Inlyta

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

Take Inlyta exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended starting oral dose of Inlyta is 5 mg twice daily. Take Inlyta doses approximately 12 hours apart with or without food. Inlyta should be swallowed whole with a glass of water.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people taking axitinib have developed a perforation (a hole or tear) or a fistula (an abnormal passageway) within the stomach or intestines. Call your doctor if you have severe stomach pain, or if you feel like you are choking and gagging when you eat or drink.

Also call your doctor at once if you have:

• any unexpected pain or swelling, any wound that will not heal;

• a light-headed feeling, like you might pass out;

• chest pain or pressure, pain spreading to your jaw or shoulder, trouble breathing;

• shortness of breath (even with mild exertion), swelling, rapid weight gain;

• sudden vision loss, headache, confusion, thinking problems, seizure (convulsions);

• easy bruising, unusual bleeding (nosebleeds, bleeding gums), heavy menstrual bleeding, or any other bleeding that will not stop;

• signs of stomach bleeding--severe stomach pain, red or pink urine, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• symptoms of a blood clot--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs;

• signs of a thyroid problem--sudden weight gain or loss, feeling very weak or tired, muscle pain, feeling hot or cold, hair loss, changes in your menstrual periods, hoarse or deepened voice; or

• dangerously high blood pressure-severe headache, blurred vision, buzzing in your ears, anxiety, shortness of breath, uneven heartbeats.

Common side effects may include:

• nausea, vomiting, diarrhea, constipation;

• rash, blisters, oozing, or severe pain in the palms of your hands or the soles of your feet;

• increased blood pressure;

• weakness, tired feeling;

• decreased appetite, weight loss; or

• hoarse voice.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma following failure of one prior systemic therapy.1 2 3 13

In the U.S.

• Inlyta

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Tyrosine Kinase Inhibitor

If you will be taking this medicine for a long time, it is very important that your doctor check you at regular visits for any unwanted effects caused by this medicine. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. This medicine may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Use an effective form of birth control to keep from getting pregnant. Men should use condoms during sexual intercourse. If you think you have become pregnant or your partner has become pregnant while using this medicine, tell your doctor right away.

Your blood pressure should be checked regularly during therapy with this medicine. The symptoms of high blood pressure are blurred vision, dizziness, nervousness, headache, pounding in the ears, or a slow or fast heartbeat.

This medicine may cause serious heart and blood vessel problems. Call your doctor right away if you have chest pain or discomfort, numbness or weakness on one side of your body, pain or discomfort in your arms, jaw, back or neck, shortness of breath, trouble talking, or vision changes.

If you are rapidly gaining weight, having shortness of breath, chest pain or discomfort, extreme tiredness or weakness, irregular breathing, irregular heartbeat, or excessive swelling of the hands, wrist, ankles, or feet, check with your doctor immediately. These may be symptoms of heart problems or your body keeping too much water.

Check with your doctor right away if you have severe stomach burning, cramps, or pains, bloody or black, tarry stools, trouble breathing, heartburn, indigestion, nausea, or vomiting of material that looks like coffee grounds. These could be symptoms of a serious bowel problem.

This medicine may increase your chance of bleeding and cause a delay in wound healing. To help with this problem, stay away from rough sports or other situations where you could be bruised, cut, or injured. Brush and floss your teeth gently. Be careful when using sharp objects, including razors and fingernail clippers.

Make sure any doctor who treats you knows that you are using this medicine. You may need to stop using this medicine at least 24 hours before surgery.

This medicine may increase your chance of having a brain condition called reversible posterior leukoencephalopathy syndrome (RPLS). Check with your doctor right away if you have headaches, seizures, extreme drowsiness, confusion, or problems with vision while you are using this medicine.

This medicine may cause a serious skin problem called hand-foot syndrome. Check with your doctor right away if you have a skin rash or any redness, pain, swelling, or blisters on the palms of your hands or the soles of your feet.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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

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.

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.

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.

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).

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.

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 (5.12), 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.

Inlyta tablets are supplied as follows:

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) [see USP Controlled Room Temperature].

Pfizer

NDC 0069-0145-01

Inlyta®
(axitinib) tablets

1 mg

180 Tablets

Rx only

Inlyta (axitinib) interferes with the growth of some cancer cells.

Inlyta is used to treat advanced kidney cancer.

Inlyta is usually given after other cancer medicine has been tried without success.

Usual Adult Dose for Renal Cell Carcinoma:

5 mg orally twice daily.

If you vomit after taking the medicine, or if you miss a dose, take the medicine at your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Applies to axitinib: oral tablet

General

The most common adverse reactions included diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, decreased weight, vomiting, asthenia, and constipation.[Ref]

Cardiovascular

Very common (10% or more): Hypertension (40%)
Common (1% to 10%): Deep vein thrombosis, cardiac failure events, venous thromboembolic events, arterial thromboembolic events, myocardial infarction
Rare (less than 0.1%): Hypertensive crisis[Ref]

Hypertension has been reported in up to 40% or patients, with grade 3 or 4 hypertension and hypertensive crisis in 16% and less than 1% of those patients, respectively. The median onset time for hypertension was within the first month, with increases observed as early as 4 days after starting the drug. Less than 1% of patients discontinued therapy due to hypertension.

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715) and venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).

Cardiac failure was reported in 2% (6 of 359) patients; grade 3 or 4 in 1% (2 of 359).[Ref]

Nervous system

Very common (10% or more): Headache (15%), dysgeusia (11%)
Common (1% to 10%): Dizziness, transient ischemic attack
Rare (less than 0.1%): Posterior reversible encephalopathy syndrome
Frequency not reported: Cerebrovascular accidents[Ref]

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715).

Three cases of reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome (PRES) were reported during clinical trials.[Ref]

Ocular

Arterial thromboembolic events including transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusions were reported in 2% of patients (17 of 715). Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).[Ref]

Common (1% to 10%): Retinal vein occlusion/thrombosis
Frequency not reported: Retinal artery occlusions[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (55%), nausea (32%), vomiting (24%), constipation (20%), stomatitis (15%), abdominal pain (14%), increased lipase (27%), increased amylase (25%)
Common (1% to 10%): Upper abdominal pain, hemorrhoids, glossodynia, rectal hemorrhage, dyspepsia, flatulence
Uncommon (0.1% to 1%): Gastrointestinal perforation, fistulas
Frequency not reported: Lower gastrointestinal hemorrhage, melena[Ref]

Hepatic

Very common (10% or more): Transaminase increases (20% to 22%), alkaline phosphatase increases (30%), hypoalbuminemia (15%)[Ref]

Renal

Very common (10% or more): Increased creatinine (55%), proteinuria (11%)
Common (1% to 10%): Hematuria, renal failure[Ref]

Other

Very common (10% or more): Fatigue (39%), asthenia (21%),
Common (1% to 10%): Tinnitus[Ref]

Dermatologic

Very common (10% or more): Hand-foot syndrome (27%), rash (13%)
Common (1% to 10%): Pruritus, alopecia, erythema, dry skin[Ref]

Endocrine

Hypothyroidism was reported in 20.9% of patients and hyperthyroidism in 1.1%. Among patients with TSH levels less than 5 micromoles/mL prior to treatment, elevations to greater 10 micromoles/mL occurred in greater than 32.2%[Ref]

Very common (10% or more): Hypothyroidism (20%),
Common (1% to 10%): Hyperthyroidism, increased thyroid stimulating hormone (TSH)[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin (35%), decreased lymphocytes (33%) decreased platelets (15%), WBC decreased (11%)
Common (1% to 10%): Anemia, polycythemia, increased hemoglobin
Uncommon (0.1% to 1%): Neutropenia, leukopenia[Ref]

Metabolic

Very common (10% or more): Decreased appetite (34%), weight loss (25%), decreased bicarbonate (44%), hypocalcemia (39%), hyperglycemia (28%), hypernatremia (17%), hyperkalemia (15%), hypoglycemia (11%), hyponatremia (13%), hypophosphatemia (13%)
Common (1% to 10%): Dehydration[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (15%), extremity pain (14%),
Common (1% to 10%): Myalgia,[Ref]

Respiratory

Very common (10% or more): Dysphonia (31%), cough (15%), mucosal inflammation (15%), dyspnea (15%)
Common (1% to 10%): Epistaxis, pulmonary embolism, hemoptysis[Ref]

Venous thromboembolic events including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, and retinal vein thrombosis were reported in 3% of patients (22 of 715).[Ref]

Some side effects of Inlyta may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.