Inlyta

Axitinib.

Each film-coated tablet contains 1 mg or 5 mg axitinib.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors. ATC code: L01XE17.
Pharmacology: Pharmacodynamics: Mechanism of action: Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumor vasculature that expressed the target in vivo and produced tumor growth delay, regression, and inhibition of metastases in many experimental models of cancer.
Pharmacodynamics effects: In a randomized, 2-way crossover study, 35 healthy subjects were administered a single oral dose of axitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that axitinib plasma exposures up to 2-fold greater than the therapeutic levels expected following a 5 mg dose did not produce clinically-significant QT interval prolongation.
Clinical efficacy: The safety and efficacy of axitinib were evaluated in a randomized, open-label, multicenter Phase 3 study. Patients (N=723) with advanced RCC whose disease had progressed on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to receive axitinib (n=361) or sorafenib (n=362). The primary endpoint, progression-free survival (PFS), was assessed using a blinded independent central review. Secondary endpoints included objective response rate (ORR) and overall survival (OS).
Of the patients enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251 patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or interferon-alfa), 59 patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had received 1 prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the axitinib and sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment.
In the overall patient population and the two main subgroups (prior sunitinib treatment and prior cytokine treatment), there was a statistically significant advantage for axitinib over sorafenib for the primary endpoint of PFS (see Table 1 and Figure 1, Figure 2 and Figure 3). The magnitude of median PFS effect was different in the subgroups by prior therapy. Two of the subgroups were too small to give reliable results (prior temsirolimus treatment or prior bevacizumab treatment). There were no statistically significant differences between the arms in OS in the overall population or in the subgroups by prior therapy.


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Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with axitinib in all subsets of the paediatric population for treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: After oral administration of axitinib tablets, the mean absolute bioavailability is 58% compared to intravenous administration. The plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Dosing of axitinib at 5 mg twice daily resulted in <2-fold accumulation compared to administration of a single dose. Based on the short half-life of axitinib, steady state is expected within 2 to 3 days of the initial dose.
Absorption and distribution: Peak axitinib concentrations in plasma are generally reached within 4 hours following oral administration of axitinib with the median T_max ranging from 2.5 to 4.1 hours. Administration of axitinib with a moderate fat meal resulted in 10% lower exposure compared to overnight fasting. A high fat, high-calorie meal resulted in 19% higher exposure compared to overnight fasting. Axitinib may be administered with or without food.
The average C_max and AUC increased proportionally over an axitinib dosing range of 5 to 10 mg. In vitro binding of axitinib to human plasma proteins is >99% with preferential binding to albumin and moderate binding to α₁-acid glycoprotein. At the 5 mg twice daily dose in the fed state, the geometric mean peak plasma concentration and 24-hour AUC were 27.8 ng/mL and 265 ng h/mL, respectively in patients with advanced RCC. The geometric mean oral clearance and apparent volume of distribution were 38 L/h and 160 L, respectively.
Metabolism and elimination: Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, 30%-60% of the radioactivity was recovered in feces and 23% of the radioactivity was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.
The sulfoxide and N-glucuronide metabolites show approximately 400-fold and 8000-fold less in vitro potency, respectively, against VEGFR-2 compared to axitinib.
Special populations: Gender, race and age: Population pharmacokinetic analyses in patients with advanced cancer (including advanced RCC) and healthy volunteers indicate that there are no clinically relevant effects of age, gender, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 genotype.
Pediatric population: Axitinib has not been studied in patients <18 years of age.
Hepatic impairment: In vitro and in vivo data indicate that axitinib is primarily metabolized by the liver. Compared to subjects with normal hepatic function, systemic exposure following a single dose of axitinib was similar in subjects with mild hepatic impairment (Child-Pugh class A) and higher (approximately 2-fold) in subjects with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).
Renal impairment: Unchanged axitinib is not detected in the urine.
Axitinib has not been studied in subjects with renal impairment. In clinical studies with axitinib for the treatment of patients with RCC, patients with serum creatinine >1.5 times the ULN or calculated creatinine clearance <60 mL/min were excluded. Population pharmacokinetic analyses have shown that axitinib clearance was not altered in subjects with renal impairment and no dose adjustment of axitinib is required.
Toxicology: Preclinical safety data: Repeat dose toxicity: Major toxicity findings in mice and dogs following repeated dosing for up to 9 months were the gastrointestinal, haematopoietic, reproductive, skeletal and dental systems, with No Observed Adverse Effect Levels (NOAEL) approximately equivalent to or below expected human exposure at the recommended clinical starting dose (based on AUC levels).
Carcinogenicity: Carcinogenicity studies have not been performed with axitinib.
Genotoxicity: Axitinib was tested using a series of genetic toxicology assays consisting of in vitro bacterial reverse mutation (Ames), human lymphocyte chromosome aberration, and in vivo mouse bone marrow micronucleus assays. Axitinib was not mutagenic or clastogenic in these assays.
Impairment of fertility: Axitinib has the potential to impair reproductive function and fertility in humans. Findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms) at ≥100 mg/kg/day in mice (approximately 306 times the AUC at the recommended starting dose in humans) and ≥3 mg/kg/day in dogs (approximately 0.5 times the AUC at the recommended starting dose in humans). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥10 mg/kg/day (approximately equivalent to the AUC at the recommended starting dose in humans).
Axitinib did not affect mating or fertility in male mice at any dose tested up to 100 mg/kg/day. However, reduced testicular weights, sperm density and count were noted at ≥30 mg/kg/day (approximately 72 times the AUC at the recommended starting dose in humans) following at least 70 days of treatment with axitinib. No adverse male reproductive effects in mice were noted at 10 mg/kg/day (approximately 21 times the AUC at the recommended starting dose in humans). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥30 mg/kg/day) following at least 15 days of treatment with axitinib (approximately 64 times the AUC at the recommended starting dose in humans).
Developmental toxicity: Pregnant mice exposed to axitinib at an oral dose level of 3 mg/kg/day (approximately 3 times the AUC at the recommended starting dose in humans), showed an increased occurrence of cleft palate and common variations in skeletal ossification. No fetal alterations were observed in mice at a dose level of 1 mg/kg/day (approximately equivalent to the AUC at the recommended starting dose in humans).
Toxicity studies in juvenile animals: Physeal dysplasia was observed in immature mice and dogs given axitinib at doses of ≥30 mg/kg/day for at least 1 month (approximately 37 times the AUC at the recommended starting dose in humans); the incidence and severity was dose-related and the effects were reversible when treatment stopped. Dental caries were observed in mice treated for more than 1 month at axitinib doses of ≥10 mg/kg/day (approximately 9 times the AUC at the recommended starting dose in humans); residual findings, indicative of partial reversibility, were observed when treatment stopped. For physeal dysplasia, no effect levels of 10 mg/kg/day in mouse (approximately 8 times the AUC at the recommended starting dose in humans) and 10 mg/kg/day in dogs (approximately equivalent to the AUC at the recommended starting dose in humans) were determined in animals given axitinib for 1 month. A no effect level was not defined for caries of the incisors in mice. Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Axitinib is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) of clear cell histology after failure of one prior systemic therapy with sunitinib, cytokine or sorafenib (see Pharmacology: Pharmacodynamics under Actions).
Axitinib should be prescribed by a qualified healthcare professional who is experienced in the use of anti-neoplastic therapy.

Posology: Treatment with Axitinib should be initiated by a physician experienced in the use of anticancer therapies.
The recommended starting oral dose of Axitinib is 5 mg twice daily. Administer axitinib doses approximately 12 hours apart with or without food (see Pharmacology: Pharmacokinetics under Actions). Axitinib should be swallowed whole with a glass of water.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs, that cannot be managed by concomitant medications or dose adjustments.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
Dose adjustments: Dose increase or reduction is recommended based on individual safety and tolerability.
Patients who tolerate the Axitinib starting dose of 5 mg twice daily with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]) for two consecutive weeks, are normotensive, and are not receiving antihypertensive medication, may have their dose increased to 7 mg twice daily. Subsequently, using the same criteria, patients who tolerate the axitinib dose of 7 mg twice daily, may have their dose increased to a maximum of 10 mg twice daily.
Management of some adverse drug reactions may require temporary or permanent discontinuation and/or dose reduction of axitinib therapy. When dose reduction is necessary, the axitinib dose may be reduced to 3 mg twice daily and further to 2 mg twice daily.
Dose adjustment is not required on the basis of patient age, race, gender, or body weight.
Concomitant strong CYP3A4/5 inhibitors: Co-administration of axitinib with strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) as they may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended.
Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of axitinib to approximately half the dose (e.g., from a starting dose of 5 mg twice daily to a reduced dose of 2 mg twice daily) is recommended. If co-administration of the strong inhibitor is discontinued, a return to the axitinib dose used prior to initiation of the strong CYP3A4/5 inhibitor should be considered (after 3-5 half-lives of the inhibitor).
Concomitant strong CYP3A4/5 inducers: Co-administration of axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [also known as St. John's wort]) may decrease axitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal CYP3A4/5 induction potential is recommended.
Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inducers, if a strong CYP3A4/5 inducer must be co-administered, a gradual dose increase of axitinib is recommended. If the dose of axitinib is increased, the patient should be monitored carefully for toxicity. If co-administration of the strong inducer is discontinued, the axitinib dose should be immediately returned to the dose used prior to initiation of the strong CYP3A4/5 inducer.
Use in pediatrics: The safety and efficacy of axitinib in children (<18 years) have not been established. No data are available.
Use in the elderly (≥65 years): No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required when administering axitinib to patients with mild hepatic impairment (Child-Pugh class A). A dose decrease is recommended when administering Axitinib to patients with moderate hepatic impairment (Child-Pugh class B) [e.g., the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily]. Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Renal impairment: No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Virtually no data are available regarding axitinib treatment in patients with a creatinine clearance of <15 mL/min.

There is no specific treatment for axitinib overdose.
In a controlled clinical study with axitinib for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).
In a clinical dose finding study with axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.
In cases of suspected overdose, axitinib should be withheld and supportive care instituted.

Hypersensitivity to axitinib or to any of the excipients.

Specific safety events should be monitored before initiation of, and periodically throughout, treatment with axitinib as described as follows.
Cardiac failure events: In a controlled clinical study with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiopulmonary failure, left ventricular dysfunction, and right ventricular failure) were reported in 6/359 patients (1.7%) receiving axitinib and 3/355 patients (0.8%) receiving sorafenib. Grade 3/4 cardiac failure events were observed in 2/359 patients (0.6%) receiving axitinib and 1/355 patients (0.3%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (0.6%) receiving axitinib and 1/355 patients (0.3%) receiving sorafenib.
In clinical studies with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 12/672 patients (1.8%) receiving axitinib. Grade 3/4 cardiac failure events were reported in 7/672 patients (1.0%) and fatal cardiac failure events were reported in 2/672 patients (0.3%) receiving axitinib.
Monitor for signs or symptoms of cardiac failure periodically throughout treatment with axitinib. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of axitinib therapy.
Hypertension: In a controlled clinical study with axitinib for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving axitinib and 103/355 patients (29%) receiving sorafenib. Grade 3 hypertension was observed in 55/359 patients (15%) receiving axitinib and 38/355 patients (11%) receiving sorafenib and Grade 4 hypertension was observed in 1/359 patients (<1%) receiving axitinib and 1/355 patients (<1%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving axitinib and none of the patients (0%) receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of axitinib or sorafenib treatment and blood pressure increases have been observed as early as 4 days after starting axitinib. Hypertension was managed with standard antihypertensive therapy. Discontinuation of axitinib treatment due to hypertension occurred in 1/359 patients (<1%) receiving axitinib and none of the patients (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hypertension was reported in 344/672 patients (51%) receiving axitinib. Grade 3 hypertension was reported in 148/672 patients (22%) receiving axitinib. Grade 4 hypertension was reported in 7/672 patients (1%) receiving axitinib.
Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In the case of persistent hypertension despite use of antihypertensive medications, the axitinib dose should be reduced. For patients who develop severe hypertension, temporarily interrupt axitinib treatment and restart at a lower dose once the patient is normotensive (see Dosage & Administration). If axitinib is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.
In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome (see as follows), a diagnostic brain magnetic resonance image (MRI) should be considered.
Aneurysms and artery dissections: The use of Vascular Endothelial Growth Factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating axitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. In pooled clinical studies with axitinib for the treatment of patients with RCC, aneurysms and artery dissections was not reported in patients receiving axitinib.
Thyroid dysfunction: In a controlled clinical study with axitinib for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving axitinib and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving axitinib and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving axitinib and 25/232 patients (11%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hypothyroidism was reported in 165/672 patients (25%) receiving axitinib. Hyperthyroidism was reported in 11/672 patients (2%) receiving axitinib.
Monitor thyroid function before initiation of, and periodically throughout, treatment with axitinib. Hypothyroidism and hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state.
Arterial thromboembolic events: In a controlled clinical study with axitinib for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving axitinib and 4/355 patients (1%) receiving sorafenib. The most frequent arterial thromboembolic event was transient ischemic attack (1%). Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving axitinib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, arterial thromboembolic events were reported in 19/672 patients (3%) receiving axitinib. Grade 3 arterial thromboembolic events were reported in 8/672 patients (1%). Grade 4 arterial thromboembolic events were reported in 9/672 patients (1%). Fatal arterial thromboembolic events were reported in 2 patients (<1%) receiving axitinib.
In monotherapy studies with axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 16/699 patients (2%).
Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.
Venous thromboembolic events: In a controlled clinical study with axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving axitinib and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving axitinib (including pulmonary embolism, deep vein thrombosis, and retinal-vein occlusion/thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving axitinib and none of the patients (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 19/672 patients (3%) receiving axitinib. Grade 3 venous thromboembolic events were reported in 6/672 patients (1%). Grade 4 venous thromboembolic events were reported in 8/672 patients (1%). Fatal venous thromboembolic events were reported in 1/672 patients (<1%) receiving axitinib.
Axitinib should be used with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous thromboembolic event within the previous 6 months.
Elevation of hemoglobin or hematocrit: Increases in hemoglobin or hematocrit, reflective of increases in red blood cell mass, may occur during treatment with axitinib. An increase in red blood cell mass may increase the risk of thromboembolic events.
Elevated hemoglobin above the upper limit of normal (ULN) was observed in 31/320 patients (10%) receiving axitinib and 3/316 patients (1%) receiving sorafenib.
Monitor hemoglobin or hematocrit before initiation of, and periodically throughout, treatment with axitinib. If hemoglobin or hematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease hemoglobin or hematocrit to an acceptable level.
Hemorrhage: In a controlled clinical study with axitinib for the treatment of patients with RCC, in which patients with untreated brain metastasis were excluded, hemorrhagic events were reported in 58/359 patients (16%) receiving axitinib and 64/355 patients (18%) receiving sorafenib. The most common hemorrhagic events in patients treated with axitinib were epistaxis (6%), hematuria (3%), hemoptysis (2%), and rectal hemorrhage (2%). Grade 3/4 hemorrhagic events were reported in 5/359 patients (1%) receiving axitinib (including cerebral hemorrhage, haematuria, hemoptysis, lower gastrointestinal hemorrhage, and melaena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving axitinib (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hemorrhagic events were reported in 173/672 patients (26%) receiving axitinib. Grade 3 hemorrhagic events were reported in 20/672 patients (3%). Grade 4 hemorrhagic events were reported in 7/672 patients (1%) and fatal hemorrhagic events were reported in 3/672 patients (<1%) receiving axitinib.
Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the axitinib dose.
Gastrointestinal perforation and fistula formation: In a controlled clinical study with axitinib for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving axitinib and none of the patients (0%) receiving sorafenib. In addition to cases of gastrointestinal perforation, fistulas were reported in 2/359 patients (1%) receiving axitinib and 1/355 patients (<1%) receiving sorafenib. In pooled clinical studies with axitinib for the treatment of patients with RCC, gastrointestinal perforation and fistula were reported in 13/672 patients (2%) receiving axitinib. In monotherapy studies with axitinib (N=699), fatal gastrointestinal perforation was reported in 1/699 patient (<1%). In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).
Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with axitinib.
Wound healing complications: No formal studies of the effect of axitinib on wound healing have been conducted.
Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery. The decision to resume axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.
Reversible posterior leukoencephalopathy syndrome: In a controlled clinical study with axitinib for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving axitinib and none of the patients (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, RPLS was reported in 2/672 patients (<1%) receiving axitinib.
RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. In patients with signs/symptoms of RPLS, temporarily interrupt or permanently discontinue axitinib. The safety of reinitiating axitinib therapy in patients previously experiencing RPLS is not known.
Proteinuria: In a controlled clinical study with axitinib for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving axitinib and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving axitinib and 6/355 patients (2%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, proteinuria was reported in 142/672 patients (21%) receiving axitinib. Grade 3 proteinuria was reported in 32/672 patients (5%) receiving axitinib. Grade 4 proteinuria was reported in 1/672 patients (<1%) receiving axitinib.
Monitoring for proteinuria before initiation of, and periodically throughout, treatment with axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt axitinib treatment.
Elevation of liver enzymes: In a clinical dose-finding study, concurrent elevations of alanine aminotransferase [ALT] (12 times the ULN) and bilirubin (2.3 times the ULN), considered to be drug-related hepatotoxicity, were observed in 1 patient who received axitinib at a starting dose of 20 mg twice daily (4 times the recommended starting dose). In a controlled clinical study with axitinib for the treatment of patients with RCC, no concurrent elevations of ALT (>3 times the ULN) and bilirubin (>2 times the ULN) were observed for axitinib (N=359) or sorafenib (N=355).
Monitor liver function tests before initiation of, and periodically throughout, treatment with axitinib.
Hepatic impairment: In clinical studies with axitinib, the systemic exposure to axitinib was approximately 2-fold higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering axitinib to patients with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Effects on ability to drive and use machines: No studies on the effect of axitinib on the ability to drive and use machines have been performed. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with axitinib.

Women of childbearing potential: Women of childbearing potential must use effective contraception during and up to 1 week after treatment.
Pregnancy: Axitinib may cause fetal harm when administered to a pregnant woman. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposure at the recommended starting dose. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all dose tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose) (see Pharmacology: Toxicology: Preclinical safety data under Actions).
There are no adequate and well-controlled studies in pregnant women using axitinib. Women of childbearing potential should be advised to avoid becoming pregnant while receiving axitinib. Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with this medicinal product. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Lactation: No studies have been conducted in humans to assess the effect of axitinib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether axitinib is excreted in human milk. A risk to suckling child cannot be excluded.
Since many drugs are commonly excreted in human milk, and because of the potential for serious adverse reactions in nursing infants due to exposure to axitinib, a decision should be made whether to discontinue nursing or to discontinue axitinib, taking into account the benefit of breast feeding for child and the benefit of therapy for the woman.
Fertility: Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans (see Pharmacology: Toxicology: Preclinical safety data under Actions).

The data described as follows reflect exposure to axitinib in 672 patients with advanced RCC who participated in the pivotal randomized clinical study or 4 additional studies with axitinib in patients with advanced RCC.
The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received axitinib and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse event occurred in 199/359 patients (55%) receiving axitinib and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse event occurred in 33/359 patients (9%) receiving axitinib and 46/355 patients (13%) receiving sorafenib.
The most common (≥20%) adverse reactions observed following treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation.
The following risks, including appropriate action to be taken, are discussed in greater detail in Precautions: cardiac failure events, hypertension, thyroid dysfunction, arterial thromboembolic events, venous thromboembolic events, elevation of hemoglobin or hematocrit, haemorrhage, gastrointestinal perforation and fistula formation, wound healing complications, RPLS, proteinuria, and elevation of liver enzymes.
Table 2 presents adverse reactions reported in patients who received axitinib.
The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 2a and Table 2b.)


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In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.
CYP3A4/5 inhibitors: Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased the mean area under the curve (AUC) 2-fold and C_max 1.5-fold of a single 5-mg oral dose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) should be avoided. Grapefruit may also increase axitinib plasma concentrations. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, the axitinib dose should be reduced (see Dosage & Administration).
CYP3A4/5 inducers: Rifampin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily for 9 days, reduced the mean AUC by 79% and C_max by 71% of a single 5-mg dose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [also known as St. John's wort]) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible (see Dosage & Administration).
CYP1A2 and CYP2C19 inhibitors: CYP1A2 and CYP2C19 constitute minor (<10%) pathways in axitinib metabolism. The effect of strong inhibitors of these isozymes on axitinib pharmacokinetics has not been studied. Caution should be exercised due to the risk of increased axitinib plasma concentrations in patients taking strong inhibitors of these isozymes.
CYP1A2 induction by smoking: CYP1A2 constitutes a minor (<10%) pathway in axitinib metabolism. The effect of smoking related CYP1A2 induction on axitinib pharmacokinetics has not been fully characterised. The risk of decreased axitinib plasma concentrations should be considered when administering axitinib to smokers.
In vitro studies of CYP and UGT inhibition and induction: In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations.
In vitro studies indicated that axitinib has a potential to inhibit CYP1A2. Therefore, co-administration of axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g., theophylline).
In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, co-administration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition.
In vitro studies in human hepatocytes also indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5. Therefore co-administration of axitinib is not expected to reduce the plasma concentration of co-administered CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo.
In vitro studies with P-glycoprotein: In vitro studies indicated that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, co-administration of axitinib is not expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, in vivo.

Special precautions for disposal and other handling: Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Store below 30°C.

Targeted Cancer Therapy

L01EK01 - axitinib ; Belongs to the class of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.

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