axitinib (Rx)

>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

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

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

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

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

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.

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)