INLYTA

Main information

  • Trade name:
  • INLYTA axitinib 3mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • INLYTA axitinib 3mg tablet blister pack
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 213873
  • Last update:
  • 09-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

213873

INLYTA axitinib 3mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Pfizer Australia Pty Ltd

Postal Address

38-42 Wharf Road,WEST RYDE, NSW, 2114

Australia

ARTG Start Date

30/04/2014

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. INLYTA axitinib 3mg tablet blister pack

Product Type

Single Medicine Product

Effective date

5/04/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

For the treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

Al/Al

3 Years

Store below 30

degrees Celsius

Not recorded

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

28 tablets

(S4) Prescription Only Medicine

56 tablets

(S4) Prescription Only Medicine

Components

1. INLYTA axitinib 3 mg tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

Red, round, film-coated tablet debossed with Pfizer on one side and 3XNB

on the other.

Active Ingredients

Axitinib

3 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 10:50:11 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

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PRODUCT INFORMATION

INLYTA (axitinib)

NAME OF THE MEDICINE

Axitinib

chemical

name

N

-methyl-2-[3-((

E

)-2-pyridin-2-yl-vinyl)-1

H

-indazol-

6-ylsulfanyl]-benzamide. The molecular formula is C

OS and the molecular weight is

386.47 Daltons. The CAS Registry Number is 319460-85-0. The chemical structure is:

DESCRIPTION

Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in

aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2

g/mL. The partition

coefficient (n-octanol/water) is 3.5.

INLYTA is supplied as red film-coated tablets containing 1 mg, 3 mg, 5 mg, or 7 mg of

axitinib

together

with

cellulose

microcrystalline,

lactose,

croscarmellose

sodium,

magnesium stearate, and Opadry II red 32K15441 as inactive ingredients. The Opadry II red

32K15441 film coating contains lactose, HPMC 2910/Hypromellose 15cP, titanium dioxide,

glycerol triacetate, and iron oxide red.

PHARMACOLOGY

Mechanism of Action

Axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors

(VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathological

angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown

to inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the

phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target

in

vivo

and produced tumour growth delay, regression, and inhibition of metastases in many

experimental models of cancer.

Pharmacodynamics

In a randomized, 2-way crossover study, 35 healthy subjects were administered a single oral

dose of INLYTA (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days.

Results of this study indicated that INLYTA 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.

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Pharmacokinetics

Absorption and Distribution

After oral administration of INLYTA tablets, the mean absolute bioavailability is 58%

compared to intravenous administration. The plasma half-life of INLYTA ranges from 2.5 to

6.1 hours. Dosing of INLYTA 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.

Peak axitinib concentrations in plasma are generally reached within 4 hours following oral

administration

INLYTA

with

median

ranging

from

hours.

Administration of INLYTA 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. INLYTA may be administered with or without food (See

Dosage and Administration

The average C

and area under the curve (AUC) increased proportionally over an INLYTA

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 α

-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 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 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, Ethnicity, Elderly (>65 years) patients

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.

Children and Adolescents

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

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Renal Impairment

Unchanged axitinib is not detected in the urine. INLYTA has not been studied in subjects

with renal impairment. In clinical studies with INLYTA for the treatment of patients with

RCC,

patients

with

serum

creatinine

>1.5

times

upper

limit

of normal

(ULN)

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 INLYTA is recommended.

Hepatic Impairment

In vitro

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 INLYTA was similar to subjects with mild hepatic impairment (Child-Pugh class A)

and higher (approximately 2-fold) in subjects with moderate hepatic impairment (Child-Pugh

class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-

Pugh class C) (See

Precautions; Dosage and Administration

CLINICAL TRIALS

The safety and efficacy of INLYTA were evaluated in a randomized, open-label, multicenter

Phase 3 study. Patients (N=723) with advanced renal cell carcinoma (RCC) whose disease

had progressed on or after treatment with one prior systemic therapy, including sunitinib-,

bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to

receive INLYTA (n=361) or sorafenib (n=362). The primary endpoint, progression-free

survival

(PFS),

assessed

using

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-

based

therapy,

patients

(34.7%)

received

prior

cytokine-based

therapy

(interleukin-2 or interferon-alpha), 59 patients (8.2%) had received one prior bevacizumab-

based therapy, and 24 patients (3.3%) had received one prior temsirolimus-based therapy.

The baseline demographic and disease characteristics were similar between the INLYTA and

sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group

(ECOG) performance status, geographic region, and prior treatment.

There was a statistically significant advantage for INLYTA over sorafenib for the primary

endpoint of PFS (see Table 1 and Figure 1). There was no statistically significant difference

between the arms in OS.

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Table 1: Efficacy Results by Independent Assessment

Endpoint / Study Population

INLYTA

Sorafenib

HR (95% CI)

P-value

PFS

a,b

Overall ITT

Median, months (95% CI)

N = 361

6.7 (6.3, 8.6)

N = 362

4.7 (4.6, 5.6)

0.67 (0.54, 0.81)

<0.0001

Sunitinib-refractory subgroup

Median, months (95% CI)

N = 194

4.8 (4.5, 6.4)

N = 195

3.4 (2.8, 4.7)

0.74 (0.57, 0.96)

0.0107

Cytokine-refractory subgroup

Median, months (95% CI)

N = 126

12.1 (10.1, 13.9)

N = 125

6.5 (6.3, 8.3)

0.46 (0.32, 0.68)

<0.0001

OS

Median, months (95% CI)

20.1 (16.7, 23.4)

19.2 (17.5, 22.3)

0.97 (0.80, 1.17)

0.374

ORR

% (95% CI)

N = 361

19.4 (15.4, 23.9)

N = 362

9.4 (6.6, 12.9)

2.06

(1.41, 3.00)

0.0001

CI: Confidence interval; HR: Hazard ratio (INLYTA/sorafenib); ITT: Intent to treat; ORR: Objective response

rate; OS: Overall survival; PFS: Progression-free survival

Time from randomization to progression or death due to any cause, whichever occurs first.

Assessed by independent radiology review according to RECIST.

One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy

(comparison is considered statistically significant if the one-sided p-value is <0.023).

One-sided p-value from a log-rank test of treatment stratified by ECOG performance status.

One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy.

Risk ratio is used for ORR. A risk ratio >1 indicated a higher likelihood of responding in the axitinib arm; a

risk ratio <1 indicated a higher likelihood of responding in the sorafenib arm.

One-sided p-value from Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status

and prior therapy.

Figure 1: Kaplan-Meier Curve for Progression-Free Survival by Independent

Assessment for the Overall Population

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INDICATIONS

INLYTA is indicated for the treatment of patients with advanced renal cell carcinoma after

failure of one prior systemic therapy.

CONTRAINDICATIONS

Hypersensitivity to axitinib or to any of the excipients.

PRECAUTIONS

Cardiac Failure Events

In a controlled clinical study with INLYTA 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 1.7% of patients receiving INLYTA (N=359)

and 0.8% of patients receiving sorafenib (N=355) (see

Adverse Effects

). Grade 3/4 cardiac

failure events were observed in 0.6% of patients receiving INLYTA and 0.3% of patients

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

and 0.3% of patients 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 1.8%

of patients receiving INLYTA. Grade 3/4 cardiac failure events were reported in 1.0% and

fatal cardiac failure events were reported in 0.3% of patients receiving INLYTA.

Monitor for signs or symptoms of cardiac failure periodically throughout treatment with

INLYTA. Management of cardiac failure events may require temporary interruption or

permanent discontinuation and/or dose reduction of INLYTA therapy.

Hypertension

controlled

clinical

study

with

INLYTA

treatment

patients

with

RCC,

hypertension was reported in 40.4% of patients receiving INLYTA (N=359) and 29.0%

receiving sorafenib (N=355) (see

Adverse Effects

). Grade 3 hypertension was observed in

15.3% of patients receiving INLYTA and 10.7% of patients receiving sorafenib and Grade 4

hypertension was observed in 0.3% of patients receiving INLYTA and 0.3% of patients

receiving sorafenib. Hypertensive crisis was reported in 0.6% of patients receiving INLYTA

and in none of the patients 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 INLYTA or sorafenib treatment and blood pressure increases have

been observed as early as 4 days after starting INLYTA. Hypertension was managed with

standard

antihypertensive

therapy.

Discontinuation

INLYTA

treatment

hypertension occurred in 0.3% of patients receiving INLYTA and in none of the patients

receiving sorafenib (see

Adverse Effects

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

hypertension was reported in 51.2% of patients receiving INLYTA. Grade 3 hypertension

was reported in 22.0% of patients receiving INLYTA. Grade 4 hypertension was reported in

1.0% of patients receiving INLYTA.

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Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be

monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In

the case of persistent hypertension despite use of anti-hypertensive medications, the INLYTA

dose should be reduced. For patients who develop severe hypertension, temporarily interrupt

INLYTA and restart at a lower dose once the patient is normotensive. If INLYTA is

interrupted,

patients

receiving

antihypertensive

medications

should

monitored

hypotension (see

Dosage and Administration

Thyroid Dysfunction

controlled

clinical

study

with

INLYTA

treatment

patients

with

RCC,

hypothyroidism was reported in 19.2% of patients receiving INLYTA (N=359) and 8.2% of

patients receiving sorafenib (N=355) (see

Adverse Effects

). Hyperthyroidism was reported

in 1.1% of patients receiving INLYTA and 1.1% of patients receiving sorafenib. In patients

who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH

to ≥10 μU/mL occurred in 32.2% of patients receiving INLYTA and 10.8% of patients

receiving sorafenib (see

Adverse Effects

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

hypothyroidism was reported in 24.6% of patients receiving INLYTA. Hyperthyroidism was

reported in 1.6% of patients receiving INLYTA.

Monitor thyroid function before initiation of, and periodically throughout, treatment with

INLYTA. Hypothyroidism or hyperthyroidism should be treated according to standard

medical practice to maintain euthyroid state.

Arterial Thromboembolic Events

In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4

arterial

thromboembolic

events

were

reported

1.1%

patients

receiving

INLYTA

(N=359) and 1.1% of patients receiving sorafenib (N=355). The most frequent arterial

thromboembolic event was transient ischaemic attack (1.0%) (see

Adverse Effects

). Fatal

cerebrovascular accident was reported in 0.3% of patients receiving INLYTA and none (0%)

of the patients receiving sorafenib.

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

arterial

thromboembolic

events

were

reported

2.8%

patients

receiving

INLYTA.

Grade 3 arterial thromboembolic events were reported in 1.2% of patients. Grade 4 arterial

thromboembolic events were reported in 1.3% of patients. Fatal arterial thromboembolic

events were reported in 2 patients (0.3%) receiving INLYTA.

In monotherapy studies with INLYTA (N=699), arterial thromboembolic events (including

transient ischaemic attack, cerebrovascular accident, myocardial infarction, and retinal artery

occlusion) were reported in 2.3% of patients receiving INLYTA.

INLYTA should be used with caution in patients who are at risk for, or who have a history of,

these events. INLYTA 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 INLYTA for the treatment of patients with RCC, venous

thromboembolic events were reported in 3.1% of patients receiving INLYTA (N=359) and

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0.6% of patients receiving sorafenib (N=355). Grade 3/4 venous thromboembolic events

were reported in 2.5% of patients receiving INLYTA (including pulmonary embolism, deep

vein thrombosis, and retinal vein occlusion/thrombosis) and 0.6% of patients receiving

sorafenib (see

Adverse Effects

). Fatal pulmonary embolism was reported in one patient

(0.3%) receiving INLYTA and in none of the patients receiving sorafenib.

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

venous

thromboembolic

events

were

reported

2.8%

patients

receiving

INLYTA.

Grade 3 venous thromboembolic events were reported in 0.9% of patients. Grade 4 venous

thromboembolic events were reported in 1.2% of patients. Fatal venous thromboembolic

events were reported in 1 patient (0.1%) receiving INLYTA.

INLYTA should be used with caution in patients who are at risk for, or who have a history of,

these events. INLYTA has not been studied in patients who had a venous thromboembolic

event within the previous 6 months.

Elevation of Haemoglobin or Haematocrit

Increases in haemoglobin or haematocrit, reflective of increases in red blood cell mass, may

occur during treatment with INLYTA. An increase in red blood cell mass may increase the

risk of thromboembolic events.

Elevated haemoglobin above the ULN was observed in 9.7% of patients receiving INLYTA

(N=320) and 0.9% of patients receiving sorafenib (N=316).

Monitor

haemoglobin

haematocrit

before

initiation

periodically

throughout,

treatment with INLYTA. If haemoglobin or haematocrit becomes elevated above the normal

level,

patients

should

treated

according

standard

medical

practice

decrease

haemoglobin or haematocrit to an acceptable level.

Haemorrhage

In a controlled clinical study with INLYTA for the treatment of patients with RCC, in which

patients with untreated brain metastasis were excluded, haemorrhagic events were reported in

16.2% of patients receiving INLYTA (N=359) and 18.0% of patients receiving sorafenib

(N=355). The most common haemorrhagic events in patients treated with INLYTA were

epistaxis (6.1%), haematuria (3.3%), haemoptysis (2.2%), and rectal haemorrhage (2.2%)

(see

Adverse Effects

). Grade 3/4 haemorrhagic events were reported in 1.4% of patients

receiving

INLYTA

(including

cerebral

haemorrhage,

haematuria,

haemoptysis,

lower

gastrointestinal haemorrhage, and melaena) and 3.1% of patients receiving sorafenib. Fatal

haemorrhage was reported in one patient (0.3%) receiving INLYTA (gastric haemorrhage)

and three patients (0.8%) receiving sorafenib.

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

haemorrhagic events were reported in 25.7% of patients receiving INLYTA. Grade 3

haemorrhagic events were reported in 3.0% of patients. Grade 4 haemorrhagic events were

reported in 1.0% of patients and fatal haemorrhagic events were reported in 3 patients (0.4%)

receiving INLYTA.

INLYTA 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 INLYTA dose.

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Gastrointestinal Perforation and Fistula Formation

controlled

clinical

study

with

INLYTA

treatment

patients

with

RCC,

gastrointestinal perforation was reported 0.3% of patients receiving INLYTA (N=359) and in

none of the patients receiving sorafenib (N=355). In addition to cases of gastrointestinal

perforation, fistulas were reported in 0.6% of patients receiving INLYTA and 0.3% of

patients receiving sorafenib.

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

gastrointestinal perforation and fistula were reported in 1.9% of patients receiving INLYTA.

monotherapy

studies

with

INLYTA

(N=699),

fatal

gastrointestinal

perforation

reported in one patient (0.1%).

Monitor for symptoms of gastrointestinal perforation periodically throughout treatment with

INLYTA.

Wound Healing Complications

No formal studies of the effect of INLYTA on wound healing have been conducted.

Treatment with INLYTA should be stopped at least 24 hours prior to scheduled surgery. The

decision to resume INLYTA therapy after surgery should be based on clinical judgment of

adequate wound healing.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible

posterior

leukoencephalopathy

syndrome

(RPLS)

reported

patient

(0.3%)

receiving INLYTA (N=359) and in none of the patients receiving sorafenib (N=355) (see

Adverse Effects

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

RPLS was reported in 0.3% of patients receiving INLYTA.

RPLS

neurological

disorder

which

present

with

headache,

seizure,

lethargy,

confusion,

blindness

other

visual

neurologic

disturbances.

Mild

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 INLYTA. The safety of reinitiating INLYTA therapy in patients

previously experiencing RPLS is not known.

Proteinuria

controlled

clinical

study

with

INLYTA

treatment

patients

with

RCC,

proteinuria was reported in 10.9% of patients receiving INLYTA (N=359) and 7.3% of

patients receiving sorafenib (N=355) (see

Adverse Effects

). Grade 3 proteinuria was

reported in 3.1% of patients receiving INLYTA and 1.7% of patients receiving sorafenib.

In pooled clinical studies with INLYTA for the treatment of patients with RCC (N=672),

proteinuria was reported in 21.1% of patients receiving INLYTA. Grade 3 proteinuria was

reported in 4.8% of patients receiving INLYTA. Grade 4 proteinuria was reported in 0.1% of

patients receiving INLYTA.

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Monitoring for proteinuria before initiation of, and periodically throughout, treatment with

INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce

the dose or temporarily interrupt INLYTA treatment (See

Dosage and Administration

INLYTA should be discontinued if the patient develops nephrotic syndrome.

Elevation of Liver Enzymes

In a clinical dose-finding study, concurrent elevations of alanine aminotransferase (ALT) (12

times the upper limit of normal [ULN]) and bilirubin (2.3 times the ULN), considered to be

drug-related hepatotoxicity, were observed in 1 patient who received INLYTA at a starting

dose of 20 mg twice daily (4 times the recommended starting dose). In a controlled clinical

study with INLYTA 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 INLYTA (N=359)

or sorafenib (N=355).

Monitor liver function tests before initiation of, and periodically throughout, treatment with

INLYTA.

Use in Hepatic Impairment

In clinical studies with INLYTA, the systemic exposure to INLYTA 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

INLYTA

patients

with

moderate

hepatic

impairment

(Child-Pugh

class

(see

Pharmacokinetics

INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class

Use in Renal Impairment

A dedicated renal impairment trial for axitinib has not been conducted. Based on the

population pharmacokinetic analyses, no significant difference in axitinib clearance was

observed in patients with mild to severe renal impairment (creatinine clearance [CrCL] from

15 to 89 mL/min). No dose adjustment is needed for patients with mild to severe renal

impairment. Caution should be used in patients with end-stage renal disease (CrCL <15

mL/min).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of

galactose

intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this

medicinal product.

Effects on Fertility

INLYTA 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) in mice and dogs. 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/or count were noted at ≥ 10 mg/kg/day (approximately 4 times the AUC at the

recommended starting dose in humans) following at least 70 days of treatment with axitinib.

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Male reproductive toxicity was evident in the dog at ≥ 3 mg/kg/day, 0.2 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. 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 11 times the

AUC at the recommended starting dose in humans). Female reproductive toxicity in the dog

was observed at ≥ 10 mg/kg/day.

Use in Pregnancy

Category D

There are no studies in pregnant women using INLYTA. As angiogenesis is a critical

component

embryonic

fetal

development,

INLYTA

cause

fetal

harm

administered to a pregnant woman. Axitinib has been shown to be embryotoxic and

teratogenic when administered to mice and rabbits at exposures similar to or below clinical

exposure.

An increase in post-implantation loss and reduced embryonic survival was observed in

female mice exposed to axitinib (30 mg/kg/day, or 11 times the AUC at the recommended

starting dose in humans) prior to mating and through the first week of pregnancy. Pregnant

mice exposed to axitinib showed an increased occurrence of cleft palate at an oral dose level

of 3 mg/kg/day (approximately half the AUC at the recommended starting dose in humans)

and common variations in skeletal ossification at ≥ 1 mg/kg/day (approximately 0.15 times

the AUC at the recommended starting dose in humans). Limited investigations in rabbits

showed high embryo and fetal loss at exposures considerably lower than the recommended

clinical dose.

INLYTA should not be used during pregnancy. Women of childbearing potential must be

advised to avoid becoming pregnant while receiving treatment with INLYTA. If this drug is

used during pregnancy, or if the patient becomes pregnant while receiving this drug, the

patient should be apprised of the potential hazard to the fetus. Adequate contraception should

be used during therapy and for at least 4 weeks after completion of therapy.

Use in 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 of the breast-fed child. It is unknown whether

axitinib is excreted in human milk. 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, women should discontinue breastfeeding during treatment with axitinib.

Paediatric Use

The safety and efficacy of INLYTA in children and adolescents (<18 years) have not been

studied. Physeal dysplasia was observed in immature mice and dogs given axitinib at doses ≥

30 mg/kg/day for at least 1 month (approximately 6 times the AUC at the recommended

starting dose in humans); the incidence and severity were 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 ≥ 10 mg/kg/day (approximately 2 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 mice (approximately 1.4 times the AUC at the recommended starting dose in

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humans) and 10 mg/kg/day in dogs 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 paediatric patients have not been evaluated in juvenile animals.

Use in the Elderly

In a controlled clinical study with INLYTA for the treatment of patients with RCC, 34.3% of

patients treated with INLYTA were ≥ 65 years of age. Although greater sensitivity in some

older individuals cannot be ruled out, no overall differences were observed in the safety and

effectiveness of INLYTA between patients who were ≥ 65 years of age and younger.

No dosage adjustment is required in elderly patients (see

Pharmacokinetics

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 in these assays, but induced

polyplody in human lymphocytes

in vitro,

and was aneugenic in the micronucleus assay at

exposure levels approximately 154 times the recommended starting dose in humans.

Carcinogenicity

Carcinogenicity studies have not been performed with axitinib.

INTERACTIONS WITH OTHER MEDICINES

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 AUC 2-fold and C

1.5-fold of a single 5-mg oral dose of

INLYTA in healthy volunteers.

Co-administration

INLYTA

with

strong

CYP3A4/5

inhibitors

(e.g.,

ketoconazole,

itraconazole,

clarithromycin,

atazanavir,

indinavir,

nefazodone,

nelfinavir,

ritonavir,

saquinavir, and telithromycin) may increase axitinib plasma concentrations. 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, a dose adjustment

of INLYTA is recommended (See

Dosage and 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

by 71% of a single 5-mg dose of INLYTA in

healthy volunteers.

Co-administration

INLYTA

with

strong

CYP3A4/5

inducers

(e.g.,

rifampin,

dexamethasone,

phenytoin,

carbamazepine,

rifabutin,

rifapentin,

phenobarbital,

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Hypericum perforatum

[also known as St. John’s wort]) may decrease axitinib plasma

concentrations.

Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is

recommended. If a strong CYP3A4/5 inducer must be co-administered, a dose adjustment of

INLYTA is recommended (See

Dosage and Administration

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

INLYTA

with

CYP1A2

substrates

result

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 INLYTA 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 INLYTA 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 INLYTA is not expected to increase the plasma concentration of digoxin, or

other P-glycoprotein substrates,

in vivo

Effects on Ability to Drive and Use of Machines

No studies on the effect of INLYTA 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 INLYTA.

ADVERSE EFFECTS

The safety of

INLYTA has been evaluated in

672 patients

with advanced RCC who

participated in the pivotal randomised clinical study or four additional monotherapy studies

with INLYTA.

In the pivotal study the median duration of treatment was 6.4 months (range 0.03 to 22.0) for

patients who received INLYTA 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 55.4% of patients receiving INLYTA and 61.9% of patients receiving

sorafenib. Permanent discontinuation due to an adverse event occurred in 9.2% of patients

receiving INLYTA and 13.0% of patients receiving sorafenib.

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In another Phase 3 study, the median duration of treatment was 9.2 months (range 0.1 to 23.7)

for patients who received INLYTA and 7.0 months (range 0.03 to 22.0) for patients who

received sorafenib. Dose modifications or temporary delay of treatment due to an adverse

event occurred in 52.6% of patients receiving INLYTA and 37.7% of patients receiving

sorafenib. Permanent discontinuation due to an adverse event occurred in 16.3% of patients

receiving INLYTA and 10.1% of patients receiving sorafenib.

The most common (≥20%) adverse reactions observed following treatment with INLYTA

were

diarrhoea,

hypertension,

fatigue,

decreased

appetite,

nausea,

dysphonia,

weight

decreased,

palmar-plantar

erythrodysaesthesia

(hand-foot

syndrome),

haemorrhage,

hypothyroidism,

vomiting,

proteinuria,

cough,

constipation.

Severe

(Grade

≥3)

diarrhoea, hypertension and fatigue were very common (>10%).

The following risks, including appropriate action to be taken, are discussed in greater detail

under

Precautions:

cardiac

failure

events,

hypertension,

thyroid

dysfunction,

arterial

thromboembolic

events,

venous

thromboembolic

events,

elevation

haemoglobin

haematocrit, haemorrhage, gastrointestinal perforation and fistula formation, wound healing

complications,

reversible

posterior

leukoencephalophathy

syndrome,

proteinuria,

elevation of liver enzymes.

Table 2 presents adverse reactions reported in patients who received INLYTA. The adverse

reactions

listed

system

organ

class,

frequency

category

grade

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).

Table 2: Adverse Reactions Reported in Patients with advanced RCC who Received

INLYTA in the Pooled Trials (N=672)

Adverse Reaction

a,b

Frequency Category

c

All Grades (%)

Grades 3 & 4 (%)

Blood & Lymphatic

Anaemia

Common

Polycythaemia

Common

Endocrine

Hypothyroidism

Very Common

24.6

Hyperthyroidism

Common

Metabolism & Nutrition

Appetite Decreased

Very Common

39.0

Dehydration

Common

Hyperkalaemia

Common

Hypercalcaemia

Common

Nervous System

Headache

Very Common

16.2

Dysgeusia

Very Common

11.5

Dizziness

Common

RPLS

Uncommon

Ear & Labyrinth

Tinnitus

Common

Cardiac

Cardiac Failure Events

Common

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Adverse Reaction

a,b

Frequency Category

c

All Grades (%)

Grades 3 & 4 (%)

Vascular

Hypertension

Very Common

51.2

23.0

Haemorrhage

Very Common

25.7

Venous TEE

Common

Arterial TEE

Common

Respiratory

Dyspnoea

Very Common

17.1

Cough

Very Common

20.4

Dysphonia

Very Common

32.7

Gastrointestinal

Diarrhoea

Very Common

55.4

10.2

Vomiting

Very Common

23.7

Nausea

Very Common

33.0

Abdominal Pain

Very Common

14.7

Stomatitis

Very Common

15.5

Constipation

Very Common

20.2

Dyspepsia

Very Common

11.2

Upper Abdominal Pain

Common

Haemorrhoids

Common

Glossodynia

Common

GI Perforation / Fistula

Common

Hepatobiliary

Hyperbilirubinaemia

Common

Skin

Very Common

32.1

Rash

Very Common

14.3

Dry Skin

Very Common

10.1

Erythema

Common

Pruritus

Common

Alopecia

Common

Musculoskeletal

Arthralglia

Very Common

17.7

Pain in Extremity

Very Common

14.1

Myalgia

Common

Renal & Urinary

Proteinuria

Very Common

21.1

General

Fatigue

Very Common

45.1

10.9

Asthenia

Very Common

13.8

Mucosal Inflammation

Very Common

13.7

Investigations

Weight Decreased

Very Common

32.7

Lipase Increased

Common

Creatinine Increased

Common

ALT Increased

Common

Alk Phos Increased

Common

AST Increased

Common

Amylase Increased

Common

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RPLS: Reversible Posterior Leukoencephalopathy Syndrome. TEE: Thrombolic Event. GI: Gastrointestinal. PPE: Palmar-

Plantar Erythrodysaesthesia. ALT: Alanine aminotransferase. AST: Aspartate aminotransferase.

Includes fatal events.

Adverse reactions are listed according to treatment-emergent, all-causality frequency

National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0.

Frequency categories are based on the “all grades” values

Reversible posterior leukoencephalopathy syndrome includes the preferred term: leukoencephalopathy.

Cardiac failure events includes the preferred terms: cardiac failure, cardiac failure congestive, cardiopulmonary failure,

ejection fraction decreased, left ventricular dysfunction, and right ventricular failure.

Hypertension includes the preferred terms: accelerated hypertension, blood pressure increased, hypertension and

hypertensive crisis.

Haemorrhage includes the preferred terms: activated partial thromboplastin time prolonged, anal haemorrhage, arterial

haemorrhage, blood urine present, central nervous system haemorrhage, cerebral haemorrhage, coagulation time

prolonged, conjunctival haemorrhage, contusion, diarrhoea haemorrhagic, dysfunctional urterine 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,

increased

tendency

bruise,

international

normalised

ratio

increased,

lower

gastrointestinal

haemorrhage,

melaena,

petechiae,

pharyngeal

haemorrhage,

prothrombin time prolonged, pulmonary haemorrhage, purpura, , rectal haemorrhage , red blood cell count decreased,

renal haemorrhage, scleral haemorrhage, scrotal haematocoele, splenic haemotoma, splinter haemorrhage, subarachnoid

haemorrhage, tongue haemorrhage, upper gastrointestinal haemorrhage, and vaginal haemorrhage .

Venous thromboembolic events includes the preferred terms: Budd-Chiari syndrome, deep vein thrombosis, jugular vein

thrombosis, pelvic venous thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, subclavian

vein thrombosis, venous thrombosis, and venous thrombosis limb..

Arterial thrombotic events includes the preferred terms: acute myocardial infarction, embolism, myocardial infarction,

retinal artery occlusion, and transient ischaemic attack.

Gastrointestinal perforation and fistula includes the preferred terms: abdominal abscess, anal abscess, anal fistula, fistula,

gastrointestinal anastomotic leak, gastrointestinal perforation, large intestine perforation, oesophagobronchial fistula and

peritonitis.

Proteinuria includes the preferred terms: protein urine, protein urine present and proteinuria.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of axitinib:

Cardiac Disorders

Cases of cardiac failure events have been reported.

Gastrointestinal Disorders

Cases of glossodynia have been reported.

DOSAGE AND ADMINISTRATION

Recommended Dose

The recommended starting oral dose of INLYTA is 5 mg twice daily. INLYTA may be taken

with or without food.

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 Adjustment

Dose increase or reduction is recommended based on individual safety and tolerability.

Patients who tolerate the INLYTA starting dose of 5 mg twice daily with no adverse

reactions

>Grade

(according

Common

Toxicity

Criteria

Adverse

Events

[CTCAE])

consecutive

weeks,

normotensive,

receiving

anti-

hypertensive medication, may have their dose increased to 7 mg twice daily. Subsequently,

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using the same criteria, patients who tolerate the INLYTA dose of 7 mg twice daily, may

have their dose increased to a maximum of 10 mg twice daily.

Management

some

adverse

drug

reactions

require

temporary

permanent

discontinuation and/or dose reduction of INLYTA therapy (see

Precautions

). When dose

reduction is necessary, the INLYTA 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

INLYTA

with

strong

CYP3A4/5

inhibitors

(e.g.,

ketoconazole,

itraconazole,

clarithromycin,

atazanavir,

indinavir,

nefazodone,

nelfinavir,

ritonavir,

saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may

also

increase

axitinib

plasma

concentrations.

Selection

alternate

concomitant

medication with no or minimal CYP3A4/5 inhibition potential is recommended.

Although

INLYTA

dose

adjustment

been

studied

patients

receiving

strong

CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose

decrease of INLYTA 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 INLYTA dose used prior to initiation of the

strong CYP3A4/5 inhibitor should be considered.

Concomitant Strong CYP3A4/5 Inducers

Co-administration

INLYTA

with

strong

CYP3A4/5

inducers

(e.g.,

rifampin,

dexamethasone,

phenytoin,

carbamazepine,

rifabutin,

rifapentin,

phenobarbital,

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

INLYTA

dose

adjustment

been

studied

patients

receiving

strong

CYP3A4/5 inducers, if a strong CYP3A4/5 inducer must be co-administered, a gradual dose

increase of INLYTA is recommended. If the dose of INLYTA is increased, the patient

should be monitored carefully for toxicity. If co-administration of the strong inducer is

discontinued, the INLYTA dose should be immediately returned to the dose used prior to

initiation of the strong CYP3A4/5 inducer.

Use in Hepatic Impairment

No dose adjustment is required when administering INLYTA to patients with mild hepatic

impairment (Child-Pugh class A). A dose decrease is recommended when administering

INLYTA 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]. INLYTA has

not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

No dose adjustment is required (see

Pharmacokinetics

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Use in Children

The safety and efficacy of INLYTA in children and adolescents (<18 years) have not been

established.

Use in the Elderly

No dose adjustment is required (see

Pharmacokinetics

OVERDOSAGE

There is no specific treatment for INLYTA overdose. For information on the management of

overdose, contact the Poison Information Centre on 131126.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, one

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 INLYTA, patients 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 haemoptysis.

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

PRESENTATION AND STORAGE CONDITIONS

Store below 30°C.

INLYTA 1 mg tablets

Red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other.

Blister packs containing 28 or 56* tablets.

HDPE bottle with desiccant and a child-resistant closure containing 180 tablets.*

INLYTA 3 mg tablets

Red, film-coated, round tablets, debossed with “Pfizer” on one side and “3 XNB” on the

other.

Blister packs containing 28 or 56* tablets.

HDPE bottle with desiccant and a child-resistant closure containing 60 tablets.*

INLYTA 5 mg tablets

Red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the

other.

Blister packs containing 28 or 56* tablets.

HDPE bottle with desiccant and a child-resistant closure containing 60 tablets.*

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INLYTA 7 mg tablets

Red, film-coated, diamond tablets, debossed with “Pfizer” on one side and “7 XNB” on the

other.

Blister packs containing 28 or 56* tablets.

HDPE bottle with desiccant and a child-resistant closure containing 60 tablets.*

*Not marketed.

NAME AND ADDRESS OF THE SPONSOR

Pfizer Australia Pty Ltd

A.B.N. 5000 8422 348

38-42 Wharf Road

WEST RYDE NSW 2114

POISON SCHEDULE OF THE MEDICINE

S4 (Prescription Only Medicine)

DATE OF FIRST INCLUSION IN THE ARTG

26 July 2012

DATE OF MOST RECENT AMENDMENT

3 April 2017

Registered trademark.

7-8-2018

Inlyta (Pfizer Europe MA EEIG)

Inlyta (Pfizer Europe MA EEIG)

Inlyta (Active substance: Axitinib) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)5429 of Tue, 07 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2406/T/24

Europe -DG Health and Food Safety