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
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
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`
`
`
`Warnings and Precautions, Pregnancy (5.13)
`MM/2018
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`
`
`
`
`--------------------------- 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)
`
`
`
`
`
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`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
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`1 mg and 5 mg tablets (3)
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`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`None (4)
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`
`
`
`
`----------------------- 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)
`
`
`
`Cardiac failure has been observed and can be fatal. Monitor for signs or
`
`symptoms of cardiac failure throughout treatment with INLYTA. (5.5)
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`•
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`•
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`•
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`
`•
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`•
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`•
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`•
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`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1
`Recommended Dosing
`
`
`2.2
`Dose Modification Guidelines
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`Hypertension and Hypertensive Crisis
`5.1
`
`
`5.2
`Arterial Thromboembolic Events
`
`
`5.3
`Venous Thromboembolic Events
`
`
`5.4
`Hemorrhage
`
`
`5.5
`Cardiac Failure
`
`
`
`5.6
`Gastrointestinal Perforation and Fistula Formation
`
`
`5.7
`Thyroid Dysfunction
`
`
`
`5.8 Wound Healing Complications
`
`
`
`5.9
`Reversible Posterior Leukoencephalopathy Syndrome
`
`
`5.10
`Proteinuria
`
`
`5.11
`Elevation of Liver Enzymes
`
`
`5.12 Hepatic Impairment
`
`
`5.13
`Pregnancy
`
`
`6 ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`7 DRUG INTERACTIONS
`
`
`CYP3A4/5 Inhibitors
`7.1
`
`Reference ID: 4305235
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`•
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`•
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`•
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`•
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`•
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`•
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`•
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`
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`Gastrointestinal perforation and fistula, including death, have occurred.
`
`
`
`
`
`Use with caution in patients at risk for gastrointestinal perforation or
`
`
`fistula. (5.6)
`
`
`
`
`Hypothyroidism requiring thyroid hormone replacement has been
`
`
`
`
`reported. Monitor thyroid function before initiation of, and periodically
`
`
`
`throughout, treatment with INLYTA. (5.7)
`
`
`
`
`
`
`
`Stop INLYTA at least 24 hours prior to scheduled surgery. (5.8)
`
`
`
`Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been
`
`
`
`
`observed. Permanently discontinue INLYTA if signs or symptoms of
`
`
`RPLS occur. (5.9)
`
`
`
`
`• 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. (5.10)
`
`
`
`
`
`
`Liver enzyme elevation has been observed during treatment with
`
`
`
`
`
`INLYTA. Monitor ALT, AST and bilirubin before initiation of, and
`
`
`
`periodically throughout, treatment with INLYTA. (5.11)
`
`
`
`
`
`
`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, 5.12)
`
`
`
`
`INLYTA can cause fetal harm. Advise patients of the potential risk to
`
`
`
`the fetus and to use effective contraception. (5.13, 8.1, 8.3)
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`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`The most common (≥20%) adverse reactions are diarrhea, hypertension,
`
`
`fatigue, decreased appetite, nausea, dysphonia, palmar-plantar
`
`
`
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`erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting,
`
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`asthenia, and constipation. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at
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`
`
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`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
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`
`
`------------------------------ DRUG INTERACTIONS------------------------------­
`
`
`Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA
`
`•
`
`dose. (2.2, 7.1)
`
`
`Avoid strong CYP3A4/5 inducers. (7.2)
`
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`•
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`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`
`Lactation: Advise not to breastfeed. (8.2)
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`•
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`Females and males of reproductive potential: May impair fertility.
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`•
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`Counsel patients on pregnancy planning and prevention. (8.3)
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`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
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`
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`
`Revised: M/2018
`
`
`
`CYP3A4/5 Inducers
`7.2
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
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`
`8.6
`Hepatic Impairment
`
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`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
`
`
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
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`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`
`listed
`
`

`

`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
` INDICATIONS AND USAGE
`
`
` 1
`
`
` INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior
`
`
` systemic therapy.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`
`2.1
`Recommended Dosing
`
`
`
`
`
`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
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`
`
`
`
`
`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
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`
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`daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.
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`
`
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`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, 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 (5.12), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
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`
`
`Reference ID: 4305235
`
`
`
` 2
`
`

`

`CONTRAINDICATIONS
`
`None
`
`
`
`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
`
`
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`“5 XNB” on the other side.
`
`
`
`4
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`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 (<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.
`
`
`
`
`
`
`3
`
`
`
`Reference ID: 4305235
`
`

`

`
`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
`Cardiac Failure
`
`
`
`In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was
`
`
`
`
`
`
`reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4
`
`
`cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving
`
`
`
`
`sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients
`
`
`
`
`(<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with
`
`
`
`INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.
`
`
`5.6 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.
`
`Thyroid Dysfunction
`5.7
`
`
`
`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.
`
`
`
`5.8 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
`5.9
`
`
`
`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
`
`
`
`
`Reference ID: 4305235
`
`
`4
`
`

`

`
`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.
`
`
`5.10 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.
`
`
`5.11 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.
`
`5.12 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)].
`
`
`5.13 Pregnancy
`
`
`
`Based on its mechanism of action and findings from animal studies, INLYTA can cause fetal harm when
`
`
`
`
`administered to a pregnant woman. There are no available human data to inform the drug-associated risk. 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.
`
`Advise females of reproductive potential of the potential risk to the fetus and to use effective
`
`
`contraception during treatment with INLYTA and for 1 week after the last dose. Advise males with female
`
`partners of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week
`
`
`
`
`
`
`
`
`after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
`
`ADVERSE REACTIONS
`
`
` 6
`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)]: hypertension, arterial thromboembolic events, venous
`
`
`
`thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid
`
`
`dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment
`
`
`
`
`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
`
`
`
`
`
`5
`
`
`
`Reference ID: 4305235
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 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
`
`
`
` Sorafenib
`
`
`
` (N=359)
` (N=355)
`Adverse Reactiona
`
` All Gradesb Grade 3/4 All Gradesb Grade 3/4
`
`
`
`
`
`
` %
` %
` %
` %
` Diarrhea
`
`
` 55
`
` 11
`
` 53
`
` 7
` Hypertension
`
`
` 40
`
` 16
`
` 29
` 11
`
` Fatigue
`
` 39
`
` 11
`
` 32
`
` 5
` Decreased appetite
`
` 34
`
` 29
`
` 4
`
` 5
`
` Nausea
`
` 32
`
` 3
`
` 22
`
` 1
` Dysphonia
`
`
` 31
`
` 0
`
` 14
`
` 0
` Palmar-plantar erythrodysesthesia syndrome
`
`
` 27
`
` 5
`
` 51
` 16
`
`
` Weight decreased
`
` 25
`
` 2
`
` 21
`
` 1
` Vomiting
`
`
` 24
`
` 3
`
` 17
`
` 1
`
` Asthenia
`
` 21
`
` 5
`
` 14
`
` 3
` Constipation
`
`
` 20
`
` 1
`
` 20
`
` 1
` Hypothyroidism
`
`
`
` 19
` <1
`
` 0
`
` 8
`
` Cough
`
`
` 15
` 17
`
` 1
`
` 1
` Mucosal inflammation
`
` 12
`
` 15
`
` 1
`
` 1
`
` Arthralgia
`
` 15
`
` 2
`
` 11
`
` 1
`
` Stomatitis
`
`
` 15
`
` 1
`
` 12
` <1
`
` Dyspnea
`
` 15
`
` 3
`
` 12
`
` 3
` Abdominal pain
`
` 14
`
` 2
`
` 11
`
` 1
`
` Headache
`
` 14
`
` 1
`
` 11
`
` 0
` Pain in extremity
`
`
` 13
`
` 1
`
` 14
`
` 1
`
` Rash
`
`
` 13
` <1
`
` 32
`
` 4
`
` Proteinuria
`
` 11
`
` 2
`
`
` 3
` 7
`
` Dysgeusia
`
` 11
`
` 0
`
` 8
`
` 0
`
` Dry skin
`
`
` 10
`
` 0
` 11
`
` 0
`
` Dyspepsia
`
` 10
`
` 0
`
` 0
`
` 2
`
` Pruritus
`
`
` 0
` 12
`
` 0
`
` 7
` Alopecia
`
` 32
`
` 4
`
` 0
`
` 0
`
`
` 2
`
` 0
`
` 10
` <1
` Erythema
`
`
`
`
`
` a Percentages are treatment-emergent, all-causality events
`
` b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
`
`
`
`
`
`
`Reference ID: 4305235
`
`
`6
`
`

`

`
`
`
`
` 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%), glossodynia (3%), pulmonary
`
`
`
`
` embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein
`
` occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (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
` INLYTA
`
`
`
`
`
` Sorafenib
` Laboratory
`
`
`
` All Gradesa Grade 3/4
` All Gradesa Grade 3/4
`
`
`
`
` N
` Abnormality
`
`N
`
` %
`
`
`
` %
` %
` %
`
`
`
`
`
`
`
` Hematology
`
`
`
`
` 35
` <1
` 316
` 52
` 4
`
` 320
` Hemoglobin decreased
`
`
` 4
`
` 36
`
` 309
`
` 33
`
`
` 317
` Lymphocytes (absolute) decreased
` 3
`
` 15
` <1
`
` 310
`
` 14
`
` 0
`
` 312
`
` Platelets decreased
`
`
` 11
`
` 315
`
` 16
` <1
`
` 0
`
` 320
` White blood cells decreased
`
`
`
`
`
`
`
` Chemistry
`
`
`
`
`
` 55
` 0
` 318
` 41
` <1
`
` 336
` Creatinine increased
`
` <1
`
` 43
`
` 291
`
` 44
`
` 0
`
` 314
`
` Bicarbonate decreased
`
` 1
`
` 39
`
` 319
`
` 59
`
` 2
`
` 336
`
` Hypocalcemia
`
` 1
`
` 30
`
` 319
`
` 34
`
` 1
`
` 336
`
` ALP increased
`
` 2
`
` 28
`
` 319
`
` 23
`
` 2
`
` 336
` Hyperglycemia
`
`
` 5
`
`
` 27
`
` 319
`
` 46
` 15
`
` 338
` Lipase increased
`
`
` 2
`
` 25
`
` 319
`
` 33
`
` 2
`
` 338
`
` Amylase increased
`
` <1
`
` 22
`
` 313
`
` 22
`
` 2
`
` 331
`
` ALT increased
`
` <1
`
` 20
`
` 311
`
` 25
`
` 1
`
` 331
`
` AST increased
`
`
` 17
`
` 319
`
` 13
`
` 1
`
` 338
`
` Hypernatremia
` 1
` <1
`
` 15
`
` 319
`
` 18
`
` 1
`
` 337
`
` Hypoalbuminemia
`
`
` 15
`
` 314
`
` 10
`
` 3
`
` 333
`
` Hyperkalemia
` 3
` <1
`
`
` 11
`
` 319
` <1
`
`
` 336
`
` Hypoglycemia
` 8
`
`
` 4
`
` 13
`
` 319
` 11
`
`
` 338
`
` Hyponatremia
` 2
`
` 49
`
` 2
`
` 13
`
` 318
` 16
`
` 336
`
` Hypophosphatemia
`
` 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) and hypercalcemia (6% for INLYTA versus 2% 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.
`
`
`
`
` 7.1
` CYP3A4/5 Inhibitors
`
`
`
` 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 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
`
`
`
`7
`
`
`
`
`
`Reference ID: 4305235
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` 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, 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.
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`
`8.1
`Pregnancy
`Risk Summary
`
`
`Based on findings in animal studies and its mechanism of action, INLYTA can cause fetal harm when
`
`
`administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In
`
`
`
`developmental toxicity studies, axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower
`
`than human exposures at the recommended starting dose (see Data). Advise females of reproductive potential of
`
`
`
`the potential risk to a fetus.
`
`The background risk of major birth defects and miscarriage for the indicated populations are unknown.
`
`
`
`However, the background risk in the United States (U.S.) general population of major birth defects is 2%-4%
`
`and of miscarriage is 15%-20% of clinically recognized pregnancies.
`
`
`
`Data
`
`
`Animal Data
`
`
`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).
`
`
`8.2
`Lactation
`
`
`
`Risk Summary
`
`
`There are no data on the presence of axitinib in human milk, or its effects on the breastfed child or on
`
`
`
`milk production. Because of the potential for serious adverse reactions in a breastfed child from INLYTA,
`
`
`advise lactating women not to breastfeed during treatment and for 2 weeks after the final dose.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4305235
`
`
`8
`
`

`

`
`
`
`
`
` Females and Males of Reproductive Potential
` 8.3
`
`
` Pregnancy Testing
`Based on findings in animal studies, INLYTA can cause fetal harm when administered to a pregnant
`
`woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test
`
`prior to starting treatment with INLYTA.
`
`
`Contraception
`
`Females
`
`
`INLYTA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations
`
`
`
`
`
`
`(8.1)]. Advise females of reproductive potential to use effective contraception during treatment with INLYTA
`
`and for 1 week after the last dose.
`
`
`Males
`
`
`
`Based on findings in animal studies, advise males with female partners of reproductive potential to use
`
`
`
`
`effective contraception during treatment and for 1 week after the last dose.
`
`Infertility
`
`Females and Males
`
`
`
`Based on fi