Axitinib-mili-5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AXITINIB-MILI-1 AXITINIB-MILI-5 (AXITINIB-MILI-1) AXITINIB-MILI-5)

Composition:

Active substance: axitinib;

1 coated tablet contains axitinib 1 mg or 5 mg;

Excipients: anhydrous lactose, microcrystalline cellulose (Grade-102); colloidal silicon dioxide, hydroxypropylcellulose, sodium croscarmellose, talc, magnesium stearate;

Coating composition: Opadry Red (32K550022)*, purified water.

* Opadry Red (32K550022): hypromellose (E 464), lactose monohydrate, titanium dioxide (E 171), triacetin, iron oxide red (E 172).

Pharmaceutical form. Coated tablets.

Main physical and chemical properties:
1 mg tablets: red, capsule-shaped, biconvex coated tablets with "S 14" imprinted on one side and smooth on the other side;

5 mg tablets: red, triangular-shaped, biconvex coated tablets with "S 15" imprinted on one side and smooth on the other side.

Pharmacotherapeutic group.
Antineoplastic agents. Protein kinase inhibitors. ATC code L01X E17.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

It has been established that axitinib, at therapeutic plasma concentrations, inhibits tyrosine kinase receptors, including vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3. These receptors are involved in pathological angiogenesis, tumor growth, and progression of malignant neoplasms. Axitinib inhibited VEGF-induced proliferation and survival of endothelial cells in vitro and in mouse models. In mouse tumor xenograft models, axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2.

A randomized, double-blind, two-period crossover study was conducted in 35 healthy volunteers to evaluate the effect of a single oral dose of axitinib (5 mg) on QTc interval duration when administered with 400 mg ketoconazole and as monotherapy. During the first 3 hours after dosing, no notable changes in mean QTc interval duration (i.e., greater than 20 ms) were observed compared to placebo. However, a small increase in mean QTc interval duration (i.e., less than 10 ms) cannot be ruled out.

Pharmacokinetics.

Population pharmacokinetic analysis combined data from 17 studies involving healthy volunteers and oncology patients. The concentration-time profile of axitinib was adequately described by a two-compartment distribution model with first-order absorption and a lag time.

Absorption and distribution. The median Tmax after a single 5 mg oral dose ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady-state is expected to be reached within 2–3 days of dosing. Administration of axitinib at 5 mg twice daily resulted in approximately 1.4-fold greater drug accumulation compared to a single dose. The pharmacokinetics of axitinib at steady state are nearly linear within the dose range of 1 to 20 mg. The mean absolute bioavailability of axitinib after a single 5 mg oral dose is 58%.

Administration of axitinib with a moderately fat-rich meal resulted in approximately a 10% decrease in AUC compared to administration in the fasted state in the morning. Administration with a high-fat, high-calorie meal increased the AUC by 19% compared to administration in the fasted state in the morning. Axitinib may be taken with or without food (see "Dosage and administration").

Axitinib is almost completely (>99%) bound to human plasma proteins, primarily to albumin, with moderate binding to α1-acid glycoprotein. In patients with advanced renal cell carcinoma (n = 20) receiving the drug at 5 mg twice daily after food, geometric mean values of Cmax and AUC0-24 were 27.8 ng/mL (79%) and 265 ng·h/mL (77%), respectively. Clearance and apparent volume of distribution were 38 L/h (80%) and 160 L (105%), respectively (values in parentheses indicate % CV).

Metabolism and elimination. The elimination half-life of axitinib from plasma ranges from 2.5 to 6.1 hours. Axitinib is primarily metabolized in the liver via CYP3A4/5. CYP1A2, CYP2C19, and UGT1A1 play a lesser role in axitinib metabolism. After oral administration of 5 mg radiolabeled axitinib, approximately 41% of radioactivity was excreted in feces and about 23% in urine. The main component identified in feces was unchanged axitinib, accounting for 12% of the administered dose. Unchanged axitinib was not detected in urine. The majority of radioactivity in urine was due to carboxylic acid and sulfoxide metabolites of the active substance. The main radioactive component in plasma is the N-glucuronide metabolite, accounting for 50% of circulating plasma radioactivity. Unchanged axitinib and the sulfoxide metabolite each account for approximately 20% of circulating plasma radioactivity.

The in vitro affinity of the sulfoxide and N-glucuronide metabolites for VEGFR-2 is approximately ≥400-fold lower than that of axitinib.

Effect of other drugs on axitinib. Axitinib is primarily metabolized in the liver by the CYP3A4/5 enzyme. In addition, the aqueous solubility of axitinib is pH-dependent: solubility decreases as pH increases. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are shown in Table 1 (see also sections "Dosage and administration" and "Interaction with medicinal products and other types of interactions").

Effect on the pharmacokinetics of axitinib by concomitantly administered medicinal products and hepatic impairment

Table 1

AUC – area under the plasma concentration-time curve.

Cmax – maximum concentration.

* See section "Dosage and administration".

PK – pharmacokinetics.

CI – confidence interval.

Pharmacokinetics in special patient groups

Children. Axitinib has not been studied in patients under 18 years of age.

Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of axitinib is presented in Table 1 (see also sections "Dosage and administration", "Special warnings and precautions for use").

Renal impairment. A population pharmacokinetic analysis was conducted in 590 healthy volunteers and patients based on renal function parameters. Among the analyzed patients, five had severe renal impairment (creatinine clearance ranging from 15 to < 29 mL/min), 64 had moderate renal impairment (30 to < 59 mL/min), and 139 had mild renal impairment (creatinine clearance from 60 to < 89 mL/min). Mild to severe renal impairment did not show a significant effect on the pharmacokinetics of axitinib. Data on the use of the drug in patients with end-stage renal disease are available for only one patient.

Other individual factors. Results of population pharmacokinetic analysis indicate no clinically significant effect of age, sex, race, body weight and body surface area, UGT1A1 genotype, or CYP2C19 genotype on axitinib clearance.

Clinical characteristics.

Indications.

Treatment of advanced renal cell carcinoma if a previous course of systemic therapy has been ineffective.

Contraindications.

Hypersensitivity to axitinib or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

CYP3A4/5 inhibitors

Concomitant administration of ketoconazole (a strong CYP3A4/5 inhibitor) increased plasma exposure levels of axitinib in healthy volunteers. Concomitant use of axitinib with strong CYP3A4/5 inhibitors should be avoided. Consumption of grapefruit or grapefruit juice may also increase axitinib plasma concentrations. Therefore, the combination of these products with axitinib should also be avoided. It is recommended to select concomitant medications with no or minimal potential to inhibit CYP3A4/5 activity. If co-administration of axitinib with a strong CYP3A4/5 inhibitor is necessary, the axitinib dose should be reduced (see sections "Dosage and administration" and "Pharmacokinetics").

CYP1A2 and CYP2C19 inhibitors

CYP1A2 and CYP2C19 play a minor role (< 10%) in axitinib metabolism. The effect of strong inhibitors of these isoenzymes on axitinib pharmacokinetics has not been studied. Due to the risk of increased axitinib plasma levels, caution should be exercised when administering strong inhibitors of these isoenzymes concomitantly with axitinib.

CYP3A4/5 inducers

Concomitant administration of rifampicin (a strong CYP3A4/5 inducer) decreased axitinib plasma exposure levels in healthy volunteers. Concomitant use of axitinib with strong CYP3A4/5 inducers (such as rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St John's wort) should be avoided. For concomitant use with axitinib, it is recommended to select a medicinal product with no or minimal potential to induce CYP3A4/5 activity. Moderate CYP3A4/5 inducers (such as bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce axitinib plasma exposure levels. The use of these agents should also be avoided whenever possible.

In vitro studies of CYP and UGT inhibition and induction

In vitro studies have shown that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations.

In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2. Therefore, concomitant administration of axitinib with CYP1A2 substrates may lead to increased plasma levels of CYP1A2 substrates (such as theophylline).

In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, concomitant administration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased paclitaxel plasma concentrations in patients with advanced cancer, suggesting no clinically relevant inhibition of CYP2C8.

In vitro studies in human hepatocytes also demonstrated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5. Therefore, concomitant administration of axitinib is not expected to reduce plasma levels of CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo.

In vitro studies with P-glycoprotein

In vitro studies showed that axitinib inhibits P-glycoprotein. However, axitinib is not expected to have an inhibitory effect on P-glycoprotein at therapeutic plasma concentrations. Therefore, concomitant administration of axitinib is not expected to increase plasma concentrations of digoxin or other P-glycoprotein substrates in vivo.

Special precautions for use.

Arterial hypertension and hypertensive crisis

Discontinuation of treatment with axitinib-containing medicinal products due to arterial hypertension occurred in 1/359 patients (<1%) receiving axitinib, and in none of the patients receiving sorafenib (see section "Adverse reactions"). Before initiating treatment with axitinib-containing medicinal products, arterial blood pressure should be well controlled. Patients should be monitored for the development of arterial hypertension and treated as necessary with standard antihypertensive therapy. Axitinib treatment should be interrupted, then dose reduced, or permanently discontinued depending on the severity of arterial hypertension (see section "Dosage and administration"). When treatment with axitinib is temporarily interrupted, patients concurrently receiving antihypertensive medications should be monitored for timely detection of hypotension (see section "Dosage and administration").

Arterial thromboembolism

Arterial thromboembolic events (including transient ischaemic attacks, cerebrovascular accidents, myocardial infarction, and retinal artery occlusion), including fatal cases, have been reported during clinical trials with axitinib. Fatal cerebrovascular events were reported in 1/359 patients (<1%) receiving axitinib and in none of the patients receiving sorafenib (see section "Adverse reactions").

Axitinib has not been studied in patients who have experienced arterial thromboembolism within the previous 12 months. In clinical trials with axitinib, arterial thromboembolic events (including transient ischaemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), including two fatal events due to cerebrovascular accident.

Axitinib treatment should be permanently discontinued if an arterial thromboembolic event occurs during treatment.

Venous thromboembolism

Venous thromboembolic events (including pulmonary embolism, deep vein thrombosis, and occlusion or thrombosis of retinal veins), including fatal cases, have been reported during clinical trials. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving axitinib and in none of the patients receiving sorafenib.

Axitinib has not been studied in patients who experienced a venous thromboembolic event (VTE) within the previous 6 months. In clinical trials with axitinib, venous thromboembolic events were reported in 22/715 patients (3%), including two fatal events secondary to pulmonary embolism.

Patients should be monitored for signs and symptoms of VTE and pulmonary embolism. Axitinib should be interrupted, then resumed at the same dose or permanently discontinued depending on the severity of VTE.

Elevated haemoglobin or haematocrit

Treatment with axitinib may lead to increased haemoglobin or haematocrit, reflecting an increase in red blood cell mass. Increased red blood cell mass may increase the risk of embolic and thrombotic events.

Haemoglobin or haematocrit should be monitored before starting and periodically during axitinib treatment. If haemoglobin or haematocrit exceeds the normal range, patients should be treated according to standard medical practice to reduce haemoglobin or haematocrit to acceptable levels.

Bleeding

Bleeding events, such as intracranial haemorrhage, haematuria, haemoptysis, lower gastrointestinal bleeding, and melaena, including fatal bleeding, have been reported. Fatal bleeding was reported in 1/359 patients (<1%) receiving axitinib (gastric haemorrhage) and in 3/355 patients (1%) receiving sorafenib.

Axitinib has not been studied in patients with untreated brain metastases or recent active gastrointestinal bleeding and should not be used in such patients. Axitinib treatment should be interrupted, then dose reduced or permanently discontinued depending on the severity and persistence of bleeding.

Heart failure

In a controlled clinical trial of axitinib for the treatment of patients with renal cell carcinoma, heart failure occurred in 6/359 patients (2%) receiving axitinib and in 3/355 patients (1%) receiving sorafenib. Grade 3/4 heart failure occurred in 2/359 patients (1%) receiving axitinib and in 1/355 patients (<1%) receiving sorafenib. Fatal heart failure occurred in 2/359 patients (1%) receiving axitinib and in 1/355 patients (<1%) receiving sorafenib. Patients should be monitored for signs or symptoms of heart failure throughout axitinib treatment. Management of heart failure may require dose reduction, treatment interruption, or permanent discontinuation of axitinib (see section "Dosage and administration").

Gastrointestinal perforation and fistula formation

Gastrointestinal perforations, including one fatal case, have been reported during clinical trials. Cases of fistula formation have also been reported.

Patients should be periodically monitored during axitinib treatment for signs of gastrointestinal perforation or fistula formation.

Thyroid dysfunction

Thyroid function parameters should be monitored before starting and periodically during axitinib treatment. Hypothyroidism and hyperthyroidism, which may occur during treatment, should be managed according to standard medical practice to maintain normal thyroid function.

Impaired wound healing

Impaired wound healing may occur in patients receiving agents that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, axitinib may adversely affect wound healing.

Axitinib treatment should be discontinued at least 2 days prior to planned surgery. The drug should not be used for at least 2 weeks after major surgery and until adequate wound healing has occurred. Treatment with axitinib may be resumed at a reduced dose or discontinued depending on the severity and persistence of impaired wound healing. The safety of resuming axitinib after resolution of wound healing complications has not been established (see section "Dosage and administration").

Posterior reversible encephalopathy syndrome (PRES)

PRES is a neurological disorder that may present with headache, seizures, lethargy, confusion, blindness, visual disturbances, and other neurological disorders. Arterial hypertension of any degree (from mild to severe) may also be observed. MRI is required to confirm the diagnosis of PRES. Axitinib should be permanently discontinued in patients who develop PRES. The safety of resuming axitinib therapy in patients with a prior history of PRES has not been established (see section "Dosage and administration").

Proteinuria

Monitoring for proteinuria is recommended before starting and periodically during axitinib treatment. For patients who develop moderate or severe proteinuria, axitinib should be discontinued and then dose reduced (see "Dosage and administration").

Elevated liver enzyme activity

ALT, AST, and bilirubin levels should be monitored before starting and periodically during axitinib treatment.

Hepatic impairment

In a dedicated study of patients with hepatic impairment, systemic exposure levels after single doses of axitinib in patients with mild hepatic impairment (Child-Pugh class A) were similar to those in patients with normal liver function, while systemic exposure in patients with moderate hepatic impairment (Child-Pugh class B) was higher than in patients with normal liver function. If axitinib is administered to patients with moderate hepatic impairment (Child-Pugh class B), a reduced starting dose is recommended. The use of axitinib in patients with severe hepatic impairment (Child-Pugh class C) has not been studied (see sections "Dosage and administration" and "Pharmacokinetics").

Axitinib in combination with avelumab or pembrolizumab

Axitinib in combination with avelumab or pembrolizumab may cause hepatotoxicity with a higher frequency of grade 3 and 4 elevations in ALT and AST than expected. Liver enzymes should be monitored before starting and periodically during treatment. More frequent monitoring of liver enzymes should be considered compared to monotherapy. Treatment with axitinib and avelumab or pembrolizumab should be interrupted or permanently discontinued in case of elevated liver enzymes, and corticosteroids should be administered if necessary (see section "Dosage and administration").

When axitinib was combined with avelumab, grade 3 and 4 elevations in ALT and AST were reported in 9% and 7% of patients, respectively. Among patients with ALT levels ≥3 times the upper limit of normal (ULN) (grades 2–4, n=82), ALT decreased to grades 0–1 in 92%. Among 73 patients who were rechallenged with avelumab (n=3), axitinib (n=25), or both agents (n=45), ALT recurrence ≥3 ULN was not observed in any patient receiving avelumab, in 6 patients receiving axitinib, and in 15 patients receiving both avelumab and axitinib. Twenty-two (88%) patients with ALT recurrence ≥3 ULN subsequently recovered to grades 0–1. Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation of treatment in 7%, and immune-mediated hepatitis led to permanent discontinuation of avelumab or axitinib in 5% of patients. Thirty-four patients received corticosteroid treatment and one patient received non-steroidal immunosuppressive therapy. Hepatitis occurred in 31 of 35 patients at the time of study discontinuation.

When axitinib was combined with pembrolizumab, grade 3 and 4 elevations in ALT (20%) and AST (13%) were observed. Systemic corticosteroids were administered in 59% of patients with elevated ALT. Among patients with ALT ≥3 times ULN (grades 2–4, n=116), ALT decreased to grades 0–1 in 94%. Among 92 patients who were rechallenged with pembrolizumab (n=3), axitinib (n=34), or both agents (n=55), ALT recurrence ≥3 ULN occurred in 1 patient receiving pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both pembrolizumab and axitinib. All patients with ALT recurrence ≥3 ULN subsequently recovered.

Elderly patients and race

In a controlled clinical trial of axitinib for the treatment of renal cell carcinoma, 34% of patients in the axitinib treatment group were elderly. The majority of patients were Caucasian (77%) or of Asian origin (21%). Although increased sensitivity to the drug in elderly patients and Asians cannot be entirely ruled out, overall, no differences in safety and efficacy parameters were observed between elderly and younger patients, or between Caucasians and other racial groups.

Dose adjustment based on patient age or race is not required (see sections "Dosage and administration" and "Pharmacokinetics").

Lactose

This medicinal product contains lactose. It should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

There are insufficient data in humans to establish the risk of use. Due to the mechanism of action and findings from animal studies, axitinib may cause harm to the foetus if administered to pregnant women. In animal developmental toxicity studies, axitinib showed teratogenic, embryotoxic, and fetotoxic effects at exposure levels lower than those in humans at the recommended starting doses.

Women of reproductive potential should be informed of the potential risk to the foetus and the need to use effective contraception during treatment with axitinib and for one week after the last dose. Men with female partners of reproductive potential should use effective contraception during treatment with axitinib and for one week after the last dose. Animal studies have shown that axitinib may impair fertility in both women and men with reproductive potential.

Currently, there is no information on the presence of axitinib in human breast milk, or its effects on the breastfed infant or milk production. Due to the potential for serious adverse reactions in breastfed infants exposed to axitinib, breastfeeding women are recommended to discontinue breastfeeding during treatment and for 2 weeks after the last dose.

Ability to affect reaction speed when driving or operating machinery

Patients should be warned about the possible development of dizziness, somnolence, and visual disturbances during axitinib treatment and advised not to drive or operate machinery if these symptoms occur (see sections "Adverse reactions" and "Special precautions for use").

Administration and Dosage.

The recommended starting oral dose of axitinib is 5 mg twice daily. The interval between doses of axitinib should be approximately 12 hours; the drug may be taken independently of food intake (see section "Pharmacodynamics"). Swallow tablets whole with a glass of water.

If vomiting occurs after taking a dose or if a dose is missed, an additional dose should not be taken. The next scheduled dose should be taken at the appropriate time.

Dosage modification recommendations.

Dose increases or reductions should be made based on individual safety and tolerability.

Dose escalation of axitinib may be considered in patients who have tolerated the treatment well for at least two consecutive weeks without experiencing adverse reactions of grade 2 or higher severity (according to the Common Terminology Criteria for Adverse Events), who have normal blood pressure, and who are not receiving antihypertensive medications. If dose escalation is recommended while on a regimen of 5 mg twice daily, the axitinib dose may be increased to 7 mg twice daily. Further escalation to 10 mg twice daily may be considered using the same criteria as for the prior dose increase.

During the course of axitinib treatment, management of certain adverse reactions may require temporary or permanent discontinuation and/or dose reduction. If dose reduction from the 5 mg twice-daily regimen is required, the recommended dosage is 3 mg twice daily. If further dose reduction is needed, the recommended dosage is 2 mg twice daily.

Dosage modification recommendations for adverse reactions to axitinib are provided in Table 2.

Table 2

Dosage modification recommendations for axitinib in the event of adverse reactions

Dosage adjustments due to interactions with other medicinal products

Potent CYP3A4/5 inhibitors.

Concomitant use of the medicinal product with potent CYP3A4/5 inhibitors (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) should be avoided. For concomitant use with axitinib, an alternative medicinal product with no or minimal potential to inhibit CYP3A4/5 activity should be considered. The possibility of adjusting the axitinib dosage in patients receiving potent CYP3A4/5 inhibitors has not been investigated. However, if concomitant administration of axitinib and a potent CYP3A4/5 inhibitor is necessary, it is recommended to reduce the axitinib dose by approximately half, as such reduction is considered sufficient to return AUC values to the range observed when the medicinal product is used without inhibitors. Subsequently, the axitinib dose may be increased or decreased based on individual safety and tolerability. After discontinuation of the potent inhibitor (after 3–5 half-lives of the inhibitor), the axitinib dose should be increased again to the level prescribed before initiating the potent CYP3A4/5 inhibitor (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment. When prescribing axitinib to patients with mild hepatic impairment (Child–Pugh class A), no reduction in the initial dose of the medicinal product is required. Based on pharmacokinetic data, patients with moderate hepatic impairment (Child–Pugh class B) should have their initial axitinib dose reduced by approximately half at the start of treatment. Subsequently, the axitinib dose may be increased or decreased based on individual safety and tolerability. The use of axitinib for the treatment of patients with severe hepatic impairment (Child–Pugh class C) has not been studied (see sections "Special precautions for use" and "Pharmacokinetics in special patient populations").

Renal impairment.

No dedicated studies have been conducted on the use of axitinib in patients with renal impairment. Population pharmacokinetic analyses showed no significant differences in axitinib clearance in patients with pre-existing mild, moderate, or severe renal impairment (creatinine clearance from ≤15 ml/min to <89 ml/min) (see section "Pharmacokinetics"). Patients with pre-existing mild, moderate, or severe renal impairment do not require adjustment of the initial dose. The medicinal product should be used with caution in patients with end-stage renal disease (creatinine clearance <15 ml/min).

Use in elderly patients

Elderly patients do not require dose adjustment of the medicinal product (see sections "Pharmacokinetics" and "Special precautions for use").

Children.

The safety and efficacy of axitinib in children under real clinical conditions have not been established.

Safety and efficacy have been evaluated under real clinical conditions but were not established in two open-label studies: a dose-finding study of axitinib as monotherapy in 17 children aged 5 to <17 years with recurrent or refractory solid tumors (ADVL1315, NCT02164838), and a randomized study of axitinib as monotherapy or in combination in 7 children aged 7 to <17 years (AREN1721, NCT03595124).

In these studies, no new safety concerns were observed in children.

Exposure in children receiving axitinib at the maximum tolerated dose was lower than that previously observed in adults receiving the approved recommended initial dose.

Overdose.

There is no specific antidote in case of axitinib overdose.

During a controlled clinical trial of axitinib for the treatment of renal cell carcinoma, one patient inadvertently received the medicinal product at a dose of 20 mg twice daily for 4 days and experienced mild dizziness.

In a clinical trial aimed at determining the axitinib dose, adverse reactions including arterial hypertension, seizures associated with arterial hypertension, and haemoptysis with fatal outcome occurred in participants who received initial doses of 10 or 20 mg twice daily.

If axitinib overdose is suspected, administration of the medicinal product should be discontinued and symptomatic treatment initiated.

Adverse reactions

The following clinically significant adverse reactions are described in more detail in the section "Special warnings and precautions for use":

• arterial hypertension and hypertensive crisis;
• arterial thromboembolism;
• venous thromboembolism;
• bleeding;
• heart failure;
• gastrointestinal perforation and fistula formation;
• thyroid dysfunction;
• posterior reversible encephalopathy syndrome (PRES);
• proteinuria;
• elevated liver enzymes;
• hepatic impairment.

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in clinical trials of one drug product cannot be directly compared with the frequency in clinical trials of another drug product; also, such frequencies may not reflect those observed in clinical practice.

The safety profile of axitinib was evaluated in clinical trials involving 715 patients receiving axitinib, of whom 537 had advanced renal cell carcinoma. The data presented in the section "Adverse reactions" refer to the administration of axitinib to 359 patients with advanced renal cell carcinoma who participated in a randomized clinical trial comparing axitinib with sorafenib.

Clinical trial experience

The median duration of treatment was 6.4 months (range: 0.03 to 22 months) for patients receiving axitinib and 5 months (range: 0.03–20.1 months) for those receiving sorafenib. Dose modifications or temporary treatment interruption due to adverse reactions were required in 199 out of 359 patients (55%) receiving axitinib and in 220 out of 355 patients (62%) receiving sorafenib. Treatment was permanently discontinued due to adverse reactions in 34 out of 359 patients (9%) receiving axitinib and in 46 out of 355 patients (13%) receiving sorafenib.

The most common (incidence ≥ 20%) adverse reactions observed with axitinib were: diarrhea, arterial hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia, weight decrease, vomiting, asthenia, and constipation.

Table 2 lists adverse reactions reported in ≥ 10% of patients receiving axitinib or sorafenib.

Table 2

The adverse reactions (of all severity grades) observed in patients receiving axitinib treatment with a frequency of < 10% are listed below. These include dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), increased lipase levels (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

Table 3 lists the most common laboratory test abnormalities reported in ≥ 10% of patients receiving axitinib or sorafenib.

Table 3

The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0:

ALP – alkaline phosphatase; ALT – alanine aminotransferase; AST – aspartate aminotransferase.

Changes in individual laboratory parameters (of all grades) were observed in < 10 % of patients receiving axitinib, including elevated hemoglobin levels above the upper normal limit (9 % in the axitinib group vs. 1 % in the sorafenib group) and hypercalcemia (6 % in the axitinib group vs. 2 % in the sorafenib group).

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of axitinib. Because these reports are submitted voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular disorders: Arterial aneurysms (including aortic), dissections, and ruptures.

Hepatobiliary disorders: Common: cholecystitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 1 mg coated tablets: 10 tablets per blister, 3 blisters per cardboard box; 5 mg coated tablets: 14 tablets per blister, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Shilpa Medikea Limited / Shilpa Medicare Limited.

Manufacturer's address.
Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India / Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahabооbnagar, Telangana, 509301, India.