HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`INLYTA safely and effectively. See full prescribing information for
`INLYTA.
`
`
` INLYTA® (axitinib) tablets for oral administration
` Initial U.S. Approval: 2012
`
`---------------------------INDICATIONS AND USAGE-----------------------
`
`INLYTA is a kinase inhibitor indicated for the treatment of advanced
`renal cell carcinoma after failure of one prior systemic therapy. (1)
`
`
`
`
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION-----------------
`
`The starting dose is 5 mg orally twice daily. Dose adjustments can
`
`•
`be made based on individual safety and tolerability. (2.1, 2.2)
`Administer INLYTA dose approximately 12 hours apart with or
`
`
`without food. (2.1)
`
`INLYTA should be swallowed whole with a glass of water. (2.1)
`
`If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA
`
`dose by approximately half. (2.2)
`
`For patients with moderate hepatic impairment, decrease the starting
`dose by approximately half. (2.2)
`
`
`------------------------DOSAGE FORMS AND STRENGTHS--------------
`
`1 mg and 5 mg tablets (3)
`--------------------------------CONTRAINDICATIONS------------------------
`None (4)
`------------------------WARNINGS AND PRECAUTIONS------------------
`
`Hypertension including hypertensive crisis has been observed.
`
`•
`Blood pressure should be well-controlled prior to initiating
`INLYTA. Monitor for hypertension and treat as needed. For
`
`persistent hypertension despite use of anti-hypertensive medications,
`
`reduce the INLYTA dose. (5.1)
`
`Arterial and venous thrombotic events have been observed and can
`be fatal. Use with caution in patients who are at increased risk for
`these events. (5.2, 5.3)
`Hemorrhagic events, including fatal events, have been reported.
`
`INLYTA has not been studied in patients with evidence of untreated
`brain metastasis or recent active gastrointestinal bleeding and should
`not be used in those patients. (5.4)
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`
`2.2 Dose Modification Guidelines
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypertension and Hypertensive Crisis
`5.2 Arterial Thromboembolic Events
`
`5.3 Venous Thromboembolic Events
`
`5.4 Hemorrhage
`5.5 Gastrointestinal Perforation and Fistula Formation
`5.6
`Thyroid Dysfunction
`5.7 Wound Healing Complications
`5.8 Reversible Posterior Leukoencephalopathy Syndrome
`
`5.9
`Proteinuria
`5.10 Elevation of Liver Enzymes
`
`
`
`5.11 Hepatic Impairment
`5.12 Pregnancy
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`7 DRUG INTERACTIONS
`
`
`7.1 CYP3A4/5 Inhibitors
`
`7.2 CYP3A4/5 Inducers
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`
`Reference ID: 3078397
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`Gastrointestinal perforation and fistula, including death, have
`occurred. Use with caution in patients at risk for gastrointestinal
`perforation or fistula. (5.5)
`Hypothyroidism requiring thyroid hormone replacement has been
`
`reported. Monitor thyroid function before initiation of, and
`periodically throughout, treatment with INLYTA. (5.6)
`Stop INLYTA at least 24 hours prior to scheduled surgery. (5.7)
`
`Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has
`been observed. Permanently discontinue INLYTA if signs or
`
`symptoms of RPLS occur. (5.8)
`
`
`• Monitor for proteinuria before initiation of, and periodically
`throughout, treatment with INLYTA. For moderate to severe
`
`
`proteinuria, reduce the dose or temporarily interrupt treatment with
`INLYTA. (5.9)
`
`Liver enzyme elevation has been observed during treatment with
`INLYTA. Monitor ALT, AST and bilirubin before initiation of, and
`periodically throughout, treatment with INLYTA. (5.10)
`The starting dose of INLYTA should be decreased if used in
`patients with moderate hepatic impairment. INLYTA has not been
`
`studied in patients with severe hepatic impairment. (2.2, 5.11)
`
`
`INLYTA can cause fetal harm when administered to a pregnant
`woman based on its mechanism of action. Women of childbearing
`potential should be advised of the potential hazard to the fetus and
`to avoid becoming pregnant while receiving INLYTA. (5.12, 8.1)
`
`------------------------------ADVERSE REACTIONS--------------------------
`The most common (≥20%) adverse reactions are diarrhea, hypertension,
`
`fatigue, decreased appetite, nausea, dysphonia, palmar-plantar
`erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting,
`
`asthenia, and constipation. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer,
`
`Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`---------------------------------DRUG INTERACTIONS-----------------------
`
`Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the
`•
`INLYTA dose. (2.2, 7.1)
`
`Avoid strong CYP3A4/5 inducers. (7.2)
`
`
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Hypertension
`
`
`17.2 Arterial/Venous Thromboembolic Events
`17.3 Hemorrhage
`17.4 Gastrointestinal Disorders
`
`17.5 Abnormal Thyroid Function
`17.6 Wound Healing Complications
`
`17.7 Reversible Posterior Leukoencephalopathy Syndrome
`17.8 Pregnancy
`17.9 Concomitant Medications
`*Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`
`

`

`
`
` INDICATIONS AND USAGE
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of
`one prior systemic therapy.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`2.1
`The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses
`approximately 12 hours apart with or without food [see Clinical Pharmacology (12.3)]. INLYTA
`should be swallowed whole with a glass of water.
`
`If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed
`dose should be taken at the usual time.
`
`Dose Modification Guidelines
`2.2
`Dose increase or reduction is recommended based on individual safety and tolerability.
`
`Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks
`with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse
`Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may
`have their dose increased. When a dose increase from 5 mg twice daily is recommended, the
`INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the
`
`same criteria.
`Over the course of treatment, management of some adverse drug reactions may require temporary
`interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see
`Warnings and Precautions (5)]. If dose reduction from 5 mg twice daily is required, the
`
`recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended
`dose is 2 mg twice daily.
`Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be
`avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
`nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate
`concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended.
`
`Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5
`inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA
`by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib
`area under the plasma concentration vs time curve (AUC) to the range observed without
`inhibitors. The subsequent doses can be increased or decreased based on individual safety and
`tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should
`be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the strong
`CYP3A4/5 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to
`patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data,
`2
`
`
`
`
`Reference ID: 3078397
`
`

`

`
`
`the INLYTA starting dose should be reduced by approximately half in patients with baseline
`moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or
`decreased based on individual safety and tolerability. INLYTA has not been studied in patients
`with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions (5.11), Use
`in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1
`XNB” on the other side.
`5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side
`and “5 XNB” on the other side.
`
`
`4
`None
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`
`CONTRAINDICATIONS
`
`
`5.1 Hypertension and Hypertensive Crisis
`In a controlled clinical study with INLYTA for the treatment of patients with 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%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for
`
`hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was
`within the first month of the start of INLYTA treatment and blood pressure increases have been
`observed as early as 4 days after starting INLYTA. Hypertension was managed with standard
`
`antihypertensive 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 (6.1)].
`Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be
`monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the
`case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA
`dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive
`therapy and dose reduction of INLYTA, and discontinuation should be considered if there is
`evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive
`medications should be monitored for hypotension [see Dosage and Administration (2.2)].
`
`
`Arterial Thromboembolic Events
`5.2
`In clinical trials, arterial thromboembolic events have been reported, including deaths. In a
`controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial
`thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355
`patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients
`3
`
`
`
`
`Reference ID: 3078397
`
`

`

`
`
`(<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions
`(6.1)].
`In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic
`attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were
`reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.
`
`Use INLYTA 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
`5.3
`
`In clinical trials, venous thromboembolic events have been reported, including deaths. In a
`controlled clinical study with INLYTA for the treatment of patients with 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 were reported in
`9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis,
`retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib.
`Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of
`the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events
`were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.
`
`Use INLYTA with caution in patients who are at risk for, or who have a history of, these events.
`INLYTA has not been studied in patients who had a venous thromboembolic event within the
`previous 6 months.
`
`
`5.4 Hemorrhage
`In a controlled clinical study with INLYTA for the treatment of patients with 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 (1%) patients receiving
`INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal
`hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was
`reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients
`(1%) receiving sorafenib.
`
`INLYTA has not been studied in patients who have evidence of untreated brain metastasis or
`recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding
`
`requires medical intervention, temporarily interrupt the INLYTA dose.
`
`5.5 Gastrointestinal Perforation and Fistula Formation
`
`In a controlled clinical study with INLYTA for the treatment of patients with RCC,
`gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of
`the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was
`reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal
`perforation, fistulas were reported in 4/715 patients (1%).
`
`Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment
`with INLYTA.
`
`
`
`Reference ID: 3078397
`
`4
`
`
`

`

`
`
` Thyroid Dysfunction
`5.6
`
`In a controlled clinical study with INLYTA for the treatment of patients with RCC,
`hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients
`(8%) receiving sorafenib. 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 (6.1)].
`
`Monitor thyroid function before initiation of, and periodically throughout, treatment with
`INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to
`maintain euthyroid state.
`
`5.7 Wound Healing Complications
`No formal studies of the effect of INLYTA on wound healing have been conducted.
`
`Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume
`
`INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.
`
`
`Reversible Posterior Leukoencephalopathy Syndrome
`5.8
`In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible
`posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving
`INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. There were
`two additional reports of RPLS in other clinical trials with INLYTA.
`
`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. Discontinue
`
`INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients
`previously experiencing RPLS is not known.
`
`5.9
`Proteinuria
`
`In a controlled clinical study with INLYTA for the treatment of patients with 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 (6.1)].
`
`Monitoring for proteinuria before initiation of, and periodically throughout, treatment with
`INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the
`dose or temporarily interrupt INLYTA treatment.
`
`5.10 Elevation of Liver Enzymes
`In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine
`aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with
`Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm.
`Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically
`throughout treatment with INLYTA.
`
`
`
`Reference ID: 3078397
`
`5
`
`
`

`

`
`
`5.11 Hepatic Impairment
`The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment
`(Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is
`recommended when administering INLYTA 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) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and
`Clinical Pharmacology (12.3)].
`
`
`5.12 Pregnancy
`INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism
`
`of action. There are no adequate and well-controlled studies in pregnant women using INLYTA.
`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.
`
`Women of childbearing potential should be advised to avoid becoming pregnant while receiving
`INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving
`this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific
`Populations (8.1)].
`
`
`6
`ADVERSE REACTIONS
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in clinical practice.
`The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which
`included 537 patients with advanced RCC. The data described [see Adverse Reactions (6.1)]
`
`reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a
`randomized clinical study versus sorafenib [see Clinical Studies (14)].
`
`
`The following risks, including appropriate action to be taken, are discussed in greater detail in
`other sections of the label [see Warnings and Precautions (5.1-5.10 and 5.12)]: hypertension,
`arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal
`perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS,
`proteinuria, elevation of liver enzymes, and fetal development.
`
`Clinical Trials Experience
`6.1
`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 reaction occurred in 199/359
`patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent
`discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA
`and 46/355 patients (13%) receiving sorafenib.
`
`The most common (≥20%) adverse reactions observed following treatment with INLYTA were
`diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar
`
`
`
`Reference ID: 3078397
`
`6
`
`
`

`

`
`
`erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.
`Table 1 presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.
`
`Table 1. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or
`Sorafenib
`
`
`
`INLYTA
`(N=359)
`All
`Grade
`Gradesb
`
`
`3/4
`%
`%
`11
`55
`
`
`16
`40
`
`
`11
`39
`
`
`5
`34
`32
`3
`
`31
`0
`
`27
`5
`25
`2
`24
`3
`
`21
`5
`
`20
`1
`
`19
`<1
`
`15
`1
`
`15
`1
`
`15
`2
`
`15
`1
`15
`3
`
`14
`2
`
`14
`1
`
`13
`1
`13
`<1
`
`11
`3
`
`11
`0
`10
`0
`
`10
`0
`7
`0
`4
`0
`2
`0
`
`Sorafenib
`(N=355)
`All
`Grade
`Gradesb
`
`
`3/4
`%
`%
`53
`7
`
`29
`11
`
`
`32
`5
`
`29
`4
`22
`1
`
`14
`0
`
`51
`16
`21
`1
`17
`1
`
`14
`3
`
`20
`1
`
`8
`0
`17
`1
`
`12
`1
`
`11
`1
`
`12
`<1
`12
`3
`
`11
`1
`
`11
`0
`
`14
`1
`32
`4
`
`7
`2
`8
`0
`11
`
`0
`2
`0
`12
`0
`
`32
`0
`
`10
`<1
`
`
`
`
`Adverse Reactiona
`
`Diarrhea
`Hypertension
`
`Fatigue
`Decreased appetite
`Nausea
`Dysphonia
`
`Palmar-plantar erythrodysesthesia syndrome
`
`Weight decreased
`
`Vomiting
`Asthenia
`Constipation
`
`Hypothyroidism
`Cough
`
`Mucosal inflammation
`
`Arthralgia
`Stomatitis
`Dyspnea
`
`Abdominal pain
`Headache
`Pain in extremity
`Rash
`
`Proteinuria
`Dysgeusia
`Dry skin
`
`Dyspepsia
`Pruritus
`Alopecia
`Erythema
`a Percentages are treatment-emergent, all-causality events
`b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
`
`
`Selected adverse reactions (all grades) that were reported in <10% of patients treated with
`INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%),
`
` epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased
`(3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein
`
`
`
`Reference ID: 3078397
`
`
`7
`
`
`

`

`
`
`thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic
`attack (1%), and RPLS (<1%).
`
`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
`
`Laboratory
`Abnormality
`
`
`
`
`N
`
`
`
`N
`
`Sorafenib
`INLYTA
`All
`Grade
`Grade
`All
`Gradesa
`Gradesa
`
`
`3/4
`3/4
`
`
`%
`
`%
`%
`%
`Hematology
`
`
`
`
`
`
`
`Hemoglobin decreased
`4
`52
`316
`<1
`35
`320
`
`
`
`
`
`Lymphocytes (absolute) decreased
`36
`4
`309
`33
`3
`317
`
`
`
`
`Platelets decreased
`14
`0
`310
`15
`<1
`312
`
`White blood cells decreased
`16
`<1
`315
`11
`0
`320
`
`
`
`
`Chemistry
`
`
`
`
`
`
`
`Creatinine increased
`41
`<1
`318
`55
`0
`336
`
`
`
`
`Bicarbonate decreased
`43
`0
`291
`44
`<1
`314
`Hypocalcemia
`59
`2
`319
`39
`1
`336
`
`
`
`
`ALP increased
`34
`1
`319
`30
`1
`336
`
`
`
`
`Hyperglycemia
`23
`2
`319
`28
`2
`336
`
`
`
`
`Lipase increased
`46
`15
`319
`27
`5
`338
`Amylase increased
`33
`2
`319
`25
`338
`2
`
`ALT increased
`22
`2
`313
`22
`331
`<1
`
`
`
`
`
`AST increased
`25
`1
`311
`20
`331
`<1
`
`
`
`
`
`Hypernatremia
`13
`1
`319
`17
`338
`1
`
`
`
`
`Hypoalbuminemia
`18
`1
`319
`15
`337
`<1
`
`
`
`
`Hyperkalemia
`10
`3
`314
`15
`333
`3
`
`
`
`
`Hypoglycemia
`11
`336
`<1
`8
`<1
`
` 319
`
`
`Hyponatremia
`11
`319
`13
`338
`4
`2
`
`
`
`
`Hypophosphatemia
`49
`318
`13
`336
`16
`2
`
`
`
`
`
` a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
`
`ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase
`
` Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with
`
`INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA
`versus 1% for sorafenib).
`
`
`7
`DRUG INTERACTIONS
`In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent,
`CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.
`
`
`
`CYP3A4/5 Inhibitors
`7.1
`
`Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma
`exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5
`
`
`
`Reference ID: 3078397
`
`
`8
`
`
`

`

`
`
`inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma
`concentrations and should be avoided. Selection of concomitant medication with no or minimal
`CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co­
`administered, the INLYTA dose should be reduced [see Dosage and Administration (2.2) and
`Clinical Pharmacology (12.3)].
`
`
`CYP3A4/5 Inducers
`7.2
`Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of
`axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers
`(e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital,
`and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal
`CYP3A4/5 induction potential is recommended [see Dosage and Administration (2.2) and
`Clinical Pharmacology (12.3)]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz,
`etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should
`be avoided if possible.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category D [see Warnings and Precautions (5.12)].
`There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA
`can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
`Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human
`exposures at the recommended starting dose. If this drug is used during pregnancy, or if the
`patient becomes pregnant while receiving this drug, the patient should be apprised of the potential
`hazard to the fetus.
`Oral axitinib administered twice daily to female mice prior to mating and through the first week
`of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose,
`approximately 10 times the systemic exposure (AUC) in patients at the recommended starting
`dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of
`0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-
`fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at
`1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose)
`and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in
`patients at the recommended starting dose).
`
`Nursing Mothers
`8.3
`It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in
`human milk and because of the potential for serious adverse reactions in nursing infants from
`
`INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug,
`taking into account the importance of the drug to the mother.
`
`
`Pediatric Use
`8.4
`The safety and efficacy of INLYTA in pediatric patients have not been studied.
`
`9
`
`
`
`
`Reference ID: 3078397
`
`

`

`
`
`Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib
`twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice
`and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure
`(AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth
`(including dental caries, malocclusions and broken and/or missing teeth) were observed in mice
`administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in
`patients at the recommended starting dose). Other toxicities of potential concern to pediatric
`patients have not been evaluated in juvenile animals.
`
`8.5 Geriatric Use
`In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359
`patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some
`
`older individuals cannot be ruled out, no overall differences were observed in the safety and
`effectiveness of INLYTA between patients who were ≥65 years of age and younger.
`
`No dosage adjustment is required in elderly patients [see Dosage and Administration (2.2) and
`Clinical Pharmacology (12.3)].
`
`8.6 Hepatic Impairment
`In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function,
`systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild
`hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic
`impairment (Child-Pugh class B).
`
`No starting dose adjustment is required when administering INLYTA to patients with mild
`hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when
`administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B) [see
`Dosage and Administration (2.2), Warnings and Precautions (5.11), and Clinical Pharmacology
`(12.3)].
`INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).
`
`Renal Impairment
`8.7
`No dedicated renal impairment trial for axitinib has been conducted. Based on the population
`pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients
`
`with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89
`mL/min) [see Clinical Pharmacology (12.3)]. No starting dose adjustment is needed for patients
`with pre-existing mild to severe renal impairment. Caution should be used in patients with end-
`stage renal disease (CLcr <15 mL/min).
`
`OVERDOSAGE
`10
`There is no specific treatment for INLYTA overdose.
`
`In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient
`inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade
`1).
`
`
`
`
`Reference ID: 3078397
`
`
`
` 10
`
`
`

`

`
`
` In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg
`
`twice daily or 20 mg twice daily experienced adverse reactions which included hypertension,
`seizures associated with hypertension, and fatal hemoptysis.
`
`In cases of suspected overdose, INLYTA should be withheld and supportive care instituted.
`
`DESCRIPTION
`11
`INLYTA (axitinib) is a kinase inhibitor. Axitinib has the chemical name N-methyl-2-[3-((E)­
`
`2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. The molecular formula is C22H18N4OS
`and the molecular weight is 386.47 Daltons. The chemical structure is:
`
`
`
`
`
`Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous
`media over the range pH 1.1 to pH 7.8 is in excess of 0.2 μg/mL. The partition coefficient (n­
`octanol/water) is 3.5.
`INLYTA is supplied as red, film-coated tablets containing either 1 mg or 5 mg of axitinib
`together with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium,
`magnesium stearate, and Opadry® II red 32K15441 as inactive ingredients. The Opadry II red
` 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium
`
`
` dioxide, triacetin (glycerol triacetate), and red iron oxide.
`
`12
`
`
`
` CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`Axitinib has been sh