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Axitinib

Pronunciation

(ax I ti nib)

Index Terms

  • AG-013736

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Inlyta: 1 mg, 5 mg

Brand Names: U.S.

  • Inlyta

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Axitinib is a selective second generation tyrosine kinase inhibitor which blocks angiogenesis and tumor growth by inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3).

Absorption

Rapid (Rugo, 2005)

Distribution

Vd: 160 L

Metabolism

Hepatic; primarily via CYP3A4/5 and to a lesser extend via CYP1A2, CYP2C19 and UGT1A1

Excretion

Feces (~41%; 12% as unchanged drug); urine (~23%; as metabolites)

Time to Peak

2.5 to 4 hours

Half-Life Elimination

2.5 to 6.1 hours

Protein Binding

>99%; to albumin (primarily) and to alpha1 acid glycoprotein (AAG)

Special Populations: Hepatic Function Impairment

Systemic exposure was higher in subjects with moderate impairment (Child-Pugh class B).

Use: Labeled Indications

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

Contraindications

There are no contraindications listed within the manufacturer’s labeling.

Dosing: Adult

Renal cell cancer, advanced: Oral: Initial: 5 mg twice daily (approximately every 12 hours)

Dose increases: If dose is tolerated (no adverse events above grade 2, blood pressure is normal and no antihypertensive use) for at least 2 consecutive weeks, may increase the dose to 7 mg twice daily, and then further increase (using the same tolerance criteria) to 10 mg twice daily.

Dose decreases: For adverse events, reduce dose from 5 mg twice daily to 3 mg twice daily; further reduce to 2 mg twice daily if adverse events persist.

Dosage adjustment for strong CYP3A4 inhibitors: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, telithromycin, voriconazole, grapefruit juice); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, ~50% dosage reduction is recommended; adjust dose based on individual tolerance and safety. When the strong CYP3A4 inhibitor is discontinued, resume previous axitinib dose after 3-5 half-lives of the inhibitor have passed.

Thyroid cancer, differentiated, advanced (off-label use): Oral: Initial: 5 mg twice daily on an empty stomach; increase or decrease dose in 20% increments based on response or toxicity; continue until disease progression or unacceptable toxicity (Cohen 2014) or Initial: 5 mg twice daily with food; if tolerated for 2 consecutive weeks, may increase to 7 mg twice daily, and then to 10 mg twice daily (unless receiving antihypertensive medication or blood pressure >150/90 mm Hg); for grade 3 or higher toxicity, interrupt therapy and/or reduce dose to 3 mg twice daily, if further dose reduction necessary, reduce to 2 mg twice daily; continue until disease progression or unacceptable toxicity (Locati 2014).

Dosing: Geriatric

Refer to adult dosing. No adjustment necessary.

Dosing: Renal Impairment

Mild to severe renal impairment (CrCl 15 to <89 mL/minute): No initial dosage adjustment necessary.

End-stage renal disease (ESRD): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No starting dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Reduce starting dose by ~50%; increase or decrease based on individual tolerance.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Adverse events: May require temporary interruption, dose decreases (reduce dose from 5 mg twice daily to 3 mg twice daily; further reduce to 2 mg twice daily) or discontinuation

Cardiac failure: May require permanent discontinuation

Hypertension: Treat with standard antihypertensive therapy.

Persistent hypertension: May require dose reduction

Severe, persistent (despite antihypertensives and dose reduction), or evidence of hypertensive crisis: Discontinue treatment

Hemorrhage: Any bleeding requiring medical intervention: Temporarily interrupt treatment.

Proteinuria (moderate-to-severe): Reduce dose or temporarily interrupt treatment.

Extemporaneously Prepared

Hazardous agent – use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). When manipulating tablets, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

For patients unable to swallow tablets whole, a suspension may be prepared for nasogastric tube administration (for doses of 2 to 10 mg). Place a 20 mL tightly capped amber syringe in a small drinking glass, with the open end of the syringe pointing up. Place the appropriate axitinib dose in the open syringe barrel; add 15 mL of USP grade water (do not use tap water or bottled water) to the syringe. Allow at least 10 minutes to dissolve the tablets; avoid direct light. Place the plunger of the syringe into the barrel, invert the syringe so the tip is pointing upward and remove the cap. Expel excess air; replace the cap until ready for use (keep syringe tip facing up). Prior to administration, gently invert the syringe several times to ensure a uniform suspension. Flush the nasogastric feeding tube with 15 mL of USP grade water before administration. After administering the dose, draw up 10 mL of USP grade water (into the same syringe which contained the dose) and flush the feeding tube; repeat this step 5 additional times to ensure the entire dose has been administered. Lastly, flush the feeding tube with a separate syringe containing 15 mL of USP grade water. Administer within 15 minutes of preparation.

Borst DL, Arruda LS, MacLean E, Pithavala YK, Morgado JE. Common questions regarding clinical use of axitinib in advanced renal cell carcinoma. Am J Health Syst Pharm. 2014;71(13):1092-1096.

Administration

Oral: Swallow tablet whole with a glass of water. May be taken with or without food. If a dose is missed or vomited, do not make up; resume dosing with the next scheduled dose. A suspension may be prepared for nasogastric administration (refer to Extemporaneously Prepared information).

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of an intact tablet. Although the manufacturer recommends swallowing whole, if it is necessary to manipulate the tablets (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Storage

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).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Axitinib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Axitinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Axitinib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Axitinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (40%; grades 3/4: 16%)

Central nervous system: Fatigue (39%), voice disorder (31%), headache (14%)

Dermatologic: Palmar-plantar erythrodysesthesia (27%; grades 3/4: 5%), skin rash (13%; grades 3/4: <1%)

Endocrine & metabolic: Decreased serum bicarbonate (44%), hypocalcemia (39%), hyperglycemia (28%), weight loss (25%), hypothyroidism (19%; grades 3/4: <1%), hypernatremia (17%), hyperkalemia (15%), hypoalbuminemia (15%), hyponatremia (13%), hypophosphatemia (13%), hypoglycemia (11%)

Gastrointestinal: Diarrhea (55%; grades 3/4: 11%), decreased appetite (34%), nausea (32%; grades 3/4: 3%), increased serum lipase (3% to 27%), increased serum amylase (25%), vomiting (24%; grades 3/4: 3%), constipation (20%), mucosal inflammation (15%), stomatitis (15%), abdominal pain (8% to 14%), dysgeusia (11%)

Genitourinary: Proteinuria (11%; grade 3: 3%)

Hematologic and Oncologic: Anemia (4% to 35%; grades 3/4: <1%), lymphocytopenia (33%; grades 3/4: 3%), hemorrhage (16%; grades 3/4 1%), thrombocytopenia (15%; grades 3/4: <1%), leukopenia (11%)

Hepatic: Increased serum alkaline phosphatase (30%), increased serum ALT (22%; grades 3/4: <1%), increased serum AST (20%; grades 3/4: <1%)

Neuromuscular & skeletal: Weakness (21%), arthralgia (15%), limb pain (13%)

Renal: Increased serum creatinine (55%)

Respiratory: Cough (15%), dyspnea (15%)

1% to 10%:

Cardiovascular: Venous thrombosis (grades 3/4: 3%), arterial thrombosis (2%; grade 3/4: 1%), pulmonary embolism (2%) deep vein thrombosis (1%), transient ischemic attack (1%), retinal vein occlusion (≤1%), retinal thrombosis (≤1%)

Central nervous system: Dizziness (9%)

Dermatologic: Xeroderma (10%), pruritus (7%), alopecia (4%), erythema (2%)

Endocrine & metabolic: Dehydration (6%), hyperthyroidism (1%)

Gastrointestinal: Dyspepsia (10%), hemorrhoids (4%), gastrointestinal fistula (1%), gastrointestinal perforation (≤1%)

Genitourinary: Hematuria (3%)

Hematologic and Oncologic: Increased hemoglobin (9%), rectal hemorrhage (2%), polycythemia (1%)

Neuromuscular & skeletal: Myalgia (7%)

Otic: Tinnitus (3%)

Respiratory: Epistaxis (6%), hemoptysis (2%)

<1% (Limited to important or life-threatening): Cardiac failure, cerebral hemorrhage, cerebrovascular accident, fever, hypertensive crisis, neutropenia, reversible posterior leukoencephalopathy syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac effects: Cardiac failure, including fatal events, has been observed rarely. Monitor for signs/symptoms of cardiac failure throughout therapy; management may require permanent therapy discontinuation.

• Gastrointestinal events: Gastrointestinal perforation and fistulas (including a fatality) have been reported. Monitor for signs/symptoms throughout treatment.

• Hemorrhage: Hemorrhagic events (cerebral hemorrhage, gastrointestinal hemorrhage, hematuria, hemoptysis, and melena) have been reported (with some fatalities). Temporarily interrupt treatment with any hemorrhage requiring medical intervention.

• Hypertension: May cause hypertension; the median onset is within the first month, and has been observed as early as 4 days after treatment initiation. Hypertensive crisis has been reported. Blood pressure should be well-controlled prior to treatment initiation. Monitor blood pressure and treat with standard antihypertensive therapy. Persistent hypertension (despite antihypertensive therapy) may require dose reduction; discontinue if severe and persistent despite concomitant antihypertensives (or dose reduction), or with evidence of hypertensive crisis. Monitor for hypotension if on antihypertensive therapy and axitinib is withheld or discontinued.

• Proteinuria: Proteinuria is associated with use. Monitor for proteinuria at baseline and periodically throughout therapy. If moderate or severe proteinuria occurs, reduce dose or temporarily withhold treatment.

• Reversible posterior leukoencephalopathy syndrome (RPLS): Cases of RPLS have been reported. Symptoms of RPLS include confusion, headache, hypertension (mild-to-severe), lethargy, seizure, blindness and/or other vision or neurologic disturbances; interrupt treatment and manage hypertension. MRI is recommended to confirm RPLS diagnosis. Discontinue axitinib if RPLS is confirmed. The safety of reinitiating axitinib in patients previously experiencing RPLS is unknown.

• Thrombotic events: Arterial thrombotic events (cerebrovascular accident, MI, retinal artery occlusion, and transient ischemic attack), with fatalities, have been reported. Venous thrombotic events, including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis, have been observed (with some fatalities). Use with caution in patients with a history of or risks for arterial or venous thrombotic events; has not been studied in patients within 12 months of an arterial thrombotic event or within 6 months of a venous thrombotic event.

• Thyroid dysfunction: Hypothyroidism occurs commonly with tyrosine kinase inhibitors, including axitinib. Hyperthyroidism has also been reported. Monitor thyroid function at baseline and periodically throughout therapy. Thyroid disorders should be treated according to standard practice to achieve/maintain euthyroid state.

• Wound healing complications: Although the effect on wound healing has not been studied with axitinib, vascular endothelial growth factor (VEGF) receptor inhibitors are associated with impaired wound healing. Discontinue treatment at least 24 hours prior to scheduled surgery; treatment reinitiation should be guided by clinical judgment and wound assessment.

Disease-related concerns:

• Brain metastases: Has not been studied in patients with evidence of untreated brain metastases; use is not recommended.

• Gastrointestinal bleeding: Has not been studied in patients with recent active gastrointestinal bleeding; use is not recommended.

• Hepatic impairment: Systemic exposure to axitinib is increased in patients with moderate impairment (Child-Pugh class B); dose reductions are recommended. Has not been studied in patients with severe impairment (Child-Pugh class C). Increases in ALT have been observed; monitor liver function tests prior to therapy initiation and periodically throughout treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Hepatic function (ALT, AST, and bilirubin; baseline and periodic), thyroid function (baseline and periodic), urinalysis (for proteinuria; baseline and periodically); blood pressure, signs/symptoms of RPLS, gastrointestinal bleeding/perforation/fistula, signs/symptoms cardiac failure

Thyroid function testing recommendations (Hamnvik, 2011):

Preexisting levothyroxine therapy: Obtain baseline TSH levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months

Without preexisting thyroid hormone replacement: TSH at baseline, then monthly for 4 months, then every 2-3 months

Pregnancy Risk Factor

D

Pregnancy Considerations

Teratogenic, embryotoxic, and fetotoxic events were observed in animal reproduction studies when administered in doses less than the normal human dose. Based on its mechanism of action and because axitinib inhibits angiogenesis (a critical component of fetal development), adverse effects on pregnancy would be expected. Women of childbearing potential should be advised to avoid pregnancy during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience change in taste, diarrhea, nausea, vomiting, lack of appetite, mouth irritation, constipation, joint pain, or dry skin. Have patient report immediately to prescriber signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), chest, arm, back, or jaw pain, coughing up blood, confusion, severe headache, severe abdominal pain, severe loss of strength and energy, temperature sensitivity, weight gain or loss, redness or irritations of the palms or soles of feet, muscle pain, muscle cramps, seizures, blindness, change in voice, or hair loss (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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