axitinib

AX-i-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

First-line treatment of advanced renal cell carcinoma (in combination with avelumab or pembrolizumab).
Advanced renal cell carcinoma following failure of one other systemic therapy.

Inhibits tyrosine kinases on various receptors including vascular endothelial growth factor receptors that may be involved in tumor angiogenesis/growth and cancer progression.

Therapeutic effects:

Inhibited tumor growth with decreased disease progression.

Absorption: Well absorbed (58%) following oral administration.

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Mostly metabolized by the CYP3A4/5 isoenzymes, some metabolism by CYP2C19 and UGT1A1 systems. 41% eliminated in feces (12% as unchanged drug); 23% eliminated in urine as metabolites.

Half-Life: 2.5–6.1 hr.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION‡
PO	unknown	2.5–4.1 hr	12 hr

‡Decreased progression of disease may last up to 18 mo.

Contraindicated in:

Untreated brain metastases;
Recent active GI bleeding;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Hypertension (must be well controlled prior to/during therapy);
Moderate hepatic impairment (dose ↓ recommended);
Surgery (discontinue 24 hr prior if possible);
End-stage renal disease (CCr <15 mL/min);
Rep: Woman of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: hypertension, AORTIC ANEURYSM, ARTERIAL/VENOUS THROMBOEMBOLIC EVENTS, CARDIAC DEATH (WITH AVELUMAB), MI (WITH AVELUMAB), HF

Derm: dry skin, palmar-plantar erythrodysesthesia (hand-foot syndrome), rash, alopecia, erythema, wound healing impairment, pruritus

EENT: dysphonia

Endo: hypothyroidism

F and E: ↓bicarbonate, hyperglycemia, hyperkalemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, hypercalcemia

GI: hepatotoxicity, abdominal pain, altered taste, ↓appetite, ↓weight, constipation, diarrhea, nausea, ↑liver enzymes, stomatitis, burning mouth, GI PERFORATION/FISTULA

GU: ↑serum creatinine, proteinuria

Hemat: anemia, neutropenia, thrombocytopenia, BLEEDING

MS: arthralgia, extremity pain

Neuro: dysphoria, fatigue, headache, REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (RPLS)

Resp: cough

Drug-drug:

Strong CYP3A4/5 inhibitors, including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, voriconazole may ↑ levels and the risk of toxicity; avoid concurrent use, if possible; if concurrent use cannot be avoided, select alternative agent. If none is acceptable, ↓ axitinib dose by 50%..
Strong CYP3A4/5 inducers, including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentin as well as moderate CYP3A4/5 inducers, including bosentan, efavirenz, etravirine, modafanil, and nafcillinmay ↓ levels and effectiveness; avoid concurrent use, if possible.

Drug-Natural Products:

St. John's wort may ↓ levels and should be avoided.

Grapefruit/grapefruit juice may ↑ levels and should be avoided.

First-Line Treatment of Advanced Renal Cell Carcinoma

PO (Adults ): In combination with avelumab: 5 mg twice daily, approximately 12 hr apart initially; after tolerating therapy for ≥2 consecutive wk (i.e. no adverse reactions Grade >2, remaining normotensive, and are not receiving antihypertensive medications), may ↑ to 7 mg twice daily; after tolerating adjusted dose for ≥2 consecutive wk (using same criteria), may ↑ to 10 mg twice daily. Continue treatment until unacceptable toxicity or disease progression. In combination with pembrolizumab: 5 mg twice daily, approximately 12 hr apart initially; after tolerating therapy for ≥6 wk (i.e. no adverse reactions Grade >2, remaining normotensive, and are not receiving antihypertensive medications), may ↑ to 7 mg twice daily; after tolerating adjusted dose for ≥6 consecutive wk (using same criteria), may ↑ to 10 mg twice daily. Continue treatment until unacceptable toxicity or disease progression. Concurrent use of strong CYP3A4/5 inhibitors: ↓dose by approximately 50%.

Hepatic Impairment

PO (Adults ): Moderate hepatic impairment: ↓dose by 50%.

Second-Line Treatment of Advanced Renal Cell Carcinoma

PO (Adults ): 5 mg twice daily, approximately 12 hr apart initially; after tolerating therapy for ≥2 consecutive wk (i.e. no adverse reactions Grade >2, remaining normotensive, and are not receiving antihypertensive medications), may ↑ to 7 mg twice daily; after tolerating adjusted dose for ≥2 consecutive wk (using same criteria), may ↑ to 10 mg twice daily. Continue treatment until unacceptable toxicity or disease progression.Concurrent use of strong CYP3A4/5 inhibitors: ↓dose by approximately 50%.

Hepatic Impairment

PO (Adults ): Moderate hepatic impairment: ↓dose by 50%.

Tablets : 1 mg; 5 mg

Ensure BP is well controlled before starting therapy. Monitor BP periodically during therapy. If SBP >150 mm Hg or DBP >100 mm Hg despite antihypertensive treatment, reduce dose by one level. If SBP > 160 mm Hg or DBP > 105 mm Hg, hold until BP <150/100 mm Hg. Resume at a reduced dose. If Grade 4 or hypertensive crisis occurs, permanently discontinue axitinib.
Monitor for bleeding during therapy. If Grade 3 or 4 hemorrhage occurs, hold until resolution to Grade 0 or 1 or baseline. Either resume at reduced dose or discontinue based on severity and persistence of adverse reaction.
Monitor for signs or symptoms of cardiac failure during therapy. If asymptomatic cardiomyopathy (left ventricular ejection fraction >20% but <50% below baseline or below the lower limit of normal if baseline was not obtained), hold until resolution to Grade 0 or 1 or baseline. Resume at a reduced dose. If CHF with clinical signs and symptoms occurs, discontinue axitinib permanently.
Axitinib in combination with avelumab may cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Manage cardiovascular risk factors, (hypertension, diabetes, dyslipidemia). If Grade 3 or 4 cardiovascular events occur, permanently discontinue axitinib and avelumab.
May cause diarrhea when in combination with avelumab or pembrolizumab. If Grade 1–2 diarrhea occurs, start antidiarrheal medications. If Grade 3 diarrhea occurs, hold axitinib and start antidiarrheals. If diarrhea is controlled, axitinib may be resumed at either same dose or reduced by 1 level. If Grade 4 diarrhea occurs, hold axitinib until resolution to Grade <2, then restart axitinib with dose reduced by 1 level.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.Monitor serum thyroid prior to and periodically during therapy. May cause hypothyroidism or hyperthyroidism. Treat with standard therapy.
- Monitor for proteinuria prior to and periodically during therapy. If ≥ 2 g proteinuria/24 hr occurs, hold until resolution to <2 g/24 hr. Resume at a reduced dose.
- Monitor liver function tests prior to and periodically during therapy. May cause ↑ ALT, AST and bilirubin. In combination with avelumab or pembrolizumab,If ALT or AST ≥ 3x upper limit of normal (ULN) but <10x ULN without concurrent total bilirubin ≥ 2x ULN, hold both axitinib and avelumab or pembrolizumab until resolution to Grades 0–1. Consider rechallenge with axitinib and/or avelumab or pembrolizumab. If ALT or AST increases to >3x ULN with concurrent total bilirubin ≥2x ULN or ALT or AST ≥10x ULN, discontinue both axitinib and avelumab or pembrolizumab permanently.
- May cause ↑ serum creatinine, alkaline phosphatase, blood sugar, lipase, amylase, sodium, potassium and ↓ hemoglobin, absolute lymphocytes, platelets, bicarbonate, serum calcium, albumin, blood sugar, sodium, and phosphate.

Do not confuse axitinib with apixaban.
Dose Modification Guidelines: Dose Increase: Dose may be increased in patients who have no adverse reactions Grade >2, are normotensive, and are not receiving antihypertension medication for at least two consecutive wk. Starting dose: 5 mg twice daily. 1st dose increase: 7 mg twice daily. 2nd dose increase: 10 mg twice daily. Dose Reduction: 1st dose reduction:3 mg twice daily. 2nd dose reduction: 2 mg twice daily.
May impair wound healing. Hold therapy for at least 2 days prior to elective surgery. Do not administer for at least 2 wk following major surgery and until adequate wound healing. Resume therapy at a reduced dose or discontinue based on severity and persistence of impaired wound healing. Safety of resuming axitinib after resolution of wound healing complications has not been established.
PO: Administer twice daily with doses 12 hr apart. May be administered with or without food. DNC: Swallow tablets whole followed by a full glass of water.

Instruct patient to take axitinib as directed. If a dose is vomited or missed, omit dose and take next dose at regular time; do not double doses. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Advise patient to avoid drinking grapefruit juice or eating grapefruit during axitinib therapy.
Advise patient to notify health care professional of therapy prior to treatment, dental procedure, or surgery. Axitinib therapy should be interrupted in patients undergoing major surgery; hold dose for at least 2 days before surgery and for at least 2 wk after surgery and until adequate wound healing occurs.
May cause bleeding or blood clots. Advise patient to notify health care professional immediately if unexpected bleeding or bleeding that lasts a long time; unusual bleeding of gums; heavier than normal menstrual bleeding; severe or uncontrollable bleeding; pink or brown urine; red or black stools; vomiting blood or dark “coffee ground” looking; unexpected pain, swelling, or joint pain; headaches; feeling dizzy; or weakness occur or if chest pain or pressure; pain in arms, back, neck, or jaw; shortness of breath; numbness or weakness on one side of body; difficulty talking; headache; or vision changes occur.
May cause stomach tear or intestinal wall perforation. Caution patient to notify health care professional if severe abdominal pain, vomiting blood, or red or black stools occur.
Advise patient to notify health care professional promptly if signs and symptoms of RPLS (headache, seizures, weakness, confusion, high BP, blindness or change in vision, problems thinking), thyroid problems (worsening or persistent tiredness, feeling hot or cold, voice deepening, weight gain or weight loss, hair loss, muscle cramps and aches), or HF (tiredness, swelling abdomen, legs or ankles, shortness of breath, protruding neck veins) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's Wort.
Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during therapy and for 1 wk after last dose. Advise female patients to avoid breastfeeding during therapy and for 2 wk after last dose. May impair fertility in male and female patients.

Decreased growth and spread of advanced renal cell carcinoma.

Inlyta

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