Axitinib 1 MG, 3mg, 5mg Film-Coated Tablets SMPC - Taj Pharmaceuticals

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RX Axitinib 7 mg film-coated tablet

Each film-coated tablet contains 82.3 mg of
AXITINIB FILM-COATED lactose monohydrate.
TABLETS For the full list of excipients, see section 6.1.
1MG,3MG,5MG,7MG 3. PHARMACEUTICAL FORM
1.NAME OF THE MEDICINAL Film-coated tablet (tablet).
PRODUCT Axitinib 1 mg film-coated tablets
Axitinib 1 mg film-coated tablets Red oval film-coated tablet.
Axitinib 3 mg film-coated tablets Axitinib 3 mg film-coated tablets
Axitinib 5 mg film-coated tablets Red round film-coated tablet.
Axitinib 7 mg film-coated tablets Axitinib 5 mg film-coated tablets
Red triangular film-coated tablet.
2. QUALITATIVE AND
QUANTITATIVE COMPOSITION Axitinib 7 mg film-coated tablets
Axitinib 1 mg film-coated tablets Red diamond shaped film-coated tablet.
Each film-coated tablet contains 1 mg of 4. CLINICAL PARTICULARS

axitinib.
4.1 Therapeutic indications
Axitinib 3 mg film-coated tablets Axitinib is indicated for the treatment of adult
patients with advanced renal cell carcinoma
Each film-coated tablet contains 3 mg of (RCC) after failure of prior treatment with
axitinib. sunitinib or a cytokine.
Axitinib 5 mg film-coated tablets
4.2 Posology and method of
Each film-coated tablet contains 5 mg of administration
axitinib.
Treatment with Axitinib should be conducted by
Axitinib 7 mg film-coated tablets a physician experienced in the use of anticancer
Each film-coated tablet contains 7 mg of therapies.
axitinib. Posology
Excipients with known effect The recommended dose of axitinib is 5 mg twice
Axitinib 1 mg film-coated tablet daily.
Each film-coated tablet contains 33.6 mg of Treatment should continue as long as clinical
lactose monohydrate. benefit is observed or until unacceptable toxicity
occurs that cannot be managed by concomitant
Axitinib 3 mg film-coated tablet medicinal products or dose adjustments.
Each film-coated tablet contains 35.3 mg of If the patient vomits or misses a dose, an
lactose monohydrate. additional dose should not be taken. The next
prescribed dose should be taken at the usual
Axitinib 5 mg film-coated tablet
time.
Each film-coated tablet contains 58.8 mg of
Dose adjustments
lactose monohydrate.
Dose increase or reduction is recommended Co-administration of axitinib with strong

based on individual safety and tolerability. CYP3A4/5 inducers may decrease axitinib
plasma concentrations (see section 4.5).
Patients who tolerate the axitinib starting dose of Selection of an alternate concomitant medicinal
5 mg twice daily with no adverse reactions > product with no or minimal CYP3A4/5
Grade 2 (i.e. without severe adverse reactions induction potential is recommended.
according to the Common Terminology Criteria
for Adverse Events [CTCAE] version 3.0) for Although axitinib dose adjustment has not been
two consecutive weeks may have their dose studied in patients receiving strong CYP3A4/5
increased to 7 mg twice daily unless the patient's inducers, if a strong CYP3A4/5 inducer must be
blood pressure is > 150/90 mmHg or the patient co-administered, a gradual dose increase of
is receiving antihypertensive treatment. axitinib is recommended. Maximal induction
Subsequently, using the same criteria, patients with high-dose strong CYP3A4/5 inducers has
who tolerate an axitinib dose of 7 mg twice daily been reported to occur within one week of
may have their dose increased to a maximum of treatment with the inducer. If the dose of axitinib
10 mg twice daily. is increased, the patient should be monitored
carefully for toxicity. Management of some
Management of some adverse reactions may adverse reactions may require temporary or
require temporary or permanent discontinuation permanent discontinuation and/or dose reduction
and/or dose reduction of axitinib therapy (see of axitinib therapy (see section 4.4). If co-
section 4.4). When dose reduction is necessary, administration of the strong inducer is
the axitinib dose may be reduced to 3 mg twice
discontinued, the axitinib dose should be
daily and further to 2 mg twice daily.
immediately returned to the dose used prior to
Dose adjustment is not required on the basis of initiation of the strong CYP3A4/5 inducer (see
patient age, race, gender, or body weight. section 4.5).
Concomitant strong CYP3A4/5 inhibitors Special populations
Co-administration of axitinib with strong Elderly (≥ 65 years)
CYP3A4/5 inhibitors may increase axitinib
No dose adjustment is required (see sections 4.4
plasma concentrations (see section 4.5). and 5.2).
Selection of an alternate concomitant medicinal
product with no or minimal CYP3A4/5 Renal impairment
inhibition potential is recommended.
No dose adjustment is required (see section 5.2).
Although axitinib dose adjustment has not been Virtually no data are available regarding axitinib
studied in patients receiving strong CYP3A4/5 treatment in patients with a creatinine clearance
inhibitors, if a strong CYP3A4/5 inhibitor must of < 15 mL/min.
be co-administered, a dose decrease of axitinib
to approximately half the dose (e.g. the starting Hepatic impairment
dose should be reduced from 5 mg twice daily to No dose adjustment is required when
2 mg twice daily) is recommended. Management administering axitinib to patients with mild
of some adverse reactions may require hepatic impairment (Child-Pugh class A). A
temporary or permanent discontinuation of dose decrease is recommended when
axitinib therapy (see section 4.4). If co- administering axitinib to patients with moderate
administration of the strong inhibitor is hepatic impairment (Child-Pugh class B) (e.g.
discontinued, a return to the axitinib dose used the starting dose should be reduced from 5 mg
prior to initiation of the strong CYP3A4/5 twice daily to 2 mg twice daily). Axitinib has
inhibitor should be considered (see section 4.5). not been studied in patients with severe hepatic
Concomitant strong CYP3A4/5 inducers impairment (Child-Pugh class C) and should not
be used in this population (see sections 4.4 and
5.2).
Paediatric population Blood pressure should be well-controlled prior

to initiating axitinib. Patients should be
The safety and efficacy of Axitinib in children monitored for hypertension and treated as
and adolescents < 18 years have not been needed with standard antihypertensive therapy.
established. No data are available.
In the case of persistent hypertension, despite
Method of administration use of antihypertensive medicinal products, the
axitinib dose should be reduced. For patients
Axitinib is for oral use. The tablets should be who develop severe hypertension, temporarily
taken orally twice daily approximately 12 hours interrupt axitinib and restart at a lower dose once
apart with or without food (see section 5.2). the patient is normotensive. If axitinib is
They should be swallowed whole with a glass of interrupted, patients receiving antihypertensive
water. medicinal products should be monitored for
4.3 Contraindications hypotension (see section 4.2).
Hypersensitivity to axitinib or to any of the In case of severe or persistent arterial

excipients listed in section 6.1. hypertension and symptoms suggestive of
posterior reversible encephalopathy syndrome
(PRES) (see below), a diagnostic brain magnetic
4.4 Special Warnings and precautions for resonance image (MRI) should be considered.
use
Thyroid dysfunction
Specific safety events should be monitored
before initiation of, and periodically throughout, In clinical studies with axitinib for the treatment
treatment with axitinib as described below. of patients with RCC, events of hypothyroidism
and, to a lesser extent, hyperthyroidism, were
Cardiac failure events reported (see section 4.8).
In clinical studies with axitinib for the treatment Thyroid function should be monitored before
of patients with RCC, cardiac failure events initiation of, and periodically throughout,
(including cardiac failure, cardiac failure treatment with axitinib. Hypothyroidism or
congestive, cardiopulmonary failure, left hyperthyroidism should be treated according to
ventricular dysfunction, ejection fraction standard medical practice to maintain euthyroid
decreased, and right ventricular failure) were state.
reported (see section 4.8).
Arterial embolic and thrombotic events
Signs or symptoms of cardiac failure should
periodically be monitored throughout treatment In clinical studies with axitinib, arterial embolic
with axitinib. Management of cardiac failure and thrombotic events (including transient
events may require temporary interruption or ischemic attack, myocardial infarction,
permanent discontinuation and/or dose reduction cerebrovascular accident and retinal artery
of axitinib therapy. occlusion) were reported (see section 4.8).
Hypertension Axitinib should be used with caution in patients
who are at risk for, or who have a history of,
In clinical studies with axitinib for the treatment these events. Axitinib has not been studied in
of patients with RCC, hypertension was very patients who had an arterial embolic or
commonly reported (see section 4.8). thrombotic event within the previous 12 months.
In a controlled clinical study, the median onset Venous embolic and thrombotic events
time for hypertension (systolic blood pressure >
150 mmHg or diastolic blood pressure > 100 In clinical studies with axitinib, venous embolic
mmHg) was within the first month of the start of and thrombotic events (including pulmonary
axitinib treatment and blood pressure increases embolism, deep vein thrombosis, and retinal
have been observed as early as 4 days after vein occlusion/thrombosis) were reported (see
starting axitinib. section 4.8).
Axitinib should be used with caution in patients should be based on clinical judgment of
who are at risk for, or who have a history of, adequate wound healing.
these events. Axitinib has not been studied in
patients who had a venous embolic or Posterior reversible encephalopathy syndrome
thrombotic event within the previous 6 months. (PRES)
Elevation of haemoglobin or haematocrit In clinical studies with axitinib, events of PRES

were reported (see section 4.8).
Increases in haemoglobin or haematocrit,
reflective of increases in red blood cell mass, PRES is a neurological disorder which can
may occur during treatment with axitinib (see present with headache, seizure, lethargy,
confusion, blindness and other visual and
section 4.8, polycythaemia). An increase in red
neurologic disturbances. Mild to severe
blood cell mass may increase the risk of embolic
and thrombotic events. hypertension may be present. Magnetic
resonance imaging is necessary to confirm the
Haemoglobin or haematocrit should be diagnosis of PRES. In patients with signs or
monitored before initiation of, and periodically symptoms of PRES, temporarily interrupt or
throughout, treatment with axitinib. If permanently discontinue axitinib treatment. The
haemoglobin or haematocrit becomes elevated safety of reinitiating axitinib therapy in patients
above the normal level, patients should be previously experiencing PRES is not known.
treated according to standard medical practice to
Proteinuria
decrease haemoglobin or haematocrit to an
acceptable level. In clinical studies with axitinib, proteinuria,
Haemorrhage including that of Grade 3 and 4 severity, was
reported (see section 4.8).
In clinical studies with axitinib, haemorrhagic
events were reported (see section 4.8). Monitoring for proteinuria before initiation of,
and periodically throughout, treatment with
Axitinib has not been studied in patients who axitinib is recommended. For patients who
have evidence of untreated brain metastasis or develop moderate to severe proteinuria, reduce
recent active gastrointestinal bleeding, and the dose or temporarily interrupt axitinib
should not be used in those patients. If any treatment (see section 4.2). Axitinib should be
bleeding requires medical intervention, discontinued if the patient develops nephrotic
temporarily interrupt the axitinib dose. syndrome.
Gastrointestinal perforation and fistula Liver-related adverse reactions
formation
In a controlled clinical study with axitinib for
In clinical studies with axitinib, events of the treatment of patients with RCC, liver-related
gastrointestinal perforation and fistulas were adverse reactions were reported. The most
reported (see section 4.8). commonly reported liver-related adverse
reactions included increases in alanine
Symptoms of gastrointestinal perforation or aminotransferase (ALT), aspartate
fistula should be periodically monitored for aminotransferase (AST), and blood bilirubin
throughout treatment with axitinib.
(see section 4.8). No concurrent elevations of
Wound healing complications ALT (> 3 times the upper limit of normal
[ULN]) and bilirubin (> 2 times the ULN) were
No formal studies of the effect of axitinib on observed.
wound healing have been conducted.
In a clinical dose-finding study, concurrent
Treatment with axitinib should be stopped at elevations of ALT (12 times the ULN) and
least 24 hours prior to scheduled surgery. The bilirubin (2.3 times the ULN), considered to be
decision to resume axitinib therapy after surgery drug-related hepatotoxicity, were observed in 1
patient who received axitinib at a starting dose
of 20 mg twice daily (4 times the recommended CYP1A2, CYP2C19, and uridine diphosphate-
starting dose). glucuronosyltransferase (UGT) 1A1.
Liver function tests should be monitored before CYP3A4/5 inhibitors
initiation of, and periodically throughout,
treatment with axitinib. Ketoconazole, a strong inhibitor of CYP3A4/5,
administered at a dose of 400 mg once daily for
Hepatic impairment 7 days, increased the mean area under the curve
(AUC) 2-fold and Cmax 1.5-fold of a single 5-mg
In clinical studies with axitinib, the systemic oral dose of axitinib in healthy volunteers. Co-
exposure to axitinib was approximately two-fold administration of axitinib with strong
higher in subjects with moderate hepatic
CYP3A4/5 inhibitors (e.g. ketoconazole,
impairment (Child-Pugh class B) compared to
itraconazole, clarithromycin, erythromycin,
subjects with normal hepatic function. A dose atazanavir, indinavir, nefazodone, nelfinavir,
decrease is recommended when administering ritonavir, saquinavir, and telithromycin) may
axitinib to patients with moderate hepatic increase axitinib plasma concentrations.
impairment (Child-Pugh class B) (see section Grapefruit may also increase axitinib plasma
4.2).
concentrations. Selection of concomitant
Axitinib has not been studied in patients with medicinal products with no or minimal
severe hepatic impairment (Child-Pugh class C) CYP3A4/5 inhibition potential is recommended.
and should not be used in this population. If a strong CYP3A4/5 inhibitor must be co-
administered, a dose adjustment of axitinib is
Elderly (≥ 65 years) and race recommended (see section 4.2).
In a controlled clinical study with axitinib for CYP1A2 and CYP2C19 inhibitors
the treatment of patients with RCC, 34% of
patients treated with axitinib were ≥ 65 years of CYP1A2 and CYP2C19 constitute minor (<
age. The majority of patients were White (77%) 10%) pathways in axitinib metabolism. The
or Asian (21%). Although greater sensitivity to effect of strong inhibitors of these isozymes on
develop adverse reactions in some older patients axitinib pharmacokinetics has not been studied.
and Asian patients cannot be ruled out, overall, Caution should be exercised due to the risk of
no major differences were observed in the safety increased axitinib plasma concentrations in
and effectiveness of axitinib between patients patients taking strong inhibitors of these
who were ≥ 65 years of age and non-elderly, and isozymes.
between White patients and patients of other CYP3A4/5 inducers
races.
Rifampicin, a strong inducer of CYP3A4/5,
No dosage adjustment is required on the basis of administered at a dose of 600 mg once daily for
patient age or race (see sections 4.2 and 5.2).
9 days, reduced the mean AUC by 79% and
Lactose Cmax by 71% of a single 5 mg dose of axitinib in
healthy volunteers.
This medicinal product contains lactose. Patients
with rare hereditary problems of galactose Co-administration of axitinib with strong
intolerance, Lapp lactase deficiency or glucose- CYP3A4/5 inducers (e.g. rifampicin,
galactose malabsorption should not take this dexamethasone, phenytoin, carbamazepine,
medicinal product. rifabutin, rifapentin, phenobarbital,
and Hypericum perforatum [St. John's wort])
4.5 Interaction with other medicinal may decrease axitinib plasma concentrations.
products and other forms of interaction Selection of concomitant medicinal products
with no or minimal CYP3A4/5 induction
In vitro data indicate that axitinib is metabolised
potential is recommended. If a strong CYP3A4/5
primarily by CYP3A4/5 and, to a lesser extent,
inducer must be co-administered, a dose
adjustment of axitinib is recommended (see pregnancy unless the clinical condition of the
section 4.2). woman requires treatment with this medicinal
product.
In vitro studies of CYP and UGT inhibition and
induction Women of childbearing potential must use
effective contraception during and up to 1 week
In vitro studies indicated that axitinib does not after treatment.
inhibit CYP2A6, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at Breast-feeding
therapeutic plasma concentrations.
It is unknown whether axitinib is excreted in
In vitro studies indicated that axitinib has a human milk. A risk to the suckling child cannot
potential to inhibit CYP1A2. Therefore, co- be excluded. Axitinib should not be used during
administration of axitinib with CYP1A2 breast-feeding.
substrates may result in increased plasma
Fertility
concentrations of CYP1A2 substrates (e.g.
theophylline). Based on non-clinical findings, axitinib has the
In vitro studies also indicated that axitinib has potential to impair reproductive function and
the potential to inhibit CYP2C8. However, co- fertility in humans (see section 5.3).
administration of axitinib with paclitaxel, a 4.7 Effects on ability to drive and use
known CYP2C8 substrate, did not result in machines
increased plasma concentrations of paclitaxel in Axitinib has minor influence on the ability to
patients with advanced cancer, indicating lack of drive and use machines. Patients should be
clinical CYP2C8 inhibition. advised that they may experience events such as
In vitro studies in human hepatocytes also dizziness and/or fatigue during treatment with
indicated that axitinib does not induce CYP1A1, axitinib.
CYP1A2, or CYP3A4/5. Therefore co- 4.8 Undesirable Effects
administration of axitinib is not expected to
reduce the plasma concentration of co- Summary of the safety profile
administered CYP1A1, CYP1A2, or CYP3A4/5
The following risks, including appropriate action
substrates in vivo.
to be taken, are discussed in greater detail in
In vitro studies with P-glycoprotein section 4.4: cardiac failure events, hypertension,
thyroid dysfunction, arterial thromboembolic
In vitro studies indicated that axitinib inhibits P- events, venous thromboembolic events,
glycoprotein. However, axitinib is not expected elevation of haemoglobin or haematocrit,
to inhibit P-glycoprotein at therapeutic plasma haemorrhage, gastrointestinal perforation and
concentrations. Therefore, co-administration of fistula formation, wound healing complications,
axitinib is not expected to increase the plasma PRES, proteinuria, and elevation of liver
concentration of digoxin, or other P- enzymes.
glycoprotein substrates, in vivo.
The most common (≥ 20%) adverse reactions
4.6 Fertility, pregnancy and lactation observed following treatment with axitinib were
Pregnancy diarrhoea, hypertension, fatigue, decreased
appetite, nausea, weight decreased, dysphonia,
There are no data regarding the use of axitinib in palmar-plantar erythrodysaesthesia (hand-foot)
pregnant women. Based on the pharmacological syndrome, haemorrhage, hypothyroidism,
properties of axitinib, it may cause foetal harm vomiting, proteinuria, cough, and constipation.
when administered to a pregnant woman.
Studies in animals have shown reproductive Tabulated list of adverse reactions
toxicity including malformations (see section Table 1 presents adverse reactions reported in a
5.3). Axitinib should not be used during pooled dataset of 672 patients who received
axitinib in clinical studies for the treatment of Vascular Very Hypertensiong 51.2 22.0 1.0
patients with RCC (see section 5.1). disorders common c,d,h
Haemorrhage 25.7 3.0 1.0
The adverse reactions are listed by system organ Common Venous embolic 2.8 0.9 1.2
and thrombotic
class, frequency category and grade of severity. eventsc,d,i
Frequency categories are defined as: very Arterial embolic 2.8 1.2 1.3
common (≥ 1/10), common (≥ 1/100 to < 1/10), and thrombotic
uncommon (≥ 1/1,000 to < 1/100), rare (≥ eventsc,d,j
1/10,000 to < 1/1,000), very rare (< 1/10,000), Respiratory, Very Dyspnoead 17.1 3.6 0.6
thoracic and common
and not known (cannot be estimated from the mediastinal Cough 20.4 0.6 0
available data). The current safety database for disorders
Dysphonia 32.7 0 0.1
axitinib is too small to detect rare and very rare
adverse reactions. Common Oropharyngeal pain 7.4 0 0
Gastrointesti Very Diarrhoea 55.4 10.1 0.1
Categories have been assigned based on absolute nal disorders common
Vomiting 23.7 2.7 0.1
frequencies in the pooled clinical studies data.
Within each system organ class, adverse Nausea 33.0 2.2 0.1
reactions with the same frequency are presented Abdominal pain 14.7 2.5 0.3
in order of decreasing seriousness.
Constipation 20.2 1.0 0
Table 1. Adverse reactions reported in RCC Stomatitis 15.5 1.8 0
studies in patients who received axitinib (N = Dyspepsia 11.2 0.1 0
672)
Common Upper abdominal 9.4 0.9 0
Gra pain
All Grad
System Frequency de Flatulence 4.5 0 0
Adverse reactionsa b
Grades e 3 b
organ class category 4b
% %
% Haemorrhoids 3.3 0 0
Blood and Common Anaemia 6.3 1.2 0.4 Glossodynia 2.8 0 0
lymphatic
system Thrombocytopenia 1.6 0.1 0 Gastrointestinal 1.9 0.9 0.3
disorders perforation and
Polycythaemiac 1.5 0.1 0
fistulac,k
Uncommo Neutropaenia 0.3 0.1 0 Hepatobiliar Common Hyperbilirubinaemi 1.3 0.1 0.1
n y disorders a
Leukopaenia 0.4 0 0
Skin and Very Palmar-plantar 32.1 7.6 0
Endocrine Very Hypothyroidismc 24.6 0.3 0 subcutaneous common erythrodysaesthesia
disorders common tissue (hand-foot
Common Hyperthyroidismc 1.6 0.1 0.1 disorders syndrome)
Rash 14.3 0.1 0
Metabolism Very Decreased appetite 39.0 3.6 0.3
and nutrition common Dry skin 10.1 0.1 0
disorders Common Dehydration 6.7 3.1 0.3
Common Pruritus 6.0 0 0
Hyperkalaemia 2.7 1.2 0.1
Erythema 3.7 0 0
Hypercalcaemia 2.2 0.1 0.3
Alopecia 5.7 0 0
Nervous Very Headache 16.2 0.7 0
Musculoskel Very Arthralgia 17.7 1.9 0.3
system common
Dysgeusia 11.5 0 0 etal and common
disorders
connective Pain in extremity 14.1 1.0 0.3
Common Dizziness 9.1 0.6 0 tissue
disorders Common Myalgia 8.2 0.6 0.1
Uncommo Posterior reversible 0.3 0.1 0
l
n encephalopathy Renal and Very Proteinuria 21.1 4.8 0.1
syndromee urinary common
Ear and Common Tinnitus 3.1 0 0 disorders Common Renal failurem 1.6 0.9 0.1
labyrinth
disorders General Very Fatigue 45.1 10.6 0.3
disorders and common
Cardiac Common Cardiac failure 1.8 0.3 0.7 administratio
disorders eventsc,d,f Asthaeniad 13.8 2.8 0.3
n site Mucosal 13.7 1.0 0 haemostasis, increased tendency to bruise,

conditions inflammation international normalized ratio increased, lower
Investigation Very Weight decreased 32.7 4.9 0 gastrointestinal haemorrhage, melaena,
s common
petechiae, pharyngeal haemorrhage,
Common Lipase increased 3.7 0.7 0.7
prothrombin time prolonged, pulmonary
Alanine 6.5 1.2 0 haemorrhage, purpura, rectal haemorrhage, red
aminotransferase
increased blood cell count decreased, renal haemorrhage,
Amylase increased 3.4 0.6 0.4 scleral haemorrhage, scrotal haematocoele,
splenic haemotoma, splinter haemorrhage,
Aspartate 6.1 1.0 0
aminotransferase subarachnoid haemorrhage, tongue
increased haemorrhage, upper gastrointestinal
Alkaline 4.8 0.3 0 haemorrhage and vaginal haemorrhage.
phosphatase
increased i
Including Budd-Chiari syndrome, deep vein
Creatinine 5.7 0.4 0 thrombosis, jugular vein thrombosis, pelvic
increased
venous thrombosis, pulmonary embolism, retinal
Thyroid stimulating 7.9 0 0
hormone increased
vein occlusion, retinal vein thrombosis,
a subclavian vein thrombosis, venous thrombosis,
Adverse reactions are according to treatment-
and venous thrombosis limb.
emergent, all causality frequency.
j
b Including acute myocardial infarction,
National Cancer Institute Common
embolism, myocardial infarction, retinal artery
Terminology Criteria for Adverse Events,
occlusion and transient ischaemic attack.
Version 3.0
k
c Gastrointestinal perforation and fistula includes
See Description of selected adverse reactions
the following preferred terms: abdominal
section.
abscess, anal abscess, anal fistula, fistula,
d
Fatal (Grade 5) cases were reported. gastrointestinal anastomotic leak,
e gastrointestinal perforation, large intestine
Including Leukoencephalopathy. perforation, oesophagobronchial fistula and
f peritonitis.
Including cardiac failure, cardiac failure
congestive, cardiopulmonary failure, ejection l
Proteinuria includes the following preferred
fraction decreased, left ventricular dysfunction terms: protein urine, protein urine present and
and right ventricular failure. proteinuria.
g
Including accelerated hypertension, blood m
Including acute renal failure
pressure increased, hypertension and
hypertensive crisis. Description of selected adverse reactions
h
Including activated partial thromboplastin time Cardiac failure events (see section 4.4)
prolonged, anal haemorrhage, arterial
In a controlled clinical study with axitinib (N =
haemorrhage, blood urine present, central
359) for the treatment of patients with RCC,
nervous system haemorrhage, cerebral
cardiac failure events were reported in 1.7 %
haemorrhage, coagulation time prolonged,
patients receiving axitinib, including cardiac
conjunctival haemorrhage, contusion, diarrhea
failure (0.6%), cardiopulmonary failure (0.6%),
haemorrhagic, dysfunctional uterine bleeding,
left ventricular dysfunction (0.3%), and right
epistaxis, gastric haemorrhage, gastrointestinal
ventricular failure (0.3%). Grade 4 cardiac
haemorrhage, gingival bleeding, haematemesis,
failure adverse reactions were reported in 0.6 %
haematochezia, haematocrit decreased,
of patients receiving axitinib. Fatal cardiac
haematoma, haematuria, haemoglobin
failure was reported in 0.6 % of patients
decreased, haemoptysis, haemorrhage,
receiving axitinib.
haemorrhage coronary artery, haemorrhage
urinary tract, haemorrhoidal haemorrhage,
In monotherapy studies with axitinib (N = 672) embolic and thrombotic events were reported in
for the treatment of patients with RCC, cardiac 1.2% of patients. Fatal venous embolic and
failure events (including cardiac failure, cardiac thrombotic events were reported 0.1% patients
failure congestive, cardiopulmonary failure, left receiving axitinib.
ventricular dysfunction, ejection fraction
decreased, and right ventricular failure) were Arterial embolic and thrombotic events (see
reported in 1.8% patients receiving axitinib. section 4.4)
Grade 3/4 cardiac failure events were reported in In a controlled clinical study with axitinib for
1.0% patients and fatal cardiac failure events the treatment of patients with RCC, arterial
were reported in 0.3% patients receiving embolic and thrombotic adverse reactions were
axitinib. reported in 4.7% of patients receiving axitinib,
Thyroid dysfunction (see section 4.4) including myocardial infarction (1.4%), transient
ischemic attack (0.8%) and cerebrovascular
In a controlled clinical study with axitinib for accident (0.6%). Grade 3/4 arterial embolic and
the treatment of patients with RCC, thrombotic adverse reactions were reported in
hypothyroidism was reported in 20.9% of 3.3% of patients receiving axitinib. A fatal acute
patients and hyperthyroidism was reported in myocardial infarction and cerebrovascular
1.1% of patients. Thyroid stimulating hormone accident was reported in one patient each
(TSH) increased was reported as an adverse (0.3%). In monotherapy studies with axitinib (N
reaction in 5.3% of patients receiving axitinib. = 850), arterial embolic and thrombotic adverse
During routine laboratory assessments, in reactions (including transient ischemic attack,
patients who had TSH < 5 μU/mL before myocardial infarction, and cerebrovascular
treatment, elevations of TSH to ≥ 10 μU/mL accident) were reported in 5.3% of patients
occurred in 32.2% of patients receiving axitinib. receiving axitinib.
In pooled clinical studies with axitinib (N = 672) In pooled clinical studies with axitinib (N = 672)
for the treatment of patients with RCC, for the treatment of patients with RCC, arterial
hypothyroidism was reported in 24.6% of embolic and thrombotic events were reported in
patients receiving axitinib. Hyperthyroidism was 2.8% of patients receiving axitinib. Grade 3
reported in 1.6% of patients receiving axitinib. arterial embolic and thrombotic events were
reported in 1.2% of patients. Grade 4 arterial
Venous embolic and thrombotic events (see embolic and thrombotic events were reported in
section 4.4)
1.3% of patients. Fatal arterial embolic and
In a controlled clinical study with axitinib for thrombotic events were reported in 0.3%
the treatment of patients with RCC, venous patients receiving axitinib.
embolic and thrombotic adverse reactions were
Polycythaemia (see Elevation of haemoglobin or
reported in 3.9% of patients receiving axitinib, haematocrit in section 4.4)
including pulmonary embolism (2.2%), retinal
vein occlusion/thrombosis (0.6%) and deep vein In a controlled clinical study with axitinib for
thrombosis (0.6%). Grade 3/4 venous embolic the treatment of patients with RCC,
and thrombotic adverse reactions were reported polycythaemia was reported in 1.4% of patients
in 3.1% of patients receiving axitinib. Fatal receiving axitinib. Routine laboratory
pulmonary embolism was reported in one patient assessments detected elevated haemoglobin
(0.3%) receiving axitinib. above ULN in 9.7% of patients receiving
axitinib. In four clinical studies with axitinib for
In pooled clinical studies with axitinib (N = 672) the treatment of patients with RCC (N = 537),
for the treatment of patients with RCC, venous elevated haemoglobin above ULN was observed
embolic and thrombotic events were reported in in 13.6% receiving axitinib.
2.8% of patients receiving axitinib. Grade 3
venous embolic and thrombotic events were In pooled clinical studies with axitinib (N = 672)
reported in 0.9% of patients. Grade 4 venous for the treatment of patients with RCC,
polycythaemia was reported in 1.5% of patients In pooled clinical studies with axitinib (N = 672)
receiving axitinib. for the treatment of patients with RCC,
gastrointestinal perforation and fistula were
Haemorrhage (see section 4.4) reported in 1.9% of patients receiving axitinib.
In a controlled clinical study with axitinib for Reporting of suspected adverse reactions
the treatment of patients with RCC that excluded
patients with untreated brain metastasis, Reporting suspected adverse reactions after
haemorrhagic adverse reactions were reported in authorisation of the medicinal product is
21.4% of patients receiving axitinib. The important. It allows continued monitoring of the
haemorrhagic adverse reactions in patients benefit/risk balance of the medicinal product.
treated with axitinib included epistaxis (7.8%),
haematuria (3.6%), haemoptysis (2.5%), rectal 4.9 Overdose
haemorrhage (2.2%), gingival bleeding (1.1%), There is no specific treatment for axitinib
gastric haemorrhage (0.6%), cerebral overdose.
haemorrhage (0.3%) and lower gastrointestinal In a controlled clinical study with axitinib for
haemorrhage (0.3%). Grade ≥ 3 haemorrhagic the treatment of patients with RCC, one patient
adverse reactions were reported in 3.1% of inadvertently received a dose of 20 mg twice
patients receiving axitinib (including cerebral daily for 4 days and experienced dizziness
haemorrhage, gastric haemorrhage, lower (Grade 1).
gastrointestinal haemorrhage and haemoptysis).
Fatal haemorrhage was reported in one patient In a clinical dose finding study with axitinib,
(0.3%) receiving axitinib (gastric haemorrhage). subjects who received starting doses of 10 mg
In monotherapy studies with axitinib (N = 850), twice daily or 20 mg twice daily experienced
haemoptysis was reported in 3.9% of patients; adverse reactions which included hypertension,
Grade ≥ 3 haemoptysis was reported in 0.5% of seizures associated with hypertension, and fatal
patients. haemoptysis.
In pooled clinical studies with axitinib (N = 672) In cases of suspected overdose, axitinib should
for the treatment of patients with RCC, be withheld and supportive care instituted.
haemorrhagic events were reported in 25.7% of 5. PHARMACOLOGICAL
patients receiving axitinib. Grade 3
PROPERTIES
haemorrhagic adverse reactions were reported in
3% of patients. Grade 4 haemorrhagic adverse 5.1 Pharmacodynamic properties
reactions were reported in 1% of patients and Pharmacotherapeutic group: Antineoplastic
fatal haemorrhage were reported in 0.4% of agents, protein kinase inhibitors, ATC code:
patients receiving axitinib. L01XE17
Gastrointestinal perforation and fistula Mechanism of action
formation (see section 4.4)
Axitinib is a potent and selective tyrosine kinase
In a controlled clinical study with axitinib for inhibitor of vascular endothelial growth factor
the treatment of patients with RCC, receptors (VEGFR)-1, VEGFR-2 and VEGFR-3.
gastrointestinal perforation-type events were These receptors are implicated in pathologic
reported in 1.7% of patients receiving axitinib, angiogenesis, tumour growth, and metastatic
including anal fistula (0.6%), fistula (0.3%) and progression of cancer. Axitinib has been shown
gastrointestinal perforation (0.3%). In to potently inhibit VEGF-mediated endothelial
monotherapy studies with axitinib (N = 850), cell proliferation and survival. Axitinib inhibited
gastrointestinal perforation-type events were the phosphorylation of VEGFR-2 in xenograft
reported in 1.9% of patients and fatal tumour vasculature that expressed the target in
gastrointestinal perforation was reported in one vivo and produced tumour growth delay,
patient (0.1%). regression, and inhibition of metastases in many
experimental models of cancer.
Effect on QTc interval (prior temsirolimus treatment or prior

bevacizumab treatment). There were no
In a randomised, 2-way crossover study, 35 statistically significant differences between the
healthy subjects were administered a single oral arms in OS in the overall population or in the
dose of axitinib (5 mg) in the absence and subgroups by prior therapy.
presence of 400 mg ketoconazole for 7 days.
Results of this study indicated that axitinib Table 2. Efficacy results
plasma exposures up to two-fold greater than
therapeutic levels expected following a 5 mg
dose, did not produce clinically-significant QT Endpoint / axitinib sorafenib HR (95% p-value
study CI)
interval prolongation. population
Clinical efficacy and safety Overall N = 361 N = 362

ITT
The safety and efficacy of axitinib were
evaluated in a randomised, open-label, Median 6.8 (6.4, 4.7 (4.6, 0.67 (0.56, < 0.0001c
PFS a,b in 8.3) 6.3) 0.81)
multicentre Phase 3 study. Patients (N = 723) months
with advanced RCC whose disease had (95% CI)
progressed on or after treatment with one prior Median 20.1 19.2 0.97 (0.80, NS
systemic therapy, including sunitinib-, OS d in (16.7, (17.5, 1.17)
bevacizumab-, temsirolimus-, or cytokine- months 23.4) 22.3)
(95% CI)
containing regimens were randomised (1:1) to
receive axitinib (N = 361) or sorafenib (N = ORR b,e % 19.4 9.4 (6.6, 2.06f (1.41, 0.0001g
362). The primary endpoint, progression-free (95% CI) (15.4, 12.9) 3.00)
23.9)
survival (PFS), was assessed using a blinded
independent central review. Secondary Prior N = 194 N = 195
endpoints included objective response rate sunitinib
treatment
(ORR) and overall survival (OS).
Median 4.8 (4.5, 3.4 (2.8, 0.74 (0.58, 0.0063h
Of the patients enrolled in this study, 389 PFS a,b in 6.5) 4.7) 0.94)
patients (53.8%) had received one prior months
(95% CI)
sunitinib-based therapy, 251 patients (34.7%)
had received one prior cytokine-based therapy Median 15.2 16.5 1.00 (0.78, NS
(interleukin-2 or interferon-alpha), 59 patients OS d in (12.8, (13.7, 1.27)
months 18.3) 19.2)
(8.2%) had received one prior bevacizumab- (95% CI)
based therapy, and 24 patients (3.3%) had
received one prior temsirolimus-based therapy. ORR b,e % 11.3 (7.2, 7.7 (4.4, 1.48f (0.79, NS
(95% CI) 16.7) 12.4) 2.75)
The baseline demographic and disease
characteristics were similar between the axitinib Prior N = 126 N = 125
and sorafenib groups with regard to age, gender, cytokine
treatment
race, Eastern Cooperative Oncology Group
(ECOG) performance status, geographic region, Median 12.0 6.6 (6.4, 0.52 (0.38, < 0.0001h
PFS a,b in (10.1, 8.3) 0.72)
and prior treatment. months 13.9)
(95% CI)
In the overall patient population and the two
main subgroups (prior sunitinib treatment and Median 29.4 27.8 0.81 (0.56, NS
prior cytokine treatment), there was a OS d in (24.5, (23.1, 1.19)
months NE) 34.5)
statistically significant advantage for axitinib (95% CI)
over sorafenib for the primary endpoint of PFS
(see Table 2 and Figures 1, 2 and 3). The ORR b,e % 32.5 13.6 (8.1, 2.39f (1.43- 0.0002i
(95% CI) (24.5, 20.9) 3.99)
magnitude of median PFS effect was different in 41.5)
the subgroups by prior therapy. Two of the
subgroups were too small to give reliable results
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-free survival.
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 Figure 2. Kaplan-Meier curve of progression-
One-sided p-value from a log-rank test of free survival by independent assessment for
treatment stratified by ECOG performance status the prior sunitinib subgroup
and prior therapy.
d
Cut-off date: 01 November 2011.
e
Cut-off date: 31 August 2010.
f
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.
g
One-sided p-value from Cochran-Mantel-
Haenszel test of treatment stratified by ECOG
performance status and prior therapy.
h
One-sided p-value from a log-rank test of Figure 3. Kaplan-Meier curve of progression-
treatment stratified by ECOG performance free survival by independent assessment for
status. the prior cytokine subgroup
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
the overall population
Paediatric population
The European Medicines Agency has waived the
obligation to submit the results of studies with
axitinib in all subsets of the paediatric
population for treatment of kidney and renal
pelvis carcinoma (excluding nephroblastoma,
nephroblastomatosis, clear cell sarcoma, of the radioactivity was recovered in urine.

mesoblastic nephroma, renal medullary Unchanged axitinib, accounting for 12% of the
carcinoma and rhabdoid tumour of the kidney) dose, was the major component identified in
(see section 4.2 for information on paediatric faeces. Unchanged axitinib was not detected in
use). urine; the carboxylic acid and sulfoxide
metabolites accounted for the majority of
5.2 Pharmacokinetic properties radioactivity in urine. In plasma, the N-
After oral administration of axitinib tablets, the glucuronide metabolite represented the
mean absolute bioavailability is 58% compared predominant radioactive component (50% of
to intravenous administration. The plasma half- circulating radioactivity) and unchanged axitinib
life of axitinib ranges from 2.5 to 6.1 hours. and the sulfoxide metabolite each accounted for
Dosing of axitinib at 5 mg twice daily resulted in approximately 20% of the circulating
less than two-fold accumulation compared to radioactivity.
administration of a single dose. Based on the The sulfoxide and N-glucuronide metabolites
short half-life of axitinib, steady state is show approximately 400-fold and 8000-fold
expected within 2 to 3 days of the initial dose. less in vitro potency, respectively, against
Absorption and distribution VEGFR-2 compared to axitinib.
Peak axitinib concentrations in plasma are Special populations

generally reached within 4 hours following oral Elderly, gender, and race
administration of axitinib with median
Tmax ranging from 2.5 to 4.1 hours. Population pharmacokinetic analyses in patients
Administration of axitinib with a moderate fat with advanced cancer (including advanced RCC)
meal resulted in 10% lower exposure compared and healthy volunteers indicate that there are no
to overnight fasting. A high fat, high-calorie clinically relevant effects of age, gender, body
meal resulted in 19% higher exposure compared weight, race, renal function, UGT1A1 genotype,
to overnight fasting. Axitinib may be or CYP2C19 genotype.
administered with or without food (see section
Paediatric population
4.2).
Axitinib has not been studied in patients < 18
The average Cmax and AUC increased
years of age.
proportionally over an axitinib dosing range of 5
to 10 mg. In vitro binding of axitinib to human Hepatic impairment
plasma proteins is > 99% with preferential
binding to albumin and moderate binding to α1- In vitro and in vivo data indicate that axitinib is
acid glycoprotein. At the 5 mg twice daily dose primarily metabolised by the liver.
in the fed state, the geometric mean peak plasma Compared to subjects with normal hepatic
concentration and 24-hour AUC were 27.8 function, systemic exposure following a single
ng/mL and 265 ng.h/mL, respectively, in dose of axitinib was similar in subjects with
patients with advanced RCC. The geometric mild hepatic impairment (Child-Pugh class A)
mean oral clearance and apparent volume of and higher (approximately two-fold) in subjects
distribution were 38 L/h and 160 L, respectively. with moderate hepatic impairment (Child-Pugh
Biotransformation and elimination class B). Axitinib has not been studied in
subjects with severe hepatic impairment (Child-
Axitinib is metabolised primarily in the liver by Pugh class C) and should not be used in this
CYP3A4/5 and to a lesser extent by CYP1A2, population (see section 4.2 for dose adjustment
CYP2C19, and UGT1A1. recommendations).
Following oral administration of a 5 mg Renal impairment
radioactive dose of axitinib, 30-60% of the
radioactivity was recovered in faeces and 23% Unchanged axitinib is not detected in the urine.
Axitinib has not been studied in subjects with approximately 57-fold the expected human
renal impairment. In clinical studies with exposure. Findings in females included signs of
axitinib for the treatment of patients with RCC, delayed sexual maturity, reduced or absent
patients with serum creatinine > 1.5 times the corpora lutea, decreased uterine weights and
ULN or calculated creatinine clearance < 60 uterine atrophy at exposures approximately
mL/min were excluded. Population equivalent to the expected human exposure.
pharmacokinetic analyses have shown that Reduced fertility and embryonic viability were
axitinib clearance was not altered in subjects observed in female mice at all doses tested, with
with renal impairment and no dose adjustment of exposure levels at the lowest dose approximately
axitinib is required. 10-fold the expected human exposure.
5.3 Preclinical safety data Pregnant mice exposed to axitinib showed an
increased occurrence of cleft palate
Repeat dose toxicity malformations and skeletal variations, including
Major toxicity findings in mice and dogs delayed ossification, at exposure levels below
following repeated dosing for up to 9 months the expected human exposure. Perinatal and
were the gastrointestinal, haematopoietic, postnatal developmental toxicity studies have
reproductive, skeletal and dental systems, with not been conducted.
No Observed Adverse Effect Levels (NOAEL) Toxicity findings in immature animals
approximately equivalent to or below expected
human exposure at the recommended clinical Reversible physeal dysplasia was observed in
starting dose (based on AUC levels). mice and dogs given axitinib for at least 1 month
at exposure levels approximately six-fold higher
Carcinogenicity than the expected human exposure. Partially
Carcinogenicity studies have not been performed reversible dental caries were observed in mice
with axitinib. treated for more than 1 month at exposure levels
similar to the expected human exposure. Other
Genotoxicity toxicities of potential concern to paediatric
Axitinib was not mutagenic or clastogenic in patients have not been evaluated in juvenile
conventional genotoxicity assays in vitro. A animals.
significant increase in polyploidy was 6. PHARMACEUTICAL
observed in vitro at concentrations > 0.22 PARTICULARS
µg/mL, and an elevation in micronucleated
polychromatic erythrocytes was observed in
vivo with No Observed Effect Level (NOEL) 69- 6.1 List of excipients
fold the expected human exposure. Genotoxicity
findings are not considered clinically relevant at Tablet core Microcrystalline cellulose
exposure levels observed in humans. Lactose monohydrate
Reproduction toxicity Croscarmellose sodium
Axitinib-related findings in the testes and Magnesium stearate
epididymis included decreased organ weight,
atrophy or degeneration, decreased numbers of Tablet film-coating
germinal cells, hypospermia or abnormal sperm Hypromellose 2910 (15 mPa·s)
forms, and reduced sperm density and count.
These findings were observed in mice at Titanium dioxide (E171)
exposure levels approximately 12-fold the
Lactose monohydrate
expected human exposure, and in dogs at
exposure levels below the expected human Triacetin (E1518)
exposure. There was no effect on mating or
fertility in male mice at exposure levels Iron oxide red (E172)
6.2 Incompatibilities Any unused medicinal product or waste material

Not applicable. should be disposed of in accordance with local
requirements.
6.3 Shelf life
7. MANUFACTURER:
3 years.
6.4 Special precautions for storage
This medicinal product does not require any
special storage conditions. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
6.5 Nature and contents of container Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Axitinib 1 mg film-coated tablet Athiyawad, Dabhel,
Aluminium/aluminium blister containing 14 Daman- 396210 (INDIA)
film-coated tablets. Each pack contains 28 or 56
film-coated tablets.
HDPE bottle with a silica gel desiccant and a
polypropylene closure containing 180 film-
coated tablets.
Aluminium/aluminium blister containing 14
polypropylene closure containing 60 film-coated
tablets.
tablets.
tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and
other handling

Axitinib 1 MG, 3mg, 5mg Film-Coated Tablets SMPC - Taj Pharmaceuticals

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Axitinib 1 mg, 3mg, 5mg, 7mg fil m-coated tablets SMPC, Taj Phar maceuticals

RX Axitinib 7 mg film-coated tablet

Axitinib 1 mg film-coated tablets Red diamond shaped film-coated tablet.

Each film-coated tablet contains 1 mg of 4. CLINICAL PARTICULARS

Dose increase or reduction is recommended Co-administration of axitinib with strong

Paediatric population Blood pressure should be well-controlled prior

Hypersensitivity to axitinib or to any of the In case of severe or persistent arterial

Elevation of haemoglobin or haematocrit In clinical studies with axitinib, events of PRES

n site Mucosal 13.7 1.0 0 haemostasis, increased tendency to bruise,

Effect on QTc interval (prior temsirolimus treatment or prior

Clinical efficacy and safety Overall N = 361 N = 362

CI = Confidence interval, HR = Hazard ratio

nephroblastomatosis, clear cell sarcoma, of the radioactivity was recovered in urine.

Peak axitinib concentrations in plasma are Special populations

6.2 Incompatibilities Any unused medicinal product or waste material

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