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.

II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.

is indicated for the treatment of adult patients with advanced kidney cancer (ACR) after failure of previous treatment with sunitinib or cytokine.

Specific events should be monitored before initiation of axitinib therapy and periodically throughout the duration of axitinib therapy, as described below.

Cardiac failure events

Cardiac failure events (including heart failure, congestive heart failure, cardiopulmonary failure, left ventricular dysfunction, decrease in right ventricular fraction and impairment) have been reported in clinical studies evaluating axitinib in patients with CCR.

Cardiac failure signs or symptoms should be monitored regularly during treatment with axitinib.

Management of cardiac failure events may require temporary or permanent interruption and/or reduction of the dose of d-axistinib.

Hypertension for axitinib disorder is a high-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level.

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. 12.2 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. 12.3 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.

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 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.

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%) C max and AUC 0–24 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.

Figure 1.

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

Specific Populations Patients with Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1.

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 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.

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.

INLYTA 5 mg was administered in combination with avelumab 10 mg/kg, the respective exposures of INLYTA and avelumab were comparable to the single agents.

There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.

INLYTA 5 mg was administered in combination with pembrolizumab 200 mg, the respective exposures of INLYTA and pembrolizumab were comparable to the single agents.

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Table 1 presents the adverse reactions reported in a group of clinical studies that are axibetic.

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 5 mg orally twice daily with avelumab 800 mg every 2 weeks.

• INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks.

• INLYTA as a single agent the starting dose is 5 mg orally twice daily.

• Dose adjustments can be made based on individual safety and tolerability.

• Administer INLYTA dose approximately 12 hours apart with or without food.

• INLYTA should be swallowed whole with a glass of water.

• See Full Prescribing Information for dosage modifications for adverse reactions.

• If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose by approximately half.

• For patients with moderate hepatic impairment, decrease the starting dose by approximately half. 2.1 Recommended Dosing First-Line Advanced RCC INLYTA in Combination with Avelumab The recommended starting dosage of INLYTA is 5 mg orally taken twice daily (12 hours apart) with or without food in combination with avelumab 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

INLYTA is used in combination with avelumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of two weeks or longer.

Information for recommended avelumab dosing information.

The recommended starting dosage of INLYTA is 5 mg orally twice daily (12 hours apart) with or without food in combination with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

INLYTA is used in combination with pembrolizumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of six weeks or longer.

Information for recommended pembrolizumab dosing information.

INLYTA is used as a single agent, the recommended starting oral dose is 5 mg twice daily.

INLYTA doses approximately 12 hours apart with or without food.

Important Administration Instructions Advise patients to swallow INLYTA whole with a full glass of water.

If the patient vomits or misses a dose, an additional dose should not be taken.

Advise the patient to take the next prescribed dose at the usual time. 2.2 Dose Modification Guidelines Dose increase or reduction is recommended based on individual safety and tolerability.

Recommended INLYTA dosage increases and reductions are provided in Table 1.

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.

Table 1: Recommended Dosage Increases and Reductions for INLYTA Dose Modification Dose Regimen Recommended starting dosage 5 mg twice daily Dosage increase First dose increase 7 mg twice daily Second dose increase 10 mg twice daily Dosage reduction for management of adverse drug reactions First dose reduction from 5 mg twice daily 3 mg twice daily Second dose reduction 2 mg twice daily Recommended dosage modifications for adverse reactions for INLYTA are provided in Table 2.

Table 2: Recommended Dosage Modification for INLYTA for Adverse Reactions Adverse Reaction Severity Dosage Modifications for INLYTA Hypertension SBP >150 mmHg or DBP >100 mmHg despite antihypertensive treatment.

• Reduce dose by one level.

SBP >160 mmHg or DBP >105 mmHg.

• Withhold until BP <150/100 mmHg.

• Resume at a reduced dose.

Grade 4 or hypertensive crisis.

• Permanently discontinue.

Grade 3 or 4.

• Withhold until resolution to Grade 0 or 1 or baseline.

• Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction.

Cardiac failure

Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained).

Clinically manifested congestive heart failure.

Impaired wound healing Any

• The safety of resumption of INLYTA after resolution of wound healing has not been established.

• Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction.

Reversible Posterior Leukoencephalopathy Syndrome Any

Proteinuria 2 or more grams proteinuria per 24 hours.

• Withhold until resolution to less than 2 grams per 24 hours.

Grade 3.

• Reduce dosage by one level.

Grade 4.

• Withhold until resolution to Grade 2.

Table 3 represents additional recommended dosage modifications for adverse reactions when INLYTA is administered in combination with avelumab or pembrolizumab.

Information for additional dosage information for avelumab or pembrolizumab including dose modifications for immune-mediated adverse reactions.

Table 3: Recommended Dosage Modification for Adverse Reactions for INLYTA in Combination with Avelumab or Pembrolizumab Treatment Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal INLYTA in combination with avelumab OR pembrolizumab Liver enzyme elevations Consider corticosteroid therapy ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN.

• Withhold both INLYTA and avelumab or pembrolizumab until resolution to Grades 0–1.

• Consider rechallenge with INLYTA and/or avelumab or pembrolizumab If rechallenging with INLYTA, consider dosage reduction per Table 1.

Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery.

ALT or

AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST at least 10 times ULN.

• Permanently discontinue both INLYTA and avelumab or pembrolizumab Diarrhea Grade 1–2.

• Initiate symptomatic medications.

• Interrupt INLYTA and initiate symptomatic medications.

If diarrhea is controlled, INLYTA may be resumed at either the same dose or reduced by 1 dose level.

• Withhold INLYTA until resolution to Grade <2, then restart INLYTA dose reduced by 1 dose level INLYTA in combination with avelumab Major Adverse Cardiovascular Events (MACE) Grade 3 or 4.

• Permanently discontinue 2.3 Dosage Modification for Drug Interactions 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.

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. 2.4 Dosage Modification for 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).

INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) .

• 1 mg tablets are red film-coated, oval tablets debossed with "Pfizer" on one side and "1 XNB" on the other; available in bottles of 180: NDC 0069-0145-01.

• 5 mg tablets are red film-coated, triangular tablets debossed with "Pfizer" on one side and "5 XNB" on the other; available in bottles of 60: NDC 0069-0151-11.

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

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.

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.

INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy information.

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).

The safety and effectiveness of

INLYTA in pediatric patients have not been established.

INLYTA were assessed, but not established, in two open label studies: a dose finding study of INLYTA as a single agent in 17 pediatric patients aged to <17 years with recurrent or refractory solid tumors (ADVL1315, NCT02164838) and a randomized study of INLYTA as a single agent or in combination in 7 pediatric patients aged to <17 years (AREN1721, NCT03595124).

No new safety signals were observed with INLYTA in pediatric patients across these studies.

Exposure in pediatric patients who received

INLYTA at the maximum tolerated dosage were lower than those previously observed in adults who received the approved recommended starting dosage.

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 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.

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.

Of the 434 patients randomized to INLYTA 5 mg twice daily administered in combination with avelumab 10 mg/kg in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older.

No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger.

Of the 432 patients randomized to INLYTA 5 mg twice daily administered in combination with pembrolizumab 200 mg in the KEYNOTE-426 trial, 40% were 65 years or older.

No dosage adjustment is required in elderly patients.