Expiration date: 03/2025

Available on request

Form release

tablets

Composition

Active substance: afatinib dimaleate 20, 30, 40 and 50 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, silicon colloidal anhydrous dioxide, crospovidone, magnesium stearate

Packaging

30 PCs.

Pharmacological action

Giotrif is an antitumor drug, an inhibitor of protein tyrosine kinase. Afatinib is a powerful, selective and irreversible blocker of the protein tyrosine kinase receptors of the EGb family (epidermal growth factor receptors). Afatinib covalently binds and irreversibly blocks signaling from all Homo - and heterodimers formed by the ErbB family (EGFR (ErbB1), HER2 (ErbB2), and ErbB4 ErbB?).

In preclinical models of tumors created by impaired regulation of the ErbB system, afatinib, used as a single drug, effectively blocks ErbB receptors, and leads to inhibition of tumor growth or tumor regression. Models of non-small cell lung cancer caused by EGFR mutations (L858R or Del 19) are particularly sensitive to afatinib treatment. Afatinib retains significant antitumor activity in vitro on cell lines of non-small cell lung cancer and in vivo on tumor models (models using xenotransplants or transgenic models) that are induced by mutant EGFR isoforms (e.g. T790M) with known resistance to reversible EGFR inhibitors such as erlotinib and gefitinib.

Pharmacokinetics

Suction and distribution

After application of the drug inside Geotrip Cmax of Affinia noted in approximately 2-5 h. In the dose range of 20 mg to 50 mg average values Smahi AUC0-? increased in a proportionate degree. The use of the drug together with food led to a significant reduction in the exposure of afatinib in the blood by about 50% (Cmax) and 39% (AUC0-?) compared with the use of fasting. It was found that in the case of eating for 3 hours before taking the drug Giotrif or 1 h after taking the drug AUC values in equilibrium during the reception decreased by an average of 26%. After oral administration in the form of tablets, the average relative bioavailability compared with oral solution is 92% (the ratio of the adjusted average values of AUC0-?).

The binding of afatinib to human plasma proteins in vitro is about 95%. Css afatinib in plasma is achieved within 8 days after repeated use of afatinib.

Metabolism and excretion

Metabolic reactions catalyzed by enzymes play a minor role in the metabolism of afatinib in vivo. The main circulating metabolites of afatinib are products of covalent binding to proteins.

After taking a solution containing 15 mg of afatinib, inside 85.4% of the dose is found in the feces and 4.3% - in the urine. Unchanged afatinib was 88% of the value of the output dose. The final T1/2 consist of 37 h

Pharmacokinetics in special clinical cases

Significant influence of age (in the range from 28 to 87 years) on the pharmacokinetics of afatinib is not established. No special studies have been conducted in children.

Compared to a patient weighing 62 kg (average body weight across the patient population) exposition of Affinia in plasma (AUC) in a patient with body weight of 42 kg is increased by 26%, and in a patient with a body weight of 95 kg is reduced by 22%.

In women, the plasma concentration of afatinib (AUC estimate with correction for body weight) was 15% higher than in men.

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

Less than 5% of a single dose of afatinib is excreted by the kidneys. The exposure of afatinib moderately increases with decreasing QC. In patients with impaired renal function mild or moderate in severity, a dose modification is not required.

Afatinib is excreted mainly in the bile and then in the feces. In patients with mild (grade a on the child Pugh scale) or moderate (grade B on the child Pugh scale) hepatic impairment and in healthy subjects after a single dose of the drug (50 mg), the exposure of afatinib in the blood was similar. In patients with mild or moderate hepatic impairment changes in the initial dose are not required. In patients with severe hepatic impairment (grade C on the child-Pugh scale), the pharmacokinetics of afatinib has not been studied.

The effect of LDH activity and total protein concentration on afatinib exposure and ECOG (Eastern Cooperative Oncology Group/Eastern United Cancer Group) questionnaire assessment was not clinically significant. The presence in the history of Smoking, alcohol or liver metastases had no significant effect on the pharmacokinetics of afatinib.

Giotrif, indications for use

As 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 mutation (mutations) of the epidermal growth factor receptor EGFR.

Contraindications

• hypersensitivity to afatinib or to any component of the drug;
  
• severe hepatic impairment;
  
• child and adolescence to 18 years;
  
• pregnancy;
  
• lactation (breastfeeding).
  

With caution: keratitis; ulcerative keratitis; severe dry eyes; interstitial lung disease; left ventricular ejection fraction disorders; concomitant heart disease; galactose intolerance, galactose/glucose malabsorption syndrome or lactase deficiency.

Method of application and doses

The drug is taken orally, on an empty stomach, at least 1 hour before a meal or 3 hours after a meal. Tablets are swallowed whole, washed down with water.

At small cell lung cancer as first-line therapy or in patients who have not previously received an EGFR inhibitor proteincontaining the recommended dose is 40 mg 1 time per day.

Treatment should continue until the disease progresses or signs of unacceptable toxicity develop.

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

Side effect

From the nervous system: often - violation of taste sensitivity.

From the organ of vision: often-conjunctivitis, dry eyes; infrequently-keratitis.

From the respiratory system: very often - bleeding from the nose; often-rhinorrhea; infrequently-interstitial lung disease; shortness of breath, cough, pneumonitis, distress syndrome.

From the digestive system: very often - diarrhea, stomatitis; often-cheilitis, dyspepsia: nausea, vomiting, constipation.

From the hepatobiliary system: often - increased activity of ALT, AST; increased concentration of total bilirubin, cytolytic hepatitis, liver failure.

From the skin and subcutaneous tissues: very often - rash, acne, itching, dry skin; often-Palmar-plantar syndrome (erythrodysesthesia); nail changes.

From the cardiovascular system: heart failure.

From the side of musculoskeletal system: often - muscle spasms, back pain.

From the urinary system: often-renal dysfunction / renal failure.

From the metabolism: very often - decreased appetite; often-dehydration, hypokalemia.

Infections and infestations: very often - paronychia; often-cystitis.

Common reactions: often-pyrexia; fatigue.

Drug interaction

Interaction with p-glycoprotein inducers/inhibitors

Based on the data obtained in vitro, it was found that afatinib is a substrate for P-glycoprotein. Changes in the concentrations of other substrates of p-glycoprotein in plasma during the use of the drug Giotrif is considered unlikely. Clinical evidence suggests that concomitant use of strong p-glycoprotein inhibitors or inducers may alter the effects of afatinib.

Geotrip can be safely combined with inhibitors of P-glycoprotein (such as ritonavir) simultaneously with or after administration of the drug Gitrif. If strong inhibitors of P-glycoprotein (including, for example, ritonavir, cyclosporine, ketoconazole, Itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir and amiodarone) are used before taking the drug Giotrif, it is possible to increase the effect of afatinib; in these cases, Giotrif should be used with caution.

Strong p-glycoprotein inducers (including, for example, carbamazepine, phenytoin, phenobarbital or Hypericum perforatum) can reduce the exposure of afatinib.

Drug transport systems

Data obtained in vitro indicate that drug interactions with affinion by inhibiting the transport of molecules OATP1B1, OATP1B3, OATP2B1B1, OAT1, OAT3, OST1, OCT2 and OCT3 unlikely. In vitro studies have shown that afatinib is a substrate and Transporter inhibitor of breast cancer resistance protein.

Effect of CYP isoenzyme inducers and inhibitors on afatinib

Data obtained in vitro indicate that drug interactions with affinion due to inhibition or induction of CYP isozymes at the same time that medicines are unlikely. In humans, it was found that metabolic reactions, catalyzed by enzymes, play a minor role in the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3 and by SUR3A4-dependent N-demethylation, the metabolite content was so low that it was not quantified.

UDP glucuronosyltransferase 1A1

Data obtained in vitro indicate that drug interactions with affinion due to inhibition of UDP-glucuronosyltransferase 1A1 is unlikely.

Overdose

Symptoms: in clinical studies, a limited number of patients studied doses of 160 mg 1 time/day for 3 days and 100 mg 1 time/day for 2 weeks. Adverse reactions that were observed when taking the drug at these doses were primarily skin rashes (rash/acne) and gastrointestinal disorders (mainly diarrhea). The use of the drug at a dose of 360 mg in conjunction with other drugs was accompanied by the following undesirable reactions: nausea, vomiting, asthenia, dizziness, headache, abdominal pain and an increase in amylase levels (exceeding IOP more than 1.5 times).

Treatment: if you suspect an overdose, you need to cancel the Giotrif and conduct symptomatic therapy. If there are indications to remove nevsosavsheysya afatinib can be by washing the stomach or causing vomiting. There is no specific antidote in case of overdose.

Storage conditions

In a dark place, in a well-sealed container, at a temperature not exceeding 25 °C.

Shelf life

3 years