References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
2. Rini BI, Escudier B, Hariharan S, et al. Long-term safety with axitinib in previously treated patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015;13(6):540-547.
mRCC=metastatic renal cell carcinoma; TKI=tyrosine kinase inhibitor.
INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION
Initial U.S. Approval: 2012
Brief Summary of Prescribing Information
INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma
(RCC) after failure of one prior systemic therapy.
DOSAGE AND ADMINISTRATION
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. 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. 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. 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.
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).
DOSAGE FORMS AND STRENGTHS
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.
CONTRAINDICATIONS: None
WARNINGS AND PRECAUTIONS
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.
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.
Arterial Thromboembolic Events. 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.
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. 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.
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. 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.
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. 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.
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.
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. 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. 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.
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.
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.
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.
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).
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.
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 reflect exposure to INLYTA in 359 patients with
advanced RCC who participated in a randomized clinical study versus sorafenib.
The following risks, including appropriate action to be taken, are discussed in greater detail in other
sections of the label: 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. 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.
The following table presents adverse reactions reported in ≥10% patients who received INLYTA
or sorafenib.