Giotrif - instructions for use, doses, side effects, contraindications

Active substanceAfatinibAfatinib

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Giotrif®

pills inwards

Boehringer Ingelheim International GmbH Germany

Dosage form: & nbspfilm coated tablets

Composition:

One 20 mg tablet contains:

Active substance: aphatinib dimaleate - 29.56 mg, which corresponds to 20 mg of apathinib base;

Excipients: lactose monohydrate - 123.86 mg, microcrystalline cellulose - 18.48 mg, silicon dioxide colloidal anhydrous - 0.9 mg, crospovidone - 3.6 mg, magnesium stearate - 3.6 mg;

Film membrane: hypromellose 2910-2.5 mg, macrogol 400-0.5 mg, titanium dioxide (E171) 1.2 mg, talc 0.65 mg, polysorbate 80-0.15 mg.

One 30 mg tablet contains:

The active substance: aphatinib dimaleate - 44.34 mg, which corresponds to 30 mg of apathinib base;

Excipients: lactose monohydrate 185.79 mg, microcrystalline cellulose 27.72 mg, silicon dioxide colloidal anhydrous 1.35 mg, crospovidone 5.4 mg, magnesium stearate 5.4 mg;

Film membrane: hypromellose 2910-3.5 mg, macrogol 400 0.7 mg, titanium dioxide (E171) 0.66825 mg, talc 1.6625 mg. polysorbate 80 - 0.21 mg, dye indigo carmine lacquer aluminum 11-14% (E132) - 0.245 mg.

One 40 mg tablet contains:

The active substance: afatiniba dimaleate - 59.12 mg, which corresponds to 40 mg of apathinib base;

Excipients: lactose monohydrate - 247.72 mg, microcrystalline cellulose - 36.96 mg, silicon dioxide colloidal anhydrous - 1.8 mg, crospovidone - 7.2 mg, magnesium stearate - 7.2 mg;

Film membrane: hypromellose 2910 - 4.0 mg, macrogol 400 - 0.8 mg, titanium dioxide (E171) - 1.808 mg, talc - 1.04 mg, polysorbate 80 - 0.24 mg, dye indigo carmine lacquer aluminum 11-14 % (E132) 0.112 mg.

One 50 mg tablet contains:

The active substance: aphatinib dimaleate - 73.9 mg, which corresponds to 50 mg of apathinib base;

Excipients: lactose monohydrate - 309.65 mg, microcrystalline cellulose - 46.2 mg, silicon dioxide colloidal anhydrous - 2.25 mg, crospovidone - 9.0 mg, magnesium stearate - 9.0 mg;

Film membrane: hypromellose 2910 - 5.0 mg, macrogol 400 - 1.0 mg, titanium dioxide (E171) - 0.97 mg, talc - 2.375 mg, polysorbate 80 - 0.3 mg, dye indigo carmine lacquer aluminum 11-14 % (E132) 0.35 mg.

Description:

Tablets 20 mg

Round biconvex with beveled edges of the tablet, covered with a film shell from white to slightly yellowish color, on the cross section the nucleus is almost white, with an engraving of the symbol of Boehringer Ingelheim on one side and "T20" on the other side of the tablet.

Tablets 30 mg

Round biconvex with bevelled edges of the tablet, covered with a film shell of blue color, on the cross section, the nucleus is almost white, with the engraving of the symbol of Boehringer Ingelheim on one side and "T30" on the other side of the tablet.

Tablets 40 mg

Round biconvex with bevelled edges of the tablet, covered with a film shell of blue color, on the cross section the nucleus is almost white, with an engraving of the symbol of Boehringer Ingelheim on one side and "T40" on the other side of the tablet.

50 mg tablets

Oval biconvex tablets covered with a film shell of blue color, on the cross section the nucleus is almost white, with an engraving of the Boehringer Ingelheim symbol on one side and "T50" on the other side of the tablet.

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E Protein kinase inhibitors

L.01.X.E.13 Afatinib

Pharmacodynamics:

Afatinib is a potent, selective and irreversible E protein receptor blockerrbB (receptors of the epidermal growth factor). Afatinib covalently binds and irreversibly blocks the transmission of signals from all homo- and heterodimers formed by the E familyrbAT (EGFR (ErbBl), HER2 (ErbB2), ErbO3 and ErbAT 4).

On preclinical models of tumors created by disorders of the regulation of system ErbAT, apathinib, used as a single drug, effectively blocks the E receptorsrbB, and leads to inhibition of tumor growth or to tumor regression.Especially sensitive to the treatment with apathinib of the non-small cell lung cancer model caused by mutations EGFR (L858R or Del 19). Afatinib retains significant antitumor activity vitro on the cell lines of non-small cell lung cancer and in vivo on tumor models (xenograft models or transgenic models) that are induced by mutant isoforms EGFR (for example, T790M) with known resistance to reversible inhibitors EGFR, such as erlotinib and gefitinib.

Pharmacokinetics:

Suction and distribution

After application of the GIOTRIF preparation inside maximum concentrations (Cmax) of apathinib were noted after about 2-5 hours. In the dose range from 20 mg to 50 mg, the average values of Cmax and AUC₀-_∞ (area under the curve "concentration-time") increased in a proportional degree. The use of the drug together with food resulted in a significant decrease in the exposure of apathinib in the blood by approximately 50% (Cmah) and 39% (AUC₀-_∞) compared with fasting. It is established that in case of eating food for 3 hours before taking the drug GIOTRIF or 1 hour after taking the drug values AUC_t_,_ss (under stationary conditions for the dosing period) decreased by an average of 26%. After oral administration in the form of tablets, the average relative bioavailability compared with the oral solution is 92% (the ratio of the adjusted average values AUC₀-_∞).

The association of apatinib with plasma proteins in vitro is about 95% in humans.

Metabolism and excretion

Metabolic reactions catalyzed by enzymes play an insignificant role in the metabolism of aphatinib in vivo. The main circulating metabolites of apathinib are the products of a covalent bond with proteins.

After taking a solution containing 15 mg of apathinib, 85.4% of the dose was detected in the stool and 4.3% in the urine. Unchanged apathinib was 88% of the output dose. The final half-life is 37 hours. The equilibrium concentration of apathinib in plasma is reached within 8 days after multiple use of apathinib.

Pharmacokinetics in special groups patients

Age

Significant influence of age (range: 28-87 years) on the pharmacokinetics of apathinib has not been established. Special studies in children were not conducted.

Body mass

Compared with a patient weighing 62 kg (average body weight of patients in the entire population of patients), the exposure of apathinib in plasma AUC_t_,_ss) Have a patient with a body weight of 42 kg is increased by 26%, and in a patient with a body weight of 95 kg is reduced by 22%.

Floor

In women, the concentration of apathinib in plasma (evaluation AUC_t_,_sswith a correction for body weight) was 15% higher than that of men.

Race

There was no statistically significant difference in the pharmacokinetics of apathinib between different races.

Renal impairment

Through the kidneys, less than 5% of a single dose of apathinib is excreted. The exposure of apathinib moderately increases as the creatinine clearance decreases. In patients with mild or moderate severity, impaired renal function is not required to change the dose.

Dysfunction of the liver

Afatinib is excreted mainly with bile and then with feces. In patients with lungs (grade A on the Child-Pugh scale) or moderate severity (class B on the Child-Pugh scale), violations of liver function and in healthy subjects after a single dose of the drug (50 mg), the exposure of apathinib in the blood was similar. In patients with mild or moderate severity of liver function disorders, changes in the initial dose are not required.In patients with severe impairment of liver function (class C on the Child-Pugh scale), the pharmacokinetics of apathinib have not been studied.

Other characteristics / characteristics of patients

Effect on the exposure of apathinib activity of lactate dehydrogenase, alkaline phosphatase and total protein concentration, evaluation according to the questionnaire ECOG (Eastern Cooperative Oncology Group, Eastern United Oncology Group) was clinically insignificant. The presence of a history of smoking, alcohol consumption or metastases in the liver did not have a significant effect on the pharmacokinetics of apathinib.

Indications:

The GIOTRIF is shown as a monotherapy for patients who have not previously received tyrosine kinase inhibitors for the treatment of locally advanced or metastatic non-small cell lung cancer with the mutation of the epidermal growth factor receptor EGFR.

Contraindications:

- hypersensitivity to apathinib or to any component of the drug;

- severe violations of liver function;

- children's age till 18 years;

- pregnancy and the period of breastfeeding.

Carefully:

- keratitis;

- ulcerative keratitis;

- severe dry eyes;

- interstitial lung disease;

- violation of the left ventricular ejection fraction;

- concomitant diseases of the heart;

- intolerance to galactose, a syndrome of malabsorption of galactose / glucose, or deficiency of lactase.

Pregnancy and lactation:

Pregnancy

Studies in pregnant women have not been conducted. Therefore, the potential risk to humans is unknown. In pre-clinical studies of apathinib, there were no signs of teratogenicity when doses reaching and exceeding lethal doses for female animals were used. Undesirable changes were noted only when doses significantly exceeded the toxic dose.

Women with preserved fertility should be advised to avoid pregnancy during treatment. During therapy and for at least 2 weeks after the last dose of the drug, adequate contraceptive methods should be used. If the GIOTRIF is used during pregnancy, or if the pregnancy develops during the use of the GIOTRIF drug, the patient should be informed of the potential hazard to the fetus.

Breast-feeding

Based on the data from pre-clinical studies, the penetration of apathinib into breast milk is considered probable. It is impossible to exclude the risk for an infant. During treatment, patients should be advised to refuse breastfeeding.

Fertility

Studies of fertility using the drug GIOTRIF in humans have not been conducted. Existing preclinical data on toxicology indicate the effect of the drug on the reproductive organs in the case of high doses. Therefore, it is not possible to exclude the negative effect of therapy on fertility in humans.

Dosing and Administration:

Tablets are taken orally, on an empty stomach, at least 1 hour before meals or 3 hours after eating. The tablets are swallowed whole, washed down with water.

Non-small cell lung cancer

As first-line therapy or in patients who have not previously received EGFR protein tyrosine kinase inhibitors, the recommended dose is 40 mg, once a day. Treatment should continue until the disease progresses or signs of unacceptable toxicity develop (see Table 1). The maximum daily dose in all clinical cases is 50 mg.

Special instructions for dosing

Increase in dose

In case of drug tolerance

GIOTRIF at a dose of 40 mg / day for the first 3 weeks of treatment, i.e. in the absence of diarrhea, skin rash, stomatitis and other undesirable effects caused by the drug (severity> 1 according to the classification of STAEA¹) the dose of the drug can be increased to 50 mg / day. The dose of the drug should not be increased in cases when it previously decreased.

Dose change in case of adverse reactions

Overcome undesirable reactions of the body (for example, severe persistent diarrhea or skin rash) can be by interruption in treatment or a reduction in the dose of the drug (see Table 1).

Table 1. Information on dose changes in case of undesirable reactions

The phenomenon caused by the drug is undesirable (in accordance with the classification of CTCAE¹)	Recommended methods of dosing the drug GIOTRIF
1 or 2 severity	Break is not required²	Dosing does not change
2 severity (prolonged ²or intolerable reactions) or ≥3 degrees of severity	Break before gravity down to 0/1²	Renewal with a gradual decrease in dose every 10 mg⁴

¹Common terminology criteria for NCI (NCI Common Terminology Criteria for Adverse Events V 3.0)

² In the case of diarrhea, antidiarrhoeic agents should be used immediately (for example, loperamide). Their application continues until the cessation of diarrhea.

³ For diarrhea - more than 48 hours, for rashes - more than 7 days.

⁴ If the patient does not tolerate a dose of 20 mg / day, the final cancellation of the drug should be considered.

If the patient develops acute or worsens chronic respiratory symptoms, the possibility of developing IBL should be taken into account. In these cases, the GIOTRIF should be temporarily canceled until the results of the survey are obtained. If the presence of the IBL is confirmed, the drug should be discontinued. If necessary, appropriate treatment is provided.

Dose skip

If the dose is missed, it should be taken on the same day as the patient remembers it. But if there is not more than 8 hours left before the next scheduled dose, the missed dose should not be taken.

Impaired renal function

In patients with mild or moderate severity, impaired renal function does not require a change in the initial dose of the drug.Treatment with GIOTRIF patients with severe impairment of kidney function (creatinine clearance <30 ml / min) is not recommended.

Dysfunction of the liver

In patients with mild or moderate severity of liver function disorders (class A and B on the Child-Pugh scale), no change in the initial dose of the drug is required. In patients with severe impairment of liver function (class C on the Child-Pugh scale) apathinib not studied. Treatment with GIOTRIF in these patients is not recommended.

Age, race, gender

Dose changes are not required depending on the age, race or sex of patients.

Alternative method of admission

If the intake of whole drug tablets is not possible, they can be dispersed in approximately 100 ml of still fresh drinking water. Other liquids are not used for this. The tablet should be placed in water without breaking, and periodically stir the slurry for 15 minutes until the tablet breaks up into very small particles. The resulting suspension must be taken immediately. A glass should be rinsed with approximately 100 ml of water, which must also be drunk. The dispersion can also be used with a gastric probe.

Side effects:

The incidence of adverse reactions listed below is described in accordance with the following gradation: very often (> 1/10); often (> 1/100; <1/10); infrequently (> 1/1000; <1/100); rarely (> 1/10000; <1/1000); very rarely (<1/10000).

Disturbances from the nervous system

Often - a violation of taste sensitivity.

Disturbances on the part of the organ of sight

Often - conjunctivitis, dry eyes; infrequently keratitis.

Disturbances from the respiratory system

Very often bleeding from the nose; often - rhinorrhea; infrequently - interstitial lung disease; shortness of breath *, cough *, pneumonitis *, distress syndrome *.

Disorders from the gastrointestinal tract

Very often - diarrhea, stomatitis; often - cheilitis, dyspepsia; nausea, vomiting, constipation.

Disorders from the hepatobiliary system

Often - increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT); an increase in the concentration of total bilirubin *, cytolytic hepatitis *, liver failure *.

Disturbances from the skin and subcutaneous tissues

Very often - a rash, acneiform dermatitis, itching, dry skin; often - palmar dyspnea syndrome (erythrodysesthesia); changes of nails *.

Disorders from the cardiovascular system

Heart failure*.

Disturbances from musculoskeletal system and connective tissue

Hasto - muscle spasms; backache*.

Disorders from the kidneys and urinary tract

Often - a violation of kidney function / renal failure.

Infections and invasions

Very often - paronychia; often - cystitis.

Metabolic disorders and eating disorders

Very often - a decrease in appetite; often - dehydration, hypokalemia.

Common Disorders

Often - pyrexia; fatigue *.

Abnormalities identified in studies

Often - weight reduction; anemia *, neutropenia *, increased activity of alkaline phosphatase *.

* - these adverse reactions were observed during clinical trials, but the connection with the use of the GIOTRIF preparation was not proved.

Overdose:

Symptoms

In clinical trials, a limited number of patients were studied doses of 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The undesirable phenomena observed with the use of these doses were, first of all, skin rashes (rash / acne) and gastrointestinal disorders (mainly diarrhea). The use of the drug in a dose of 360 mg together with other medicines was accompanied by the following undesirable phenomena: nausea, vomiting, asthenia, dizziness, headache,pain in the abdomen and an increase in the level of amylase (exceeding the upper limit of the norm by more than 1.5 times).

Treatment

There is no specific antidote for overdose. If there is a suspicion of overdose, it is necessary to cancel the GIOTRIF and carry out symptomatic therapy. If there are indications, remove the non-sucked apathinib can be by washing the stomach or causing vomiting.

Interaction:

Interactions with inducers / inhibitors of glycoprotein-P

Based on the data obtained in vitro, determined that apathinib is a substrate for glycoprotein-P. Changes in the concentrations of other glycoprotein-P substrates in plasma during the application of the GIOTRIF preparation are considered unlikely. Clinical data indicate that the simultaneous use of strong inhibitors or inducers of glycoprotein-P can alter the effects of apathinib.

The GIOTRIF can be safely combined with glycoprotein-P inhibitors (such as ritonavir) concomitantly with taking or after taking the drug GIOTRIF. If strong inhibitors of glycoprotein-P (including, for example, ritonavir, ciclosporin, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir and amiodarone) are used before the GIOTRIF preparation, an increase in the effect of apathinib is possible; in these cases, the GIOTRIF should be used with caution.

Strong inductors of glycoprotein-P (including, for example, carbamazepine, phenytoin, phenobarbital or St. John's Wort (Hypericum perforatum) can reduce the exposure of apatinib.

Medicinal transport systems

Data received in vitro, indicate that inter-drug interactions with aphatinib due to inhibition of transport molecules OATB1B1, OATP1B3, OATP2B1, OAT1, OATZ, OST1, OST2 and OST3 are unlikely. Research in vitro showed that apathinib is a substrate and inhibitor of the transporter protein of resistance to breast cancer.

Effects of inducers and inhibitors of isoenzymes CYP on apathinib

Data received in vitro, suggest that the inter-drug interactions with aphatinib due to inhibition or induction of isoenzymes CYP simultaneously used drugs are unlikely. In humans, it has been established that metabolic reactions catalyzed by enzymes play an insignificant role in the metabolism of apathinib. Approximately 2% of the dose of apathinib was metabolized FM03 and by CYRPA4-dependent N-detylation, the content of metabolites was so low that it was not quantified.

UDP-glucuronosyltransferase 1A1

Data received in vitro, suggest that the inter-drug interactions with apathinib due to inhibition UDP-glucuronosyltransferase 1A1 are unlikely.

Special instructions:

Assessment of the status of the EGFR mutation

To assess the status of the EGFR mutation in a patient it is important to use a well-tested 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 with the appearance of the first signs. Treatment consists in replenishment of water loss by the body and simultaneous use of antidiarrheal agents (loperamide), the dose of which, if necessary, should be increased to the maximum recommended. Antidiarrheal drugs should be available to patients so that treatment can begin at the first sign of diarrhea and continue until the stool is absent for 12 hours.Patients with severe diarrhea may require interruption of treatment, dose reduction or discontinuation of therapy. In the case of dehydration, intravenous use of electrolytes and liquids may be required.

Skin Reactions

Patients who are forced to stay in the sun are advised to wear sunscreen and / or use sunscreens. Timely intervention with dermatological reactions (eg, emollients, antibiotics) may allow further treatment. Patients with prolonged or severe skin reactions may also need temporary interruption of therapy, dose reduction, additional therapeutic intervention and advice from a specialist experienced in treating similar dermatological reactions. If the patient develops a serious bullous rash. blisters or exfoliative changes, the drug should be discontinued or discontinued.

Female sex, low body weight and concomitant renal dysfunction

In women, patients with a lower body weight and with concomitant renal dysfunction may increase the risk of developing adverse events such as diarrhea,rash / acne and stomatitis. If these risk factors are present, more careful monitoring of the patients' condition is recommended.

Interstitial lung diseases (IBL)

Studies in patients with a history of IBL have not been conducted. In all patients with acute onset and / or unexplained increase in pulmonary symptoms (dyspnea, cough, fever), a thorough examination should be conducted to exclude IBL. Before the completion of this survey, the drug should be discontinued. If the diagnosis of the IBL is established, the GIOTRIF should be discontinued. If necessary, appropriate treatment should be given.

Significant liver dysfunction

In patients with concomitant liver diseases, periodic check of liver function is recommended. In case of impaired liver function, interruption of drug treatment may be required. In patients with severe impairment of liver function, the drug should be discontinued.

Keratite

In the case of the appearance of such first appeared or increased symptoms, like eye inflammation, lacrimation, photophobia. blurred vision, pain in the eyes and / or redness of the eyes, the patient should immediately consult an ophthalmologist.If the diagnosis of ulcerative keratitis is confirmed, treatment with GIOTRIF should be interrupted or discontinued. It is necessary to carefully weigh the benefits and risks of continuing treatment. In patients with keratitis, ulcerative keratitis or severe dry eyes in the history of the GIOTRIF should be used with caution. The risk of keratitis and corneal ulcers is also caused by the use of contact lenses.

Function of the left ventricle of the heart

Inhibition of the HER2 receptor can lead to left ventricular dysfunction. In a daily dose of 50 mg after a single and repeated use in patients with relapsing or refractory solid tumors does not cause a significant prolongation of the QTcF interval. Changes in indicators that would cause clinical concern were not observed, indicating that there is no significant effect on the QTcF interval. However, in patients with disturbances of the left ventricular ejection fraction or in patients with serious comorbidities of the heart, the GIOTRIF was not studied. In patients with risk factors for heart disease and diseases that may violate the left ventricular ejection fraction, it is recommended to evaluate the left ventricular ejection fraction before the administration of the GIOTRIF preparation and during treatment.If cardiac signs / symptoms develop during treatment, cardiac monitoring should be performed, including an assessment of the left ventricular ejection fraction. In those cases where the values of the left ventricular ejection fraction fall below the lower limit of the norm established in this medical institution, it is recommended that the cardiologist consult and consider interrupting or stopping treatment with the drug.

Combination with vinorelbine in patients with NOTR2-positive metastatic breast cancer

An early interim analysis of the overall survival of patients with HER2-positive metastatic breast cancer in a randomized study III phase showed a higher mortality in patients receiving the GIOTRIF in combination with vinorelbine, compared with a combination of trastuzumab and vinorelbine. The incidence of side effects (such as diarrhea, rash) and fatalities associated with infection and progression of the tumor was also higher in patients taking the combination of the drug GIOTRIF with vinorelin compared with a combination of trastuzumab and vinorelbine.GYOTRIF in combination with vinorelbine should not be used in patients with HER2-positive metastatic breast cancer.

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

Studies on the effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions have not been conducted.

Form release / dosage:

Tablets, film-coated 20 mg, 30 mg, 40 mg and 50 mg.

Packaging:

For 30 tablets in a bottle of polypropylene with a screwed plastic lid with a moisture absorber. One bottle together with instructions for use in a cardboard box.

Storage conditions:

Store in a tightly closed vial in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002275

Date of registration:11.10.2013 / 03.04.2014

Expiration Date:11.10.2018

The owner of the registration certificate:Boehringer Ingelheim International GmbHBoehringer Ingelheim International GmbH Germany

Manufacturer: & nbsp

BOEHRINGER INGELHEIM PHARMA, GmbH Austria

Representation: & nbspBERINGER INGELCHAIM INTERNATIONAL GmbH BERINGER INGELCHAIM INTERNATIONAL GmbH Germany

Information update date: & nbsp03.10.2014

Illustrated instructions

Instructions

Giotrif® (Giotrif®)