Axitinib

Uses

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

Axitinib is also used to associated treatment for these conditions: Severe Aplastic Anemia (SAA), Advanced Thyroid cancer, Refractory Aplastic anemia

How Axitinib works

Axitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3.

Dosage

Axitinib dosage

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), arenormotensive, and are not receiving anti-hypertensionmedication, 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.

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%).

Toxicity

Some of the more serious toxic effects seen in patients taking axitinib include, but are not limited to, hypertension, thrombotic events, hemorrhage, and GI perforation.

Precaution

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.

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.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of axitinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of axitinib.
• Take with a full glass of water.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of axitinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients treated with axitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Axitinib may be administered with or without food.

Axitinib Hypertension interaction

[Moderate] The use of axitinib may causes hypertension.

Blood pressure should be well-controlled prior to initiating axitinib and treated as needed with standard anti-hypertensive therapy.

It is recommended to reduce the dose in case of persistent hypertension despite use of anti-hypertensive medications and to discontinue therapy if hypertension is severe and persistent despite these measures.

Discontinuation of therapy should be considered if there is evidence of hypertensive crisis.

Close monitoring is recommended.

Axitinib Drug Interaction

Minor: esomeprazoleUnknown: aripiprazole, paclitaxel protein-bound, fentanyl, fentanyl, charcoal, doxorubicin, albumin human, aspirin, diphenhydramine, rosuvastatin, hydromorphone, fentanyl, sodium iodide, levetiracetam, fenofibrate, morphine, oxycodone, acetaminophen, cholecalciferol

Axitinib Disease Interaction

Major: hemorrhagic eventsModerate: cardiac failure, GI perforation, hepatic impairment, hypertension, proteinuria, renal impairment, RPL syndrome, thromboembolism, thyroid dysfunction, lung toxicity

Volume of Distribution

The volume of distribution is 160 L.

Elimination Route

After one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration.

Half Life

Axitinib has a half life of 2.5 to 6.1 hours.

Clearance

The average clearance of axitinib is 38 L/h.

Elimination Route

Axitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are metabolites.

Pregnancy & Breastfeeding use

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.

Special Warning

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

Acute Overdose

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 Condition

Store at 20°C to 25°C

Innovators Monograph

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