AXITINIB ACCORD 3mg tablets medication leaflet

Axitinib Accord 1 mg film-coated tablets

Axitinib Accord 3 mg film-coated tablets

Axitinib Accord 5 mg film-coated tablets

Axitinib Accord 1 mg film-coated tablets

Each film-coated tablet contains 1 mg of axitinib.

Axitinib Accord 3 mg film-coated tablets

Each film-coated tablet contains 3 mg of axitinib.

Axitinib Accord 5 mg film-coated tablets

Each film-coated tablet contains 5 mg of axitinib.

Axitinib Accord 1 mg film-coated tablet

Each film-coated tablet contains 54.2 mg of lactose.

Axitinib Accord 3 mg film-coated tablet

Each film-coated tablet contains 32.5 mg of lactose.

Axitinib Accord 5 mg film-coated tablet

Each film-coated tablet contains 54.2 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Axitinib Accord 1 mg film-coated tablets

Red colored, modified capsule shaped biconvex film-coated tablets debossed with 'S14' on one side andplain on other side. The size of the tablet is approximately 9.1 ± 0.2 mm X 4.6 ± 0.2 mm.

Axitinib Accord 3 mg film-coated tablets

Red colored, round, biconvex film-coated-tablet debossed with 'S95' on one side and plain on the otherside. The size of the tablet is approximately 5.3 ± 0.3 X 2.6 mm ± 0.3 mm.

Axitinib Accord 5 mg film-coated tablets

Red colored, triangular shaped biconvex film-coated tablets debossed with 'S15' on one side and plainon other side. The size of the tablet is approximately 6.4 ± 0.3 mm X 6.3 ± 0.3 mm.

Axitinib Accord is indicated for the treatment of adult patients with advanced renal cell carcinoma(RCC) after failure of prior treatment with sunitinib or a cytokine.

Treatment with Axitinib Accord should be conducted by a physician experienced in the use ofanticancer therapies.

The recommended dose of axitinib is 5 mg twice daily.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occursthat cannot be managed by concomitant medicinal products or dose adjustments.

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed doseshould be taken at the usual time.

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(i.e. without severe adverse reactions according to the Common Terminology Criteria for Adverse

Events [CTCAE] version 3.0) for two consecutive weeks may have their dose increased to 7 mg twicedaily unless the patient’s blood pressure is > 150/90 mmHg or the patient is receiving antihypertensivetreatment. Subsequently, using the same criteria, patients who tolerate an axitinib dose of 7 mg twicedaily may have their dose increased to a maximum of 10 mg twice daily. Other products are availablefor the increased dose of 7 mg.

Management of some adverse reactions may require temporary or permanent discontinuation and/ordose reduction of axitinib therapy (see section 4.4). When dose reduction is necessary, the axitinibdose 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 may increase axitinib plasmaconcentrations (see section 4.5). Selection of an alternate concomitant medicinal product with no orminimal CYP3A4/5 inhibition potential is recommended.

Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of axitinib toapproximately half the dose (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mgtwice daily) is recommended. Management of some adverse reactions may require temporary orpermanent discontinuation of axitinib therapy (see section 4.4). If co-administration of the stronginhibitor is discontinued, a return to the axitinib dose used prior to initiation of the strong CYP3A4/5inhibitor should be considered (see section 4.5).

Concomitant strong CYP3A4/5 inducers

Co-administration of axitinib with strong CYP3A4/5 inducers may decrease axitinib plasmaconcentrations (see section 4.5). Selection of an alternate concomitant medicinal product with no orminimal CYP3A4/5 induction potential is recommended.

Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5inducers, if a strong CYP3A4/5 inducer must be co-administered, a gradual dose increase of axitinib isrecommended. Maximal induction with high-dose strong CYP3A4/5 inducers has been reported tooccur within one week of treatment with the inducer. If the dose of axitinib is increased, the patientshould be monitored carefully for toxicity. Management of some adverse reactions may requiretemporary or permanent discontinuation and/or dose reduction of axitinib therapy (see section 4.4). Ifco-administration of the strong inducer is discontinued, the axitinib dose should be immediatelyreturned to the dose used prior to initiation of the strong CYP3A4/5 inducer (see section 4.5).

No dose adjustment is required (see sections 4.4 and 5.2).

No dose adjustment is required (see section 5.2). Virtually no data are available regarding axitinibtreatment in patients with a creatinine clearance of < 15 mL/min.

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 withmoderate hepatic impairment (Child-Pugh class B) (e.g. the starting dose should be reduced from 5 mgtwice daily to 2 mg twice daily). Axitinib has not been studied in patients with severe hepaticimpairment (Child-Pugh class C) and should not be used in this population (see sections 4.4 and 5.2).

The safety and efficacy of Axitinib Accord in children and adolescents < 18 years have not beenestablished. No data are available.

Axitinib is for oral use. The tablets should be taken orally twice daily approximately 12 hours apart withor without food (see section 5.2). They should be swallowed whole with a glass of water.

Hypersensitivity to axitinib or to any of the excipients listed in section 6.1.

Specific safety events should be monitored before initiation of, and periodically throughout, treatmentwith axitinib as described below.

Cardiac failure events

In clinical studies with axitinib for the treatment of patients with RCC, cardiac failure events (includingcardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejectionfraction decreased, and right ventricular failure) were reported (see section 4.8).

Signs or symptoms of cardiac failure should periodically be monitored throughout treatment withaxitinib. Management of cardiac failure events may require temporary interruption or permanentdiscontinuation and/or dose reduction of axitinib therapy.

In clinical studies with axitinib for the treatment of patients with RCC, hypertension was verycommonly reported (see section 4.8).

In a controlled clinical study, 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 ofaxitinib treatment and blood pressure increases have been observed as early as 4 days after startingaxitinib.

Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored forhypertension and treated as needed with standard antihypertensive therapy. In the case of persistenthypertension, despite use of antihypertensive medicinal products, the axitinib dose should be reduced.

For patients who develop severe hypertension, temporarily interrupt axitinib and restart at a lower doseonce the patient is normotensive. If axitinib is interrupted, patients receiving antihypertensive medicinalproducts should be monitored for hypotension (see section 4.2).

In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversibleencephalopathy syndrome (PRES) (see below), a diagnostic brain magnetic resonance image (MRI)should be considered.

In clinical studies with axitinib for the treatment of patients with RCC, events of hypothyroidism and, toa lesser extent, hyperthyroidism, were reported (see section 4.8).

Thyroid function should be monitored before initiation of, and periodically throughout, treatment withaxitinib. Hypothyroidism or hyperthyroidism should be treated according to standard medical practiceto maintain euthyroid state.

Arterial embolic and thrombotic events

In clinical studies with axitinib, arterial embolic and thrombotic events (including transient ischemicattack, myocardial infarction, cerebrovascular accident and retinal artery occlusion) were reported (seesection 4.8).

Axitinib should be used with caution in patients who are at risk for, or who have a history of, theseevents. Axitinib has not been studied in patients who had an arterial embolic or thrombotic event withinthe previous 12 months.

Venous embolic and thrombotic events

In clinical studies with axitinib, venous embolic and thrombotic events (including pulmonary embolism,deep vein thrombosis, and retinal vein occlusion/thrombosis) were reported (see section 4.8).

Axitinib should be used with caution in patients who are at risk for, or who have a history of, theseevents. Axitinib has not been studied in patients who had a venous embolic or thrombotic event withinthe previous 6 months.

Elevation of haemoglobin or haematocrit

Increases in haemoglobin or haematocrit, reflective of increases in red blood cell mass, may occurduring treatment with axitinib (see section 4.8, polycythaemia). An increase in red blood cell mass mayincrease the risk of embolic and thrombotic events.

Haemoglobin or haematocrit should be monitored before initiation of, and periodically throughout,treatment with axitinib. If haemoglobin or haematocrit becomes elevated above the normal level,patients should be treated according to standard medical practice to decrease haemoglobin orhaematocrit to an acceptable level.

In clinical studies with axitinib, haemorrhagic events were reported (see section 4.8).

Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recentactive gastrointestinal bleeding, and should not be used in those patients. If any bleeding requiresmedical intervention, temporarily interrupt the axitinib dose.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Axitinib Accord, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm.

Gastrointestinal perforation and fistula formation

In clinical studies with axitinib, events of gastrointestinal perforation and fistulas were reported (seesection 4.8).

Symptoms of gastrointestinal perforation or fistula should be periodically monitored for throughouttreatment with axitinib.

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 toresume axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.

Posterior reversible encephalopathy syndrome (PRES)

In clinical studies with axitinib, events of PRES were reported (see section 4.8).

PRES 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 PRES. In patients with signs orsymptoms of PRES, temporarily interrupt or permanently discontinue axitinib treatment. The safety ofreinitiating axitinib therapy in patients previously experiencing PRES is not known.

Proteinuria

In clinical studies with axitinib, proteinuria, including that of Grade 3 and 4 severity, was reported (seesection 4.8).

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with axitinib isrecommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarilyinterrupt axitinib treatment (see section 4.2). Axitinib should be discontinued if the patient developsnephrotic syndrome.

Liver-related adverse reactions

In a controlled clinical study with axitinib for the treatment of patients with RCC, liver-related adversereactions were reported. The most commonly reported liver-related adverse reactions included increasesin alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin (seesection 4.8). No concurrent elevations of ALT (> 3 times the upper limit of normal [ULN]) andbilirubin (> 2 times the ULN) were observed.

In a clinical dose-finding study, concurrent elevations of ALT (12 times the ULN) and bilirubin(2.3 times the ULN), considered to be drug-related hepatotoxicity, were observed in 1 patient whoreceived axitinib at a starting dose of 20 mg twice daily (4 times the recommended starting dose).

Liver function tests should be monitored before initiation of, and periodically throughout, treatmentwith axitinib.

In clinical studies with axitinib, the systemic exposure to axitinib was approximately two-fold higher insubjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normalhepatic function. A dose decrease is recommended when administering axitinib to patients withmoderate hepatic impairment (Child-Pugh class B) (see section 4.2).

Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) andshould not be used in this population.

Elderly (≥ 65 years) and race

In a controlled clinical study with axitinib for the treatment of patients with RCC, 34 % of patientstreated with axitinib were ≥ 65 years of age. The majority of patients were White (77 %) or Asian(21 %). Although greater sensitivity to develop adverse reactions in some older patients and Asianpatients cannot be ruled out, overall, no major differences were observed in the safety and effectivenessof axitinib between patients who were ≥ 65 years of age and non-elderly, and between white patientsand patients of other races.

No dosage adjustment is required on the basis of patient age or race (see sections 4.2 and 5.2).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per film-coated tablet, that is to sayessentially ‘sodium-free’.

In vitro data indicate that axitinib is metabolised 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 for7 days, increased the mean area under the curve (AUC) 2-fold and Cmax 1.5-fold of a single 5-mg oraldose of axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inhibitors(e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone,nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations.

Grapefruit may also increase axitinib plasma concentrations. Selection of concomitant medicinalproducts with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5inhibitor must be co-administered, a dose adjustment of axitinib is recommended (see section 4.2).

CYP1A2 and CYP2C19 inhibitors

CYP1A2 and CYP2C19 constitute minor (< 10 %) pathways in axitinib metabolism. The effect ofstrong inhibitors of these isozymes on axitinib pharmacokinetics has not been studied. Caution shouldbe exercised due to the risk of increased axitinib plasma concentrations in patients taking stronginhibitors of these isozymes.

CYP3A4/5 inducers

Rifampicin, 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 Cmax by 71 % of a single 5 mg dose of axitinib in healthyvolunteers.

Co-administration of axitinib with strong CYP3A4/5 inducers (e.g. rifampicin, dexamethasone,phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [St. John’swort]) may decrease axitinib plasma concentrations. Selection of concomitant medicinal products withno or minimal CYP3A4/5 induction potential is recommended. If a strong CYP3A4/5 inducer must beco-administered, a dose adjustment of axitinib is recommended (see section 4.2).

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-administrationof axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2substrates (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 increasedplasma 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 plasmaconcentration 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 toinhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, co-administration of axitinib isnot expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, invivo.

There are no data regarding the use of axitinib in pregnant women. Based on the pharmacologicalproperties of axitinib, it may cause foetal harm when administered to a pregnant woman. Studies inanimals have shown reproductive toxicity including malformations (see section 5.3). Axitinib shouldnot be used during pregnancy unless the clinical condition of the woman requires treatment with thismedicinal product.

Women of childbearing potential must use effective contraception during and up to 1 week aftertreatment.

It is unknown whether axitinib is excreted in human milk. A risk to the suckling child cannot beexcluded. Axitinib should not be used during breast-feeding.

Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertilityin humans (see section 5.3).

Axitinib has minor influence on the ability to drive and use machines. Patients should be advised thatthey may experience events such as dizziness and/or fatigue during treatment with axitinib.

The following risks, including appropriate action to be taken, are discussed in greater detail insection 4.4: cardiac failure events, hypertension, thyroid dysfunction, arterial thromboembolic events,venous thromboembolic events, elevation of haemoglobin or haematocrit, haemorrhage, gastrointestinalperforation and fistula formation, wound healing complications, PRES, proteinuria, and elevation ofliver enzymes.

The most common (≥ 20 %) adverse reactions observed following treatment with axitinib werediarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting,proteinuria, cough, and constipation.

Table 1 presents adverse reactions reported in a pooled dataset of 672 patients who received axitinib inclinical studies for the treatment of patients with RCC (see section 5.1). Post-marketing adversereactions identified in clinical studies are also included.

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), and not known (cannotbe estimated from the available data). The current safety database for axitinib is too small to detectrare and very rare adverse reactions.

Categories have been assigned based on absolute frequencies in the pooled clinical studies data.

Within each system organ class, adverse reactions with the same frequency are presented in order ofdecreasing seriousness.

Table 1. Adverse reactions reported in RCC studies in patients who received axitinib (N = 672)

System organ Frequency Adverse reactionsa All Grade Gradeclass category Gradesb% 3b % 4b %

Blood and Common Anaemia 6.3 1.2 0.4lymphatic Thrombocytopenia 1.6 0.1 0system Polycythaemiac 1.5 0.1 0disorders Uncommon Neutropaenia 0.3 0.1 0

Leukopaenia 0.4 0 0

Endocrine Very Hypothyroidismc 24.6 0.3 0disorders common

Common Hyperthyroidismc 1.6 0.1 0.1

Metabolism and Very Decreased appetite 39.0 3.6 0.3nutrition disorders common

Common Dehydration 6.7 3.1 0.3

Hyperkalaemia 2.7 1.2 0.1

Hypercalcaemia 2.2 0.1 0.3

Nervous system Very Headache 16.2 0.7 0disorders common Dysgeusia 11.5 0 0

Common Dizziness 9.1 0.6 0

Uncommon Posterior 0.3 0.1 0reversibleencephalopathysyndromee

Ear and labyrinth Common Tinnitus 3.1 0 0disorders

Cardiac disorders Common Cardiac failure 1.8 0.3 0.7eventsc,d,f

Vascular disorders Very Hypertensiong 51.2 22.0 1.0common Haemorrhagec,d,h 25.7 3.0 1.0

Common Venous embolic and 2.8 0.9 1.2thrombotic eventsc,d,i

Arterial embolic and 2.8 1.2 1.3thrombotic eventsc,d,j

Not known Aneurysms and - - -artery dissectionsd

System organ Frequency Adverse reactionsa All Grade Gradeclass category Gradesb% 3b % 4b %

Respiratory, Very Dyspnoead 17.1 3.6 0.6thoracic and common Cough 20.4 0.6 0mediastinal Dysphonia 32.7 0 0.1disorders Common Oropharyngeal pain 7.4 0 0

Gastrointestinal Very Diarrhoea 55.4 10.1 0.1disorders common Vomiting 23.7 2.7 0.1

Nausea 33.0 2.2 0.1

Abdominal pain 14.7 2.5 0.3

Constipation 20.2 1.0 0

Stomatitis 15.5 1.8 0

Dyspepsia 11.2 0.1 0

Common Upper abdominal 9.4 0.9 0pain

Flatulence 4.5 0 0

Haemorrhoids 3.3 0 0

Glossodynia 2.8 0 0

Gastrointestinal 1.9 0.9 0.3perforation andfistulac,k

Hepatobiliary Common Hyperbilirubinaemia 1.3 0.1 0.1disorders Cholecystitisn 1.0 0.6 0.1

Skin and Very Palmar-plantar 32.1 7.6 0subcutaneous common erythrodysaesthesiatissue disorders (hand-footsyndrome)

Rash 14.3 0.1 0

Dry skin 10.1 0.1 0

Common Pruritus 6.0 0 0

Erythema 3.7 0 0

Alopecia 5.7 0 0

Musculoskeletal Very Arthralgia 17.7 1.9 0.3and connective common Pain in extremity 14.1 1.0 0.3tissue disorders Common Myalgia 8.2 0.6 0.1

Renal and urinary Very Proteinuria1 21.1 4.8 0.1disorders common

Common Renal failurem 1.6 0.9 0.1

General disorders Very Fatigue 45.1 10.6 0.3and administration common Asthaeniad 13.8 2.8 0.3site conditions Mucosal 13.7 1.0 0inflammation

Investigations Very Weight decreased 32.7 4.9 0common

Common Lipase increased 3.7 0.7 0.7

Alanine 6.5 1.2 0aminotransferaseincreased

Amylase increased 3.4 0.6 0.4

Aspartate 6.1 1.0 0aminotransferaseincreased

Alkaline 4.8 0.3 0phosphataseincreased

Creatinine increased 5.7 0.4 0

Thyroid stimulating 7.9 0 0hormone increaseda Adverse reactions are according to treatment-emergent, all causality frequency.b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0c See Description of selected adverse reactions section.d Fatal (Grade 5) cases were reported.e Including Leukoencephalopathy.f Including cardiac failure, cardiac failure congestive, cardiopulmonary failure, ejection fraction decreased,left ventricular dysfunction and right ventricular failure.g Including accelerated hypertension, blood pressure increased, hypertension and hypertensive crisis.h Including activated partial thromboplastin time prolonged, anal haemorrhage, arterial haemorrhage, bloodurine present, central nervous system haemorrhage, cerebral haemorrhage, coagulation time prolonged,conjunctival haemorrhage, contusion, diarrhea haemorrhagic, dysfunctional uterine bleeding, epistaxis,gastric haemorrhage, gastrointestinal haemorrhage, gingival bleeding, haematemesis, haematochezia,haematocrit decreased, haematoma, haematuria, haemoglobin decreased, haemoptysis, haemorrhage,haemorrhage coronary artery, haemorrhage urinary tract, haemorrhoidal haemorrhage, haemostasis, increasedtendency to bruise, international normalized ratio increased, lower gastrointestinal haemorrhage, melaena,petechiae, pharyngeal haemorrhage, prothrombin time prolonged, pulmonary haemorrhage, purpura, rectalhaemorrhage, red blood cell count decreased, renal haemorrhage, scleral haemorrhage, scrotal haematocoele,splenic haemotoma, splinter haemorrhage, subarachnoid haemorrhage, tongue haemorrhage, uppergastrointestinal haemorrhage and vaginal haemorrhage.i Including Budd-Chiari syndrome, deep vein thrombosis, jugular vein thrombosis, pelvic venous thrombosis,pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, subclavian vein thrombosis, venousthrombosis, and venous thrombosis limb.j Including acute myocardial infarction, embolism, myocardial infarction, retinal artery occlusion andtransient ischaemic attack.k Gastrointestinal perforation and fistula includes the following preferred terms: abdominal abscess, analabscess, anal fistula, fistula, gastrointestinal anastomotic leak, gastrointestinal perforation, large intestineperforation, oesophagobronchial fistula and peritonitis.l Proteinuria includes the following preferred terms: protein urine, protein urine present and proteinuria.m Including acute renal failuren Cholecystitis includes Cholecystitis acute, Cholecystitis, Cholecystitis infective.

Cardiac failure events (see section 4.4)

In a controlled clinical study with axitinib (N = 359) for the treatment of patients with RCC, cardiacfailure events were reported in 1.7 % patients receiving axitinib, including cardiac failure (0.6 %),cardiopulmonary failure (0.6 %), left ventricular dysfunction (0.3 %), and right ventricular failure(0.3 %). Grade 4 cardiac failure adverse reactions were reported in 0.6 % of patients receiving axitinib.

Fatal cardiac failure was reported in 0.6 % of patients receiving axitinib.

In monotherapy studies with axitinib (N = 672) for the treatment of patients with RCC, cardiac failureevents (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventriculardysfunction, ejection fraction decreased, and right ventricular failure) were reported in 1.8 % patientsreceiving axitinib. Grade 3/4 cardiac failure events were reported in 1.0 % patients and fatal cardiacfailure events were reported in 0.3 % patients receiving axitinib.

Thyroid dysfunction (see section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC, hypothyroidismwas reported in 20.9 % of patients and hyperthyroidism was reported in 1.1 % of patients. Thyroidstimulating hormone (TSH) increased was reported as an adverse reaction in 5.3 % of patientsreceiving axitinib. During routine laboratory assessments, in patients who had TSH < 5 μU/mLbefore treatment, elevations of TSH to ≥ 10 μU/mL occurred in 32.2 % of patients receiving axitinib.

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC,hypothyroidism was reported in 24.6 % of patients receiving axitinib. Hyperthyroidism was reportedin 1.6 % of patients receiving axitinib.

Venous embolic and thrombotic events (see section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC, venous embolicand thrombotic adverse reactions were reported in 3.9 % of patients receiving axitinib, includingpulmonary embolism (2.2 %), retinal vein occlusion/thrombosis (0.6 %) and deep vein thrombosis(0.6 %). Grade 3/4 venous embolic and thrombotic adverse reactions were reported in 3.1 % ofpatients receiving axitinib. Fatal pulmonary embolism was reported in one patient (0.3 %) receivingaxitinib.

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, venousembolic and thrombotic events were reported in 2.8 % of patients receiving axitinib. Grade 3 venousembolic and thrombotic events were reported in 0.9 % of patients. Grade 4 venous embolic andthrombotic events were reported in 1.2 % of patients. Fatal venous embolic and thrombotic eventswere reported 0.1 % patients receiving axitinib.

Arterial embolic and thrombotic events (see section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC, arterial embolicand thrombotic adverse reactions were reported in 4.7 % of patients receiving axitinib, includingmyocardial infarction (1.4 %), transient ischemic attack (0.8 %) and cerebrovascular accident(0.6 %). Grade 3/4 arterial embolic and thrombotic adverse reactions were reported in 3.3 % ofpatients receiving axitinib. A fatal acute myocardial infarction and cerebrovascular accident wasreported in one patient each (0.3 %). In monotherapy studies with axitinib (N = 850), arterialembolic and thrombotic adverse reactions (including transient ischemic attack, myocardialinfarction, and cerebrovascular accident) were reported in 5.3 % of patients receiving axitinib.

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, arterialembolic and thrombotic events were reported in 2.8 % of patients receiving axitinib. Grade 3 arterialembolic and thrombotic events were reported in 1.2 % of patients. Grade 4 arterial embolic andthrombotic events were reported in 1.3 % of patients. Fatal arterial embolic and thrombotic eventswere reported in 0.3 % patients receiving axitinib.

Polycythaemia (see Elevation of haemoglobin or haematocrit in section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC, polycythaemiawas reported in 1.4 % of patients receiving axitinib. Routine laboratory assessments detectedelevated haemoglobin above ULN in 9.7 % of patients receiving axitinib. In four clinical studieswith axitinib for the treatment of patients with RCC (N = 537), elevated haemoglobin above ULNwas observed in 13.6 % receiving axitinib.

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC,polycythaemia was reported in 1.5 % of patients receiving axitinib.

Haemorrhage (see section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC that excludedpatients with untreated brain metastasis, haemorrhagic adverse reactions were reported in 21.4 %of patients receiving axitinib. The haemorrhagic adverse reactions in patients treated with axitinibincluded epistaxis (7.8 %), haematuria (3.6 %), haemoptysis (2.5 %), rectal haemorrhage (2.2 %),gingival bleeding (1.1 %), gastric haemorrhage (0.6 %), cerebral haemorrhage (0.3 %) and lowergastrointestinal haemorrhage (0.3 %). Grade > 3 haemorrhagic adverse reactions were reported in3.1 % of patients receiving axitinib (including cerebral haemorrhage, gastric haemorrhage, lowergastrointestinal haemorrhage and haemoptysis). Fatal haemorrhage was reported in one patient(0.3 %) receiving axitinib (gastric haemorrhage). In monotherapy studies with axitinib (N = 850),haemoptysis was reported in 3.9 % of patients; Grade > 3 haemoptysis was reported in 0.5% ofpatients.

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC,haemorrhagic events were reported in 25.7 % of patients receiving axitinib. Grade 3 haemorrhagicadverse reactions were reported in 3 % of patients. Grade 4 haemorrhagic adverse reactions werereported in 1 % of patients and fatal haemorrhage were reported in 0.4 % of patients receivingaxitinib.

Gastrointestinal perforation and fistula formation (see section 4.4)

In a controlled clinical study with axitinib for the treatment of patients with RCC, gastrointestinalperforation-type events were reported in 1.7 % of patients receiving axitinib, including anal fistula(0.6 %), fistula (0.3 %) and gastrointestinal perforation (0.3 %).In monotherapy studies withaxitinib (N = 850), gastrointestinal perforation-type events were reported in 1.9% of patients andfatal gastrointestinal perforation was reported in one patient (0.1 %).

In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC,gastrointestinal perforation and fistula were reported in 1.9% of patients receiving axitinib.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for axitinib overdose.

In a controlled clinical study with axitinib for the treatment of patients with RCC, one patientinadvertently 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 twicedaily or 20 mg twice daily experienced adverse reactions which included hypertension, seizuresassociated with hypertension, and fatal haemoptysis.

In cases of suspected overdose, axitinib should be withheld and supportive care instituted.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EK01

Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factorreceptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologicangiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potentlyinhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited thephosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo andproduced tumour growth delay, regression, and inhibition of metastases in many experimental modelsof cancer.

Effect on QTc interval

In a randomised, 2-way crossover study, 35 healthy subjects were administered a single oral dose ofaxitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this studyindicated that axitinib plasma exposures up to two-fold greater than therapeutic levels expectedfollowing a 5 mg dose, did not produce clinically-significant QT interval prolongation.

The safety and efficacy of axitinib were evaluated in a randomised, open-label, multicenter Phase 3study. Patients (N = 723) with advanced RCC whose disease had progressed on or after treatment withone prior systemic therapy, including sunitinib, bevacizumab, temsirolimus, or cytokine-containingregimens were randomised (1:1) to receive axitinib (N = 361) or sorafenib (N = 362). The primaryendpoint, 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 (53.8 %) had received one prior sunitinib-basedtherapy, 251 patients (34.7 %) had received one prior cytokine-based therapy (interleukin-2 orinterferon-alpha), 59 patients (8.2 %) had received one prior bevacizumab-based therapy, and24 patients (3.3 %) had received one prior temsirolimus-based therapy. The baseline demographic anddisease characteristics were similar between the axitinib and sorafenib groups with regard to age,gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, andprior treatment.

In the overall patient population and the two main subgroups (prior sunitinib treatment and priorcytokine treatment), there was a statistically significant advantage for axitinib over sorafenib for theprimary endpoint of PFS (see Table 2 and Figures 1, 2 and 3). The magnitude of median PFS effect wasdifferent 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 significantdifferences between the arms in OS in the overall population or in the subgroups by prior therapy.

Table 2. Efficacy results

Endpoint/study population axitinib sorafenib HR (95% CI) p-value

Overall ITT N = 361 N = 362

Median PFS a,b in months 6.8 (6.4, 8.3) 4.7 (4.6, 6.3) 0.67 (0.56, 0.81) < 0.0001c(95% CI)

Median OSd in months 20.1 (16.7, 23.4) 19.2 (17.5, 22.3) 0.97 (0.80, 1.17) NS(95% CI)

ORRb,e % (95% CI) 19.4 (15.4, 23.9) 9.4 (6.6, 12.9) 2.06f (1.41, 3.00) 0.0001g

Prior sunitinib treatment N = 194 N = 195

Median PFSa,b in months 4.8 (4.5, 6.5) 3.4 (2.8, 4.7) 0.74 (0.58, 0.94) 0.0063h(95% CI)

Median OSd in months 15.2 (12.8, 18.3) 16.5 (13.7, 19.2) 1.00 (0.78, 1.27) NS(95% CI)

ORRb,e % (95% CI) 11.3 (7.2, 16.7) 7.7 (4.4, 12.4) 1.48f (0.79, 2.75) NS

Prior cytokine treatment N = 126 N = 125

Median PFSa,b in months 12.0 (10.1, 13.9) 6.6 (6.4, 8.3) 0.52 (0.38, 0.72) < 0.0001h(95% CI)

Median OSd in months 29.4 (24.5, NE) 27.8 (23.1, 34.5) 0.81 (0.56, 1.19) NS(95% CI)

ORRb,e% (95% CI) 32.5 (24.5, 41.5) 13.6 (8.1, 20.9) 2.39f (1.43-3.99) 0.0002i

CI = Confidence interval, HR = Hazard ratio (axitinib/sorafenib); ITT: Intent-to-treat; NE: not estimable; NS:not statistically significant; ORR: Objective response rate; OS: Overall survival; PFS: Progression-freesurvival.a Time from randomisation to progression or death due to any cause, whichever occurs first. Cutoff date: 03

June 2011.b Assessed by independent radiology review according to Response Evaluation Criteria in Solid Tumours(RECIST).c One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy.d Cutoff date: 01 November 2011.e Cutoff date: 31 August 2010.f Risk ratio is used for ORR. A risk ratio > 1 indicated a higher likelihood of responding in the axitinib a rm; a riskratio < 1 indicated a higher likelihood of responding in the sorafenib arm.g One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status andprior therapy.h One-sided p-value from a log-rank test of treatment stratified by ECOG performance status.i One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status.

Figure 1. Kaplan-Meier curve of progression-free survival by independent assessment for theoverall population

Figure 2. Kaplan-Meier curve of progression-free survival by independent assessment for theprior sunitinib subgroup

Figure 3. Kaplan-Meier curve of progression-free survival by independent assessment for theprior cytokine subgroup

The European Medicines Agency has waived the obligation to submit the results of studies with axitinibin all subsets of the paediatric population for treatment of kidney and renal pelvis carcinoma (excludingnephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullarycarcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).

After oral administration of axitinib tablets, the mean absolute bioavailability is 58 % compared tointravenous administration. The plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Dosing ofaxitinib at 5 mg twice daily resulted in less than two-fold accumulation compared to administration of asingle dose. Based on the short half-life of axitinib, steady state is expected within 2 to 3 days of theinitial dose.

Peak axitinib concentrations in plasma are generally reached within 4 hours following oraladministration of axitinib with median Tmax ranging from 2.5 to 4.1 hours. Administration of axitinibwith 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 beadministered with or without food (see section 4.2).

The average Cmax and AUC increased proportionally over an axitinib dosing range of 5 to 10 mg. Invitro binding of axitinib to human plasma proteins is > 99 % with preferential binding to albumin andmoderate binding to α1-acid glycoprotein. At the 5 mg twice daily dose in the fed state, the geometricmean peak plasma concentration and 24-hour AUC were 27.8 ng/mL and 265 ng.h/mL, respectively, inpatients with advanced RCC. The geometric mean oral clearance and apparent volume of distributionwere 38 L/h and 160 L, respectively.

Axitinib is metabolised 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 wasrecovered in faeces and 23 % of the radioactivity was recovered in urine. Unchanged axitinib,accounting for 12 % of the dose, was the major component identified in faeces. Unchanged axitinib wasnot detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority ofradioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactivecomponent (50 % of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite eachaccounted for approximately 20 % of the circulating radioactivity.

The sulfoxide and N-glucuronide metabolites show approximately 400-fold and 8000-fold less in vitropotency, respectively, against VEGFR-2 compared to axitinib.

Elderly, gender, and race

Population pharmacokinetic analyses in patients with advanced cancer (including advanced RCC) andhealthy volunteers indicate that there are no clinically relevant effects of age, gender, body weight, race,renal function, UGT1A1 genotype, or CYP2C19 genotype.

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

In vitro and in vivo data indicate that axitinib is primarily metabolised by the liver.

Compared to subjects with normal hepatic function, systemic exposure following a single dose ofaxitinib was similar in subjects with mild hepatic impairment (Child-Pugh class A) and higher(approximately two-fold) in subjects with moderate hepatic impairment (Child-Pugh class B). Axitinibhas not been studied in subjects with severe hepatic impairment (Child-Pugh class C) and should not beused in this population (see section 4.2 for dose adjustment recommendations).

Unchanged axitinib is not detected in the urine.

Axitinib has not been studied in subjects with renal impairment. In clinical studies with axitinib for thetreatment of patients with RCC, patients with serum creatinine > 1.5 times the ULN or calculatedcreatinine clearance < 60 mL/min were excluded. Population pharmacokinetic analyses have shown thataxitinib clearance was not altered in subjects with renal impairment and no dose adjustment of axitinibis required.

Major toxicity findings in mice and dogs following repeated dosing for up to 9 months were thegastrointestinal, haematopoietic, reproductive, skeletal and dental systems, with No Observed Adverse

Effect Levels (NOAEL) approximately equivalent to or below expected human exposure at therecommended clinical starting dose (based on AUC levels).

Carcinogenicity studies have not been performed with axitinib.

Axitinib was not mutagenic or clastogenic in conventional genotoxicity assays in vitro. A significantincrease in polyploidy was observed in vitro at concentrations > 0.22 µg/mL, and an elevation inmicronucleated polychromatic erythrocytes was observed in vivo with No Observed Effect Level(NOEL) 69-fold the expected human exposure. Genotoxicity findings are not considered clinicallyrelevant at exposure levels observed in humans.

Reproduction toxicity

Axitinib-related findings in the testes and epididymis included decreased organ weight, atrophy ordegeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, andreduced sperm density and count. These findings were observed in mice at exposure levelsapproximately 12-fold the expected human exposure, and in dogs at exposure levels below theexpected human exposure. There was no effect on mating or fertility in male mice at exposure levelsapproximately 57-fold the expected human exposure. Findings in females included signs of delayedsexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy atexposures approximately equivalent to the expected human exposure. Reduced fertility and embryonicviability were observed in female mice at all doses tested, with exposure levels at the lowest doseapproximately 10-fold the expected human exposure.

Pregnant mice exposed to axitinib showed an increased occurrence of cleft palate malformations andskeletal variations, including delayed ossification, at exposure levels below the expected humanexposure. Perinatal and postnatal developmental toxicity studies have not been conducted.

Toxicity findings in immature animals

Reversible physeal dysplasia was observed in mice and dogs given axitinib for at least 1 month atexposure levels approximately six-fold higher than the expected human exposure. Partially reversibledental caries were observed in mice treated for more than 1 month at exposure levels similar to theexpected human exposure. Other toxicities of potential concern to paediatric patients have not beenevaluated in juvenile animals.

6 PHARMACEUTICAL PARTICULARS

Cellulose, Microcrystalline (E460)

Silica, Colloidal anhydrous

Hydroxypropylcellulose (300-600 mPa*s)

Croscarmellose sodium (E 468)

Talc

Magnesium stearate (E 470b)

Hypromellose 2910 (15 mPa*s) (E464)

Lactose monohydrate

Titanium Dioxide (E171)

Triacetin

Iron Oxide Red (E172)

Not applicable.

Blister and bottle pack: 2 years

Shelf life after first opening of bottle: 1 mg - 45 days and 3, 5 mg - 30 days

This medicinal product does not require any special temperature storage conditions.

OPA/Aluminium/PVC/Aluminium blister:

Store in the original package in order to protect from moisture.

HDPE bottle:

Keep the bottle tightly closed to protect from moisture.

Axitinib Accord 1 mg film-coated tablet

OPA/Aluminium/PVC/Aluminium blister containing 14 film-coated tablets. Each pack contains 28 or56 film-coated tablets or perforated unit dose blisters of 28 x 1 or 56 x 1 film-coated tablets.

HDPE bottle with a silica gel desiccant and a polypropylene child resistant closure containing 180film-coated tablets.

Axitinib Accord 3 mg film-coated tablet

OPA/Aluminium/PVC/Aluminium blister containing 14 film-coated tablets. Each pack contains 28 or56 film-coated tablets or perforated unit dose blisters of 28 x 1 or 56 x 1 film-coated tablets.

HDPE bottle with a silica gel desiccant and a polypropylene child resistant closure containing 60 film-coated tablets.

Axitinib Accord 5 mg film-coated tablet

OPA/Aluminium/PVC/Aluminium blister containing 14 film-coated tablets. Each pack contains 28 or56 film-coated tablets or perforated unit dose blisters of 28 x 1 or 56 x 1 film-coated tablets.

HDPE bottle with a silica gel desiccant and a polypropylene child resistant closure containing 60 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

1 mg Film-coated tablet

EU/1/24/1847/001 28 tablets

EU/1/24/1847/002 28 x 1 tablets (unit dose)

EU/1/24/1847/003 56 tablets

EU/1/24/1847/004 56 x 1 tablets (unit dose)

EU/1/24/1847/005 180 tablets (bottle)3 mg Film-coated tablet

EU/1/24/1847/006 28 tablets

EU/1/24/1847/007 28 x 1 tablets (unit dose)

EU/1/24/1847/008 56 tablets

EU/1/24/1847/009 56 x 1 tablets (unit dose)

EU/1/24/1847/010 60 tablets (bottle)5 mg Film-coated tablet

EU/1/24/1847/011 28 tablets

EU/1/24/1847/012 28 x 1 tablets (unit dose)

EU/1/24/1847/013 56 tablets

EU/1/24/1847/014 56 x 1 tablets (unit dose)

EU/1/24/1847/015 60 tablets (bottle)

Date of first authorisation:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.