Inlyta^® (Tablets) Instructions for Use

ATC Code

L01EK01 (Axitinib)

Active Substance

Axitinib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent – protein tyrosine kinase inhibitor

Pharmacological Action

Antitumor agent, a selective inhibitor of tyrosine kinase of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3, which are involved in the mechanisms of pathological angiogenesis, tumor growth, and metastasis of malignant neoplasms.

It has been shown that Axitinib provides potent inhibition of VEGF-mediated proliferation and survival of endothelial cells.

Axitinib inhibits phosphorylation of VEGFR-2 in the vessels of malignant neoplasm xenografts expressing target receptors in vivo and provides slowing of tumor growth, regression, and inhibition of metastasis in many experimental models of malignant neoplasms.

Pharmacokinetics

After oral administration, C_max is usually reached within 4 hours. T_max ranges from 2.5 to 4.1 hours.

Taking axitinib with food with a moderate fat content leads to a 10% decrease in exposure values compared to taking on an empty stomach. Taking axitinib with a high-calorie meal leads to a 19% decrease in exposure values compared to taking on an empty stomach.

The plasma T_1/2 of axitinib is 2.5-6.1 hours. Taking axitinib at a dose of 5 mg twice daily leads to less than a twofold accumulation of axitinib compared to a single dose.

Due to the short T_1/2 of axitinib, steady state is expected to be reached within 2-3 days after the start of therapy.

Mean C_max and AUC values increase proportionally with increasing axitinib dose in the dose range from 5 mg to 10 mg. In vitro binding of axitinib to human plasma proteins is >99% (primarily to albumin, and to a moderate extent to α1-acid glycoprotein).

When taking axitinib at a dose of 5 mg twice daily after a meal, the geometric mean C_max and daily AUC value in patients with advanced renal cell carcinoma were 27.8 ng/ml and 265 ng×h/ml, respectively. The mean clearance and V_d values were 38 L/h and 160 L, respectively.

It is metabolized mainly in the liver with the participation of CYP3A4/5 isoenzymes and, to a lesser extent, by CYP1A2, CYP2C19 isoenzymes and uridine 5′-diphosphate-glucuronosyltransferase 1A1 (UGT1A1).

After oral administration of radiolabeled axitinib at a dose of 5 mg, 30-60% of the administered radioactive dose was found in the feces and 23% in the urine. Unchanged axitinib accounted for 12% of the administered dose and was the main component found in the feces, but was not detected in the urine.

In urine, a large proportion of radioactivity was accounted for by the carboxylic acid derivative of axitinib and its sulfoxide metabolite. In plasma, the N-glucuronide accounted for the largest proportion of circulating radioactivity (50%), while unchanged axitinib and its sulfoxide metabolite accounted for approximately 20% of circulating radioactivity.

The sulfoxide and N-glucuronide metabolites had approximately 400 and 8000 times less in vitro activity, respectively, against VEGFR-2 compared to unchanged axitinib.

Indications

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

ICD codes

Dosage Regimen

Tablets

Take orally.

The recommended starting dose is 5 mg twice daily with an interval between doses of approximately 12 hours.

Therapy is continued as long as a positive treatment effect is observed or until the development of severe toxicity that cannot be controlled by additional therapy or by adjusting the axitinib dose.

Dose increases and decreases are recommended based on individual safety and tolerability assessments.

To manage certain adverse reactions, temporary or complete discontinuation and/or dose reduction of axitinib may be required. If necessary, the axitinib dose can be reduced to 3 mg twice daily, then to 2 mg twice daily.

The dose of axitinib should be adjusted when it is necessary to use it concomitantly with strong inhibitors or inducers of CYP3A4/5 isoenzymes and immediately after their discontinuation.

In patients with moderate hepatic impairment (Child-Pugh class B), a reduction of the axitinib dose by approximately half is recommended.

Adverse Reactions

From the cardiovascular system: very common – increased blood pressure, bleeding (including cerebral hemorrhage); common – venous thromboembolism (including deep vein thrombosis), arterial thromboembolism (there are reports of myocardial infarction); uncommon – hypertensive crisis.

From the sensory organs: common – tinnitus; uncommon – occlusion or thrombosis of the central retinal vein.

From the digestive system: very common – diarrhea, vomiting, nausea, abdominal pain, stomatitis, constipation, dyspepsia; common – hemorrhoids, rectal bleeding, gastric bleeding, lower gastrointestinal bleeding, upper abdominal pain, gastrointestinal perforation, fistulas, flatulence, glossodynia.

From the metabolism: very common – hypothyroidism, decreased appetite; common – dehydration, hyperkalemia, hypercalcemia, hypocalcemia, hyperthyroidism.

From the nervous system: very common – headache, dysgeusia; common – dizziness; uncommon – transient ischemic attack, reversible posterior leukoencephalopathy syndrome, stroke.

From the musculoskeletal system: very common – arthralgia, limb pain; common – myalgia.

From the hematopoietic system: common – anemia, polycythemia, thrombocytopenia: uncommon – neutropenia, leukopenia.

From the respiratory system: very common – dyspnea, cough, dysphonia; common – pulmonary embolism, hemoptysis, epistaxis, oropharyngeal pain.

From the skin and subcutaneous tissues: very common – palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), skin rash, dry skin; common – erythema, skin itching, alopecia.

From the urinary system: very common – proteinuria; common – hematuria, renal failure.

From laboratory parameters: common – increased creatinine concentration, increased ALT, AST, ALP, lipase, amylase activity, hypoglycemia, hyperglycemia, decreased bicarbonate concentration, hypernatremia, hyponatremia, hypoalbuminemia, hypophosphatemia, decreased platelet, leukocyte, lymphocyte concentration, decreased hemoglobin concentration, increased TSH concentration; uncommon – hyperbilirubinemia.

Other: very common – fatigue, asthenia, mucosal inflammation, weight loss.

Contraindications

Severe hepatic impairment (Child-Pugh class C); arterial thromboembolism within the previous 12 months; venous thromboembolism within the previous 6 months); metastatic brain lesion for which appropriate treatment has not been performed; recent or current gastrointestinal bleeding; pregnancy, lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to axitinib.

Use in Pregnancy and Lactation

The use of axitinib is contraindicated during pregnancy and lactation (breastfeeding).

Women of childbearing potential should be informed about the need to avoid pregnancy during therapy with axitinib and for 1 week after the end of axitinib therapy, due to the potential risk of adverse effects on the fetus.

Special Precautions

Use with caution in patients with risk factors for arterial thromboembolism (including transient ischemic attack, myocardial infarction, and cerebrovascular accident), venous thromboembolism (including pulmonary embolism, deep vein thrombosis, and occlusion or thrombosis of the central retinal vein) or a history thereof; patients with severe renal impairment (CrCl <15 ml/min).

Hypertension mainly occurs during the first month of axitinib therapy, primarily in the first 4 days. Blood pressure should be corrected before starting axitinib therapy. Further careful monitoring of patients for increased blood pressure and, if necessary, prescription of standard antihypertensive therapy is required.

If persistent arterial hypertension develops despite the use of antihypertensive agents, a reduction in the axitinib dose is necessary. Axitinib therapy should be discontinued if severe and persistent arterial hypertension develops that is not amenable to antihypertensive therapy and does not resolve with a reduction in the axitinib dose.

The advisability of discontinuing axitinib therapy should also be assessed if signs of a hypertensive crisis appear. After discontinuation of axitinib, patients receiving antihypertensive agents should be monitored for control of arterial hypotension.

Axitinib has not been studied in patients who have had arterial thromboembolism within the previous 12 months, as well as those who have had venous thromboembolism within the previous 6 months.

It is recommended to examine thyroid function before starting axitinib therapy and then periodically during treatment. Correction of hypothyroidism and hyperthyroidism should be carried out according to standard principles until a euthyroid state is achieved.

During axitinib therapy, an increase in hemoglobin or hematocrit concentration may be observed, reflecting an increase in red blood cell mass in the body. This phenomenon may increase the risk of thromboembolism. It is recommended to monitor hemoglobin or hematocrit concentration before starting axitinib therapy and periodically during it. Correction of an increase in hemoglobin or hematocrit concentration above the upper limit of normal is carried out according to standard principles.

If any bleeding requiring medical attention occurs, axitinib therapy should be temporarily discontinued.

During axitinib therapy, periodic monitoring for clinical manifestations of gastrointestinal perforation and fistula formation should be carried out.

Axitinib therapy should be discontinued at least 24 hours before a planned surgical intervention. The decision to resume axitinib therapy in the postoperative period should be based on the results of a clinical assessment of the wound healing process.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurological disorder that may present with headache, seizures, lethargy, confusion, blindness, and other visual and neurological disorders. In this case, blood pressure may increase from mild to severe. The diagnosis of RPLS is confirmed by MRI. Axitinib should be discontinued in patients with clinical manifestations of RPLS. The safety of resuming axitinib therapy in patients with a history of RPLS is unknown.

It is recommended to examine for proteinuria before starting axitinib therapy and periodically during treatment. If proteinuria of moderate or severe degree develops, a dose reduction or temporary discontinuation of axitinib is necessary.

It is recommended to examine ALT and AST activity and bilirubin concentration before starting axitinib therapy and periodically during treatment.

Effect on ability to drive vehicles and machinery

Patients should be informed about the possibility of developing dizziness and/or fatigue during axitinib therapy.

Drug Interactions

Concomitant use with ketoconazole (a potent inhibitor of CYP3A4/5 isoenzymes) leads to an increase in the plasma concentration of axitinib in healthy volunteers. Concomitant use of axitinib with potent inhibitors of CYP3A4/5 isoenzymes (in particular, ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) should be avoided.

Grapefruit or grapefruit juice may also increase the plasma concentration of axitinib, and their concomitant use should also be avoided.

Selection of alternative drugs that do not inhibit CYP3A4/5 isoenzymes or inhibit their activity to a minimal degree is recommended. If it is necessary to combine axitinib with potent inhibitors of CYP3A4/5 isoenzymes, a reduction in its dose is recommended.

CYP1A2 and CYP2C19 isoenzymes support a smaller part (<10%) of axitinib metabolism pathways. The effect of potent inhibitors of these isoenzymes on the pharmacokinetics of axitinib has not been studied. Caution is required when using axitinib concomitantly with strong inhibitors of CYP1A2 and CYP2C19 isoenzymes, as the plasma concentration of axitinib may increase.

Concomitant use of axitinib with potent inducers of CYP3A4/5 isoenzymes (in particular, rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John’s wort preparations) should be avoided.

Rifampicin (a potent inducer of CYP3A4/5 isoenzymes) reduces the mean AUC values of axitinib in healthy volunteers. Selection of alternative drugs that do not induce CYP3A4/5 isoenzymes or induce their activity to a minimal degree for combination with axitinib is recommended.

Moderate inhibitors of CYP3A4/5 isoenzymes (such as bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma concentration of axitinib, and their concomitant use should be avoided if possible.

The effect of CYP1A2 isoenzyme induction caused by smoking on the pharmacokinetics of axitinib has not been fully studied. The possibility of a decrease in the plasma concentration of axitinib when using axitinib in smokers should be considered.

In vitro studies have also noted that Axitinib has the potential ability to inhibit the activity of the CYP1A2 isoenzyme. Therefore, concomitant administration of axitinib with substrates of the CYP1A2 isoenzyme may lead to an increase in the plasma concentration of the latter (for example, theophylline).

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.