Expiration date: 02/2025

Available on request

Pharmacological group

Nosological classification (ICD-10)

Composition

Tablets, film-coated. 1 tablet contains active substance:  

axitinib 1 or 5 mg

excipients: MCC-63.25 / 107.43 mg; lactose monohydrate-32/56 mg; sodium croscarmellose-3/5, 25 mg; magnesium stearate-0.75/1.32 mg  

film shell: Opadry red (hypromellose-1,12 / 1,96 mg, titanium dioxide-0,68 / 1,2 mg, lactose monohydrate-1,6/2,8 mg, triacetin-0,32/0,56 mg, iron oxide red dye-0,28/0,48 mg) - 4/7 mg  

Description of dosage form

Film coated tablets, 1 mg: red oval, engraved "Pfizer" on one side, "1" and "XNB" on the other.

Tablets, film-coated, 5 mg: white, triangular, with engraving "Pfizer" on one side and "5" and "XNB" on the other.

2 layers are visible on the cross section. The core of the tablet is white or almost white.

Pharmacological action

Pharmacological action-antitumor, tyrosine kinase inhibitor.

Pharmacodynamics

Mechanism of action

Axitinib is a powerful and selective tyrosine kinase inhibitor of vascular endothelial growth factor (vascular endothelial growth factor receptors — VEGFR-1, VEGFR-2 and VEGFR-3) receptors involved in the mechanisms of pathological angiogenesis, tumor growth and metastasis of malignant tumors. Axitinib has been shown to provide powerful inhibition of VEGFR-mediated endothelial cell proliferation and survival. Axitinib inhibits phosphorylation of VEGFR-2 in vessels of xenografts of malignant tumors expressing target receptors in vivo and provides tumor growth retardation, regression and inhibition of metastasis of many experimental models of malignant tumors.

Pharmacokinetics

T1/2 of axitinib from blood plasma ranges from 2.5 to 6.1 hours Reception axitinib at a dose of 5 mg 2 times a day results in less than twofold kemuliaanmu of axitinib compared with the single administration. Due to the short T1 / 2 axitinib, the equilibrium state is expected to be achieved within 2-3 days after initiation of therapy.

Suction and distribution. Tmax axitinib in blood plasma-4 h after administration; median Tmax in blood plasma varies from 2.5 to 4.1 h.

Reception of axitinib with food with moderate fat content leads to a decrease in the exposure value by 10% compared to fasting. Reception of axitinib with high-calorie food leads to a decrease in exposures to 190% compared with fasting. Thus, axitinib can be taken regardless of the meal.

The average values of Cmax and AUC increase proportionally to the increase in the dose of axitinib in the dose range from 5 to 10 mg.the binding of axitinib in vitro with human plasma proteins is ?99% (mainly — with albumin, to a moderate extent — with ?1-acid glycoprotein). When taking axitinib at a dose of 5 mg 2 times a day after meals geometric mean Cmax and daily AUC in patients with advanced renal cell carcinoma were 27.8 ng/ml and 265 ng·h / ml, respectively. The geometric mean of clearance and Vd were 38 l / h and 160 l, respectively.

Metabolism and excretion. Axitinib is mainly metabolized in the liver with the participation of isoenzymes CYP3A4 / 5 and to a lesser extent — CYP1A2, CVP2C19 and UDF-GT 1A1 (UGT1A1). After oral administration of radioactive isotope labeled axitinib at a dose of 5 mg 30-60% of the administered dose of radioactivity was found in feces and 23% — in urine. Unchanged axitinib accounted for 12% of the administered dose, and it was the main component found in the faeces, but was not found in the urine. In urine, a large proportion of radioactivity accounted for carboxylic acid-a derivative of axitinib and its sulfoxide metabolite. In blood plasma, N-glucuronide accounted for the largest share of circulating radioactivity (50%), the share of unchanged axitinib and its sulfoxide metabolite accounted for approximately 20% of circulating radioactivity.

Sulfoxide and N-glucuronide metabolites had approximately 400 and 8000 times less activity in vitro, respectively, with respect to VEGFR-2 compared with unchanged axitinib.

Special patient groups

Gender, race and age. There was no clinically significant effect of age, sex, body weight, race, kidney function, genotypes of UDF-GT 1A1 or CYP2C19 on the parameters of the pharmacokinetics of axitinib.

Children. The use of axitinib in patients under 18 years of age has not been investigated.

Impaired liver function. Studies in vitro and in vivo have shown that axitinib is metabolized primarily in the liver. Compared with patients with normal liver function, the values of systemic exposure of axitinib in patients with impaired liver function of mild severity (class a but classification child-Pugh) were identical, and in patients with impaired liver function of moderate severity (class B classification child-Pugh) — higher. The use of axitinib in patients with severe hepatic impairment (class C, child-Pugh classification) has not been studied.

Impaired renal function. The use of axitinib in patients with impaired renal function has not been studied. Based on pharmacokinetic population analysis, there were no significant differences in the clearance of axitinib in patients with moderate and severe renal impairment (15 ml/min ?Cl creatinine <89 ml/min).

The testimony of the drug Inlyta®

Common renal cell carcinoma (as a second-line therapy).

Contraindications

• hypersensitivity to axitinib and other components of the drug;
• severe hepatic impairment (class C, child-Pugh classification);
• arterial thromboembolism during the previous 12 months;
• venous thromboembolism during the previous 6 months;
• metastatic brain damage, for which no appropriate treatment was carried out;
• recently transferred or currently available gastrointestinal bleeding;
• pregnancy and breastfeeding;
• children under the age of 18 (safety and efficacy not investigated).

With caution: the presence of risk factors for arterial thromboembolism (such as transient ischemic attack, myocardial infarction and cerebral circulation); venous thromboembolism (such as pulmonary embolism, deep vein thrombosis and occlusion or Central retinal vein thrombosis) including history; lactase deficiency, lactose intolerance or glucose-galactose malabsorption; renal dysfunction severe (creatinine CL <15 ml/min).

Use during pregnancy and breast-feeding

Adequate and well-controlled studies of axitinib when used during pregnancy in humans have not been conducted. Axitinib can cause damage to the fetus when used during pregnancy. Women of childbearing age should be informed about the need to avoid pregnancy in the background and within 1 week after therapy with axitinib. When using this drug during pregnancy (for life indications, when other drugs can not be used or they are ineffective) or during pregnancy in a patient receiving axitinib, she should be informed about the potential risk of adverse effects in the fetus.

Studies of the influence of axitinib on the production of breast milk in women, its ability to penetrate into breast milk or have a negative impact on a breast-fed child have not been conducted. Given the fact that many drugs penetrate into breast milk, as well as the possibility of developing serious adverse reactions in a breastfed child, you should either stop breastfeeding or complete therapy with axitinib, taking into account the importance of this drug for the mother.

Side effect

The most frequent (?20%) adverse reactions observed during therapy with axitinib were diarrhea, increased blood PRESSURE, fatigue, decreased appetite, nausea, dysphonia, syndrome of palm-plantar erythrodysesthesia, weight loss, vomiting, asthenia and constipation.

The frequency of adverse reactions is presented in the following classification: very often — ?10%; often - ?1 and <10%; infrequently - ?0.1 and <1%; rarely - ?0.01 and <0.1%; very rarely — <0.01%; the frequency is unknown — it is impossible to determine on the basis of available data.

Of the heart and blood vessels: often — arterial hypertension, bleeding (including epistaxis, hematuria, hemoptysis, rectal bleeding, bleeding in the brain, stomach bleeding and bleeding in the lower gastrointestinal tract); often, venous embolic and thrombotic events (including pulmonary embolism, occlusion/retinal vein occlusion and deep vein thrombosis), arterial embolic and thrombotic events (including transient ischemic attack and acute cerebrovascular disease), effects of heart failure (including heart failure, congestive heart failure, cardiopulmonary failure, left ventricular dysfunction, reduced ejection fraction and right ventricular failure), in some cases — fatal; infrequently — hypertensive crisis.

From the endocrine system: very often — hypothyroidism; often-hyperthyroidism.

On the part of the organ of vision: infrequently-occlusion or thrombosis of the Central retinal vein.

On the part of the organ of hearing and labyrinth disorders: often noise in the ears.

From the blood: very often — diarrhea, vomiting, nausea, pain in the abdomen, stomatitis, constipation, dyspepsia, and often hemorrhoids, pain in the upper abdomen, perforation of the gastrointestinal tract, fistula, flatulence, glossodynia.

The liver and biliary tract: rarely — hyperbilirubinemia.

From the metabolism and nutrition: very often — decreased appetite; often — dehydration, hyperkalemia, hypercalcemia, hypocalcemia.

From the nervous system: very often — headache, dysgeusia; often — dizziness; infrequently — syndrome reversible rear leukoencephalopathy (SOSL), stroke.

From the musculoskeletal and connective tissue: very often — arthralgia, pain in the limbs; often-myalgia.

From the blood and lymphatic system: often-anemia, polycythemia, thrombocytopenia; infrequently — neutropenia, leukopenia.

From the respiratory system, chest and mediastinal organs: very often — dyspnea, cough, dysphonia; often — hemoptysis, pain in the oropharynx.

From the skin and subcutaneous tissues: very often — syndrome of Palmar-plantar erythrodysesthesia (Palmar-plantar syndrome), skin rash, dry skin; often — erythema, itching, alopecia.

From the kidneys and urinary tract: very often — proteinuria; often — renal failure.

General disorders and disorders at the site of administration: very often — increased fatigue, asthenia, inflammation of the mucous membranes.

Laboratory and instrumental data: very often — weight loss; often-increasing the concentration of creatinine, increased activity of ALT, ACT, schf, lipase, amylase; hypoglycemia, hyperglycemia, decrease in the concentration of bicarbonates, hypernatremia, hyponatremia, hypoalbuminemia, hypophosphatemia, reducing the concentration of platelets, white blood cells, lymphocytes, lowering the concentration of hemoglobin, increasing the concentration of thyroid-stimulating hormone.

Interaction

Inhibitors of the isoenzyme CYP3A4/5

Simultaneous use of axitinib with potent inhibitors of CYP3A4/5 isoenzymes, in particular ketoconazole, Itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodon, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole, should be avoided.

Simultaneous use with ketoconazole (a powerful inhibitor of CYP3A4/5 isoenzymes), leads to an increase in the concentration of axitinib in blood plasma in healthy volunteers.

Grapefruit or grapefruit juice can also increase the concentration of axitinib in the blood plasma, and their simultaneous use should also be avoided.

It is recommended to select alternative drugs that do not inhibit CYP3A4/5 isoenzymes or inhibit their activity to a minimum extent. If it is necessary to combine axitinib with powerful inhibitors of CYP3A4/5 isoenzymes, it is recommended to reduce its dose (see "Method of application and dose").

CYP1A2 and CYP2C19 isoenzyme inhibitors

The isoenzymes CYP1A2 and CYP2C19 support a smaller portion (<10%) pathways of metabolism of axitinib. The effect of powerful inhibitors of these isoenzymes on the pharmacokinetics of axitinib has not been studied. Caution should be exercised with simultaneous use of axitinib and potent inhibitors of isoenzymes CYP1A2 and CYP2C19, as the concentration of axitinib in plasma may increase.

Inducers of the isoenzyme CYP3A4/5

It should be avoided simultaneous use of axitinib with powerful inducers of CYP3A4/5 isoenzymes, in particular rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital and St. John's wort (Hypericum perforatum). Rifampicin (a powerful inducer of CYP3A4/5 isoenzymes) reduces the average AUC of axitinib in healthy volunteers. It is recommended to select alternative drugs that do not induce CYP3A4/5 isoenzymes or induce their activity to a minimum extent, for combination with axitinib. Medium-sized inhibitors of CYP3A4/5 isoenzymes (such as bosentan, efavirenz, etravirine, modafinil and nafcillin) may also reduce plasma concentrations of axitinib, and their simultaneous use should be avoided if possible.

Induction of CYP1A2 isoenzyme during Smoking

The CYP1A2 isoenzyme supports a smaller portion (<10%) pathways of metabolism of axitinib. The influence of induction of CYP1A2 isoenzyme caused by Smoking on the pharmacokinetics of axitinib fully understood. It should be taken into account the possibility of reducing the concentration of axitinib in blood plasma when using axitinib in smokers.

Studies of the ability of axitinib to inhibit and induce cytochrome P450 and uridine 5'-diphosphate glucuronosyltransferase (UGT) in vitro

It has been shown in vitro that axitinib in therapeutic plasma concentrations does not inhibit the activity of isoenzymes CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or UGT1A1.

In in vitro studies it was also noted that axitinib has a potential ability to inhibit the activity of CYP1A2 isoenzyme. Therefore, simultaneous reception of axitinib with substrates of CYP1A2 isoenzyme may lead to increased concentration of the latter (e.g. theophylline) in the blood plasma.

In in vitro studies, it has also been shown that axitinib has the potential to inhibit the CYP2C8 isoenzyme. However, the simultaneous use of axitinib with paclitaxel, which is a substrate of CYP2C8 isoenzyme, did not lead to an increase in the concentration of the LATTER in blood plasma in patients with common malignant tumors, indicating the absence of clinically significant inhibition of CYP2C8 isoenzyme in these conditions.

In in vitro studies using human hepatocytes it was noted that axitinib does not induce CYP1A1, CYP1A2 or CYP3A4/5 isoenzymes. Therefore, it is not expected to reduce the concentration of blood plasma substrates of these isoenzymes with their simultaneous use with axitinib in vivo.

Studies of the ability of axitinib to interact with P-glycoprotein in vitro

In in vitro studies have shown that axitinib is able to inhibit P-glycoprotein, but this effect is not expected in the presence of axitinib in blood plasma in therapeutic concentrations. Therefore, the therapy with axitinib is not expected to increase the concentration of digoxin or other substrates of P-glycoprotein in blood plasma in vivo.

Dosage and administration

Inside, swallowing whole, drinking a glass of water, regardless of the meal.

The recommended initial dose is 5 mg 2 times a day with an interval between doses of approximately 12 hours.

With the development of vomiting or skipping dose should not take an additional dose of the drug, and take the next dose at the usual time for her.

Therapy is continued as long as there is a positive effect of treatment or until there is a development of severe toxicity, which can not be controlled by the appointment of additional therapy or by adjusting the dose of axitinib.

Recommendations for dose adjustment

Increasing and reducing the dose is recommended depending on the individual safety assessment and tolerability.

Patients tolerate the drug Inlyta® in an initial dose (5 mg 2 times a day) without the development of adverse reactions above the 2-nd degree of gravity, according to General criteria for the assessment of the severity of adverse events (Common Terminology Criteria for Adverse Events — CTCAE) for two consecutive weeks, provided that AD does not exceed 150/90 mm Hg.and there is no need for standard antihypertensive therapy, it is possible to increase the dose to 7 mg 2 times a day. Then, using the same criteria for patients who carry axitinib at a dose of 7 mg 2 times a day, it is possible to further increase the dose to a maximum of 10 mg 2 times a day.

For correction of some adverse reactions may require temporary or complete cancellation, and/or dose reduction of axitinib. If necessary, it is allowed to reduce the dose of axitinib to 3 mg 2 times a day, then to 2 mg 2 times a day.

Dose adjustment depending on the race, sex or body weight of the patient is not required.

Concomitant use with potent inhibitors of CYP3A4/5. It is recommended to select alternative drugs that do not inhibit CYP3A4/5 isoenzymes or inhibit their activity to a minimum extent. Modes of dose adjustment of axitinib in its application in patients receiving powerful inhibitors of CYP3A4/5 isoenzymes have not been studied. If necessary, the simultaneous use of the dose of axitinib is recommended to reduce by about half (for example, from the initial dose of 5 mg 2 times a day to 2 mg 2 times a day). Subsequent doses should be increased or decreased depending on individual tolerance and safety. After the abolition of a powerful inhibitor (3-5 T1 / 2 of the inhibitor) should consider returning to the dose of axitinib, which the patient received prior to therapy with a powerful inhibitor of isoenzymes CYP3A4/5.

Concomitant use with potent inducers of the isoenzyme CYP3A4/5. It is recommended to select alternative drugs that do not induce CYP3A4/5 isoenzymes or induce their activity to a minimum extent, for combination with axitinib. Modes of dose adjustment of axitinib in its application in patients receiving powerful inducers of CYP3A4/5 isoenzymes have not been studied. If it is necessary to use simultaneously, it is recommended to gradually increase the dose of axitinib with careful monitoring of the patient's condition for the development of symptoms of toxicity. After the abolition of the powerful inducer of CYP3A4 / 5 isoenzymes, it is necessary to immediately return to the dose of axitinib, which the patient received before the start of combination therapy.

Impaired liver function. Dose adjustment in patients with impaired liver function of mild severity (class a classification child-Pugh) is not required. In patients with impaired liver function of moderate severity (class b classification child-Pugh) is recommended to reduce the dose of axitinib approximately twice. The use of the drug Inlyta® has not been studied in patients with hepatic impairment, severe (class C classification for child-Pugh).

Impaired renal function. In patients with impaired renal function of mild to moderate severity dose adjustment is not required. In patients with impaired renal function severe (creatinine Cl <15 ml/min) the drug Inlyta® should be taken with caution.

Elderly patient. Correction of the dose is not required.

Overdose

Symptoms: an unintentional overdose of the drug was reported in one patient when he took axitinib at a dose of 20 mg 2 times a day for 4 days, after which he was dizzy (1st degree of severity). In a clinical study of axitinib with the selection of doses, patients received the drug at an initial dose of 10 mg 2 times a day or 20 mg 2 times a day. At the same time, they had an increase in blood PRESSURE, associated with the development of seizures and fatal hemoptysis.

Treatment: specific treatment of axitinib overdose is not developed. If you suspect an overdose, you should suspend the therapy with axitinib and carry out the necessary supportive treatment.

Special instruction

Phenomena of heart failure. In the course of therapy with axitinib, it is necessary to periodically monitor the signs and symptoms of heart failure. Treatment of heart failure may require temporary or permanent discontinuation of axitinib and / or reduction of its dose.

Arterial hypertension. There are reports of increased blood pressure when using the drug Inlyta®. Basically, this side effect is observed during the 1st month of therapy, mainly in the first 4 days. Before starting therapy with axitinib, it is necessary to adjust blood PRESSURE. In the future, it is necessary to carefully monitor patients for increased blood PRESSURE and, if necessary, the appointment of standard hypotensive therapy. With the development of persistent hypertension, despite the use of antihypertensive drugs, it is necessary to reduce the dose of axitinib. You should stop your treatment with axitinib with the development of severe and sustained hypertension that is not amenable to antihypertensive therapy and is not relieved on a reducing dose Inlyta®. It is also necessary to assess the feasibility of discontinuation of therapy with axitinib in the appearance of signs of hypertensive crisis. It should be borne in mind that after the abolition of axitinib, patients receiving hypotensive agents should be observed for hypotension.

Arterial thromboembolism. There are reports of the development of arterial thromboembolism (including transient ischemic attack, cerebral circulation disorders, myocardial infarction and retinal artery occlusion), including 2 fatal cases associated with cerebral circulation. Care should be taken when using the drug Inlyta® in patients with risk factors for arterial thromboembolism or having similar episodes in history. It should be noted that the drug Inlyta® has not been investigated in patients undergoing arterial thromboembolism in preceding 12 months.

Venous thromboembolism. There are also reports of venous thromboembolism (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis), including fatal pulmonary embolism. Care should be taken when using the drug Inlyta® in patients with risk factors for venous thromboembolism or having similar episodes in history. It should also be noted that the drug Inlyta® has not been investigated in patients undergoing venous thromboembolism in the prior 6 months.

Disorders of the thyroid gland. It is recommended to conduct a study of thyroid function before the start of therapy with axitinib, and then periodically — during treatment. Correction of hypothyroidism and hyperthyroidism should be carried out in accordance with standard principles before reaching the euthyroid state.

Assessment of hemoglobin or hematocrit concentration. Against the background of therapy with axitinib, an increase in the concentration of hemoglobin or hematocrit can be observed, reflecting an increase in the erythrocyte mass in the body. This phenomenon may increase the risk of thromboembolism. It is recommended to monitor the concentration of hemoglobin or hematocrit before starting therapy with axitinib and periodically during it. Correction of increase of concentration of hemoglobin or hematocrit above VGN is made according to the standard principles.

Bleedings. Reported cases of development of bleeding in patients treated with axitinib (including intracranial hemorrhage, hematuria, hemoptysis, bleeding from the lower gastrointestinal tract, and melena), including 1 case with fatal outcome (gastric bleeding). Be aware that the drug Inlyta® has not been investigated in patients with signs of metastatic lesions of the brain, which was not carried out appropriate treatment, and in patients who have recently had or currently available gastrointestinal bleeding. In this regard, you should not use the drug Inlyta® in these patient groups. With the development of any bleeding that requires medical care, you should temporarily stop therapy with axitinib.

Perforation of the gastrointestinal tract and fistula formation. Clinical studies have reported cases of gastrointestinal perforation and fistula formation, including fatal cases. Against the background of therapy with axitinib, it is necessary to carry out periodic monitoring for clinical manifestations of these conditions.

Disorders of wound healing. Formal studies of the effect of axitinib on wound healing processes have not been conducted.

Therapy with axitinib should be stopped at least 24 hours before the planned surgery. The decision to resume therapy with axitinib in the postoperative period should be based on the results of clinical evaluation of the course of the wound process.

SSL. It is a neurological disorder that can be manifested by headache, seizures, retardation, confusion, blindness and other visual and neurological disorders. It is possible to increase blood PRESSURE from mild to severe. The diagnosis of SOZL is confirmed by magnetic resonance imaging. Discontinue use of the drug Inlyta® in patients with clinical manifestations SSL. The safety of the resumption of therapy with axitinib in patients with a history of SOZL is unknown.

Proteinuria. It is recommended to check for the presence of proteinuria before therapy with axitinib and periodically during treatment. With the development of proteinuria moderate or severe degree of severity required dose reduction or temporary withdrawal of the drug Inlyta®.

Increased activity of liver enzymes. It is recommended to study the activity of ALT and ACT and bilirubin concentration before the start of therapy with axitinib and periodically during treatment.

Influence on the ability to drive and other complex mechanisms. Studies of the influence of axitinib on the ability to drive a car and work with mechanisms that require increased concentration have not been conducted. Patients should be informed of the possibility of development of some adverse effects, particularly dizziness and/or fatigue, on the background of drug therapy Inlyta®.

Form release

Tablets, film-coated, 1 mg and 5 mg. In blister of aluminum foil, 14 PCs, 2 or 4 blisters in a cardboard box.

Manufacturer

Pfizer, Manufacturing Of Main GmbH. Mooswaldallee 1, 79090 Freiburg, Germany.

Claims of consumers should be sent to the address of the representative office of Pfizer h Corporation.Si.Pi. Corporation": 123317, Moscow, Presnenskaya nab., 10, BC "tower on the Embankment" (Block C).

Phone: +7 (495) 287-50-00; Fax: +7 (495) 287-53-00/287-50-67.

Storage conditions of the drug Inlyta®

At a temperature not exceeding 30 °C.

Keep out of reach of children.

The shelf life of the drug Inlyta®

3 years.