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INLYTA (axitinib)

Health Professional Information

SUMMARY PRODUCT INFORMATION

§
not commercially available in Canada

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

Tablet 1 mg, 3 mg§,

5 mg, 7 mg§

Lactose monohydrate

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

INLYTA (axitinib) is indicated for the treatment of patients with metastatic renal cell carcinoma (RCC) of clear cell histology after failure of prior systemic therapy with either a cytokine or the VEGFR-TKI, sunitinib.

The clinical effectiveness of INLYTA is based on progression-free survival (PFS) in patients with metastatic RCC in a Phase 3, controlled clinical trial which compared INLYTA to sorafenib. The overall median PFS increased by 2 months in patients treated with INLYTA as compared to those treated with sorafenib (HR = 0.67 [95% CI: 0.54, 0.81]). The difference in median PFS for patients previously treated with a cytokine was 5.6 months (HR = 0.46 [95% CI: 0.32, 0.68]), whereas the difference in patients previously treated with sunitinib was 1.4 months (HR = 0.74 [95% CI: 0.57, 0.96]). The overall survival and quality of life were not significantly different in patients treated with INLYTA as compared to those treated with sorafenib (see CLINICAL TRIALS).

INLYTA should be prescribed by a qualified healthcare professional who is experienced in the use of anti-neoplastic therapy.

Geriatrics (≥65 years of age):

In a pivotal, Phase 3 controlled study with INLYTA for the treatment of metastatic RCC, 123/359 (34%) patients treated with INLYTA were ≥ 65 years old. 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 old and patients younger than 65 years. No dosage adjustment is required in patients who are 65 years or older (see WARNING AND PRECAUTIONS, Special Populations and DOSAGE AND ADMINISTRATION).

Pediatrics (<18 years of age):

The safety and efficacy of INLYTA in pediatric patients has not been established.
Physeal dysplasia in immature mice and dogs and odontopathies in growing incisors of mice have been observed in toxicology studies. Other toxicities of potential concern to pediatric patients due to the anti-angiogenic mechanism of action of axitinib have not been evaluated in juvenile animals. Therefore, INLYTA should not be administered to children under 18. (see WARNING AND PRECAUTIONS, Special Populations and DOSAGE AND ADMINISTRATION).

Contraindications

INLYTA (axitinib tablets) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

Warnings And Precautions

Serious Warnings and Precautions

INLYTA should be prescribed by a qualified healthcare professional who is experienced in the use of anti-neoplastic therapy.

INLYTA has not been studied in patients with severe hepatic impairment (see Hepatic section below)

The following are clinically significant adverse events:

  • Hypertension and Hypertensive Crisis (see Cardiovascular section below)
  • Arterial Thromboembolism, including deaths (see Cardiovascular section below)
  • Venous Thromboembolism, including deaths (see Cardiovascular section below)
  • Hemorrhage (including gastrointestinal, cerebral and respiratory tract) (see Hematologic section below)
  • Gastrointestinal perforation, including death and gastrointestinal fistulas (see Gastrointestinal section below)
  • Reversible posterior leukoencephalopathy syndrome (see Neurologic section below)
  • Congestive heart failure/Cardiomyopathy, including deaths (see Cardiovascular section below)

General

INLYTA contains lactose and should not be taken by patients with hereditary problems of lactose intolerance.

Drug-Drug Interactions

Co-administration of INLYTA with strong inhibitors of CYP3A4/5 is not recommended as this may increase axitinib concentrations and drug toxicity. If a strong CYP3A4/5 inhibitor must be co-administered a dose reduction of INLYTA is recommended (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

Co-administration with strong inducers of CYP3A4/5 should be avoided due to the risk of reduced effectiveness of the drug. Moderate CYP3A4/5 inducers may also reduce the plasma exposure of axitinib and should be avoided if possible (see DRUG INTERACTIONS).

INLYTA is not indicated for use in combination with other anti-cancer agents.

Effects on ability to drive and use machines

No studies on the effect of INLYTA on the ability to drive or use machines have been performed. However, patients should be informed that dizziness and fatigue have been reported during treatment with INLYTA.

Carcinogenesis and Mutagenesis

Carcinogenicity studies with axitinib have not been conducted. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in an in vivo mouse bone marrow micronucleus test (see TOXICOLOGY).

Cardiovascular

Patients with uncontrolled hypertension at baseline or a recent history of myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis or pulmonary embolism were excluded from clinical studies with INLYTA.

Hypertension and Hypertensive Crisis

Hypertension is a common adverse event in patients treated with INLYTA (see ADVERSE REACTIONS) and blood pressure should be well controlled prior to initiating treatment with INLYTA. Patients were required to have diastolic BP ≤90 mm Hg and systolic BP ≤140 mm Hg for entry into the controlled Phase 3 trial. During therapy patients should be monitored for hypertension early after starting treatment (no longer than one week after starting axitinib and frequently thereafter to ensure blood pressure control), and treated promptly with a combination of standard anti-hypertensive therapy and INLYTA dose reduction or interruption as clinically warranted. INLYTA should be discontinued if hypertension is severe and persistent despite anti- hypertensive therapy or if there is evidence of hypertensive crisis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

In pooled clinical studies for the treatment of patients with RCC, hypertension was reported in 344/672 patients (51%) receiving INLYTA with 155/672 patients (23%) experiencing Grade 3/4 events.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) treated with INLYTA and none in patients treated with 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 treatment and increases in blood pressure were observed as early as 4 days after the first dose of INLYTA. Hypertension was managed with standard anti-hypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib (see ADVERSE REACTIONS).

Patients with hypertension that is not controlled by medications should not be treated with INLYTA. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension (see DOSAGE and ADMINISTRATION).

Congestive Heart Failure/Cardiomyopathy Events

Congestive heart failure/cardiomyopathy events have been reported in patients receiving INLYTA in the post-market setting. Many events have resulted in hospitalizations and some have been fatal. In clinical studies for the treatment of patients with RCC, congestive heart failure/cardiomyopathy events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 12/672 patients (2%) receiving INLYTA and 11 patients were hospitalized. Grade 3/4 congestive heart failure/cardiomyopathy events were reported in 7 patients (1%) and 2 patients (<1%) receiving INLYTA had fatal events.

In a pivotal controlled Phase 3 clinical study with INLYTA for the treatment of patients with RCC, congestive heart failure/cardiomyopathy events (including cardiac failure, cardiopulmonary failure, left ventricular dysfunction, and right ventricular failure) were reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (<1%) receiving sorafenib. Grade 3/4 congestive heart failure/cardiomyopathy events were observed in 2 patients (<1%) receiving INLYTA and 1 patient (<1%) receiving sorafenib. Fatal events were reported in 2 patients (<1%) receiving INLYTA and 1 patient (<1%) receiving sorafenib (see ADVERSE REACTIONS).

Monitor for signs or symptoms of congestive heart failure/cardiomyopathy events at baseline and periodically throughout treatment with INLYTA. Management of these events may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy.

QT Prolongation

The effect of INLYTA on the QTc interval was investigated in a randomized, 2-way crossover study where, 35 healthy subjects were administered a single, oral 5 mg dose of INLYTA alone or with 400 mg ketoconazole. Although some tyrosine kinase inhibitors are associated with QT interval prolongation, INLYTA did not result in large mean changes in the QTc interval (>20 msec) up to 3 hours post-dose. However smaller increases in the QTc interval (<10 msec) cannot be ruled out.

Decreased Heart Rate

In clinical studies with INLYTA, events of decreased heart rate have occurred (see ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).
Caution should be observed in patients who are bradycardic or considered to be at risk for bradyarrhythmias or who are receiving other heart rate-lowering drugs.

Arterial Thromboembolic Events

In pooled clinical studies for the treatment of patients with RCC, arterial thromboembolic events were reported in 19/672 patients (3%) receiving INLYTA with 17/672 patients (3%) experiencing Grade 3/4 events. Fatal arterial thromboembolic events were reported in 2 patients (<1%) receiving INLYTA.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. A fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients (0%) receiving sorafenib (see ADVERSE REACTIONS).

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 clinical studies with INLYTA, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In pooled clinical studies for the treatment of patients with RCC, venous thromboembolic events were reported in 19/672 patients (3%) receiving INLYTA with 14/672 patients (2%) experiencing Grade 3/4 events. Fatal venous thromboembolic events were reported in 1/672 patients (<1%) receiving INLYTA.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events (including pulmonary embolism, deep vein thrombosis, and retinal-vein occlusion/thrombosis) were reported in 9/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib.

INLYTA should be used with caution in patients who are at risk for venous thromboembolic events 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.

Endocrine and Metabolism

Thyroid Dysfunction

In clinical studies with INLYTA, events of hypothyroidism and hyperthyroidism have occurred (see ADVERSE REACTIONS). In pooled clinical studies for the treatment of patients with RCC, hypothyroidism was reported in 165/672 patients (25%) receiving INLYTA. In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib.

In pooled clinical studies for the treatment of patients with RCC, hyperthyroidism was reported in 11/672 patients (2%) receiving INLYTA. In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib (see ADVERSE REACTIONS).

Monitoring for thyroid function before initiation of, and periodically throughout, treatment with INLYTA is recommended. Hypothyroidism and hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state.

Gastrointestinal

Gastrointestinal Perforation and Fistula Formation

In clinical studies with INLYTA, events of gastrointestinal (GI) perforation or fistula have occurred, including a fatal GI perforation (see ADVERSE REACTIONS). In pooled clinical studies for the treatment of patients with RCC, gastrointestinal perforation and fistula were reported in 13/672 patients (2%) receiving INLYTA. In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical studies with INLYTA, GI perforation was reported in 5/715 patients (1%), including one death, and GI fistulas were reported in 4/715 patients (1%).

Monitoring for symptoms of GI perforation or fistula formation periodically throughout treatment with INLYTA is recommended.

Hematologic

Elevation of Hemoglobin or Hematocrit

In clinical studies with INLYTA, events of elevated hemoglobin have occurred. Elevated hemoglobin above the upper limit of normal (ULN) was observed in 31/320 patients (10%) receiving INLYTA and 3/316 patients (1%) receiving sorafenib. An increase in red blood cell mass may increase the risk of thromboembolic events.

Monitoring hemoglobin or hematocrit before initiation of, and periodically throughout, treatment with INLYTA is recommended. If hemoglobin or hematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease hemoglobin or hematocrit to an acceptable level.

Hemorrhagic

In clinical studies with INLYTA, hemorrhagic events have been reported, some of which were fatal (see ADVERSE REACTIONS). In pooled clinical studies for the treatment of patients with RCC, hemorrhagic events were reported in 173/672 patients (26%) receiving INLYTA with 27/672 patients (3%) experiencing Grade 3/4 events. Fatal hemorrhagic events were reported in 3/672 patients (<1%) receiving INLYTA.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 patients (1%) receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 patients (3%) receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

Since INLYTA has not been studied in patients who have evidence of untreated brain metastasis, a history of pulmonary embolism in the previous 6 months, or a history of active bleeding in the previous 3 months, treatment with INLYTA is not recommended in these patients. INLYTA should be used with caution in patients with a significant risk for hemorrhage.

Hepatic

Elevation of Liver Enzymes

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, alanine aminotransferase (ALT) elevations occurred in 74/331 patients (22%) receiving INLYTA and 68/313 patients (22%) receiving sorafenib. Grade 3/4 events were reported in 1/331 patients (<1%) receiving INLYTA and 5/313 patients (2%) receiving sorafenib (see ADVERSE REACTIONS).

Monitoring of ALT, aspartate aminotransferase (AST) and bilirubin before initiation of, and periodically throughout treatment with, INLYTA is recommended.

Hepatic Impairment

In a clinical hepatic impairment study with INLYTA (N=24 subjects), the systemic exposure of INLYTA was approximately 2-fold higher in patients with moderate hepatic impairment (Child- Pugh class B) compared to patients with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this patient population (see DOSAGE AND ADMINISTRATION, ACTION AND CLINICAL PHARMACOLOGY).

Neurologic

Reversible Posterior Leukoencephalopathy Syndrome

In pooled clinical studies for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 2/672 patients (<1%) receiving INLYTA.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, RPLS was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Two additional events of RPLS were reported in other clinical trials with INLYTA (see ADVERSE REACTIONS).

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. INLYTA should be discontinued in patients with signs/symptoms of RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

Peri-Operative Considerations

Wound Healing Complications

No formal studies of the effect of INLYTA on wound healing have been conducted. Since vascular endothelial growth factor (VEGF) inhibitors may impair wound healing, treatment with INLYTA should be stopped at least 24 hours prior to scheduled surgery. The decision to resume INLYTA after surgery should be based on clinical judgement of adequate wound healing.
INLYTA should be discontinued in patients with wound dehiscence.

Renal

Renal Impairment

Axitinib has not been studied in patients with renal impairment. Caution should be exercised when administering INLYTA to patients with end-stage renal disease. Population pharmacokinetic analyses, suggest that there is no significant change in axitinib clearance in patients with mild to severe renal impairment. No dose adjustments based on renal function are required in patients with mild to severe renal impairment (see DOSAGE AND ADMINISTRATION, ACTION AND CLINICAL PHARMACOLOGY).

Proteinuria

In pooled clinical studies for the treatment of patients with RCC, proteinuria was reported in 142/672 patients (21%) receiving INLYTA with 33/672 patients (5%) experiencing Grade 3/4 events.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib (see ADVERSE REACTIONS).

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduction of the dose or temporary interruption of INLYTA treatment is recommended.

Sexual Function/Reproduction

Based on nonclinical safety findings, male and female fertility may be impaired by treatment with axitinib (see TOXICOLOGY).

Skin and Subcutaneous Tissue Disorders

Palmar-Plantar Erythrodysesthesia Syndrome

In pooled clinical studies for the treatment of patients with RCC, palmar-plantar erythrodysesthesia syndrome (PPE) was reported in 216/672 patients (32%) receiving INLYTA with 51/672 patients (7.6%) experiencing Grade 3/4 events.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, PPE was reported in 98/359 patients (27%) receiving INLYTA and 181/355 patients (51%) receiving sorafenib (see ADVERSE REACTIONS). Grade 3 PPE was reported in 18/359 (5%) of patients in the INLYTA arm and 57/355 (16.1%) of patients in the sorafenib arm. PPE resulted in dose modification or temporary delay of treatment in 19/359 (5.3%) patients treated with INLYTA and 63/355 (17.7%) patients treated with sorafenib. PPE led to treatment discontinuation in 1/359 (0.3%) of patients treated with INLYTA and 4/355 (1.1%) of patients treated with sorafenib.

Consider initiating treatment with topical therapies as soon as symptoms occur.

Special Populations

Pregnant Women

INLYTA should not be used during pregnancy. There are no studies in pregnant women using INLYTA. Based on its anti-angiogenic mechanism of action, INLYTA is expected to cause fetal harm when used by pregnant women.

In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose (see TOXICOLOGY).

Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. It is recommended that men and women should use effective birth control during treatment with INLYTA.

Nursing Women

The safe use of axitinib during lactation has not been established. It is unknown whether INLYTA is excreted in human milk. Breastfeeding should be discontinued during treatment with INLYTA.

Many drugs are commonly excreted in human milk therefore INLYTA may be toxic to nursing infants.

Pediatrics (<18 years of age)

The safety and efficacy of INLYTA in pediatric patients have not been established. Physeal dysplasia in immature mice and dogs and odontopathies in growing incisors of mice have been observed in toxicology studies. Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals (see TOXICOLOGY). Therefore, INLYTA should not be administered to children less than 18 years of age.

Geriatrics (≥65 years of age)

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, 123/359 (34%) 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 old and patients younger than 65 years. No dosage adjustment is required in patients who are 65 years or older (see DOSAGE AND ADMINISTRATION).

Monitoring and Laboratory Tests

Prior to treatment and during the course of therapy with INLYTA, patients should be monitored for hypertension, signs or symptoms of congestive heart failure/cardiomyopathy events, decreased heart rate, thyroid dysfunction, increased hemoglobin or hematocrit, symptoms of gastrointestinal perforation and fistula formation, proteinuria and elevated liver enzymes and elevated creatinine (see WARNINGS and PRECAUTIONS, Hypertension, Thyroid Dysfunction, Elevation of Hemoglobin and Hematocrit, Gastrointestinal Perforation and Fistula Formation, Proteinuria, Elevation of Liver Enzymes).

Adverse Reactions

Adverse Drug Reaction Overview

The safety of INLYTA has been evaluated in 672 patients with metastatic RCC. The data described in this section reflect exposure to INLYTA in 359 patients with metastatic RCC who participated in the pivotal Phase 3 controlled clinical study versus sorafenib (see CLINICAL TRIALS).

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 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse event occurred in 33/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.

Clinical Trial Adverse Drug Reactions

Becauseclinicaltrialsareconductedundervery specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Potentially serious adverse reactions with INLYTA included congestive heart failure/cardiomyopathy events, hypertension and hypertensive crisis, arterial thrombotic events, venous thrombotic events, cardiac dysfunction, hemorrhagic events, gastrointestinal perforation and fistula formation, thyroid dysfunction, elevation of hemoglobin or hematocrit, wound healing complications, RPLS, proteinuria, palmar-plantar erythrodysesthesia syndrome, elevation of liver enzymes and fetal development (see WARNINGS AND PRECAUTIONS).

Table 1 presents the most common adverse reactions reported in ≥10% of patients who received INLYTA or sorafenib.

Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received INLYTA or Sorafenib
a
Percentages are treatment-emergent, all-causality events;
b
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0;
c
Includes Grade 5
d
Hemorrhage includes the following preferred terms (All Grades frequency): epistaxis (6%), haematuria (3%), haemoptysis (2%), rectal haemorrhage (2%), cerebral haemorrhage (

Adverse Reactiona

INLYTA

Sorafenib

(N=359)

(N=355)

All Gradesb

Grade 3

Grade 4

All Gradesb

Grade 3

Grade 4

%

%

%

%

%

%

Endocrine disorders

Hypothyroidism

19

<1

0

8

0

0

Gastrointestinal disorders

Diarrhea

55

10

<1

53

7

1

Nausea

32

2

<1

22

1

0

Vomiting

24

3

<1

17

1

0

Constipation

20

1

0

20

1

0

Stomatitis

15

1

0

12

<1

0

Abdominal pain

14

2

<1

11

1

0

Dyspepsia

10

0

0

2

0

0

General disorders and administration site conditions

Fatigue

39

11

1

32

5

<1

Asthenia

21c

5

1

14

2

<1

Mucosal inflammation

15

1

0

12

1

0

Investigations

Weight decreased

25

2

0

21

1

0

Metabolism and nutrition disorders

Decreased appetite

34c

5

<1

29

4

0

Musculoskeletal and connective tissue disorders

Arthralgia

15

1

1

11

1

0

Pain in extremity

13

<1

<1

14

1

0

Nervous system disorders

Headache

14

1

0

11

0

0

Dysgeusia

11

0

0

8

0

0

Renal and urinary disorders

Proteinuria

11

3

0

7

2

0

Respiratory, Thoracic and Mediastinal disorders

Dysphonia

31

0

0

14

0

0

Cough

15

1

0

17

1

0

Dyspnea

15c

2

1

12

2

1

Skin and subcutaneous tissue disorders

Palmar-plantar erythrodysesthesia syndrome

27

5

0

51

16

0

Rash

13

<1

0

32

4

0

Dry skin

10

0

0

11

0

0

Pruritus

7

0

0

12

0

0

Alopecia

4

0

0

32

0

0

Erythema

2

0

0

10

<1

0

Vascular disorders

Hypertension

40

15

<1

29

11

<1

Haemorrhaged

16c

1

<1

18

3

0

Less Common Clinical Trial Adverse Drug Reactions (<10%)

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included the following:

Blood and lymphatic disorders: anemia (4%), neutropenia (<1%), leukopenia (<1%), polycythemia (1%), thrombocytopenia (2%)

Cardiac disorder: congestive heart failure/cardiomyopathy events including cardiac failure (1%), cardiopulmonary failure (<1%), left ventricular dysfunction (<1%), right ventricular failure (<1%)

Metabolism and nutrition disorders: dehydration (6%), hypercalcemia (3%), hyperkalemia (3%)

Nervous system disorders: dizziness (9%), RPLS (<1%)

Eye disorders: retinal artery occlusion (<1%)

Ear and labyrinth disorders: tinnitus (3%)

Endocrine disorders: hyperthyroidism (1%)

Vascular disorders: hypertensive crisis (1%); venous embolic and thrombotic events including pulmonary embolism (2%), retinal-vein occlusion/thrombosis (1%), and deep vein thrombosis (1%); arterial embolic and thrombotic events including transient ischaemic attack (1%), cerebrovascular accident (<1%), and myocardial infarction (<1%)

Respiratory, thoracic and mediastinal disorders: epistaxis (6%), hemoptysis (2%), pulmonary embolism (2%)

Gastrointestinal disorders: upper abdominal pain (8%), hemorrhoids (4%), fistula (<1%), anal fistula (<1%), gastrointestinal perforation (<1%)

Muscoskeletal and connective tissue disorders: myalgia (7%)

Renal and urinary disorders: renal failure (including acute renal failure) (2%)

Skin and subcutaneous tissue disorders: glossodynia (3%)

Investigations: lipase increased (3%)

Abnormal Hematologic and Clinical Chemistry Findings

Table 2 presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.

Table 2. Laboratory Abnormalities Occurring in ≥10% of Patients who Received INLYTA or Sorafenib
a
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Laboratory Abnormality

N

INLYTA

N

Sorafenib

All Gradesa

Grade 3

Grade 4

All Gradesa

Grade 3

Grade 4

%

%

%

%

%

%

Hematology

Hemoglobin decreased

320

35

<1

0

316

52

4

<1

Lymphocytes (absolute) decreased

317

33

3

0

309

36

4

0

Platelets decreased

312

15

<1

0

310

14

0

0

White blood cells decreased

320

11

0

0

315

16

<1

0

Chemistry

Creatinine increased

336

55

0

0

318

41

<1

0

Bicarbonate decreased

314

44

0

<1

291

43

0

0

Hypocalcemia

336

39

1

1

319

59

1

1

ALP increased

336

30

1

0

319

34

1

0

Hyperglycemia

336

28

2

0

319

23

2

0

Lipase increased

338

27

4

1

319

46

13

2

Amylase increased

338

25

2

0

319

33

2

<1

ALT increased

331

22

<1

0

313

22

1

1

AST increased

331

20

<1

0

311

25

1

0

Hypernatremia

338

17

1

0

319

13

<1

1

Hypoalbuminemia

337

15

<1

0

319

18

1

0

Hyperkalemia

333

15

3

0

314

10

3

0

Hypoglycemia

336

11

<1

0

319

8

<1

0

Hyponatremia

338

13

3

<1

319

11

2

<1

Hypophosphatemia

336

13

2

0

318

49

16

0

Hemoglobin increases above the upper limit of normal were observed for 9% of patients treated with INLYTA as compared to 1% of patients treated with sorafenib. Neutrophils decreased was observed in 6% of patients treated with INLYTA and 8% of patients treated with sorafenib.

In clinical trials, INLYTA was associated with statistically significant mean increases from baseline in systolic and diastolic blood pressure. On day 15 of treatment, systolic blood pressure was increased by mean 8.0 mmHg and diastolic blood pressure by mean 5.5 mmHg. These blood pressure increases were associated with a statistically significant mean decrease from baseline in heart rate of approximately 4 to 6 beats per minute.

Hypercalcemia was observed in 6% of patients treated with INLYTA and 2% of patients treated with sorafenib.

Hyperbilirubinemia was observed in 1% of patients treated with INLYTA and 1% of patients treated with sorafenib.

Post-Marketing Experience

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

Cardiac disorder: Acute pulmonary oedema, cardiac failure, cardiac failure congestive, cardiomyopathy, cardiopulmonary failure, central venous pressure increased, diastolic dysfunction, ejection fraction decreased, left ventricular dysfunction, left ventricular failure, stress cardiomyopathy, pulmonary oedema, and ventricular dysfunction

Drug Interactions

Overview

Axitinib is metabolized in the liver, undergoing oxidative metabolism mediated primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, as well as uridine diphosphate- glucuronosyltransferase (UGT) 1A1. The aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility.

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 does not induce CYP1A1, CYP1A2, or CYP3A4/5.

In vitro studies indicated that axitinib has a potential to inhibit CYP1A2 and CYP2C8. Co- administration of INLYTA with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g., theophylline).

In vitro studies indicated that axitinib inhibits P-glycoprotein. However, INLYTA is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations.

Drug-Drug Interactions

CYP3A4/5 Inhibitors

Co-administration of INLYTA with strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) should be avoided as they may increase the plasma concentration of axitinib. 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 reduction of INLYTA is recommended (see DOSAGE AND ADMINISTRATION).

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 Cmax 1.5-fold of a single 5-mg oral dose of INLYTA in healthy volunteers.

CYP3A4/5 Inducers

Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, and phenobarbital) should be avoided due to the potential for reduced effectiveness of the drug. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma concentration of axitinib and should be avoided if possible. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended (see DOSAGE AND ADMINISTRATION).

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 Cmax by 71% of a single 5-mg dose of INLYTA in healthy volunteers.

Agents that Increase Gastric pH

The solubility of axitinib is lowered with increasing pH and co-administration of drugs that increase the gastric pH (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) could result in decreased plasma exposure to axitinib. It is recommended that antacids should be avoided for 2 hours before through 2 hours after dosing with INLYTA.

The effect of rabeprazole, a proton pump inhibitor (administered 20 mg once a day), on the steady state exposure of axitinib (dosed at 5 mg twice a day) was examined in 6 patients with solid tumors. Although the mean AUC and Cmax of axitinib were decreased by 15% (geometric mean ratio of 0.85 [90% CI: 0.59, 1.23]) and 42% (geometric mean ratio of 0.58 [90% CI: 0.26, 1.30]), respectively, in the presence of rabeprazole, the magnitude of the effect of the proton pump inhibitor was variable between patients.

Drug-Food Interactions

Grapefruit, grapefruit juice, and products containing grapefruit extract may increase axitinib plasma concentrations and should be avoided.

INLYTA may be administered with or without food (see DOSAGE AND ADMINISTRATION). 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 (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Drug-Herb Interactions

Interactions with herbal products have not been established. St. John’s wort (Hypericum perforatum), is an inducer of CYP3A4/5, that may decrease axitinib plasma concentrations and should be avoided.

Drug-Laboratory Interactions

Interactions between INLYTA and laboratory tests have not been studied.

Dosage And Administration

Recommended Dose and Dosage Adjustment

The recommended oral starting dose of INLYTA is 5 mg twice daily (see CLINICAL TRIALS). INLYTA may be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY). INLYTA should be swallowed whole with a glass of water.

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 2 (according Common Toxicity Adverse Event Criteria [CTCAE]) for two consecutive weeks, are normotensive, and are not receiving anti-hypertension medication, may have their dose increased to 7 mg twice daily. Subsequently, 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 of some adverse drug reactions may require temporary or permanent  discontinuation and/or dose reduction of INLYTA therapy (see WARNINGS AND PRECAUTIONS). When dose reduction is necessary, the INLYTA dose may be reduced from 5 mg twice daily to 3 mg twice daily and further to 2 mg twice daily.

Geriatric

No alteration of dosage, dosing frequency or route of administration is required in patients over 65 years.

Hepatic Impairment

No dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on pharmacokinetic data, the starting dose of INLYTA should be decreased by approximately half in patients with moderate hepatic impairment (Child- Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child- Pugh class C) and should not be used in this patient population as an appropriate starting dose is unknown (see WARNINGS AND PRECAUTIONS, Hepatic Impairment, ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment

Axitinib has not been studied in patients with renal impairment. Caution should be exercised when administering INLYTA to patients with end-stage renal disease. No dose adjustments based on renal function are required in patients with mild to severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY).

Strong CYP3A4/5 Inhibitors

Co-administration of INLYTA with strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations and is not recommended (see DRUG INTERACTIONS).

Missed Dose

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.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There is no specific treatment for INLYTA overdose.

In the pivotal Phase 3 controlled clinical study with INLYTA for the treatment of patients with metastatic RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).

In a clinical dose finding study with 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 hemoptysis.

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

Action And Clinical Pharmacology

Mechanism of Action

Axitinib was shown to inhibit tyrosine kinase VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic progression of cancer. In vitro, axitinib has been shown to inhibit VEGF-mediated endothelial cell proliferation and survival. In vivo, axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumor vasculature that expressed the target in vivo and produced tumor growth delay, regression, and inhibited metastases in many experimental models of cancer.

Pharmacodynamics

Electrocardiography

In a randomized, 2-way crossover study, 35 healthy subjects were administered a single oral 5 mg dose of INLYTA alone or on day 4 of a 7 day treatment with 400 mg/day ketoconazole.
Axitinib at 5 mg was associated with a mean decrease in heart rate of 5 beats per minute. INLYTA did not result in large mean changes in the QTc interval (> 20 msec) up to 3 hours post-dose, however smaller increases in the QTc interval (< 10 msec) cannot be ruled out.

Pharmacokinetics

Table 3. Axitinib Pharmacokinetic Parameter in Patients with Metastatic Renal Cell Carcinoma after Administration of 5 mg Axitinib Twice Daily for 15 Days (N=20)
a
% CV is the coefficient of variation around the arithmetic mean.
b

Tmax reported as median and range.

Cmax (ng/mL)

AUC0-24

(ng.h/mL)

Tmaxb

 

(hr)

Geometric mean (% CV)a

27.8

(79)

265

(77)

2.00

(1.0-2.5)

Absorption

Following administration of a single, oral 5 mg dose of axitinib, the median time to achieve peak concentrations ranged from 2.5 to 4.1 hours. Daily dosing results in approximately 1.4-fold accumulation as compared to administration of a single dose. Axitinib exhibits approximately linear steady-state pharmacokinetics at doses between 1 mg and 20 mg. The mean absolute bioavailability of axitinib following administration of a single, oral 5 mg dose of axitinib is 58%.

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.

Distribution

Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with metastatic RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) for clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.

Metabolism

Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.

Excretion

The plasma half life of axitinib ranges from 2.5 to 6.1 hours with steady state expected within 2 to 3 days of dosing.

Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and 23% was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide 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 and Conditions

Age, Gender, and Race: Population pharmacokinetic analyses from patients with metastatic cancer (including metastatic 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.

Pediatrics: INLYTA has not been studied in patients <18 years of age (see WARNINGS AND PRECAUTIONS, Special Populations).

Hepatic Impairment: In vitro and in vivo data indicate that axitinib is primarily metabolized by the liver. Compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in patients with mild hepatic impairment (Child-Pugh class A) and approximately 2-fold higher in patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Special Populations).

Renal Impairment: INLYTA has not been studied in patients with renal impairment. Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤CLcr <29 mL/min), 64 with moderate renal impairment (30 mL/min ≤CLcr <59 mL/min), and 139 with mild renal impairment (60 mL/min ≤CLcr <89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available.

Storage And Stability

Store at a controlled room temperature of 25°C; excursions permitted to 15-30°C.

Dosage Forms, Composition And Packaging

INLYTA tablets are supplied as follows:

  • 1 mg: red, film-coated, oval tablets debossed with “Pfizer” on one side and “1 XNB” on the other and containing 1 mg of axitinib
  • 3 mg§: red film-coated, round tablets, debossed with “Pfizer” on one side and “3 XNB” on the other side and containing 3 mg of axitinib.
  • 5 mg: red, film-coated, triangular tablets debossed with “Pfizer” on one side and “5 XNB” on the other and containing 5 mg of axitinib.
  • 7 mg§: red film-coated, diamond-shaped tablets, debossed with “Pfizer” on one side and “7 XNB” on the other side and containing 7 mg of axitinib.

Both tablets contain the following excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry II red as inactive ingredients. The Opadry II red film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.

INLYTA 1 mg tablets are presented as follows:

  • bottles of 60
  • foil/foil blister packs containing 28 ([14 tabs/blister] x [2 blisters]), or 56 ([14 tabs/blister] x [4 blisters]) tablets§.

INLYTA 3 mg§ tablets are presented as follows:

  • bottles of 60
  • foil/foil blister packs containing 28 ([14 tabs/blister] x [2 blisters]), or 56 ([14 tabs/blister] x [4 blisters]) tablets§.

INLYTA 5 mg tablets are presented as follows:

  • bottles of 60
  • foil/foil blister packs containing 28 ([14 tabs/blister] x [2 blisters]), or 56 ([14 tabs/blister] x [4 blisters]) tablets§.
§
not commercially available in Canada

 

INLYTA 7 mg§ tablets are presented as follows:

  • bottles of 60
  • foil/foil blister packs containing 28 ([14 tabs/blister] x [2 blisters]), or 56 ([14 tabs/blister] x [4 blisters]) tablets§.
§
not commercially available in Canada

 

Control #: 181783
14 July 2015

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