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 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.
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.
Special instructions for the use of Tarceva
Interstitial lung disease (ILD) , including fatal ILD, has been reported rarely in patients with non-small cell lung cancer, pancreatic cancer, or other solid tumors who received Tarceva. In patients with non-small cell lung cancer who received placebo or Tarceva, the incidence of ILD was 0.8% in each group. The incidence of ILD in pancreatic cancer patients who received Tarceva and gemcitabine was 2.5% compared with 0.4% in the group that received gemcitabine and placebo. The overall incidence of ILD in patients treated with Tarceva, including use in combination with chemotherapy, was 0.6%. ILD includes interstitial pneumonia, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary infiltration. Most cases of ILD were associated with concurrent or prior chemotherapy, radiation therapy, a history of parenchymal lung disease, lung metastasis, or infection. If new and/or progression of unexplained pulmonary symptoms (shortness of breath, cough and fever) develop, Tarceva should be temporarily discontinued until the cause is determined. If ILD develops, Tarceva should be discontinued and appropriate treatment administered. Diarrhea. If moderate or severe diarrhea occurs, loperamide should be prescribed. In some cases, a dose reduction of erlotinib may be required. In case of severe or persistent diarrhea, nausea, anorexia or vomiting with the development of dehydration, Tarceva is temporarily discontinued and rehydration is carried out. Isolated cases of hypokalemia and renal failure (including deaths) have been recorded. Some cases of renal failure have been secondary to severe dehydration resulting from diarrhea, vomiting and/or anorexia. Other cases occurred during concomitant chemotherapy. In patients at risk of developing dehydration, renal function and plasma electrolyte levels, including potassium, should be monitored. Hepatitis, liver failure: isolated cases of liver failure (including deaths) have been reported during the use of Tarceva. Additional factors include a history of concomitant liver disease and simultaneous use of hepatotoxic drugs. Therefore, in this category of patients it is necessary to periodically monitor liver function. If severe changes in liver function occur, treatment with Tarceva should be discontinued. Special instructions regarding dosing If it is necessary to adjust the dose of the drug, it is recommended to gradually reduce the dose by 50 mg. Liver dysfunction. Caution should be exercised when prescribing Tarceva to patients with impaired liver function. Renal dysfunction. The safety and effectiveness of the drug 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. Pregnancy and breastfeeding. The safety of Tarceva during pregnancy in humans has not been sufficiently studied. In preclinical studies of the reproductive toxicity of erlotinib in doses close to therapeutic and/or in doses that have a toxic effect in humans, it was established that it has embryotoxic properties. Therefore, women of reproductive age should use effective methods of contraception during treatment and for at least 2 weeks after its completion. Treatment with erlotinib in pregnant women can be carried out only if the expected effect of therapy for the mother prevails over the potential risk to the fetus. Lactation . It is not known whether the drug passes into breast milk. Therefore, it is necessary to take into account the potential risk of the drug affecting the newborn. Impact on the ability to drive vehicles and work with potentially dangerous mechanisms. Studies of the effect on the ability to drive vehicles or operate machines have not been conducted, however, the effect of erlotinib is not associated with a potential impairment of such activities.
Tarceva drug interactions
Erlotinib is metabolized in the liver with the participation of CYP3A4 enzymes, to a lesser extent - CYP1A2, and with the participation of the pulmonary isoforms of CYP1A1. Therefore, when using Tarceva in combination with drugs that are metabolized by these enzymes, or drugs that inhibit or induce these enzymes, it may be necessary to adjust their dose. CYP3A4 inhibitors (ketoconazole) reduce the metabolism of erlotinib and increase its concentration in blood plasma. 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%. If a toxic effect develops, it is necessary to reduce the dose of Tarceva. When Tarceva was used with ciprofloxacin, an inhibitor of CYP3A4 and CYP1A2 enzymes, the AUC and maximum concentration of erlotinib increased by 39 and 17%, respectively. Therefore, caution should be exercised when prescribing Tarceva with CYP3A4 inhibitors or combined CYP3A4/CYP1A2 inhibitors. In this case, if a toxic effect develops, it is necessary to reduce the dose of Tarceva. Inducers of CYP3A4 (rifampicin) increase the metabolism of erlotinib and significantly reduce its concentration in blood plasma. Induction of metabolism by CYP3A4 when administered concomitantly with rifampicin (600 mg orally 4 times daily for 7 days) leads to a 69% reduction in the median AUC of erlotinib when taking Tarceva 150 mg. Previous treatment and concomitant use of rifampicin with a single dose of Tarceva 450 mg resulted in a mean erlotinib exposure (AUC) that was 57.5% of that after a single dose of Tarceva 150 mg in the absence of rifampicin therapy. If possible, an alternative treatment without inducing CYP3A4 activity should be considered. In patients who require concomitant treatment with Tarceva and potential CYP3A4 inducers (e.g., rifampicin), an increase in the Tarceva dose to 300 mg should be considered. If well tolerated for more than 2 weeks, the dose of Tarceva should be increased to 450 mg. Higher doses of the drug have not been studied for this indication. Previous treatment or concomitant use of Tarceva did not alter the clearance of the prototype CYP3A4 substrates midazolam and erythromycin. Therefore, significant interactions with the clearance of other CYP3A4 substrates are unlikely. There was a 24% decrease in oral bioavailability of midazolam, but this was not due to an effect on CYP3A4 activity. Erlotinib solubility is pH dependent and decreases with increasing pH. When Tarceva was coadministered with the proton pump inhibitor omeprazole, the AUC and maximum blood concentration of erlotinib decreased by 46 and 61%, respectively. However, the half-life did not change. Therefore, drugs that alter the pH in the upper gastrointestinal tract may affect the solubility of erlotinib and therefore its bioavailability. It is unlikely that increasing the dose of Tarceva when used concomitantly with such medicinal products will offset the reduced exposure. In smokers, there is an induction of CYP1A1 and CYP1A2 and a 50–60% reduction in erlotinib exposure. A phase Ib study showed no significant effect of gemcitabine on the pharmacokinetics of erlotinib and no significant effect of erlotinib on the pharmacokinetics of gemcitabine. Warfarin and other coumarin derivatives. There was an increase in the international normalized ratio (INR) and the risk of bleeding, including gastrointestinal bleeding. In patients taking warfarin or other coumarin derivatives, the prothrombin time or INR should be regularly monitored.
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.
