Inlyta

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Inlyta

Inlyta is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Inlyta 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 [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

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 (5.11), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

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 [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

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

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.

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 [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.

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 [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.

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.

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) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

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

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

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

Adverse Reaction*	Inlyta		Sorafenib
	(N=359)		(N=355)
	All Grades†	Grade 3/4	All Grades†	Grade 3/4
	%	%	%	%
* Percentages are treatment-emergent, all-causality events † National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Diarrhea	55	11	53	7
Hypertension	40	16	29	11
Fatigue	39	11	32	5
Decreased appetite	34	5	29	4
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	8	0
Cough	15	1	17	1
Mucosal inflammation	15	1	12	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	3	7	2
Dysgeusia	11	0	8	0
Dry skin	10	0	11	0
Dyspepsia	10	0	2	0
Pruritus	7	0	12	0
Alopecia	4	0	32	0
Erythema	2	0	10	<1

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 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	Inlyta		N	Sorafenib
		All Grades*	Grade 3/4		All Grades*	Grade 3/4
		%	%		%	%
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase
* National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0
Hematology
Hemoglobin decreased	320	35	<1	316	52	4
Lymphocytes (absolute) decreased	317	33	3	309	36	4
Platelets decreased	312	15	<1	310	14	0
White blood cells decreased	320	11	0	315	16	<1
Chemistry
Creatinine increased	336	55	0	318	41	<1
Bicarbonate decreased	314	44	<1	291	43	0
Hypocalcemia	336	39	1	319	59	2
ALP increased	336	30	1	319	34	1
Hyperglycemia	336	28	2	319	23	2
Lipase increased	338	27	5	319	46	15
Amylase increased	338	25	2	319	33	2
ALT increased	331	22	<1	313	22	2
AST increased	331	20	<1	311	25	1
Hypernatremia	338	17	1	319	13	1
Hypoalbuminemia	337	15	<1	319	18	1
Hyperkalemia	333	15	3	314	10	3
Hypoglycemia	336	11	<1	319	8	<1
Hyponatremia	338	13	4	319	11	2
Hypophosphatemia	336	13	2	318	49	16

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).

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

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 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

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

Pregnancy

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

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

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.

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)].

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

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

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).

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.

Inlyta Description

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.

Inlyta - Clinical Pharmacology

Mechanism of Action

Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

Pharmacodynamics

The effect of a single oral dose of Inlyta (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., >20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., <10 ms) cannot be ruled out.

Pharmacokinetics

The population pharmacokinetic analysis pooled data from 17 trials in healthy subjects and patients with cancer. A two-compartment disposition model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile.

Absorption and Distribution: Following single oral 5-mg dose administration, the median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in approximately 1.4-fold accumulation compared to administration of a single dose. At steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.

Compared to overnight fasting, administration of Inlyta with a moderate fat meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 19% higher AUC. Inlyta can be administered with or without food [see Dosage and Administration (2.1)].

Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) Cmax and AUC0–24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.

Metabolism and Elimination: The plasma half life of Inlyta ranges from 2.5 to 6.1 hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.

The sulfoxide and N-glucuronide metabolites show approximately ≥400-fold less in vitro potency against VEGFR-2 compared to axitinib.

Drug-Drug Interactions

Effects of Other Drugs on Inlyta: Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are presented in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.1, 7.2)].

Figure 1. Impact of Co-administered Drugs and Hepatic Impairment on Axitinib Pharmacokinetics

Effects of Inlyta on Other Drugs: In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.

In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.

Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, Inlyta is not expected to inhibit P-gp at therapeutic plasma concentrations.

Pharmacokinetics in Specific Populations

Pediatric Use: Inlyta has not been studied in patients <18 years of age.

Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1 [see Dosage and Administration (2.2), Warnings and Precautions (5.11), and Use in Specific Populations (8.6)].

Renal Impairment: Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤CLcr <29 mL/min), 64 with moderate renal impairment (30 mL/min ≤CLcr <59 mL/min), and 139 with mild renal impairment (60 mL/min ≤CLcr <89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available [see Use in Specific Populations (8.7)].

Other Intrinsic Factors: Population pharmacokinetic analyses indicate that there are no clinically relevant effects of age, gender, race, body weight, body surface area, UGT1A1 genotype, or CYP2C19 genotype on the clearance of axitinib.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with axitinib.

Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.

Inlyta has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately