Tarceva

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Tarceva: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Tarceva

ATX code: L01XE03

Active ingredient: Erlotinib (Erlotinib)

Manufacturer: F. Hoffmann-La Roche Ltd. (F. Hoffmann-La Roche, Ltd.) (Switzerland)

Description and photo update: 2019-21-02

Prices in pharmacies: from 43,300 rubles.

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Tarceva is an antineoplastic agent, an inhibitor of protein tyrosine kinase.

Release form and composition

The drug is produced in the form of film-coated tablets: biconvex, round, white or white with a yellow tint (10 pcs. In a blister, 3 blisters in a cardboard box and instructions for use Tarceva):

dosage 25 mg: diameter 6.3–6.7 mm; thickness 3–3.6 mm; the original manufacturer's logo and the inscription TARCEVA 25 are applied on one side in orange ink;
dosage 100 mg: diameter 8.7-9.1 mm; thickness 4.4–5.4 mm; the original manufacturer's logo and the inscription TARCEVA 100 are applied on one side in gray ink;
dosage 150 mg: diameter 10.3-10.7 mm; thickness 4.9–5.9 mm; the original manufacturer's logo and the inscription TARCEVA 150 are applied on one side in brown ink.

1 tablet contains:

active substance: erlotinib hydrochloride - 27.32; 109.29 or 163.93 mg (equivalent to 25, 100, or 150 mg erlotinib);
additional components: microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate, lactose monohydrate, sodium carboxymethyl starch;
film shell: hyprolose, titanium dioxide (E171), hypromellose, macrogol 400; it is possible to use the ready-made mixture Opadry White Y-5-7068;
ink for inscription: shellac modified in denatured ethanol (methylated alcohol) 74 OP; isopropanol, denatured ethanol (methylated alcohol) 74 OP, propylene glycol, butanol, purified water; additionally for yellow ink - iron dye yellow oxide (E172); additionally for gray ink - concentrated ammonia solution, titanium dioxide (E171), iron dye yellow oxide and black oxide (E172); additionally for brown ink - iron dye red oxide (E172), concentrated ammonia solution; it is allowed to use ready-made ink Opacode Yellow S-1-22970, Opacode Gray S-1-27645 or Opacode Brown S-1-26604.

Pharmacological properties

Pharmacodynamics

Erlotinib is a potent inhibitor of epidermal growth factor receptor HER1 / EGFR tyrosine kinase (HER1 - human epidermal growth factor receptor I type / EGFR - epidermal growth factor receptor). Tyrosine kinase belongs to the enzymes of the protein kinase subclass responsible for the intracellular phosphorylation of HER1 / EGFR. Expression of HER1 / EGFR is fixed on the surface of not only normal, but also cancer cells. In the course of preclinical studies, it was revealed that inhibition of phosphotyrosine in receptors of the EGFR type blocks the growth of tumor cell lines and / or causes their death.

EGFR mutations can cause permanent activation of anti-apoptotic and proliferative signaling pathways into the cell. The high degree of efficacy of erlotinib in blocking EGFR-dependent signaling pathways in tumors carrying the EGFR mutation is due to the strong binding of erlotinib to the ATP-binding region of the mutated EGFR kinase domain. Against the background of this effect, a cascade of signaling reactions is suppressed, which leads to inhibition of cell proliferation and the launch of an internal pathway of cell death.

Pharmacokinetics

After oral administration of erlotinib at a dose of 150 mg at steady state, the median maximum plasma concentration (C _max) is 1.995 ng / ml. Before taking the next dose, 24 hours later, the median minimum concentration (C _min) of erlotinib in plasma is 1.238 ng / ml. The median of the area under the concentration-time curve (AUC) in the interdose interval when the equilibrium concentration is established is 41.3 μg / h × ml.

When taken orally, erlotinib is well absorbed and has a long absorption phase, and the average value of the period to reach C _max in plasma (T _max) is 4 hours. According to the results of a study with the participation of healthy volunteers, the bioavailability of the active substance is 59%, food intake can increase the bioavailability of Tarceva. After absorption, erlotinib is in the blood 95% bound, mainly with blood plasma proteins - albumin and alpha1-acid glycoprotein, the free fraction averages 5%.

The apparent volume of distribution (V _d) of erlotinib is 232 l with dispersion in the tumor tissue. On the 9th day of the course of therapy with the drug in a daily dose of 150 mg in tumor tissue samples, its average concentration is 1.185 ng / g, which corresponds to 63% of the plasma C _max in the equilibrium state. The content of the main active metabolites in the tumor tissue is 160 ng / g, which is proportional to 113% C _max in plasma in the equilibrium state. The metabolic transformation of erlotinib is performed by isoenzymes of the cytochrome P _{450 system}, mainly by the isoenzyme CYP3A4 and to a lesser extent - CYP1A2. The metabolic clearance of the active substance is provided by extrahepatic metabolism using the CYP1A1 isoenzyme in the lungs, the CYP3A4 isoenzyme in the intestine, and the CYP1B1 isoenzyme in the tumor tissue.

According to in vitro studies, the CYP3A4 isoenzyme is responsible for the metabolism of 80–95% of erlotinib. Biotransformation proceeds along three paths:

O-demethylation of one of the side or both chains with further oxidation to form carboxylic acids;
oxidation of the acetylene moiety of the molecule with further hydrolysis to form aryl carboxylic acid;
aromatic hydroxylation of the phenylacetylene fragment of the molecule.

Due to O-demethylation of one of the side chains, the formation of the main metabolites occurs, which have an activity comparable to that of erlotinib in in vivo tumor models and in preclinical in vitro studies. These metabolites are determined in plasma at concentrations less than 10% of the concentration of the parent substance, and their pharmacokinetics are similar to the pharmacokinetics of the latter. Trace amounts of erlotinib and its metabolites are excreted mostly (over 90%) with bile, a small amount of an orally administered dose is excreted by the kidneys.

During monotherapy with Tarceva, the mean clearance was 4.47 l / h, and the mean half-life (T _1/2) was 36.2 hours. Thus, it is assumed that the equilibrium concentration (C _ss) will be observed on 7-8 days.

No significant association was found between substance clearance, body weight, age, sex and race of the patient. The pharmacokinetics of erlotinib was dependent on the following parameters: the level of alpha-1-acid glycoprotein, total bilirubin, as well as current smoking. A decrease in clearance was recorded with an increase in the level of total bilirubin and alpha1-acid glycoprotein, and its increase was observed in smokers.

Smoking also reduces exposure to erlotinib, probably as a result of the induction of CYP1A1 isoforms in the lungs and CYP1A2 in the liver. AUC _0-infinity y for smokers is ⅓ of the AUC _0-infinity for nonsmokers and ex-smokers. In smoking patients with non-small cell lung cancer, the minimum C _ss value is 0.65 μg / ml, which is 2 times less than in non-smokers or former smokers (1.28 μg / ml), the apparent clearance of erlotinib increases by 24%. With an increase in the dose of Tarceva from 150 mg to 300 mg (the maximum tolerated dose), a dose-dependent increase in the exposure of erlotinib is noted, and the minimum C _ss when receiving a dose of 300 mg in smokers is 1.22 μg / ml.

Indications for use

first-line therapy for metastatic or locally advanced (stage IIIB – IV) non-small cell lung cancer with activating mutations in the EGFR gene;
metastatic or locally advanced non-small cell lung cancer in the absence of effect from one or more chemotherapy regimens;
maintenance treatment of metastatic or locally advanced non-small cell lung cancer in the absence of progression of the lesion after four courses of first-line chemotherapy based on platinum drugs;
first line of therapy for metastatic or locally advanced pancreatic cancer in combination with gemcitabine.

Contraindications

Absolute:

age up to 18 years;
pregnancy and the period of breastfeeding;
severe renal impairment;
severe liver dysfunction (10 or more points on the Child-Pugh scale);
severe hypersensitivity to any component of the drug.

Relative (take Tarcev tablets with extreme caution):

glucose-galactose malabsorption, galactose intolerance, lactase deficiency;
smoking;
violation of the liver;
the presence of a peptic ulcer or diverticular disease (including a history of indications);
simultaneous use with powerful inducers or inhibitors of the CYP3A4 isoenzyme, anti-angiogenic drugs, glucocorticosteroids (GCS), nonsteroidal anti-inflammatory drugs (NSAIDs);
receiving chemotherapy that includes taxanes.

Tarceva, instructions for use: method and dosage

Tarcev's tablets are taken orally 1 time per day at least 1 hour before or 2 hours after a meal.

Recommended doses of the drug, depending on the indications:

non-small cell lung cancer: 150 mg daily, long-term;
pancreatic cancer: daily, 100 mg, long-term, in combination with gemcitabine; if a rash does not appear within 4–8 weeks of the course, further erlotinib therapy should be reviewed.

If there are signs of progression of the disease, drug treatment should be discontinued.

Against the background of the concomitant use of modulators or substrates of the CYP3A4 isoenzyme, it may be necessary to change the dose of Tarceva. In this case, it is recommended to reduce the dose gradually by 50 mg.

Smoking can reduce your exposure to erlotinib by 50-60%. In smoking patients with non-small cell lung cancer, the maximum tolerated dose of Tarceva is 300 mg. The effectiveness and safety of using doses exceeding those recommended at the beginning of the course in patients who continue to smoke have not been established.

Side effects

metabolism: very often - anorexia;
hepatobiliary system: often - impaired liver function, including increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), an increase in the content of bilirubin; rarely - liver failure (up to death);
digestive system: very often - stomatitis, nausea, abdominal pain, vomiting, dyspepsia, flatulence, diarrhea; often - gastrointestinal bleeding (including isolated cases with a fatal outcome), some of them were due to the combined use of Tarceva with warfarin or NSAIDs; infrequently - perforation of the gastrointestinal tract (GIT), in some cases fatal;
respiratory system: very often - shortness of breath, cough; often - nosebleeds; infrequently - symptoms similar to interstitial lung disease (ILD), including fatal cases;
organ of vision: very often - dry keratoconjunctivitis, conjunctivitis; often - keratitis; infrequently - impaired growth of eyelashes (including excessive growth and thickening of eyelashes, ingrown eyelashes); extremely rare - corneal ulceration / perforation;
psyche: very often - depression;
nervous system: very often - headache, neuropathy;
skin and subcutaneous fat: very often - dry skin, rash (papulopustular and erythematous rashes that appear or intensify under the influence of sunlight), alopecia, itching; often - paronychia, skin cracks, mostly not of a serious nature, usually associated with dry skin and rash; infrequently - fragility and stratification of nails, eyelash / eyebrow changes, hirsutism, hyperpigmentation; cases of exfoliative, bullous and blistering skin lesions (including, very rarely, suspicions of Stevens-Johnson syndrome / toxic epidermal necrolysis, sometimes fatal);
others: very often - increased fatigue, weight loss, chills, fever, severe infections (with or without neutropenia, sepsis, pneumonia, phlegmon).

Overdose

With a single oral administration of erlotinib at a dose of up to 1000 mg to healthy volunteers and once a week in patients with oncological lesions at a dose of up to 1600 mg, the drug was well tolerated. At the same time, the repeated use of the drug by healthy volunteers 2 times a day at a dose of 200 mg was tolerated much worse after a few days.

Taking Tarceva at a dose higher than the recommended one can lead to the development of such severe adverse events as skin rashes, diarrhea, increased activity of hepatic transaminases.

If an overdose is suspected, treatment should be suspended and symptomatic therapy should be prescribed. The antidote for erlotinib is currently unknown.

special instructions

Before starting the Tarceva course, patients with non-small cell lung cancer who have not previously received chemotherapy should be tested for the presence of the L858R mutation in exon 21 or Del19 (deletion in exon 19) of the EGFR gene.

During therapy, the overall incidence of ILD-like symptoms is 0.6%. The most common diagnoses in patients with suspected such symptoms include: interstitial pneumonia, pneumonitis, allergic interstitial pneumonitis, radiation pneumonitis, obliterating (constrictive) bronchiolitis, interstitial lung disease, pulmonary fibrosis, alveolitis, lung infiltration, acute respiratory distress syndrome. These phenomena developed in the period from several days to several months after the start of the course of therapy. Most of these cases were due to a history of parenchymal lung disease, infection or metastatic lung disease, concomitant or previous chemotherapy / radiation therapy. With progression and / or the appearance of new unexplained pulmonary symptoms (cough, shortness of breath,fever) from the use of the drug Tarceva must be temporarily abandoned until the cause of their development is established. If the diagnosis of ILD has been confirmed, treatment with the drug should be discontinued and appropriate therapy should be carried out.

If severe / moderate diarrhea develops, the use of loperamide is required, sometimes it may be necessary to reduce the dose of the drug. If severe / persistent diarrhea, anorexia, nausea or vomiting with dehydration occurs, Tarceva should be discontinued and rehydration given.

During the treatment period, the appearance of renal failure and hypokalemia, including with a fatal outcome, was sometimes recorded. Some cases of renal failure have been associated with severe dehydration as a result of vomiting, diarrhea and / or anorexia, while others have been associated with concomitant chemotherapy.

Against the background of severe / persistent diarrhea, or in conditions that cause dehydration, especially in patients at risk (concomitant diseases / therapy, old age), Tarcev should be temporarily canceled and parenteral rehydration should be performed. If there is a high risk of dehydration, monitoring of serum electrolytes (including potassium) and renal function is required.

Patients with concomitant liver disease or taking hepatotoxic drugs should regularly monitor the activity of the liver and, if severe damage occurs, discontinue therapy with Tarceva.

In patients receiving Tarceva, the risk of gastrointestinal perforation, sometimes fatal, is aggravated. The threat of this complication increases with combined use with corticosteroids, NSAIDs, antiangiogenic drugs, as well as with concomitant chemotherapy based on taxanes or a history of peptic ulcers, diverticular disease.

Reception of Tarceva should be suspended or canceled if acute ophthalmic symptoms occur, including eye pain or worsening of chronic ophthalmic lesions, due to the risk of corneal perforation / ulceration.

Influence on the ability to drive vehicles and complex mechanisms

The effect of the anticancer drug Tarceva on the ability to drive vehicles or other complex moving mechanisms has not been studied. However, it is assumed that erlotinib does not adversely affect the speed of psychomotor reactions and the ability to concentrate.

Application during pregnancy and lactation

The use of erlotinib during pregnancy and breastfeeding is contraindicated.

Women need to take into account that during therapy, as well as for 14 days after its completion, it is necessary to use reliable contraception.

Pediatric use

In patients under the age of 18 years, the safety and efficacy of therapy with Tarcev's drug have not been studied, as a result, taking the drug in patients of this age category is contraindicated.

With impaired renal function

Erlotinib, like its metabolites, is excreted by the kidneys in small amounts - less than 9% of a single dose. In patients with functional impairment of the kidneys, with a serum creatinine level in the blood more than 1.5 times higher than the upper limit of normal (ULN), clinical studies have not been conducted.

The use of erlotinib in patients with impaired renal function:

renal failure mild / moderate: no change in dosing regimen is required;
severe renal impairment: taking Tarceva is contraindicated.

For violations of liver function

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

The use of erlotinib in patients with impaired liver function:

mild / moderate hepatic impairment: use Tarceva with caution;
severe hepatic impairment (score 10 and higher on the Child-Pugh scale): drug treatment is contraindicated.

In the event of pronounced undesirable effects, it is required to reduce the dose of Tarceva or interrupt therapy. In patients with severe hepatic insufficiency on the background of ALT and AST activity more than 5 times higher than ULN, the efficacy and safety of the drug have not been studied.

Use in the elderly

Special studies of the efficacy and safety of erlotinib for the treatment of elderly patients have not been conducted.

Drug interactions

Since the metabolism of erlotinib in humans occurs under the influence of such isoenzymes of the cytochrome P ₄₅₀ system such as CYP1A1, CYP1A2 and CYP3A4, inhibitors / inducers of these enzymes and drugs in whose metabolism they are involved can interact with erlotinib in the case of combined use.

Possible interaction of Tarceva with simultaneously used medicinal substances / preparations:

strong inhibitors of the isoenzyme CYP3A4: the metabolism of erlotinib decreases and the level of its content in plasma increases; ketoconazole (inhibitor of CYP3A4 isoenzymes, orally 2 times a day, 200 mg for 5 days) - increases the AUC and C _{max of} erlotinib by 86 and 69%, respectively; ciprofloxacin (an inhibitor of the isoenzyme CYP3A4 and CYP1A2) - increases AUC by 39% and C _{max of} erlotinib by 17%; a combination of the drug with powerful inhibitors of isoenzymes CYP3A4 / CYP1A2 or CYP3A4 is prescribed only if absolutely necessary; with the development of toxicity, it is required to reduce the dose of erlotinib;
rifampicin, other inducers of CYP3A4 (oral administration): the metabolism of erlotinib increases and its plasma concentration decreases rapidly; rifampicin (at a dose of 600 mg 4 times a day for 7 days) - when compared with taking erlotinib alone, the median AUC of the latter at a dose of 150 mg decreases by 69%; when taking erlotinib at a dose of 450 mg, the median AUC is 57.5% of that at a dose of 150 mg without a combination with rifampicin therapy or without prior administration; if necessary, this combination is recommended to increase the dose of Tarceva to 300 mg with careful monitoring of the safety profile, after 2 weeks, monitoring the safety of the drug, you can increase its dose to 450 mg; the use of higher doses has not been studied;
erythromycin, midazolam (substrates of the isoenzyme CYP3A4): there is no violation of the clearance of these drugs when combined with erlotinib or with its previous use; due to oral administration, the bioavailability of midazolam decreases by 24%, which does not significantly affect the activity of CYP3A4;
omeprazole (proton pump inhibitor): there is a decrease in AUC and C _{max of} erlotinib by 46 and 61%, respectively, while T _1/2 and T _max do not change; agents capable of altering the pH in the upper gastrointestinal tract may affect the solubility and bioavailability of erlotinib; it is not expected that increasing the dose of erlotinib with this combination may compensate for the decrease in its exposure;
ranitidine (at a dose of 300 mg) other blockers of histamine H2-receptors: a decrease in AUC and C _{max of} erlotinib by 33 and 54%, respectively, was recorded; it is recommended to take Tarceva at least 2 hours before or 10 hours after taking drugs of this group;
statins: myopathy caused by these drugs may be aggravated, including in rare cases the occurrence of rhabdomyolysis;
coumarin derivatives (including warfarin): there was an increase in the International Normalized Ratio (INR), as well as bleeding, in rare cases with a fatal outcome; with this combination, regular monitoring of INR or prothrombin time is necessary;
capecitabine: increases the plasma concentration of erlotinib in the blood; increases slightly C _max and statistically significant - AUC of erlotinib, no pronounced effect of the latter on the pharmacokinetics of capecitabine was found;
gemcitabine: no significant interaction of drugs on the pharmacokinetics of each other was recorded;
paclitaxel, carboplatin (platinum preparations): the plasma level of platinum in the blood increases, the AUC of total platinum increases by 10.6%, but this can also be caused by impaired renal function; the pharmacokinetics of erlotinib are not significantly affected;
substrates of uridine phosphate glucuronyltransferase 1-1 (UGT1A1): erlotinib, being an inhibitor of UGT1A1, can demonstrate interaction with its substrates, for which the reaction of conjugation with glucuronic acid is the main metabolic pathway. With a low level of expression of UGT1A1 or patients with genetic disorders that contribute to a decrease in the rate of the glucuronidation reaction (for example, with Gilbert's syndrome), caution should be exercised when prescribing erlotinib, as this can lead to an increase in the plasma concentration of bilirubin in the blood.

Analogs

Tarceva's analogs are Tarlenib, Erlotinib, Erlotinib-native, etc.

Terms and conditions of storage

Store out of the reach of children at a temperature not exceeding 30 ° C.

Shelf life is 4 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Tartsevo

The few reviews about Tarcev are mostly positive. Patients who received therapy with an anticancer agent note its high efficiency. In some cases, the drug had a restorative effect even with advanced stages of the pathological process.

The disadvantages of the Tarcevs are the presence of a large number of side effects and its high cost.

Price for Tartseva in pharmacies

Price for Tarceva, film-coated tablets, for 30 pcs. in a package the average is:

dosage of 25 mg - 35,900 rubles;
dosage of 100 mg - 63,000 rubles;
dosage 150 mg - 67,000 rubles.

Tarceva: prices in online pharmacies

Drug name

Price

Pharmacy

Tarceva 100 mg film-coated tablets 30 pcs.

RUB 43300

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Tarceva 150 mg film-coated tablets 30 pcs.

RUB 83800

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Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!