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----------------------­
`
`
`
`Warnings and Precautions, Cardiac Failure (5.5)
`08/2014
`
`
`---------------------------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*
`
`
`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
`
`
`Reference ID: 3603361
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`Cardiac failure has been observed and can be fatal. Monitor for
`
`signs or symptoms of cardiac failure throughout treatment with
`
`INLYTA. (5.5)
`
`
`
`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 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. (5.13, 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
`
`
`
`
`Revised: 08/2014
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`CYP3A4/5 Inhibitors
`7.1
`
`
`
`7.2
`CYP3A4/5 Inducers
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`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
`
`
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`
`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
`Cardiac Failure
`
`

`

`
`
`
`
`17.5 Gastrointestinal Disorders
`
`
`17.6 Abnormal Thyroid Function
`
`
`
`17.7 Wound Healing Complications
`
`
`
`17.8
`Reversible Posterior Leukoencephalopathy Syndrome
`
`
`17.9
`Pregnancy
`
`
`17.10 Concomitant Medications
`
`*Sections or subsections omitted from the Full Prescribing Information
`
`are not listed.
`
`
`Reference ID: 3603361
`
`
`2
`
`

`

`
`
`
`
`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 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, 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)].
`
`
`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.
`
`
`
`
`
`Reference ID: 3603361
`
`
`
` 3
`
`

`

`CONTRAINDICATIONS
`
`None
`
`
`
`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.
`
`
`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.
`
`
`
`
`
`Reference ID: 3603361
`
`
`4
`
`

`

`
`
`
`
`
`
`
` 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.
`
`
` Cardiac Failure
`
`
`
` 5.5
`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 resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in
`
`
`
`
`
`Reference ID: 3603361
`
`
`5
`
`

`

`
`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
`
`
`
`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)].
`
`
`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 (5.1-5.13)]: 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.
`
`
`
`
`
`
`
`Reference ID: 3603361
`
`
`6
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1
`
`
` Clinical Trials Experience
`
`
`
` 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 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=355)
`
` (N=359)
`Adverse Reactiona
`
` Grade 3/4 All Gradesb Grade 3/4
`
` All Gradesb
`
`
`
`
`
` %
` %
` %
` %
` 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: 3603361
`
`
`7
`
`
`
`

`

`
`
`
`
` 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
`
`
` Sorafenib
`
`
` INLYTA
` Laboratory
`
`
`
` All Gradesa Grade 3/4
` All Gradesa Grade 3/4
`
`
`
` Abnormality
`
`
`
` N
`N
`
` %
`
` %
`
`
` %
` %
`
`
`
`
`
`
` Hematology
`
` Hemoglobin decreased
`
`
`
` 52
` 4
`
` 316
`
` 35
` <1
`
` 320
` Lymphocytes (absolute) decreased
`
` 4
`
` 36
`
` 309
`
` 33
`
`
` 317
` 3
`
` 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
` <1
`
` 44
`
` 314
`
` Hypocalcemia
`
` 59
`
` 2
`
` 319
`
` 1
`
` 39
`
` 336
`
` ALP increased
`
` 34
`
` 1
`
` 319
`
` 1
`
` 30
`
` 336
` Hyperglycemia
`
`
` 23
`
` 2
`
` 319
`
` 2
`
` 28
`
` 336
` Lipase increased
`
`
`
` 46
` 15
`
` 319
`
` 5
`
` 27
`
` 338
`
` Amylase increased
`
` 33
`
` 2
`
` 319
`
` 2
`
` 25
`
` 338
`
` ALT increased
`
` 22
`
` 2
`
` 313
`
` <1
`
` 22
`
` 331
`
` AST increased
`
` 25
`
` 1
`
` 311
`
` <1
`
` 20
`
` 331
`
` Hypernatremia
`
` 13
`
` 1
`
` 319
`
`
` 17
`
` 338
` 1
`
` Hypoalbuminemia
`
` 18
`
` 1
`
` 319
` <1
`
` 15
`
` 337
`
` Hyperkalemia
`
` 10
`
` 3
`
` 314
`
`
` 15
`
` 333
` 3
`
` Hypoglycemia
`
` <1
`
`
` 319
` <1
`
` 11
`
` 336
` 8
`
` Hyponatremia
`
` 11
`
`
` 319
`
` 4
`
` 13
`
` 338
` 2
` Hypophosphatemia
`
` 49
` 16
`
` 318
`
` 2
`
` 13
`
` 336
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3603361
`
`
`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.
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8
`8.1
`Pregnancy
`
`
`
`Pregnancy Category D [see Warnings and Precautions (5.13)].
`
`
`
`
`
`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).
`
`
`8.3
`Nursing Mothers
`
`
`
`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.
`
`
`
`
`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
`
`
`
`
`
`
`
`
`Reference ID: 360336