Гиотриф®

General characteristics. Structure:

Active ingredient: 29,59 mg of an afatinib of a dimaleate (20 mg in terms of афатиниб), 44,34 mg of an afatinib of a dimaleate (30 mg in terms of афатиниб), 59,12 mg of an afatinib of a dimaleate (40 mg in terms of афатиниб), 73,9 mg of an afatinib of a dimaleate (50 mg in terms of афатиниб).

Excipients: lactoses monohydra, cellulose microcrystallic, silicon dioxide colloid anhydrous, кросповидон, magnesium stearate.

Structure of a film cover: gipromelloza 2910, macrogoal 400, titanium dioxide (E171), talc, polysorbate 80, dye indigo carmine varnish of aluminum 11-14% (E132).

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug, proteintirozinkinaza inhibitor. Афатиниб - a powerful, selection and irreversible blocker of a proteintirozinkinaza of receptors of the Egbv family (receptors of an epidermal growth factor). Афатиниб covalently communicates and it is irreversible blocks signaling from all gomo-and the geterodimer formed by the ErbB family (EGFR (ErbB1), HER2 (ErbB2), ERBBZ and ErbB4).

On preclinical models of the tumors created by disturbances of regulation of the ErbB system, афатиниб, applied as the only drug, effectively blocks ErbB receptors, and leads to inhibition of tumoral growth or to regress of a tumor. Models of not small-celled cancer of a lung caused by EGFR mutations are especially sensitive to treatment afatiniby (L858R or Del 19). Афатиниб keeps essential antineoplastic activity of in vitro on cellular lines of not small-celled cancer of lung and in vivo on models of tumors (model with use of heterografts or transgene models) which are induced by the mutant EGFR isoforms (for example, T790M) with the known resistance to reversible EGFR inhibitors, such as эрлотиниб and гефитиниб.

Pharmacokinetics. Absorption and distribution. After use of the drug Giotrif® in Cmax of an afatinib it was noted approximately in 2-5 h. In the range of doses from 20 mg to 50 mg average Cmax and AUC0-values ∞ increased in proportional degree. Use of drug together with food led to essential reduction of exposure of an afatinib in blood approximately for 50% (Cmax) and for 39% (AUC0-∞) in comparison with use on an empty stomach. It is established that in case of the use of food during 3 h before administration of drug of Giotrif® or in 1 h after administration of drug of AUC value in an equilibrium state during reception decreased on average by 26%. After intake in the form of tablets average relative bioavailability in comparison with solution for intake makes 92% (the relation of the skorrigirovanny average sizes AUC0-∞).

Linkng of an afatinib with proteins of plasma of the person of in vitro makes about 95%. Css of an afatinib in plasma is reached within 8 days after repeated use of an afatinib.

Metabolism and removal. The metabolic reactions catalyzed by enzymes are of little importance in metabolism of an afatinib of in vivo. The main circulating metabolites of an afatinib are products of a covalent bond with proteins.

After reception of the solution containing 15 mg of an afatinib in 85.4% of the size of a dose it is found to Calais and 4.3% - in urine. Not changed афатиниб made 88% of size of the removed dose. Final T1/2 makes 37 h.

Pharmacokinetics in special clinical cases. Significant influence of age (in the range from 28 to 87 years) on pharmacokinetics of an afatinib it is not established. Special researches at children were not conducted.

In comparison with the patient with the body weight of 62 kg (average body weight in all population of patients) exposure of an afatinib in a blood plasma (AUC) at the patient with the body weight of 42 kg increases by 26%, and at the patient with the body weight of 95 kg decreases by 22%.

At women concentration of an afatinib in plasma (AUC assessment with correction concerning body weight) was 15% higher, than at men.

Statistically significant distinction of pharmacokinetics of an afatinib between various races was not noted.

Kidneys remove less than 5% of a single dose of an afatinib. Exposure of an afatinib moderately increases in process of decrease in KK. With renal failures easy or moderate severity change of a dose is not required from patients.

Афатиниб it is removed, mainly, with bile and then with a stake. Patients with lungs (a class A on a scale of Chayld-Pyyu) or moderate severity (a class B on a scale of Chayld-Pyyu) abnormal liver functions and at healthy examinees after use of a single dose of drug (50 mg) in blood had a similar exposure of an afatinib. At patients with lungs or moderate severity abnormal liver functions of change of an initial dose did not required. At patients with heavy abnormal liver functions (a class C on a scale of Chayld-Pyyu) the pharmacokinetics of an afatinib was not studied.

Influence on exposure of an afatinib of activity of LDG, ShchF and concentration of crude protein, assessment on ECOG questionnaire (Eastern Cooperative Oncology Group / East Joint Oncological Group) was clinically not significant. Existence in the anamnesis of smoking, alcohol intake or metastasises in a liver did not exert significant impact on pharmacokinetics of an afatinib.

Indications to use:

— as monotherapy to the patients who were earlier not receiving tyrosinekinase inhibitors for treatment of locally-spread or metastatic not small-celled cancer of lung with a mutation (mutations) of a receptor of an epidermal growth factor of EGFR.

Route of administration and doses:

Drug is taken inside, on an empty stomach, not less than for 1 h before meal or later 3 h after meal. Tablets are swallowed entirely, washing down with water.

At not small-celled cancer of a lung as therapy of the first line or at patients who did not receive EGFR proteintirozinkinaza inhibitors the recommended dose earlier makes 40 mg of 1 times/days.

Treatment has to continue before progressing of a disease or development of signs of unacceptable toxicity (table 1).

The maximum daily dose in all clinical cases makes 50 mg.

Special instructions on dosing. Increase in a dose. In case of portability of the drug Giotrif® in a dose of 40 mg/days within the first 3 weeks of treatment, i.e. in case of absence of diarrhea, skin rash, stomatitis and other undesirable phenomena (severity> caused by drug 1 on classification of CTCAE1) the dose of drug can be increased to 50 mg/days. The dose should not be raised when earlier it was lowered.

Change of a dose in case of development of undesirable reactions. It is possible to overcome undesirable reactions of an organism (for example, heavy ongoing diarrhea or skin rash) by a break in treatment or reduction of a dose of drug (table 1).

Table 1. Information on change of a dose in case of undesirable reactions

Severity of side reactions (according to classification of CTCAE)	The recommended drug Giotrif® dose adjustment
1 or 2 severity	Break not trebuyetsya2	Dosing does not change
2 severity (zatyanuvshiyesya3 or intolerable reactions) or ≥3 severity	Break before decrease in severity to 0/12	Resuming with a gradual dose decline every time on 10 mg4

1 Uniform terminological criteria for undesirable phenomena NCI (NCI Common Terminology Criteria for Adverse Events v 3.0).

2 In case of development of diarrhea antidiarrheal means have to be applied immediately (for example, loperamide). Their use continues before the termination of diarrhea.

3 For diarrhea - more than 48 h, for rash - more than 7 days.

4 If the patient does not transfer a dose of 20 mg/days, it must be kept in mind final drug withdrawal.

If at the patient acute develop or chronic respiratory symptoms amplify, it is necessary to take a possibility of development of the intersticial pulmonary disease (IPD) into account. In these cases of Giotrif® it is necessary to cancel temporarily before obtaining results of inspection. If existence of IBL is confirmed, treatment by drug should be cancelled. If necessary the corresponding treatment is carried out.

Admission of a dose. If the dose of drug is passed, it needs to be accepted on the same day as soon as the patient remembers it. But if before reception of the following planned dose there were no more than 8 h, the passed dose should not be accepted.

Renal failure. With lungs or moderate severity renal failures of change of an initial dose of drug is not required from patients. Treatment by the drug Giotrif® of patients with heavy renal failures (KK <30 ml/min.) is not recommended.

Abnormal liver functions. With easy or moderate abnormal liver functions (a class A and B on a scale of Chayld-Pyyu) change of an initial dose of drug is not required from patients. At patients with heavy abnormal liver functions (a class C on a scale of Chayld-Pyyu) афатиниб it was not studied. Treatment by the drug Giotrif® at these patients is not recommended.

Age, race, floor. Change of a dose depending on age, race or a sex of patients is not required.

Alternative way of reception. If reception of the whole tablets of drug is impossible, they can be dispersed approximately in 100 ml of non-carbonated drinking water. Other liquids for this purpose are not used. The tablet should be placed in water, without breaking and to periodically stir a suspension within 15 min. until the tablet does not break up to very fine particles. The received suspension needs to be accepted immediately. The glass should be rinsed with about 100 ml of water which needs also to be drunk. Dispersion can be also applied by means of a gastric tube.

Features of use:

Pregnancy. Researches at pregnant women were not conducted. Therefore the potential risk for the person is unknown. In preclinical trials of an afatnnib when using the doses reaching and exceeding lethal doses for females of animals, signs of teratogenecity were not noted. Undesirable changes were noted only when using the doses considerably exceeding toxic.

Women with the kept ability to conceive should recommend to avoid pregnancy during treatment. During therapy and within, at least, 2 weeks after use of the last dose of drug adequate methods of contraception have to be used. If Giotrif® is used during pregnancy or if pregnancy develops in usage time of the drug Giotrif®, the patient has to be informed on potential danger to a fruit.

Breastfeeding. On the basis of these preclinical trials penetration of an afatnnib into breast milk is considered probable. It is impossible to exclude existence of risk for the baby. During treatment patients should recommend to refuse feeding by a breast.

Fertility. Fertility researches with use of the drug Giotrif® at the person were not conducted. The existing preclinical data on toxicology confirm influence of drug on reproductive organs in case of use of high doses. Therefore it is not possible to exclude negative impact of therapy on fertility at the person.

Use at abnormal liver functions. With easy or moderate abnormal liver functions (a class A and B on a scale of Chayld-Pyyu) change of an initial dose of drug is not required from patients. At patients with heavy abnormal liver functions (a class C on a scale of Chayld-Pyyu) афатиниб it was not studied. Treatment by drug Giotrif at these patients is not recommended

Use at renal failures. With lungs or moderate severity renal failures of change of an initial dose of drug is not required from patients. Treatment by drug Giotrif of patients with heavy renal failures (the clearance of creatinine <30 ml/min.) is not recommended.

Use for children. It is contraindicated to children up to 18 years.

Use for elderly patients. Change of a dose depending on age of patients is not required.

Assessment of the status of a mutation of EGFR. For assessment of the status of a mutation of EGFR at the patient it is important to use well approved and reliable method to avoid false-negative or false positive results.

Diarrhea. Preventive treatment of diarrhea is important, especially in the first 6 weeks of therapy at emergence of the first signs. Treatment consists in water loss completion by an organism and simultaneous use of antidiarrheal means (loperamide) which dose if necessary should be raised till most recommended. Anti-diarrheal means have to be at the disposal of patients that treatment could begin at the first symptoms of diarrhea and proceed until the liquid chair is not absent during 12 h. At patients with heavy diarrhea treatment interruption, reduction of a dose or the termination of therapy can be required. In case of development of dehydration can be required in/in use of electrolytes and liquids.

Skin reactions. Patients who are forced to be in the sun are recommended to wear sun-protection clothes and/or to use sun-protection screens. Timely intervention at dermatological reactions (for example, emollients, antibiotics) is able to afford to continue treatment.

At patients with the dragged-on or expressed skin reactions temporary interruption of therapy, reduction of a dose, additional therapeutic intervention and consultation of the specialist having experience of treatment of similar dermatological reactions can be also required. In case of development in the patient of serious violent rash, blisters or exfoliative changes treatment by drug needs to be interrupted or stopped.

Female, low body weight and the accompanying renal failures. At women, at patients with lower body weight and at the accompanying renal failures the risk of development of the undesirable phenomena, such as diarrhea, a rash/acne and stomatitis can increase. With these risk factors more careful control of a condition of patients is recommended.

Intersticial pulmonary diseases. Researches at patients with existence of IBL in the anamnesis were not conducted. At all patients with the acute beginning and/or with inexplicable strengthening of pulmonary symptoms (short wind, cough, fever) careful examination for IBL exception has to be conducted. Before completion of this inspection administration of drug needs to be interrupted. If the diagnosis of IBL is established, Giotrif® should be cancelled. If necessary it is necessary to appoint the corresponding treatment.

Considerable abnormal liver functions. At patients with associated diseases of a liver periodic check of function of a liver is recommended. In case of deterioration in function of a liver treatment interruption by drug can be required. At patients with heavy abnormal liver functions treatment by drug needs to be stopped.

Keratitis. In case of such for the first time arisen or amplified symptoms as an inflammation of eyes, dacryagogue, a photophobia, a sight illegibility, eye pain and/or reddening of eyes, the patient has to consult immediately with the ophthalmologist. If the diagnosis of an ulcer keratitis is confirmed, treatment by the drug Giotrif® should be interrupted or stopped. It is necessary to weigh carefully advantage and risk of continuation of treatment. At patients with a keratitis, an ulcer keratitis or the expressed xerophthalmus in the anamnesis Giotrif® it is necessary to apply with care. Risk factor of emergence of a keratitis and helcomas also is use of contact lenses.

Function of a left ventricle of heart. The inhibition of a receptor of HER2 can lead to dysfunction of a left ventricle. In a daily dose of 50 mg after single and repeated use for patients with recurrent or refractory solid tumors does not cause essential lengthening of an interval of QTcF. Changes of indicators which would cause clinical concern were not observed that testifies to lack of significant effect on QTcF interval. However patients with disturbances have fractions of emission of a left ventricle or at patients with serious associated diseases of heart of Giotrif® was not studied. At patients with risk factors of heart diseases and diseases which can break fraction of emission of a left ventricle before purpose of the drug Giotrif® and during treatment it is recommended to estimate fraction of emission of a left ventricle. In case of development during treatment of signs/symptoms of damage of heart it is necessary to carry out monitoring of a condition of heart, including assessment of fraction of emission of a left ventricle.

When values of fraction of emission of a left ventricle decrease below the lower bound of the norm established in this medical institution consultation of the cardiologist and consideration of a question of interruption or the termination of treatment is recommended by drug.

Influence of drug on ability of control of vehicles, mechanisms. Researches on influence of drug on ability to control of vehicles and to others potentially dangerous types of activity, demanding the increased concentration of attention and speed of psychomotor reactions, it was not conducted.

Side effects:

Determination of frequency of side reactions: very often (> 1/10); often (> 1/100; ≤1/10); infrequently (> 1/1000; ≤1/100); seldom (> 1/10 000; ≤1/1000); very seldom (≤1/10 000).

From a nervous system: often - disturbance of flavoring sensitivity.

From an organ of sight: often - conjunctivitis, a xerophthalmus; infrequently - a keratitis.

From respiratory system: very often - bleeding from a nose; often - a rhinorrhea; infrequently - an intersticial pulmonary disease; asthma *, cough *, pneumonitis *, distress-sindrom*.

From the alimentary system: very often - diarrhea, stomatitis; often - a cheilitis, dyspepsia: nausea *, vomiting *, запор*.

From gepatobiliarny system: often - increase in activity of ALT, ACT; increase in concentration of the general bilirubin *, cytolytic hepatitis *, hepatic недостаточность*.

Co of the side of skin and hypodermic fabrics: very often - rash, akneformny dermatitis, an itch, a xeroderma; often - a palmar and bottom syndrome (eritrodizesteziya); changes ногтей*.

From cardiovascular system: cordial недостаточность*.

From a musculoskeletal system: often - spasms of muscles, pain in спине*.

From an urinary system: often - dysfunction of kidneys / a renal failure.

From a metabolism: very often - a loss of appetite; often - dehydration, a hypopotassemia.

Infections and invasions: very often - a paronychia; often - cystitis.

General reactions: often - a pyrexia; утомляемость*.

The disturbances revealed at researches: often - a body degrowth; anemia *, neutropenia *, increase in activity of ShchF*.

* these side reactions were observed at conduct of clinical trials, however communication with administration of drug of Giotrif® is not proved.

Interaction with other medicines:

Interaction with P-glycoprotein inductors/inhibitors. On the basis of the data obtained by in vitro it is established what афатиниб is substrate for the R-glycoprotein. Changes of concentration of other substrates of the R-glycoprotein in plasma during use of the drug Giotrif® it is considered improbable. Clinical data specify that simultaneous use of strong inhibitors or inductors of a P-glycoprotein can change influence of an afatinib.

Гиотриф® it is possible to combine safely with P-glycoprotein inhibitors (such as ритонавир) along with reception or after administration of drug of Giotrif®. If strong inhibitors of a P-glycoprotein (including, for example, ритонавир, cyclosporine, кетоконазол, итраконазол, erythromycin, verapamil, quinidine, такролимус, нелфинавир, саквинавир and Amiodaronum) are applied before administration of drug of Giotrif®, increase in influence of an afatinib is possible; in these cases of Giotrif® it is necessary to apply with care.

Strong inductors of a P-glycoprotein (including, for example, carbamazepine, Phenytoinum, phenobarbital or a St. John's Wort made a hole (Hypericum perforatum) can reduce exposure of an afatinib.

Medicinal transport systems. The data obtained by in vitro demonstrate that medicinal interaction with afatiniby owing to inhibition of the transport molecules OATB1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2 and OCT3 is improbable. The researches in vitro showed what афатиниб is substrate and inhibitor of the conveyor of protein of resistance to a breast cancer.

Influence of inductors and inhibitors of isoenzymes of CYP on афатиниб. The data obtained by in vitro demonstrate that medicinal interaction with afatiniby owing to inhibition or induction of isoenzymes of CYP at the same time applied medicines is improbable. At the person it is established that the metabolic reactions catalyzed by enzymes are of little importance in metabolism of an afatinib. About 2% of the size of a dose of an afatinib were metabolized by FMO3 and way of CYP3A4-dependent N-demethylation, the maintenance of metabolites was so low that was not defined quantitatively.

UDP глюкуронозилтрансфераза 1A1. The data obtained by in vitro demonstrate that medicinal interaction with afatiniby owing to inhibition UDP глюкуронозилтрансферазы 1A1 is improbable.

Contraindications:

— hypersensitivity to an afatinib or to any component of drug;

— heavy abnormal liver functions;

— children's and teenage age up to 18 years;

— pregnancy;

— period of a lactation (breastfeeding).

With care: keratitis; ulcer keratitis; the expressed xerophthalmus; intersticial pulmonary disease; disturbances of fraction of emission of a left ventricle; associated diseases of heart; intolerance of a galactose, syndrome of disturbance of absorption of galactose/glucose or deficit of lactase.

Overdose:

Symptoms: in clinical trials at limited number of patients doses of 160 mg of 1 times/days within 3 days and 100 mg of 1 times/days within 2 weeks were studied. First of all, skin rashes (rash/acne) and gastrointestinal frustration (generally diarrhea) were undesirable reactions which were observed at administration of drug in these doses. Use of drug in a dose of 360 mg together with other medicines was followed by the following undesirable reactions: nausea, vomiting, an adynamy, dizziness, a headache, abdominal pains and increase in level of amylase (the exceeding VGN more than by 1.5 times).

Treatment: at suspicion on overdose it is necessary to cancel Giotrif® and to carry out symptomatic therapy. In the presence of indications it is possible to remove not soaked up афатиниб by a gastric lavage or having caused vomiting. There is no specific antidote on a case of overdose.

Storage conditions:

Drug should be stored in the unavailable to children, dry, protected from light place, in densely corked bottle, at a temperature not above 25 °C. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

On 30 pieces of tablets in polypropylene banks, after 1 bank in a cardboard pack.