinued.

Special dosage instructions

Concomitant therapy with CYP3A4 substrates or modulators may require a dose adjustment of Tarceva.

If correction is necessary, it is recommended to reduce the dose gradually by 50 mg.

Liver dysfunction. Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderate hepatic impairment (Child-Pugh score 7–9) and in patients without hepatic impairment, caution should be exercised when prescribing Tarceva to patients with hepatic impairment.

If severe adverse reactions occur, dose reduction or interruption of Tarceva therapy should be considered. Safety and effectiveness in patients with severe hepatic impairment have not been studied.

Renal dysfunction. Safety and effectiveness in patients with impaired renal function have not been studied.

Childhood. The safety and effectiveness of Tarceva have not been studied in patients under 18 years of age.

Smoking reduces erlotinib exposure by 50–60%. The maximum tolerated dose of Tarceva in smoking patients with non-small cell lung cancer is 300 mg.

Long-term results on efficacy and safety when using doses higher than recommended at the beginning of treatment in patients who continue to smoke have not been established.

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Overdose

Single oral doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg once weekly in cancer patients are well tolerated. However, repeated dosing of erlotinib 2 times a day at a dose of 200 mg after a few days is poorly tolerated.

Symptoms: When taking erlotinib at a dose higher than the recommended dose, severe adverse events may occur: diarrhea, skin rashes and a possible increase in liver transaminases.

Treatment: symptomatic therapy, treatment with Tartseva is suspended.

Tarceva Erlotinib _ _

Types of tumors » Medicines in this group »

Pharmacological group: Antitumor agents - protein tyrosine kinase inhibitors.

Pharmacological action: A potent inhibitor of epidermal growth factor receptor tyrosine kinase, which is responsible for the process of intracellular phosphorylation of epidermal growth factor, the expression of which is observed on the surface of both normal and tumor cells. Inhibition of phosphotyrosine epidermal factor receptors inhibits the growth of tumor cell lines and/or leads to their death.

Pharmacokinetics: Well absorbed after oral administration. TCmax - 4 hours. Bioavailability - 59%, food intake increases bioavailability. Cmax in plasma - 1.995 ng/ml. TCss - 7-8 days. Before taking the next dose, Cmin is 1.238 ng/ml. AUC in the interdose interval when Css is reached is 41.3 mcg x h/ml. The volume of distribution is 232 l (with distribution into the tumor tissue). In tumor tissue samples (lung cancer, larynx cancer) on the 9th day of treatment, the concentration of erlotinib is 1.185 ng/g, which is 63% of Cmax in plasma when Css is reached. The concentration of the main active metabolites in tumor tissue is 160 ng/g, which corresponds to 113% of Cmax in plasma when Css is reached. Cmax in tumor tissues is about 73% of the drug concentration in plasma, TCmax in tissue is 1 hour. Communication with proteins (albumin and alpha-1 acid glycoprotein) is 95%. Metabolized in the liver with the participation of the enzyme CYP3A4 (in vitro 80-95%), to a lesser extent by CYP1A2 and the pulmonary isoform CYP1A1. Metabolism occurs in three ways: O-dimethylation of one of the side chains or both, followed by oxidation to carboxylic acids; oxidation of the acetylene part of the molecule followed by hydrolysis to arylcarboxylic acid; aromatic hydroxylation of the phenylacetylene part of the molecule. The main metabolites (less than 10% of erlotinib concentration) are formed as a result of O-dimethylation of one of the side chains and have activity comparable to erlotinib; their pharmacokinetics are similar to those of erlotinib. Ground clearance - 4.47 l/h. T1/2 – 36.2 hours. Metabolites and trace amounts of erlotinib are excreted mainly in the feces (more than 90%), a small amount (less than 9% of a single dose) is excreted by the kidneys. With an increase in the concentration of total bilirubin and alpha-1 acid glycoprotein, a decrease in the clearance of erlotinib is observed, an increase in smokers.

Indications: Locally advanced or metastatic non-small cell lung cancer after failure of one or more chemotherapy regimens. First line therapy for locally advanced, unresectable or metastatic pancreatic cancer (in combination with gemcitabine).

Contraindications: Hypersensitivity, pregnancy, lactation period. With caution. Liver failure, age under 18 years.

Dosage regimen: Orally, 1 hour before or 2 hours after meals, 1 time per day. Non-small cell lung cancer: 150 mg daily, long-term. Pancreatic cancer: 100 mg daily, long-term in combination with gemcitabine. If signs of disease progression appear, therapy is stopped. If necessary, the dose is reduced gradually by 50 mg.

Side effects:

Most often (regardless of the causal relationship with the drug): rash (69-75%) and diarrhea (48-54%), mainly 1 and 2 tbsp. severity and do not require intervention. Rash and diarrhea 3/4 tbsp. severity (9% and 6%, respectively, in patients with non-small cell lung cancer and 5% in patients with pancreatic cancer). The average period of time before the onset of a rash is 8-10 days, and before the onset of diarrhea is 12-15 days. Frequency of side effects during monotherapy and in combination with gemcitabine: very often (more than 10%); often (more than 1% and less than 10%); uncommon (more than 0.001% and less than 1%); rarely (more than 0.0001 and less than 0.001%); very rare (less than 0.0001%), including isolated cases.

From the digestive system: very often - anorexia, diarrhea, vomiting, stomatitis, dyspepsia, abdominal pain, often - gastrointestinal bleeding, some of which are associated with the simultaneous use of warfarin or NSAIDs, liver dysfunction (including ALT, AST, bilirubin), mostly transient, mild to moderate. severity or associated with liver metastases.

From the senses: very often - conjunctivitis, keratoconjunctivitis sicca; often - keratitis (1 case of development into a corneal ulcer).

From the respiratory system: very often - cough, shortness of breath, often - nosebleeds; infrequently - interstitial lung diseases (interstitial pneumonia, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltration, including death).

From the nervous system: very often - headache, neuropathy, depression.

From the skin: very often - rash, alopecia, dry skin, itching.

Other: very often - fever, fatigue, chills, severe infections (pneumonia, sepsis), incl. with neutropenia, fibrous inflammation of the subcutaneous tissue, weight loss.

Overdose:

Symptoms: diarrhea, skin rash, increased activity of liver transaminases.

Treatment: symptomatic therapy.

Special instructions: Interstitial lung diseases (ILD), incl. death was rarely diagnosed in patients with non-small cell lung cancer, pancreatic cancer or other solid tumors receiving the drug. The overall incidence of ILD in patients, including use in combination with chemotherapy, is 0.6%. Most cases of ILD were associated with concomitant or previous chemotherapy, radiation therapy, a history of parenchymal lung disease, metastatic lung disease, or infection. If new and/or progression of symptoms (shortness of breath, cough and fever) develop, the drug should be interrupted until the cause is determined. If ILD develops, it is necessary to discontinue the drug and carry out appropriate treatment. If severe or moderate diarrhea occurs, loperamide may be prescribed. In some cases, a dose reduction of erlotinib may be necessary. For severe or persistent diarrhea, nausea, anorexia, or vomiting with dehydration, the drug is temporarily discontinued and rehydration is performed. During treatment and for at least 2 weeks after its completion, reliable methods of contraception should be used.

Interaction: Dose adjustment of CYP3A4 enzyme inducers or inhibitors may be required. CYP3A4 inhibitors (including ketoconazole) reduce the metabolism of erlotinib and increase its concentration in plasma: the use of ketoconazole at a dose of 200 mg orally 2 times a day for 5 days increases the AUC of erlotinib by 86% and Cmax by 69%. Caution is advised when using erlotinib in combination with CYP3A4 inhibitors. In case of toxicity development, it is necessary to reduce its dose. Inducers of CYP3A4 (including rifampicin) increase the metabolism of erlotinib and significantly reduce its plasma concentration: the use of rifampicin at a dose of 600 mg orally 4 times a day for 7 days reduces the AUC of erlotinib by 69% (clinical significance has not been established). An increase in the International Normalized Ratio (INR) and the development of bleeding, including gastrointestinal bleeding, were noted, some of which were associated with concomitant use of warfarin. When using warfarin and other coumarin derivatives simultaneously, it is necessary to regularly monitor prothrombin time or MHO.

special instructions

Interstitial lung disease (ILD). In patients with non-small cell lung cancer, pancreatic cancer or other advanced solid tumors treated with Tarceva, ILD-like symptoms, incl. with a fatal outcome, were diagnosed infrequently. In patients with non-small cell lung cancer who received placebo or Tarceva, the incidence of serious ILD-like symptoms was 0.8% in each group. The incidence of ILD-like symptoms in patients with pancreatic cancer treated with Tarceva and gemcitabine was 2.5% compared with 0.4% in the group treated with gemcitabine and placebo. The overall incidence of ILD-like symptoms in patients treated with Tarceva, including use in combination with chemotherapy, is 0.6%. Pneumonitis, interstitial pneumonia, 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. The listed phenomena occurred from several days to several months after the start of Tarceva therapy. Most cases were associated with concomitant or previous chemotherapy, radiation therapy, a history of parenchymal lung disease, metastatic lung disease, or infection. If new and/or worsening pulmonary symptoms (shortness of breath, cough and fever) develop, Tarceva should be temporarily discontinued until the cause is determined. If the diagnosis of ILD is confirmed, Tarceva should be discontinued and the necessary treatment administered.

Diarrhea, dehydration, electrolyte disturbances and renal failure. If severe or moderate diarrhea occurs, loperamide should be prescribed. In some cases, a dose reduction of Tarceva may be necessary. If severe or persistent diarrhea, nausea, anorexia, or vomiting with dehydration occurs, Tarceva therapy should be interrupted and rehydration administered. In rare cases, hypokalemia and renal failure may develop, incl. with a fatal outcome. Some cases of renal failure were caused by severe dehydration due to diarrhea, vomiting and/or anorexia, others by concomitant chemotherapy. In the most severe or persistent cases of diarrhea or conditions leading to dehydration, especially in patients at risk (elderly, concomitant medications or diseases), Tarceva is temporarily discontinued and parenteral rehydration is given. In patients at high risk of dehydration, serum electrolytes, including potassium, and renal function should be monitored.

Hepatitis and liver failure, including fatal cases, have rarely occurred while taking Tarceva. In patients with concomitant liver disease or receiving hepatotoxic drugs, it is recommended to monitor liver function. If severe liver damage develops, Tarceva should be discontinued.

During treatment with Tarceva and for at least 2 weeks after treatment, reliable methods of contraception should be used.

Tarceva is not recommended for patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Impact on the ability to drive a car and operate machinery. Studies have not been conducted to study the effect of the drug on the ability to drive a car and operate machinery. However, erlotinib does not affect concentration.

Side effects of Tarceva

The most common side effects, regardless of their causal relationship with taking the drug, are skin rash (75%) and diarrhea (54%), most are grade I–II and do not require additional therapeutic measures. Skin rashes and diarrhea of ​​III–IV severity were observed in 9 and 6% of patients with non-small cell lung cancer and in 5% of patients with pancreatic cancer who received Tarceva, each of these side effects required discontinuation of therapy in 1% of patients and dose adjustment - in 1–6% of patients. The average time before the onset of rashes is 8 days, and the average time before the onset of diarrhea is 12 days. Side effects in patients who received monotherapy with the drug at a dose of 150 mg and Tarceva at a dose of 100 mg in combination with gemcitabine were as follows. From the gastrointestinal tract : often - anorexia, diarrhea, vomiting, stomatitis, dyspepsia, abdominal pain, gastrointestinal bleeding, some of which were associated with the simultaneous use of warfarin or NSAIDs. From the hepatobiliary system : often - impaired liver function (including increased activity of ALT, AST, bilirubin level in the blood), which usually disappear quickly, of mild or moderate severity, or associated with metastases to the liver. On the part of the organ of vision : often - conjunctivitis, dry keratoconjunctivitis, keratitis, isolated cases of corneal ulcer. From the respiratory system: often - cough, shortness of breath, nosebleeds, in some cases - interstitial lung disease (interstitial pneumonia, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome and pulmonary infiltration, including fatal cases). From the nervous system and mental sphere : often - headache, neuropathy, depression. From the skin : often - rash, alopecia, dry skin, itching. Other: often - fever, fatigue, severe infections (with or without neutropenia, pneumonia, sepsis, fibrous inflammation of the subcutaneous tissue, weight loss); rarely - paronychia, hirsutism.