Dosing & Uses
Dosage Forms & Strengths
tablet
- 1mg
- 5mg
Renal Cell Carcinoma
Monotherapy
- Indicated for advanced renal cell carcinoma (RCC) in patients who failed 1 prior systemic therapy
- 5 mg PO BID initially
Combination therapy with avelumab
- Indicated in combination with avelumab for first-line treatment of advanced RCC
- Axitinib 5 mg PO BID, plus
- Avelumab 800 mg IV q2Weeks
- Continue until disease progression or unacceptable toxicity
- During combination therapy with avelumab, consider escalating dose of axitinib above 5 mg/dose in 2-week intervals or longer
- Refer the prescribing information of avelumab for dosing information
Combination therapy with pembrolizumab
- Indicated in combination with pembrolizumab for first-line treatment of advanced RCC
- Axitinib 5 mg PO BID, plus
- Pembrolizumab 200 mg IV q3Weeks or 400 mg IV q6Weeks
- Continue until disease progression or unacceptable toxicity
- During combination therapy with pembrolizumab, consider escalating dose of axitinib above 5 mg/dose in 6-week intervals or longer
- Refer the prescribing information of pembrolizumab for dosing information
Dosage Modifications
Dose increase or reduction based on individual safety and tolerability
Dose escalation
- Criteria: Tolerated for at least 2 consecutive weeks with no Grade >2 adverse reactions and are normotensive and not receiving antihypertension medications
- First dose increase: 7 mg PO BID
- Second dose increase: Using the same criteria, may further increase to 10 mg PO BID
Dose reduction
- Management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of therapy
- Current dose is 5 mg PO BID: Reduce 3 mg PO BID
- If additional dose reduction is required, reduce to 2 mg PO BID
Strong CYP3A4/5 inhibitors
- Avoid coadministration
- Use an alternative with no CYP3A4/5 inhibition potential
- Although dose adjustment has not been studied, if a strong CYP3A4/5 inhibitor must be coadministered, decrease dose of axitinib by ~50%
- Subsequent doses can be increased or decreased based on individual safety and tolerability
- If strong inhibitor is discontinued, resume axitinib dose (after 3-5 half-lives of the inhibitor) to before initiating the strong CYP3A4/5 inhibitor
Hepatotoxicity (combination with avelumab)
- Refer prescribing information for avelumab for dosage modifications
-
ALT or AST ≥3x to <5x ULN or total bilirubin ≥1.5x ULN but <3x ULN
- Withhold both axitinib and avelumab until these adverse reactions recover to Grade ≤1
- If persistent (>5 days), consider corticosteroid therapy (initial dose of 0.5-1 mg/kg/day) prednisone or equivalent followed by a taper
- Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery
- If rechallenging axitinib, consider dose reduction as listed above
-
ALT or AST ≥5x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN or total bilirubin ≥3x ULN
- Permanently discontinue both axitinib and avelumab
- Consider corticosteroid therapy (initial dose 1-2 mg/kg/day prednisone or equivalent followed by a taper)
-
Hepatotoxicity (combination with pembrolizumab)
- Refer prescribing information for pembrolizumab for dosage modifications
-
ALT or AST ≥3x to <10x ULN without concurrent total bilirubin ≥2x ULN
- Withhold both axitinib and pembrolizumab until these adverse reactions recover to Grade ≤1
- Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery
- If rechallenging axitinib, consider dose reduction as listed above
-
ALT or AST ≥10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN
- Permanently discontinue both axitinib and pembrolizumab
- Consider corticosteroid therapy
Renal & Hepatic Impairment
Renal impairment
- No dedicated renal impairment trial has been conducted
- Based on population pharmacokinetic analyses, no significant difference in clearance observed in patients with pre-existing mild-to-severe renal impairment
Hepatic impairment
- Mild (Child-Pugh A): No adjustment of initial dose is required
- Moderate (Child-Pugh B): Decrease initial dose by ~50%; subsequent doses can be increased or decreased based on individual safety and tolerability
- Severe (Child-Pugh C): Has not been studied
<18 years: Safety and efficacy not established
In clinical trials, 34% of participants 65 years or older
No overall differences were observed in the safety or efficacy between elderly and younger patients
No dosage adjustment required in elderly patients
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Diarrhea (55%)
Hypertension (40%)
Fatigue (39%)
Decreased appetite (34%)
Nausea (32%)
Dysphonia (31%)
Palmar-plantar erythrodysesthesia syndrome (27%)
Weight decreased (25%)
Vomiting (24%)
Asthenia (21%)
Constipation (20%)
Hypothyroidism (19%)
Cough (15%)
Mucosal inflammation (15%)
Arthralgia (15%)
Stomatitis (15%)
Dyspnea (15%)
Abdominal pain (14%)
Headache (14%)
Extremity pain (13%)
Rash (13%)
Proteinuria (11%)
Dysgeusia (11%)
1-10%
Dry skin (10%)
Dyspepsia (10%)
Dizziness (9%)
Upper abdominal pain (8%)
Myalgia (7%)
Pruritus (7%)
Dehydration (6%)
Epistaxis (6%)
Hypercalcemia (6%)
Anemia (4%)
Alopecia (4%)
Hemorrhoids (4%)
Hematuria (3%)
Tinnitus (3%)
Increased lipase (3%)
Glossodynia (3%)
Pulmonary embolism (2%)
Rectal hemorrhage (2%)
Hemoptysis (2%)
Erythema (2%)
DVT (1%)
Retinal vein occlusion/thrombosis (1%)
Polycythemia (1%)
TIA (1%)
<1%
Reversible posterior leukoencephalopathy syndrome
Postmarketing Reports
Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture
Warnings
Contraindications
None
Cautions
Hypertension and hypertensive crisis reported in clinical trials, typically within the first month of treatment; blood pressure increases may appear as early as 4 days after initiating; blood pressure should be well controlled before starting therapy; dosage modification or discontinuation of treatment may be required (see Dosage Modification)
Although rare, arterial thromboembolic events (including deaths) reported during clinical trials
Venous thromboembolic events (eg, DVT, PE, retinal vein occlusion, retinal vein thrombosis) reported, including deaths
Hemorrhagic events (eg, cerebral hemorrhage, hematuria, hemoptysis, GI bleeding, melena) may occur
Rare occurrences of GI perforation and fistula formation reported
May cause thyroid dysfunction; monitor thyroid function before initiating and periodically throughout therapy
Stop treatment 24 hr before scheduled surgery
May cause proteinuria; monitor proteinuria before initiating and periodically throughout therapy
Elevated liver enzymes reported; monitor ALT, AST, and bilirubin
Moderate hepatic impairment requires dose reduction (see Dosage modification)
Coadministration with strong CYP3A4/5 inhibitors or inducers should be avoided if possible (see Dosage modifications)
Cardiac failure reported with axitinib use; monitor for signs or symptoms of cardiac failure throughout treatment; may require permanent discontinuation of axitinib
Impaired wound healing
- Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway
- Therefore axitinib has the potential to adversely affect wound healing
- Withhold for at least 2 days prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing
- Safety of resumption after resolution of wound healing complications has not been established
Major adverse cardiovascular events (MACE)
- Combination therapy with avelumab may cause severe and fatal cardiovascular events
- Consider baseline and periodic evaluations of left ejection fraction; monitor signs and symptoms of cardiovascular events
- Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia
- Discontinue axitinib and avelumab for Grade 3-4 cardiovascular events
In combination with avelumab or with pembrolizumab
- Combination with avelumab or with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation; consider more frequent monitoring of liver enzymes as compared to when drugs are used as monotherapy
- Withhold axitinib and avelumab for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity; administer corticosteroids as needed
- For elevated liver enzymes, interrupt axitinib and pembrolizumab and consider administering corticosteroids as needed
Pregnancy & Lactation
Pregnancy
Based on mechanism of action and findings from animal studies, drug can cause fetal harm when administered to a pregnant woman; there are no available human data to inform drug-associated risk; in developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at recommended clinical dose
When used in combination with avelumab or pembrolizumab, refer to full prescribing information of avelumab or pembrolizumab for pregnancy information
Animal data
- Therapy administered twice daily to female mice prior to mating and through first week of pregnancy caused increase in post-implantation loss at all doses tested (greater than or equal 15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at recommended starting dose)
- Based on findings in animal studies, drug can cause fetal harm when administered to a pregnant woman; females of reproductive potential should have a pregnancy test prior to starting treatment
Contraception
- Females: Therapy can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 1 week after last dose
- Males: Based on findings in animal studies, advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose
- When is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for contraception information
Infertility
- Based on findings in animals, therapy may impair fertility in females and males of reproductive potential
Lactation
There are no data on presence of drug in human milk, or effects on breastfed child or on milk production; because of potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for 2 weeks after final dose
When used in combination with avelumab or pembrolizumab, refer to full prescribing information of avelumab or pembrolizumab for lactation information
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Multi-targeted tyrosine kinase inhibitor
Inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3
Absorption
Bioavailability: 58%
Peak Plasma Time: 2.5-4.1 hr
Peak Plasma Concentration: 27.8 ng/mL
AUC: 265 ng•h/mL
Distribution
Protein Bound: >99% (mostly to albumin, moderately to alpha1-acid glycoprotein)
Vd: 160 L
Metabolism
Metabolized primarily by CYP3A4/5 and to a lesser degree by CYP1A2, CYP2C19, and UGT1A1
Metabolites: Plasma levels detected the N-glucuronide metabolite (50%), sulfoxide metabolite (20%), and 20% unchanged drug
Elimination
Half-life: 2.5-6.1
Total body clearance: 38 L/h
Excretion: feces 41% (12% unchanged), urine 23% (as carboxylic acid and sulfoxide metabolites)
Administration
Oral Administration
Administer twice daily ~12 hr apart
May be taken with or without food
Swallow tablet whole with a glass of water; do not split, crush, or chew
If patient vomits or misses a dose, an additional dose should not be taken; the next prescribed dose should be taken at the usual time
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86°F)
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Patient Handout
Formulary
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