Version May 2024
Note: Control BP prior to initiation of axitinib. Optimize management of cardiovascular risk factors (eg, diabetes and dyslipidemia). Axitinib dose increases may be considered if dose is tolerated (no adverse events above grade 2, BP is normal, and no antihypertensive use); temporary interruption and/or dose reduction may be required due to adverse reactions. Temporarily withhold axitinib at least 2 days prior to elective surgery; do not administer axitinib for at least 2 weeks following major surgery and until adequate wound healing.
Renal cell carcinoma, advanced, first-line combination therapy:
In combination with pembrolizumab: Note: May be used regardless of risk stratification (Ref). Some experts may prefer axitinib in combination with pembrolizumab for patients with favorable-risk disease who have substantial disease burden; may also be used in patients with intermediate- or poor-risk disease who do not have symptomatic or life-threatening disease burden (eg, involving liver and/or bone) (Ref).
Oral: Initial: 5 mg every 12 hours; if tolerated, at 6-week (or longer) intervals, may increase to 7 mg every 12 hours, and then to 10 mg every 12 hours, or may reduce to 3 mg every 12 hours and then to 2 mg every 12 hours based on adverse events; continue until disease progression or unacceptable toxicity (Ref).
In combination with avelumab: Note: May be used regardless of risk stratification; although may be considered for first-line treatment, other immunotherapy combinations are preferred since this combination has not demonstrated an overall survival benefit in randomized trials (Ref).
Oral: Initial: 5 mg every 12 hours; if tolerated, at 2-week (or longer) intervals, may increase to 7 mg every 12 hours, and then to 10 mg every 12 hours, or may reduce to 3 mg every 12 hours and then to 2 mg every 12 hours based on adverse events; continue until disease progression or unacceptable toxicity (Ref).
Renal cell carcinoma, advanced, second-line single-agent therapy: Note: May be used for patients with progression on other anti-VEGFR therapies who are ineligible for immunotherapy, for those with progression on other molecularly targeted therapies, or for those with progression on prior immunotherapy with or without other anti-VEGFR therapy (Ref).
Oral: Initial: 5 mg every 12 hours; if tolerated, at 2-week (or longer) intervals, may increase to 7 mg every 12 hours, and then to 10 mg every 12 hours, or may reduce to 3 mg every 12 hours and then to 2 mg every 12 hours based on adverse events; continue until disease progression or unacceptable toxicity (Ref).
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 (Ref) 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 BP >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 (Ref).
Missed doses: If a dose is missed or vomited, do not make up; resume dosing with the next scheduled dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function prior to therapy initiation:
CrCl 15 to <89 mL/minute: No initial axitinib dosage adjustment necessary.
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
End-stage renal disease: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Kidney toxicity during treatment:
Proteinuria (≥2 grams proteinuria per 24 hours): Withhold axitinib until resolution to <2 grams per 24 hours, then resume at a reduced dose.
Hepatic impairment prior to therapy initiation:
Mild impairment (Child-Pugh class A): No initial axitinib dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): Reduce axitinib starting dose by ~50%; increase or decrease subsequent doses 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).
Hepatotoxicity during treatment:
Axitinib in combination with avelumab or pembrolizumab: Note: Consider corticosteroid therapy if clinically appropriate.
ALT or AST ≥3 but <10 times ULN without concurrent total bilirubin ≥2 times ULN: Withhold both axitinib and avelumab or pembrolizumab until resolution to grade 0 or 1. After recovery, consider rechallenge with a single drug (axitinib and/or avelumab or pembrolizumab) or sequential rechallenge with both drugs. Refer to avelumab and pembrolizumab monographs for dosage modification information.
ALT or AST >3 times ULN with concurrent total bilirubin ≥2 times ULN or ALT or AST ≥10 times ULN: Permanently discontinue axitinib (and avelumab or pembrolizumab).
Note: Axitinib dose increase or decrease is recommended based on individual safety and tolerability. Refer to avelumab and pembrolizumab monographs for information on adverse reaction management.
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Dose Modification |
Dose |
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a Over the course of treatment, if axitinib is tolerated for ≥2 consecutive weeks with no adverse reactions > grade 2, patients are normotensive, and are not receiving anti-hypertensive medication, the axitinib dose may be increased. | |
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b From 5 mg twice daily. | |
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Recommended starting dosage |
5 mg twice daily |
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Dosage increase | |
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First dose increase |
7 mg twice daily |
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Second dose increase |
10 mg twice daily |
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Dosage reduction for adverse reactions | |
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First dose reductionb |
3 mg twice daily |
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Second dose reduction |
2 mg twice daily |
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Adverse reaction |
Severity |
Axitinib dosage modification |
|---|---|---|
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a If axitinib is discontinued, a drop in BP is expected and antihypertensive therapy should be reduced and/or interrupted as clinically appropriate (ESC [Lyon 2022]). | ||
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Cardiac failure |
Asymptomatic cardiomyopathy (left ventricular ejection fraction >20% but <50% below baseline or below the lower limit of normal if baseline was not obtained. |
Withhold axitinib until resolution to grade 0 or 1 or baseline, then resume at a reduced dose. |
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Symptomatic or clinically manifested heart failure |
Permanently discontinue axitinib. | |
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Hemorrhage |
Grade 3 or 4 |
Withhold axitinib until resolution to grade 0 or 1 or baseline, then either resume at a reduced dose or discontinue, depending on the severity and persistence. |
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Hypertension |
Any |
Manage with standard anti-hypertensive therapy.a |
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Systolic blood pressure (SBP) >150 mm Hg or diastolic blood pressure (DBP) >100 mm Hg despite antihypertensive therapy. |
Reduce axitinib dose by one dose level. | |
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SBP >160 mm Hg or DBP >105 mm Hg |
Withhold axitinib until blood pressure is <150/100 mm Hg, then resume at a reduced dose. | |
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Grade 4 or hypertensive crisis |
Permanently discontinue axitinib. | |
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Reversible posterior leukoencephalopathy syndrome |
Any grade |
Permanently discontinue axitinib. |
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Thromboembolic events |
Arterial |
Permanently discontinue axitinib if an arterial thromboembolic event occurs during therapy. |
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Venous |
Withhold axitinib and then resume at the same dose or permanently discontinue, based on the severity of the event. | |
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Thyroid disorders |
Hypothyroidism or hyperthyroidism |
Manage hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. |
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Wound healing impairment |
Any grade |
Either resume axitinib at a reduced dose or discontinue axitinib, depending on the severity and persistence. |
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Other adverse reactions |
Grade 3 |
Reduce axitinib dose by one dose level. |
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Grade 4 |
Withhold axitinib until resolution to grade 2, then resume at a reduced dose. | |
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Combination regimen |
Adverse reaction |
Severity |
Axitinib dosage modification |
|---|---|---|---|
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Axitinib in combination with avelumab or pembrolizumab |
Diarrhea |
Grade 1 or 2 |
Initiate symptomatic therapy. |
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Grade 3 |
Interrupt axitinib and initiate symptomatic therapy. If diarrhea is controlled, axitinib may be resumed at either the same dose or reduced by one dose level. | ||
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Grade 4 |
Withhold axitinib until resolution to < grade 2, then resume axitinib with the dose reduced by one dose level. | ||
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Axitinib in combination with avelumab |
Major adverse cardiovascular events |
Grade 3 or 4 |
Permanently discontinue axitinib. |
Refer to adult dosing. No adjustment necessary.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Hypertension (40%; hypertensive crisis [<1%])
Dermatologic: Palmar-plantar erythrodysesthesia (27%), skin rash (13%)
Endocrine & metabolic: Decreased serum bicarbonate (44%), hyperglycemia (28%), hyperkalemia (15%), hypernatremia (17%), hypoalbuminemia (15%), hypocalcemia (39%), hypoglycemia (11%), hyponatremia (13%), hypophosphatemia (13%), hypothyroidism (19%), weight loss (25%)
Gastrointestinal: Abdominal pain (14%), constipation (20%), decreased appetite (34%), diarrhea (55%; grades 3/4: 11%), dysgeusia (11%), increased serum amylase (25%), increased serum lipase (3% to 27%), mucosal swelling (15%), nausea (32%; grades 3/4: 3%), stomatitis (15%; grades 3/4: 1%), vomiting (24%; grades 3/4: 3%)
Genitourinary: Proteinuria (11%)
Hematologic & oncologic: Decreased absolute lymphocyte count (33%; grades 3/4: 3%), decreased platelet count (15%; grades 3/4: <1%), decreased white blood cell count (11%), hemorrhage (16%; grades 3/4: 1%; including cerebral hemorrhage, gastrointestinal hemorrhage, hematuria [3%], hemoptysis [2%], and melena)
Hepatic: Increased serum alanine aminotransferase (22%), increased serum alkaline phosphatase (30%), increased serum aspartate aminotransferase (20%)
Nervous system: Asthenia (21%), fatigue (39%), headache (14%), voice disorder (31%)
Neuromuscular & skeletal: Arthralgia (15%), limb pain (13%)
Renal: Increased serum creatinine (55%)
Respiratory: Cough (15%), dyspnea (15%)
1% to 10%:
Cardiovascular: Arterial thrombosis (2%; including acute myocardial infarction, cerebrovascular accident and retinal artery occlusion), heart failure (2%), deep vein thrombosis (1%), pulmonary embolism (2%), retinal thrombosis (≤1%), transient ischemic attacks (1%), venous thrombosis (3%; including retinal vein occlusion [≤1%])
Dermatologic: Alopecia (4%), erythema of skin (2%), pruritus (7%), xeroderma (10%)
Endocrine & metabolic: Dehydration (6%), hypercalcemia (6%), hyperthyroidism (1%)
Gastrointestinal: Dyspepsia (10%), gastrointestinal fistula (1%), gastrointestinal perforation (≤1%), glossalgia (3%), hemorrhoids (4%), rectal hemorrhage (2%), upper abdominal pain (8%)
Hematologic & oncologic: Anemia (4%), increased hemoglobin (9%), polycythemia (1%)
Nervous system: Dizziness (9%)
Neuromuscular & skeletal: Myalgia (7%)
Otic: Tinnitus (3%)
Respiratory: Epistaxis (6%)
<1%: Nervous system: Reversible posterior leukoencephalopathy syndrome
Postmarketing: Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, myocardial rupture (aortic rupture and arterial rupture), coronary artery dissection
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to axitinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiac events: Cardiac failure, including fatal events, has been observed rarely with axitinib monotherapy. Axitinib in combination with avelumab may result in severe and fatal cardiovascular events. Major adverse cardiovascular events (MACE) occurred more frequently in advanced renal cell carcinoma patients receiving the combination of axitinib plus avelumab versus those treated with sunitinib in a clinical trial. Events included grade 3 or 4 myocardial infarction, grade 3 or 4 heart failure, and death due to cardiac events. The median time to MACE onset was ~4 months (range: 2 days to 24.5 months).
• GI events: GI perforation and fistulas (including a fatality) have been reported.
• Hemorrhage: Hemorrhagic events (cerebral hemorrhage, lower GI hemorrhage, hematuria, hemoptysis, and melena) have been reported (with some fatalities).
• Hepatotoxicity: AST and/or ALT elevations have occurred with single-agent axitinib or when used as a part of combination therapy (with avelumab or pembrolizumab), including grade 3 and 4 events. Higher than expected grade 3 and 4 transaminase elevations may occur when axitinib is used as part of combination therapy. In patients receiving combination therapy with avelumab or pembrolizumab who developed ALT ≥3 times ULN, ALT resolved to ≤ grade 1 in over 90% of patients; some patients required corticosteroid therapy. Administer systemic corticosteroids as necessary for hepatotoxicity.
• Hypertension: Axitinib 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. BP should be well-controlled prior to treatment initiation.
• Proteinuria: Proteinuria is associated with axitinib, including grade 3 proteinuria.
• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Symptoms of RPLS include confusion, headache, hypertension (mild to severe), lethargy, seizure, blindness, and/or other vision or neurologic disturbances. MRI is necessary to confirm RPLS diagnosis. 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; axitinib 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 with tyrosine kinase inhibitors, including axitinib. Hyperthyroidism has also been reported. Thyroid disorders should be treated according to standard practice to achieve/maintain euthyroid state.
• Wound healing complications: Vascular endothelial growth factor receptor inhibitors are associated with impaired wound healing; therefore, axitinib may affect wound healing. The safety of resuming axitinib treatment after resolution of wound healing complications has not been established.
Disease-related concerns:
• Brain metastases: Axitinib has not been studied in patients with evidence of untreated brain metastases; use is not recommended.
• GI bleeding: Axitinib has not been studied in patients with recent active GI bleeding; use is not recommended.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Inlyta: 1 mg, 5 mg
No
Tablets (Inlyta Oral)
1 mg (per each): $136.97
5 mg (per each): $410.91
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Inlyta: 1 mg, 5 mg
Available from select specialty pharmacies. Further information may be obtained at 877-744-5675 or www.inlytahcp.com.
Oral: Swallow tablet(s) whole with a full glass of water. May administer with or without food. A suspension may be prepared for NG administration (Ref).
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Renal cell carcinoma, advanced:
First-line treatment (in combination with avelumab or pembrolizumab) of advanced renal cell carcinoma.
Treatment (as a single-agent) of advanced renal cell carcinoma after failure of 1 prior systemic therapy.
Thyroid cancer (differentiated, advanced)
Axitinib may be confused with abemaciclib, acalabrutinib, afatinib, alectinib, alpelisib, apixaban, avapritinib, cabozantinib, gefitinib, imatinib, PAZOPanib, PONATinib, regorafenib, SORAfenib, SUNItinib, vandetanib, vemurafenib
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP3A4 (major), UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Artesunate: Axitinib may increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
Avelumab: Axitinib may enhance the cardiotoxic effect of Avelumab. Axitinib may enhance the hepatotoxic effect of Avelumab. Risk C: 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. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Axitinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Axitinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Axitinib. Risk C: 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. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Axitinib. Risk X: Avoid combination
Pembrolizumab: Axitinib may enhance the hepatotoxic effect of Pembrolizumab. Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Axitinib. Risk X: Avoid combination
Axitinib serum concentrations may be increased when taken with grapefruit or grapefruit juice. Management: Avoid concurrent use.
Evaluate pregnancy status prior to use in patients who could become pregnant; effective contraception should be used during axitinib therapy and for 1 week after the final axitinib dose.
Patients with partners who could become pregnant should also use effective contraception during axitinib therapy and for 1 week after the final axitinib dose.
Based on its mechanism of action and findings from animal reproduction studies, adverse effects on pregnancy would be expected.
It is not known if axitinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during axitinib therapy or for 2 weeks after the final axitinib dose.
Avoid grapefruit and grapefruit juice.
Hepatic function (ALT, AST, and bilirubin; baseline and periodic; consider more frequent monitoring when axitinib is used as part of combination therapy), thyroid function (baseline and periodic), urinalysis (for proteinuria; baseline and periodically). Monitor for signs and symptoms of cardiac failure and other cardiovascular events and optimize management of cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia. Consider baseline and periodic evaluations of left ventricular ejection fraction; monitor BP. Evaluate pregnancy status prior to therapy (in patients who could become pregnant). Monitor for signs/symptoms of GI bleeding/perforation/fistula, hemorrhage, major adverse cardiovascular events (MACE), reversible posterior leukoencephalopathy syndrome, thromboembolic events, and wound healing complications. 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.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). BP at each clinical visit (as well as daily home monitoring for first cycle, after dose increases, and every 2 to 3 weeks thereafter); baseline echocardiography in high- and very high-risk patients (repeat every 3 months during the first year and every 6 to 12 months thereafter); consider baseline echocardiography in low- and moderate-risk patients (consider repeating every 4 months and every 6 to 12 months thereafter during the first year for moderate-risk patients) (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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
Protein binding: >99%; to albumin (primarily) and to alpha1 acid glycoprotein (AAG)
Metabolism: Hepatic; primarily via CYP3A4/5 and to a lesser extend via CYP1A2, CYP2C19 and UGT1A1
Bioavailability: 58%
Half-life elimination: 2.5 to 6.1 hours
Time to peak: 2.5 to 4 hours
Excretion: Feces (~41%; 12% as unchanged drug); urine (~23%; as metabolites)
Hepatic function impairment: Systemic exposure was higher in subjects with moderate impairment (Child-Pugh class B).
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