Axitinib

Dosage Forms

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

Tablet, Oral:

Inlyta: 1 mg, 5 mg

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid (Rugo 2005)

Distribution

V_d: 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)

Use in Specific Populations

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.

Use: Off Label

Thyroid cancer (differentiated, advanced)b

Data from a multi-center phase II study in patients with advanced differentiated (papillary, follicular, or Hurthle) thyroid cancer supports the use of axitinib in the management of I¹³¹-refractory disease or in patients who could not receive I¹³¹ Cohen 2014. Data from another multi-center phase II study in advanced thyroid cancer also supports the use of axitinib in the management of I¹³¹-refractory disease Locati 2014.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to axitinib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Renal cell carcinoma, advanced: Oral: Initial: 5 mg twice daily, approximately every 12 hours (Motzer 2013; Rini 2011).

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

Dosage adjustment for surgery: Temporarily stop axitinib at least 24 hours prior to scheduled surgery; resume therapy after surgery based on clinical judgement of adequate wound healing.

Renal cell carcinoma, advanced, previously untreated (off-label combinations):

In combination with pembrolizumab: Initial: 5 mg twice daily; after 6 weeks, if tolerated, may increase to 7 mg twice daily and then may further increase to 10 mg twice daily, or reduce to 3 mg twice daily and then 2 mg twice daily based on adverse events; continue until disease progression or unacceptable toxicity (Rini 2019); refer to protocol for dosage adjustment recommendation details.

In combination with avelumab: Initial: 5 mg twice daily; if tolerated for 2 consecutive weeks, may increase to 7 mg twice daily and then 10 mg twice daily, or reduce to 3 mg twice daily and then 2 mg twice daily based on adverse events; continue until disease progression or unacceptable toxicity (Motzer 2019); refer to protocol for dosage adjustment recommendation details.

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: 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

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).

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 (High risk with Inhibitors). Monitor therapy

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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 increase the serum concentration of Axitinib. 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. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 (High risk with Inducers). 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 & 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 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 & oncologic: Increased hemoglobin (9%), rectal hemorrhage (2%), polycythemia (1%)

Neuromuscular & skeletal: Myalgia (7%)

Ophthalmic: Retinal vein occlusion (≤1%)

Otic: Tinnitus (3%)

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

<1%, postmarketing, and/or case reports: 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.

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. Pregnancy test prior to therapy in females of reproductive potential. Monitor adherence.

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 to 3 months

Pregnancy

Pregnancy Considerations

Based on its mechanism of action and findings from animal reproduction studies, adverse effects on pregnancy would be expected.

Females of reproductive potential should have a pregnancy test prior to therapy; effective contraception should be used during axitinib therapy and for 1 week after the final axitinib dose. Males with female partners of reproductive potential should also use effective contraception during axitinib therapy and for 1 week after the final axitinib dose.

Patient Education

What is this drug used for?

• It is used to treat kidney cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Heartburn
• Change in taste
• Painful extremities
• Diarrhea
• Nausea
• Vomiting
• Weight loss
• Lack of appetite
• Mouth irritation
• Mouth sores
• Muscle pain
• Constipation
• Joint pain
• Cough
• Dry skin

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Bleeding like 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 severe or persistent bleeding
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Thyroid problems like change in weight without trying, anxiety, agitation, feeling very weak, hair thinning, depression, neck swelling, trouble focusing, inability handling heat or cold, menstrual changes, tremors, or sweating
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Heart problems like 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
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Impaired skin wound healing
• Severe abdominal pain
• Severe loss of strength and energy
• Redness or irritation of the palms or soles of feet
• Sore throat
• Chills
• Change in voice
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.