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Indications

Axitinib is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Therapeutic Class

Targeted Cancer Therapy

Pharmacology

Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

Dosage & Administration

Recommended Dosing: The recommended starting oral dose of Axitinib is 5 mg twice daily. Administer Axitinib doses approximately 12 hours apart with or without food. Axitinib should be swallowed whole with a glass of water.

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose Modification Guidelines: Dose increase or reduction is recommended based on individual safety and tolerability.

Over the course of treatment, patients who tolerate Axitinib for at least two consecutive weeks with no adverse reactions > Grade 2 (according to the Common Toxicity Criteria for Adverse Events), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the Axitinib dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.

Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of Axitinib therapy. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.

Interaction

In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

CYP3A4/5 Inhibitors: Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of Axitinib with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, the Axitinib dose should be reduced 

CYP3A4/5 Inducers: Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of Axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John's wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.

Contraindications

None

Side Effects

Selected adverse reactions (all grades) that were reported in < 10% of patients treated with Axitinib included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-veinocclusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

Pregnancy & Lactation

Pregnancy Category D. Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using Axitinib. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Axitinib. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

Nursing Mothers: It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Axitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Precautions & Warnings

Patient with HTN, cardiac disease, history of or risk for thrombosis. Patients taking strong CYP3A4 inhibitors. Withhold treatment at least 24 hr prior to scheduled surgery. Moderate hepatic impairment (Child-Pugh Class B). Pregnancy.

Use in Special Populations

Hepatic Impairment: The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering Axitinib to patients with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) 

Renal Impairment: No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤ ClCr < 89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (ClCr< 15 mL/min).

Pediatric Use: The safety and efficacy of axitinib in pediatric patients have not been studied.

Geriatric Use: No dosage adjustment is required in elderly patients

Overdose Effects

There is no specific treatment for Axitinib overdose.

In a controlled clinical study with Axitinib for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).

In a clinical dose finding study with Axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.

In cases of suspected overdose, Axitinib should be withheld and supportive care instituted.

Storage Conditions

Store at 20°C to 25°C