Tyverb - instructions for use, analogs, reviews and release forms (tablets 250 mg) of a drug for the treatment of breast or breast cancer in adults, children and pregnancy. Composition and side effects

In this article, you can read the instructions for using the drug Tayverb. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors specialists on the use of Tayverba in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Tayverba in the presence of existing structural analogues. Use for the treatment of breast or breast cancer in adults, children, as well as during pregnancy and lactation. Composition and side effects of the drug.

Tayverb is a reversible selective inhibitor of intracellular tyrosine kinase that binds to EGFR (the receptor of epidermal growth factor, ErbB1) and HER2 (the receptor of epidermal growth factor of human, ErbB2) receptors. It differs from other rapidly reversible tyrosine kinase inhibitors by slower dissociation with ErbB1 and ErbB2 receptors (the dissociation period of 50% of the ligand from the ligand-receptor complex is approximately 300 minutes).

In addition to its in vitro activity (in vitro), the additive activity of lapatinib (Taiwerb active ingredient) and Fluorouracil (active metabolite capecitabine) was shown when used in combination on four lines of tumor cells. The inhibitory effect was evaluated on trastuzumab-treated cells. The combination of lapatinib and trastuzumab can provide an additive mechanism of action, as well as possible non-parallel mechanisms for overcoming resistance to anti-HER2 therapy.

Lapatinib demonstrated significant activity on the lines of HER2-positive tumor cells in media containing trastuzumab, and in combination with trastuzumab showed a synergistic effect in these cell lines.These results demonstrate the absence of cross-resistance between the two HER2 receptor ligands (ErbB2).

Composition

Lapatinib + excipients.

Pharmacokinetics

Absorption after ingestion is incomplete and variable. It is determined in the systemic blood flow on average 0.25 hours (range 0-1.5 h). The maximum concentration in the blood is reached approximately 4 hours after taking Tayverba. Systemic exposure of lapatinib increases with taking the drug simultaneously with food. When taken with food low (5% fat or 500 calories) or high (50% fat or 1000 calories), the fat content of AUC increases by 3 and 4 times (the maximum concentration in the blood is approximately 2.5 and 3 times), respectively. Lapatinib has a high degree of binding (more than 99%) with albumin and alpha-1-acid glycoprotein of blood plasma. In vitro studies have shown that lapatinib is a substrate for the carriers of BCRP (breast cancer resistance protein, ABCG2-ATP-binding cassette transporter G2) and P-glycoprotein (ABCB1 ATP-binding cassette transporter B1). Also in vitro, lapatinib had an inhibitory effect on vector data.The clinical significance of these effects and the effect on other pharmacokinetics of drugs, as well as drugs that have antitumor activity, is still unknown. Lapatinib slightly inhibits the transport of organic anions (OAT) or an organic cation carrier (OCT). Tyverb is subjected to intensive metabolism, mainly by the isoenzymes CYP3A4 and CYP3A5, to a lesser extent isoenzymes CYP2C19 and CYP2C8 with the formation of various oxidized metabolites. In vitro lapatinib at clinically significant concentrations inhibits the isoenzymes CYP3A and CYP2C8. Lapatinib slightly inhibits the following microsomal liver enzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6. Basically excreted by the intestines - an average of 27% (from 3% to 67%) in unchanged form, less than 2% of the accepted dose is excreted by the kidneys in unchanged form and in the form of metabolites.

Indications

• locally advanced or metastatic breast cancer with overexpression of HER2 (in combination with capecitabine in patients who had previously received anthracycline and taxane, who had progression with or after trastuzumab therapy for metastatic cancer);
• metastatic breast cancer with overexpression of HER2 (in combination with trastuzumab in patients who have progressed to cancer with or after trastuzumab therapy for metastatic cancer);
• hormone-receptor-positive metastatic breast cancer with overexpression of HER2 (in combination with an aromatase inhibitor in postmenopausal patients).

Forms of release

The tablets covered with a cover of 250 mg.

Instructions for use and dosing regimen

Tyverb should be taken 1 hour before meals or 1 hour after meals. The recommended daily dose can not be divided into receptions. Missed doses of lapatinib are not replenished, i.e., do not take missed doses, reducing the intervals between doses, should not be.

Locally advanced or metastatic breast cancer with overexpression of HER2

In combination with capecitabine, the recommended dose of lapatinib is 1250 mg (5 tablets) once daily, daily. The recommended dose of Capecitabine is 2000 mg per 1 sq. Km. m body surface per day, in 2 divided doses (every 12 hours) daily from 1 to 14 days of each 21-day therapy cycle. It is recommended to take capecitabine with food or within 30 minutes after eating.

In combination with trastuzumab, the recommended dose of lapatinib is 1000 mg (4 tablets) once daily, daily. The recommended dose of trastuzumab is 4 mg per 1 kg of body weight, as an intravenous loading dose, then 2 mg per 1 kg of body weight intravenously once a week.

Hormone-receptor-positive metastatic breast cancer with overexpression of HER2

The recommended dose of Tyverba is 1500 mg (6 tablets) once a day, daily in combination with an aromatase inhibitor. The recommended dose of Letrozole (one of the possible drugs - aromatase inhibitors) when taken in combination with lapatinib is 2.5 mg once daily, daily. In the event that lapatinib is prescribed in combination with another aromatase inhibitor, it is necessary to study the dosage regimen of the corresponding drug in this group.

Indications for suspension of taking or decreasing dose Tyverba:

• the appearance of symptoms of a reduction in the left ventricular ejection fraction (LVEF) to grade 3 or higher (according to the general criteria of toxicity of the National Cancer Institute of the United States) or in case of a decrease below the limit of the permissible norm.Treatment with lapatinib can be resumed no earlier than 2 weeks in a smaller dose;
• the appearance of pulmonary symptoms, indicative of the development of interstitial lung disease and / or pneumonitis of the 3rd degree or higher (according to the general toxicity criteria of the National Cancer Institute of the USA);
• diarrhea of ​​the 3rd degree, either 1st or 2nd degree with complicated symptoms (spasmodic abdominal pain from moderate to severe, nausea or vomiting of 2nd degree or higher, decreased efficiency, fever, sepsis, neutropenia, severe bleeding or dehydration). Treatment with lapatinib can be resumed at a lower dose if the severity of diarrhea has decreased to 1 st degree and lower. Treatment with Tayverb should be completely discontinued in patients with grade 4 diarrhea (according to the general toxicity criteria of the National Cancer Institute of the United States);
• a situation where the severity of the developing toxic effects is higher or equal to the 2 nd degree (according to the general toxicity criteria of the National Cancer Institute of the USA). Treatment can be resumed if the severity of toxic effects has decreased to 1 st degree and lower.In case of repeated occurrence of toxic effects, the dose of lapatinib should be reduced.

Side effect

The safety of lapatinib has been evaluated in clinical trials both in monotherapy and in combination with trastuzumab, capecitabine and letrozole. Post-registration data correspond to data obtained during clinical trials.

Side effect with monotherapy Tyverb:

• anorexia (eating disorder);
• reduction of the left ventricular ejection fraction (LVEF), manifested by shortness of breath, heart failure, palpitations;
• interstitial lung disease, pneumonitis (inflammation of the walls of the alveoli and lung parenchyma);
• diarrhea, which can lead to dehydration;
• nausea, vomiting;
• Hyperbilirubinemia, hepatotoxicity;
• rash on the skin, nail damage;
• allergic reactions, including anaphylaxis;
• general weakness.

Side-effects with the appointment of lapatinib in combination with capecitabine in addition to the undesirable phenomena observed against the background of monotherapy with lapatinib:

• dyspepsia;
• dry skin;
• stomatitis (inflammation of the oral mucosa);
• constipation, abdominal pain;
• palmar-plantar syndrome (redness, swelling and tenderness of the palms and soles);
• pain in the extremities, back pain;
• headache;
• insomnia.

When using lapatinib in combination with trastuzumab, there were no additional adverse events associated with lapatinib. There was an increased incidence of cardiotoxicity, but these phenomena by nature and severity were similar to those previously observed in the clinical trials of lapatinib.

Side-effect of the appointment of lapatinib in combination with letrozol in addition to the undesirable phenomena observed against the background of monotherapy with lapatinib:

• nose bleed;
• alopecia (alopecia), dry skin.

Contraindications

• pregnancy;
• lactation period (breastfeeding);
• children's age (lack of experience);
• hypersensitivity to lapatinib or any other component of the drug.

Application in pregnancy and lactation

There are no known cases of Tyverba during pregnancy.

Women of childbearing age should be warned about the use of adequate contraception, as well as the interruption of pregnancy during lapatinib treatment.

When used in doses toxic to the mother, lapatinib did not have teratogenic properties in studies on pregnant mice and rabbits, but at the same time was the cause of some deviations in development.

It is not known whether lapatinib is excreted in breast milk. During therapy with lapatinib, it is recommended to stop breastfeeding because of the possible occurrence of characteristic undesirable phenomena in the infant.

Use in children

Contraindicated in childhood due to lack of experience.

Application in elderly patients

There is insufficient data on the use of Tayverba in elderly patients (over 65 years of age).

special instructions

Treatment with lapatinib should be done only under the supervision of a specialist who has experience in the use of antitumor drugs.

Caution should be given to the drug in conditions that can lead to left ventricular failure, with liver function disorders, moderate or severe (7 or more Child-Pugh scores), with severe renal insufficiency, in patients older than 65 years, concomitantly with moderate inhibitors of the isoenzyme CYP3A4.

Cardiotoxicity

Before the start of treatment, it is necessary to determine LVEF to make sure that LVEF is within acceptable limits. During treatment with lapatinib, the control of LVEF should be continued so as not to miss its decrease beyond acceptable limits.

It is impossible to completely exclude the effect of lapatinib on the QT interval in the electrocardiogram (ECG), as there are reports of cases of a slight increase in the QT interval in patients with a common tumor process. Caution should be exercised in appointing Tywerb to patients with concomitant factors that affect the increase in the QT interval (such as hypokalemia, hypomagnesemia, congenital long QT interval syndrome, or simultaneous use of drugs that affect the QT interval increase). The concentration of potassium and magnesium in the blood should be corrected before starting lapatinib. ECG with QT interval control should be performed before and during the entire lapatinib treatment.

Interstitial lung disease and pneumonitis

There have been reports of cases of interstitial lung disease and pneumonitis due to lapatinib.Patients should be monitored to rule out the onset of pulmonary symptoms, indicative of the development of interstitial lung disease and / or pneumonitis.

Diarrhea

There are reports of cases of diarrhea, including severe diarrhea, with lapatinib treatment. Diarrhea usually occurred in the early stages of treatment, with almost half of these patients developing diarrhea within the first 6 days. It lasts usually 4-5 days. Lapatinib-induced diarrhea manifests itself, as a rule, in an easy degree; Diarrhea of ​​3rd and 4th degree (according to the general criteria of toxicity of the National Cancer Institute of the USA) is observed in less than 10% and less than 1% of patients, respectively. Early detection and timely treatment are of great importance for the optimal control of diarrhea. Patients should be instructed that they should immediately report any changes in the nature of the stool. It is recommended to immediately prescribe diarrhea therapy with antidiarrhoeal agents (for example, loperamide) after the first case of an unformed stool. Severe diarrhea may require the administration of electrolytes and fluid to prevent dehydration (oralor intravenously), the use of antibiotics such as fluoroquinolones (especially if diarrhea lasts for more than 24 hours and the patient experiences fever or grade 3 or 4 neutropenia), stopping or canceling the drug.

Contraception

During therapy with lapatinib, and at least 3 months after the end, reliable methods of contraception should be used.

Hepatotoxicity

Manifestations of hepatotoxicity (activity of alanine aminotransferase (ALT) or asparagine aminotransferase (AST), which exceeds the upper limit of the norm (VGN) by 3 times, the content of total bilirubin exceeding the VGN by 1.5 times) was observed in clinical trials (less than 1% of patients) and post-marketing period. Hepatotoxicity can be severe. Cases with a fatal outcome have been reported, although a causal relationship with the use of lapatinib has not been established. Hepatotoxicity can develop for several days to several months after initiation of therapy. It is necessary to monitor the laboratory parameters of liver function (aminotransferases, bilirubin and alkaline phosphatase) before the start of therapy, then every 4-6 weeks during the course of treatment and according to clinical indications.In the event of serious violations of liver function, lapatinib cancellation is necessary, re-administration of the drug is unacceptable.

Patients carrying HLA DQA1 * 02: 01 and DRB1 * 07: 01 alleles have an increased risk of hepatotoxicity associated with lapatinib. In patients who used lapatinib as a monotherapy, the overall risk of developing severe liver damage (ALT more than 5 times the normal limit, grade 3 (according to the general criteria of toxicity of the National Cancer Institute of the United States) was higher (about 8%) in carriers DQA1 * 02: 01 and DRB1 * 07: 01, than for non-carriers (0.5%). The carrier of the HLA allele is characteristic (from 15% to 25%) of the Caucasoid, Asian, African and Latin American populations, but lower (1%) in the Japanese population.

When prescribing lapatinib, patients with existing severe impairment of liver function in a history of lower lapatinib dose are recommended.

Simultaneous use of inhibitors or inducers of CYP3A4

Caution should be exercised with lapatinib in conjunction with inhibitors or inductors of the CYP3A4 isoenzyme due to the risk of increasing or decreasing (respectively) the systemic effects of lapatinib, with drugs that are substrates of CYP3A4 isoenzymes for CYP2C8 with a narrow therapeutic range.

Avoid simultaneous administration with grapefruit juice and with drugs that increase the pH of gastric juice (reduced solubility and absorption of lapatinib).

Impact on the ability to drive vehicles and manage mechanisms

Influence on the ability to drive vehicles and other activities requiring increased concentration of attention and speed of psychomotor reactions, has not been studied. Based on the mechanism of action of Tayverba, it is impossible to assume the adverse effect of the drug on such activities. However, the general condition of the patient and the profile of side effects of lapatinib should be taken into account, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Drug Interactions

Inhibitors or inducers of the CYP3A isoenzyme are able to influence the pharmacokinetics of lapatinib. With simultaneous application of Tyverba and some inhibitors of the isoenzyme CYP3A4 (eg, ketoconazole, itraconazole,grapefruit juice), care must be taken to carefully monitor the patient's clinical condition and possible adverse reactions. If simultaneous administration of a potent inhibitor of the CYP3A4 isoenzyme is necessary, the dose of lapatinib should be reduced to 500 mg per day, calculated so as to adjust the lapatinib AUC to a value corresponding to the use of lapatinib without inhibitors. However, there are currently no clinical data on the use of lapatinib with this dose adjustment in patients receiving a potent inhibitor of the CYP3A4 isoenzyme. After the cancellation of the potent inhibitor, only after removal from the body, after about 1 week, the dose of lapatinib should be increased again to the recommended dose.

With the simultaneous use of lapatinib and known inducers of the isoenzyme CYP3A4 (eg, rifampicin, carbamazepine, phenytoin, St. John's wort), care must be taken to carefully monitor the clinical condition of the patient and possible adverse reactions.

If it is necessary to simultaneously assign a powerful inducer of CYP3A4 isoenzyme to a patient, the dose of lapatinib should be selected, based on tolerability, gradually increasing it from 1250 mg per day to 4500 mg per day or from 1500 mg per day to 5,500 mg per day.This dose is calculated so as to adjust the lapatinib AUC to a value corresponding to the use of lapatinib without inducers of the CYP3A4 isoenzyme. However, there are currently no clinical data on the use of lapatinib in patients receiving a potent inducer of the isoenzyme CYP3A4. After canceling the powerful inducer of the isoenzyme CYP3A4, only after about 2 weeks should the dose of lapatinib again be reduced to the recommended one.

The solubility of lapatinib depends on pH. Avoid concomitant use of substances that increase the pH of gastric juice, since the solubility and absorption of lapatinib can decrease. Previous treatment with a proton pump inhibitor (eg, esomeprazole) reduced lapatinib activity by an average of 27% (ranging from 6% to 49%). This effect decreases with increasing age from about 40 years to 60 years. Therefore, caution should be given to lapatinib for patients taking proton pump inhibitors.

Lapatinib inhibits the in vitro isoenzyme CYP3A4 at clinically significant concentrations. Simultaneous use of lapatinib with midazolam for oral administration leads to an increase in midazolam AUC by approximately 45%.With intravenous administration of midazolam, there was no clinically significant increase in AUC. Caution is needed when concomitant administration of lapatinib and oral medications with a narrow therapeutic range, which are substrates of the isoenzyme CYP3A4.

Lapatinib inhibits the isoenzyme CYP2C8 in vitro in clinically significant concentrations. Caution should be used to prescribe lapatinib concomitantly with drugs with a narrow therapeutic range, which are substrates of the CYP2C8 isoenzyme.

Simultaneous use of lapatinib with Paclitaxel intravenously increases the effect of paclitaxel by 23% due to inhibition of lazateb in the isoenzyme CYP2C8 and / or P-glycoprotein. An increase in the incidence and severity of diarrhea and neutropenia was observed with a combination of lapatinib and paclitaxel in clinical trials. It is recommended that caution be given to lapatinib concurrently with paclitaxel.

Simultaneous use of lapatinib with docetaxel intravenously did not significantly affect AUC or the maximum concentration in the blood any active substances.However, there was an increase in the incidence of docetaxel-induced neutropenia.

Simultaneous use of lapatinib with irinotecan (when administered as part of the FOLFIRI regimen) resulted in an increase in AUC SN-38, an active metabolite of irinotecan, by approximately 40%. The exact mechanism of this interaction is not known. It is recommended that caution be given to lapatinib simultaneously with irinotecan.

Lapatinib is a substrate for transport proteins of P-glycoprotein and BCRP. Inhibitors and inducers of these proteins may alter the activity and / or distribution of lapatinib.

Tyverb inhibits the transport protein P-glycoprotein in vitro in clinically significant concentrations. Simultaneous use of lapatinib with Digoxin when ingested increases the digoxin AUC by approximately 98%. Caution should be used to administer lapatinib with concomitant use with drugs with a narrow therapeutic range, which are substrates of P-glycoprotein.

Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical significance of these effects has not been studied, but it is possible that lapatinib may affect the pharmacokinetics of BCRP substrates (eg topotecan) and OATP1B1 (eg rosuvastatin).

The combined use of lapatinib with capecitabine, letrozole or trastuzumab does not affect the pharmacokinetic parameters of these drugs.

Bioavailability of lapatinib depends on the intake of food.

Analogues of the drug Tyverb

Tyverb does not have structural analogs for the active substance.

Analogues for the pharmacological group (antitumor agents - protein kinase inhibitors):

• Albitinib;
• The Athlete;
• Bosulif;
• Vargatef;
• Votrient;
• Genfatinib;
• Gefitinib;
• Giotrip;
• Histamel;
• Gleihib;
• Glivec;
• Dasatinib;
• Djakavi;
• Zelborough;
• Ibrans;
• Iglib;
• Imagliv;
• Imatib;
• Imatinib;
• Imatinib mesylate;
• Imatinib mesylate form X;
• Imatinib mesylate form Alpha;
• Imbruvik;
• Imvek;
• Inlita;
• Iressa;
• Capresa;
• Cotellus;
• Xalqori;
• Lenwima;
• Mechinist;
• Nexavar;
• Neopax;
• Nilotinib is native;
• Nilotinib hydrochloride monohydrate;
• Ninlaro;
• Sorafenib is native;
• Sorafenib tosylate;
• Sprysel;
• Steiverg;
• Sunitinib-native;
• Sunitiniba Malate;
• Sutent;
• Tagrisso;
• Tarlenib;
• Tarceva;
• Taxis;
• Tafinlar;
• Tafinlar Combo;
• Thorizel;
• Filachromine;
• Filachromin FS;
• Everolimus 2%;
• Everolimus 9.09%;
• Erlotinib;
• Erlotinib hydrochloride.

Review of the oncologist's doctor

Almost all of the patients in our department who receive treatment with Tyverb with various forms of breast cancer are suffering a lot of treatment. And the side effects develop both with monotherapy, and with the combination of Tyverba with other medicines. Very often we see anorexia, dyspnea, heart palpitations in women. There are frequent complaints of diarrhea, skin rashes. It is not always possible to finish the course on the initially selected dose of the drug. Often it is necessary to reduce it, and sometimes completely to cancel the reception of Tayverba.

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