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Drug Monographs
Treatment Regimens
Scientific Name:
AXITINIB
Brand Name(s):
Inlyta

Drug Monograph

Pharmacology

Mechanism of Action

Axitinib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. 

Pharmacokinetics

Oral Absorption
Median time to peak concentration = 2.5 to 4.1 hours
Two-compartment disposition model with first-order absorption and lag-time
5 mg daily dose: mean absolute bioavailability is 58%; geometric mean (CV%) Cmax = 27.8 (79%) ng/mL, AUC0-24 = 265 (77%) ng.h/mL,  clearance = 38 (80%) L/h, & apparent volume of distribution = 160 (105%) L
Bioavailability increased by 18% when tablet taken with high fat meal compared to overnight fasting - take with food or on empty stomach
Distribution
Approximately linear pharmacokinetics at steady state (1-mg to 20-mg dose range)- steady state within 2 to 3 days of dosing
PPB: greater than 99% (preferential binding to albumin and moderate binding to α1-acid glycoprotein)
Metabolism
Hepatic metabolism by cytochrome P450 enzymes, by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1
Metabolites: N-glucuronide metabolite (50%), sulfoxide metabolite (20%)
Excretion
Predominately in the feces (41%); also in urine (23%)
t½ plasma = 2.5 to 6.1 hours

Side Effects

IMMEDIATE ONSET (hours to days)
   hypothyroidism (19%)
   Abdominal pain (14%), Headache (14%)
EARLY ONSET  (days to weeks)
* proteinuria (11%- 3% Grade 3)
   diarrhea (55%- 11% grade 3 or 4), or constipation (20%)
   hypertension (40%- 16% grade 3 or 4)
   hand-and-foot syndrome (Palmar-plantar erythrodysaesthesia) (27%)
   nausea (32%), vomiting (24%)
   decreased appetite (34%), fatigue (39%), asthenia (21%)
* hemorrhagic events (16%)- including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and gastrointestinal perforation and fistula
* thromboembolic events (3%)- including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis
   elevated hepatic enzymes (22%)
   wound healing complications
   neurological function consistent with RPLS (Reversible Posterior Leukoencephalopathy Syndrome- headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances)

Therapeutics

Approved Indications

Advanced renal cell carcinoma after failure of one prior systemic therapy

Routes

Oral

Administration

PO twice daily with or without food

Dosing

Oral:
• 5 mg  PO twice daily with or without food.

Dose Adjustment Criteria

Hepatic dysfunction:  (Recommended action)
• Mild hepatic impairment (Child-Pugh class A)- no dosage reduction
• Moderate hepatic impairment (Child-Pugh class B)- 50% dosage reduction (2-3 mg twice daily)
• Severe hepatic impairment (Child-Pugh class C)- Hold Axitinib

Contraindications

None

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Baseline & periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels ]
Blood pressure measurement every 2-3 weeks (or at each visit)
• Baseline & periodic thyroid function tests
• Clinical examination of any wounds, abdominal exam at each visit
Urine protein levels before each cycle of treatment
SUGGESTED CRITERIA
• Observe patients for shortness of breath. chest pain, swelling of arms or legs, or other symptoms of DVT or PE

Significant Interactions

• CYP3A4 Inhibitors: Avoid use of strong inhibitors. Consider dose reduction of axitinib when administered with strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice, ritonavir, clarithromycin). • CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid axitinib (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort). • 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.

Product Information

Commercial Product Description

Brand Name: InlytaTM 1 mg & 5 mg tablets

Pharmaceutical Considerations

Tablets: 1 mg and 5 mg tablets - red film-coated, oval (1 mg) or triangular (5 mg) tablets
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

Note

Guidelines:
Metastatic Renal Cell Carcinoma
pCODR Recommendation:  Axitinib as a second line treatment for patients with metastatic renal cell carcinoma who, based on the mutual assessment of the treating physician and the patient, are unable to tolerate ongoing use of an effective doseof everolimus or who have a contraindication to everolimus.  Use in a broader patient population was not recommended because there is too much uncertainty that the effectiveness of axitininb is similar to everolimus, due to the lack of direct evidence from randomized comparative trials. 7 March 2013

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on Axitinib for metastatic renal cell carcinoma (RCC).
• Go to "Additional Information" tab (above) for links to pCODR Reviews

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy and the CCNS Standard for Oral Systemic Therapy for Cancer
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

New Cancer Drug Fund Status (Nova Scotia)

Pharmacare funding approved for: • Treatment of renal cell cancer (when funding available)