Tayverb - instructions for use, dose, side effects, contraindications

Active substanceLapatinibLapatinib

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Dosage form: & nbspfilm-coated tablets

Composition:

Component	Content in 1 tablet,
	mg
Core tablet:
*Active substance:*
Lapatinib Ditosylate	405,0
monohydrate, in terms of lapatinib	250,0
*Excipients:*
Cellulose microcrystalline	387,0
Povidone K30	58,5
Carboxymethyl starch of sodium (type A)	40,5
Magnesium stearate	9,0
Purified water¹	q.s.
Tablet casing:
Drop * yellow YS-1-12524-A, containing:	27,0
- hypromellose	17,23
- titanium dioxide	7,13
- iron dye oxide red (E172)	0,005
- iron dye oxide yellow (E172)	0,21
- macrogol-400	2,16
- polysorbate-80	0,27

1 - removed during production.

Description:

Tablets are oval, biconvex, from light yellow to yellow, film-coated. One side of the tablet is smooth, the other is engraved with an inscription "GS XJG".

Pharmacotherapeutic group:Antitumor agent. Reversible tyrosine kinase inhibitor.

ATX: & nbsp

L.01.X.E.07 Lapatinib

Pharmacodynamics:

Mechanism of action

Lapatinib is a new reversible, selective intracellular tyrosine kinase inhibitor that binds to EGFR (epidermal growth factor receptor, receptor of epidermal growth factor, ErbBl) and HER2 (human epidermal growth factor receptor, receptor of human epidermal growth factor, ErbB2) receptors.It differs from other rapidly reversible tyrosine kinase inhibitors by slower dissociation with ErbB 1 and ErbB2 receptors (the dissociation period of the 50% ligand from the ligand-receptor complex is about 300 min).

In addition to its own activity in vitro the additive activity of lapatinib and fluorouracil (active metabolite of 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 to overcome resistance to anti-HER therapy.

Lapatinib demonstrated significant activity on the lines NOTR2-positive tumor cells in media containing trastuzumab, and in combination with trastuzumab showed a synergistic effect in these cell lines. These results demonstrate absence of cross-resistance between two ligands receptor HER2 (ErbAT 2).

Pharmacokinetics:

Suction

Absorption of lapatinib after oral administration is incomplete and variable. The coefficient of variability of the area under pharmacokinetic the concentration-time curve (AUC) is from 50 % up to 100%. Lapatinib is defined in the systemic blood stream on average 0.25 hours (range 0-1.5 h). The maximum concentration of lapatinib in the blood plasma (C_ma_x) is reached approximately in 4 hours after reception.

FROM_m_Oh in the equilibrium state with a daily intake of 1,250 mg is an average of 2.43 (1.57-3.77) μg / ml, and AUC = 36.2 (23.4-56.0) μg x hour / ml.

Systemic exposure of lapatinib increases with taking the drug simultaneously with food.

When taken with food with low (5% fat or 500 calories) or high (50% fat or 1000 calories) the fat content of AUC increases by 3 and 4 times (C_m_Oh - approximately 2.5 and 3 times), respectively.

Distribution

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 pharmacokineticsother drugs, as well as drugs that have antitumor activity, is still unknown. Lapatinib slightly inhibits the transport of organic anions (OAT) or the transporter of organic cations (OCT).

Metabolism

Lapatinib is subjected to intensive metabolism, mainly by isoenzymes CYP3A4 and CYP3A5, to a lesser extent isoenzymes CYP2C19 and CYP2C8 with the formation of various oxidized metabolites. Lapatinib at clinically significant concentrations inhibits the isoenzymes CYP3A and CYP2C8 in vitro.

Lapatinib slightly inhibits the following microsomal liver enzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6.

In healthy volunteers receiving ketoconazole (inhibitor of isoenzyme CYP3A4) at a dose of 200 mg 2 times / day for 7 days, systemic distribution of lapatinib increased approximately 3.6 times, half-life - 1.7 times.

In healthy volunteers receiving carbamazepine (inducer of isoenzyme CYP3A4) at a dose of 100 mg 2 times / day for 3 days and 200 mg 2 times / day for 17 days, the systemic distribution of lapatinib decreased by 72%.

Excretion

The half-life of lapatinib (T _1/2) increases dose-dependently when taking single doses. The equilibrium state is achieved after 6-7 days of lapatinib, T_1/2equilibrium state is 24 hours.

Lapatinib is mainly excreted through the intestine: 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.

Special patient groups

Patients with impaired renal function

The pharmacokinetics of lapatinib in patients with impaired renal function or patients on hemodialysis has not been specifically studied. but It is unlikely that the effect of renal dysfunction on the pharmacokinetics of lapatinib, since the kidneys produce less than 2% of the administered dose (in the form of lapatinib and its metabolites).

Patients with impaired hepatic function

The pharmacokinetics of lapatinib has been studied with moderate (n= 8) and heavy (n= 4) violations of liver function. AUC lapatinib after taking a single dose of 100 mg orally increases by approximately 56% and 85% in patients with moderate and severe impairment of liver function, respectively. Assign lapatinib patients with impaired liver function should be taken with caution. Patients with severe hepatic insufficiency in the history are recommended to reduce the dose of lapatinib. It is necessary to abolish therapy with lapatinib, without the subsequent resumption of its use, in patients with severe hepatotoxicity, developed against the background of its use.

Indications:

Locally distributed or metastatic breast cancer with overexpression HER2:

- in combination with capecitabine in patients who had previously received anthracyclines and taxanes who had progression with or after trastuzumab therapy, appointed about metastatic cancer.

Metastatic breast cancer with overexpression HER2:

- in combination with trastuzumab in patients with absence of expression of hormonal receptors, in whom there was progression with or after trastuzumab therapy at combination with chemotherapy, appointed for metastatic cancer.

Metastatic breast cancer with overexpression of HER2 and hormone receptor expression:

- in combination with an aromatase inhibitor in postmenopausal patients.

Contraindications:

Hypersensitivity to lapatinib or any other component of the drug. Pregnancy and lactation. Childhood (no experience of use).

Carefully:

Conditions that can lead to left ventricular failure.

Function violations liver moderate or severe degree (7 or more on the Child-Pugh scale).

Age over 65 years.

Severe kidney failure.

It should avoid simultaneous reception of inducers or powerful inhibitors of isoenzyme CYP3A4, grapefruit juice.

Simultaneous administration with moderate isoenzyme inhibitors CYP3A4. It is necessary to avoid simultaneous reception with medications, which are substrates isozymes CYP3A4 and CYP2C8 with a narrow therapeutic range.

It is necessary to avoid simultaneous reception with medications, increasing the pH of gastric juice (reduced solubility and absorption of lapatinib).

Pregnancy and lactation:

Fertility

No data.

Pregnancy

There have been no relevant and well-controlled studies of lapatinib involving pregnant women. The effect of lapatinib on the fetus is unknown. Women of reproductive age should use reliable contraception, and avoid pregnancy during lapatinib treatment.

Lapatinib did not have teratogenic properties in studies on pregnant rats and rabbits, but, at the same time,was the cause of some developmental disorders when used at doses toxic to the mother.

Breastfeeding period

It is not known whether lapatinib in breast milk. Due to the fact that many drugs enter the breast milk, during lapatinib therapy it is recommended to stop breastfeeding because of the possible appearance of characteristic undesirable reactions in an infant.

Dosing and Administration:

The drug Tyverb is taken 1 hour before food or 1 hour after-meal. 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.

Locally advanced or metastatic breast cancer with overexpression HER2

In combination with capecitabine

The recommended dose of lapatinib is 1250 mg (five tablets) once daily, daily in combination with capecitabine. The recommended dose of capecitabine is 2000 mg / m²day, in 2 divided doses (every 12 hours) daily from 1 to 14 days each 21 day cycle of therapy. It is recommended that capecitabine with food or within 30 minutes after eating.

In combination with trastuzumab

The recommended dose of lapatinib is 1000 mg (four tablets) once daily, daily in combination with trastuzumab.

The recommended dose of trastuzumab is 4 mg / kg, as an intravenous loading dose, then 2 mg / kg intravenously once a week.

Hormone-receptor-positive metastatic breast cancer with overexpression HER2

The recommended dose of lapatinib is 1500 mg (six 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. If lapatinib is prescribed in combination with another aromatase inhibitor, it is necessary to study the regimen dosing corresponding preparation of this group.

Suspension of lapatinib or dose reduction (all indications)

Disorders from the cardiovascular system

Treatment with lapatinib should be discontinued if symptoms of a reduction in the left ventricular ejection fraction (LVEF) up to grade 3 or greater (according to the general toxicity criteria of the National oncology institute of the USA) or in case of decrease below the limit of the permissible norm. Treatment with lapatinib can be resumed no earlier than 2 weeks at a lower dose (reduced from 1000 mg / day to 750 mg / day with the appointment of a combination with trastuzumab, from 1,250 mg / day to 1000 mg / day when a combination with capecitabine or with 1500 mg / day to 1,250 mg / day for prescriptions with an aromatase inhibitor) if LVEF is within normal limits and the patient has no symptoms of heart failure. According to reports, the majority of cases of LVEF decrease occur during the first 12 weeks of treatment, but there is insufficient data on the long-term effects of lapatinib.

Interstitial lung disease and / or pneumonitis

Treatment with lapatinib should be discontinued if pulmonary symptoms occur that indicate the development of interstitial lung disease and / or pneumonitis of grade 3 or higher (according to the general toxicity criteria of the National Cancer Institute of the United States).

Diarrhea

Treatment with lapatinib should be suspended in patients with grade 3 diarrhea, or grade 1 or 2 with complicated symptoms (according to the general criteria for toxicity of the National Cancer Institute of the USA) (spastic abdominal pains from moderate to severe,nausea or vomiting of 2nd degree or higher (according to general toxicity criteria of the National Cancer Institute of the USA), decreased performance, fever, sepsis, neutropenia, severe bleeding or dehydration). Treatment with lapatinib can be resumed at a lower dose (reduction from 1000 mg / day to 750 mg / day, from 1,250 mg / day to 1,000 mg / day or from 1,500 mg / day to 1,250 mg / day) if the severity of diarrhea has decreased to 1 degree and below. Treatment with lapatinib 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).

Other manifestations of drug toxicity

The decision to discontinue treatment or a break in treatment with the drug may be is taken when the expression developing toxic effects 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 at a dose of 1000 mg / day when administered in combination with trastuzumab, 1250 mg / day when administered in combination with capecitabine or 1500 mg / day when given in combination with an aromatase inhibitor if the severity of toxic effects has decreased to grade 1 and below .In case of repeated toxic effects, the dose of lapatinib should be reduced from 1 LLC mg / day to 750 mg / day when administered in combination with trastuzumab, from 1250 mg / day to 1000 mg / day when administered in combination with capecitabine or 1500 mg / day to 1250 mg / day when administered in combination with an aromatase inhibitor.

Special patient groups

Children

No experience of application.

Elderly patients

There is insufficient data on the use of lapatinib in patients older than 65 beds.

Patients with impaired renal function

There is no experience with lapatinib in patients with severe renal dysfunction, but it is unlikely that correction of the dosing regimen will be required due to the fact that less than 2 % The administered dose is excreted by the kidneys.

Patients with impaired hepatic function

Lapatinib is metabolized in the liver. Moderate and severe violations of the liver are associated with an increase in systemic exposure by 56% and 85%, respectively. It should be used with caution lapatinib patients with impaired liver function. In patients with severe impairment of liver function (class C on the Child-Pugh scale), it is necessary to reduce the dose of lapatinib.Reducing the dose from 1250 mg / day to 750 mg / day (when administered in combination with capecitabine) or from 1500 mg / day to 1 mg mg / day (when used in combination with an aromatase inhibitor) in such patients leads to normalization AUC. With the development of severe manifestations of hepatotoxicity during the use of lapatinib, drug withdrawal is necessary, reassignment is unacceptable.

Side effects:

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.

The undesirable phenomena presented below are listed in accordance with the defeat of organs, organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases).

Monotherapy with lapatinib

Disorders from the metabolism and nutrition

Highly often: anorexia,

Heart Disease

Often: decreased LVEF was noted in about 1% of patients who received lapatinib, and was asymptomatic in more than 70% of cases. After the abolition of lapatinib, more than 70% of the cases showed normalization or improvement with side of LVEF. Symptomatic reduction in LVEF was observed in approximately 0.3% of patients receiving lapatinib. The undesirable phenomena observed in this case included shortness of breath, heart failure, palpitations.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: interstitial lung disease / pneumonitis.

Disorders from the gastrointestinal tract

Highly often: diarrhea (which can lead to dehydration, however, in In most cases, diarrhea of the 1 st or 2 nd degree did not lead to withdrawal of the drug), nausea, vomiting.

Disturbances from the liver and bile ducts

Infrequently: hyperbilirubinemia, hepatotoxicity. An increase in bilirubin concentration is possible due to lapatinib inhibition of conjugation in the liver of OATP1B1 (a polypeptide carrying organic anions1B1) or inhibition of bilirubin release with bile by P-glycoprotein or BCRP.

Disturbances from the skin and subcutaneous tissues

Very often: a rash (including acneiform dermatitis, in most cases passing, not requiring withdrawal of the drug).

Often: nail damage, including paronychia.

Immune system disorders

Rarely: hypersensitivity reactions, including anaphylaxis.

General disorders and disorders at the site of administration

Very often: weakness,

The use of lapatinib in combination with capecitabine

In addition to the adverse events observed with lapatinib monotherapy, the following adverse events were observed when lapatinib was used in combination with capecitabine at a frequency greater than 5% compared with capecitabine monotherapy.

Disorders from the gastrointestinal tract

Very often: indigestion.

Disturbances from the skin and subcutaneous tissues

Very often: dry skin.

Adverse events observed with lapatinib in combination with capecitabine with the same incidence as with capecitabine monotherapy.

Disorders from the gastrointestinal tract

Very often: stomatitis, constipation, abdominal pain.

Disturbances from the skin and subcutaneous tissues

Very often: palmar-plantar syndrome.

Disturbances from musculoskeletal and connective tissue

Very often: pain in the limbs, back pain.

Disturbances from the nervous system

Often: headache.

Disorders from the psyche

Very often: insomnia.

General disorders and disorders at the site of administration

Very often: inflammation of the mucous membrane of the mouth.

The use of lapatinib in combination with trastuzumab

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.

The use of lapatinib in combination with letrozole

In addition to the adverse events observed with lapatinib monotherapy, the following adverse events were observed with lapatinib in combination with letrozole at a frequency greater than 5% compared with letrozole monotherapy.

Disturbances from the respiratory system, chest and mediastinal organs

Very often: epistaxis.

Disturbances from the skin and subcutaneous tissues

Very often: alopecia, dry skin.

Overdose:

There is no specific antidote for inhibition EGFR (ERBB1) and / or HER2/neu (ERBB2) phosphorylation of tyrosine.

The maximum daily dose in clinical studies was 1800 mg.

In clinical studies, it was shown that a more frequent intake of the drug may lead to an increase in serum lapatinib concentrations, so do not take the missed dose, reducing the intervals between doses. Reception of the drug must be resumed starting at the next scheduled daily dose.

Symptoms

Asymptomatic and symptomatic signs of an overdose were noted in patients taking lapatinib. The observed symptoms included effects associated with side effects lapatinib, and in some cases, skin ulceration, sinus tachycardia (however, with a normal ECG) and / or damage to the mucosa.

Treatment

Symptomatic therapy. Excretion lapatinib kidney is insignificant due to the high connection with plasma proteins. Therefore, it is expected that hemodialysis will not be effective to enhance the excretion of lapatinib.

Further treatment should be carried out according to clinical indications or recommendations of the National Toxicology Center, if available.

Interaction:

Inhibitors or inducers of isoenzyme CYP3A may affect the pharmacokinetics of lapatinib. With the simultaneous use of lapatinib and some inhibitors of isoenzyme CYP3A4 (for example, ketoconazole, itraconazole, grapefruit juice), care must be taken to carefully monitor the patient's clinical condition and possible adverse events. If necessary, simultaneous applications patient with a potent inhibitor of isoenzyme CYP3A4 It is necessary to reduce the dose of lapatinib up to 500 mg / day, calculated in such a way as to correct AUC lapatinib 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 isoenzyme CYP3A4. After the cancellation of a potent inhibitor, only after removing it from the body, after about 1 a week should again increase the dose of lapatinib to the recommended dose.

With the simultaneous use of lapatinib and known isoenzyme inducers CYP3A4 (for example, rifampicin, carbamazepine, phenytoin, St. John's wort), care must be taken to carefully monitor the clinical condition of the patient and possible undesirable phenomena. If necessary, simultaneous applications patient is a powerful isoenzyme inductor CYP3A4 The dose of lapatinib should be selected, based on tolerability, gradually increasing it from 1,250 mg / day to 4,500 mg / day or from 1,500 mg / day to 5,500 mg / day. This dose is calculated so as to adjust AUC lapatinib to a value corresponding to the use of lapatinib without isoenzyme inducers CYP3A4. However, there are currently no clinical data on the use of lapatinib in patients receiving a strong isoenzyme inducer CYP3A4. After canceling the powerful isoenzyme inducer, after only about 2 weeks, the dose of lapatinib should be reduced again to the recommended dose. The solubility of lapatinib depends on the 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 exercised lapatinib patients, who took proton pump inhibitors.

Lapatinib inhibits in vitro isoenzyme CYP3A4 in clinically significant concentrations. Simultaneous use of lapatinib with orally administered midazolam leads to an increase AUC midazolam by about 45%. With intravenous administration of midazolam, there was no clinically significant increase AUC. Care must be taken when simultaneously application of lapatinib with orally administered drugs with a narrow therapeutic range, being the substrates of the isoenzyme CYP3A4.

Lapatinib inhibits CYP2C8 in vitro in clinically significant concentrations. Caution should be exercised use lapatinib with simultaneous application with drugs with a narrow therapeutic range, which are substrates CYP2C8.

The simultaneous use of lapatinib with paclitaxel increases the effect of paclitaxel by 23% due to inhibition by lapatinib CYP2C8 and / or P-glycoprotein (Pgp). Increased incidence and severity of diarrhea and neutropenia was observed at The use of a combination of lapatinib and paclitaxel in clinical studies. Recommended with caution use lapatinib concurrently with paclitaxel.

The simultaneous use of lapatinib with docetaxel had no significant effect on AUC or with_m_Oh 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 a treatment regimen FOLFIRI) has led to an increase AUC an active metabolite of irinotecan, SN-38, by about 40%. The exact mechanism of this interaction is unknown. Recommended with caution use lapatinib concomitantly with irinotecan. Lapatinib is a substrate for transport proteins Pgp and BCRP. Inhibitors and inducers of these proteins may alter the activity and / or distribution of lapatinib.

Lapatinib inhibits transport protein Pgp in vitro in clinically significant concentrations. Simultaneous use of lapatinib with digoxin leads to an increase AUC digoxin at about 98 %.Caution should be exercised use lapatinib with simultaneous application with drugs with a narrow therapeutic range, which are substrates PgP.

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

The use of lapatinib in combination with capecitabine, letrozole or trastuzumab does not affect the pharmacokinetic parameters of these drugs. Bioavailability of lapatinib depends on the intake of food.

Special instructions:

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

Cardiotoxicity

The use of lapatinib was accompanied by a decrease in LVEF. 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. A small, concentration-dependent increase in the interval QTc observed in an uncontrolled open-label study with increasing lapatinib dose in patients with a common tumor process. Care should be taken when prescribing lapatinib to patients, Where there is already or may be an extension of the interval QTc, including patients with hypokalemia or hypomagnesemia, congenital syndrome of an elongated QT interval; patients receiving antiarrhythmic drugs or other drugs that lead to an extension of the interval QT. Hypokalemia, hypocalcemia or hypomagnesemia should be treated before starting lapatinib.

Interstitial lung disease and pneumonitis

There have been reports of cases of interstitial lung disease and pneumonitis due to lapatinib. Patients should be under the supervision of a specialist to avoid the occurrence of pulmonary symptoms, indicative of the development of interstitial lung disease and / or pneumonitis.

Diarrhea

There have been reports of cases of diarrhea, including severe diarrhea, with lapatinib treatment. Diarrhea can be severe, cases with a fatal outcome have been described.Typically, diarrhea occurred in the early stages of lapatinib treatment, with almost half of these patients developing diarrhea within the first 6 days. Diarrhea usually lasts 4-5 days. Lapatinib-induced diarrhea manifests itself, as a rule, in an easy degree; Diarrhea 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 symptoms of bowel impairment. It is recommended timely treatment of diarrhea with antidiarrhoeal agents (for example, loperamide) after the first case of unformed stool. Severe diarrhea may require the administration of electrolytes and fluids to maintain adequate water-salt metabolism (orally or intravenously), the use of antibiotics such as fluoroquinolones (especially if diarrhea lasts more than 24 hours, if febrile or neutropenia occurs 3rd or 4- th degree), suspension or withdrawal of 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 aspartate aminotransferase (ACT), which exceed the upper limit of the norm by 3 times; the content of total bilirubin exceeding the upper limit of the norm by a factor of 1.5) was observed in clinical trials (less than 1% of patients) and in the 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 may arise during the from several days to several months after initiation of therapy. It is necessary to monitor laboratory indicators of liver function (transaminases, bilirubin and alkaline phosphatase) before the start of therapy, then every 4-6 weeks during the course of treatment and according to clinical indications. When heavy degree the violation of liver function requires the abolition of lapatinib, re-administration of the drug is unacceptable.

Patients, carriers alleles HLA DQA1 * 02:01 and DRB1 * 07:01, have an increased risk of hepatotoxicity, Related to using lapatinib. In patients who used lapatinib as a monotherapy, the overall risk of developing severe degree of disruption of function liver (ALT more than 5 times higher than the norm, 3rd degree (according to general toxicity criteria National Cancer Institute of the USA)) was higher (about 8%) in DQA1 * 02: 01 carriers 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.

In the appointment of lapatinib patients with existing violations of liver function of a serious degree in the anamnesis recommended the use of lapatinib in a reduced dose. In patients with severe hepatotoxicity, which occurred during therapy, it is necessary to cancel lapatinib and not to renew its application.

Simultaneous use of inhibitors or inducers of CYP3A4

It is necessary to appoint with caution lapatinib together with inhibitors or inductors of the CYP3A4 isoenzyme due to the risk of increasing or decreasing (respectively) the systemic effects of lapatinib.

Effect on the ability to drive transp. cf. and fur:

Influence on the ability to drive vehicles and engage in other activities that require increased concentration and speed of psychomotor reactions, has not been studied. Based on the mechanism of action of lapatinib, one can not 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 and other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:Tablets coated with a film coating of 250 mg.

Packaging:

10 tablets in a double aluminum foil blister. Each blister is perforated by a dividing line into 2 parts. In each of the parts is 5 tablets.

For 7 blisters together with instructions for use in a cardboard bundle.

2 cartons in a group package.

In the case of primary, secondary packaging and the implementation of issuing quality control at the production site of Glaxo Wellcome SA: 140tablets in a vial of high-density polyethylene with an anti-opening device for children. The bottle is sealed with a screw cap and is provided with a membrane of paper and aluminum foil, polyester and polyethylene. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:Store below 30 ° C.

Keep out of the reach of children!

Shelf life:2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000782/08

Date of registration:15.02.2008

The owner of the registration certificate:GlaxoSmithKline Helsker, ZAO GlaxoSmithKline Helsker, ZAO Russia

Manufacturer: & nbsp

GLAXO WELLCOME OPERATIONS United Kingdom

Information update date: & nbsp27.09.2015

Illustrated instructions

Instructions

Tayverb® (Tyverb®)