Axitinib

Pronunciation: ax-I-ti-nib
Class: Tyrosine kinase inhibitor

Trade Names

Inlyta
- Tablets, oral 1 mg
- Tablets, oral 5 mg

Pharmacology

Inhibits tumor cell proliferation and survival in vitro.

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Pharmacokinetics

Absorption

Bioavailability is 58%. T max is 2.5 to 4 h. Administration with high-fat meals increased AUC by 19%.

Distribution

More than 99% bound to plasma proteins, primarily albumin. The Vd is 160 L.

Metabolism

Metabolism occurs primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.

Elimination

Half-life is 2.5 to 6 h. After oral administration, 41% was recovered in the feces (majority as unchanged axitinib) and 23% in the urine (majority as metabolites). Cl was 38 L/h.

Special Populations

Renal Function Impairment

Mild to severe renal impairment had no meaningful effect on the pharmacokinetics of axitinib.

Hepatic Function Impairment

Systemic exposure was similar in subjects with mild hepatic impairment (Child-Pugh class A) and higher in subjects with moderate impairment (Child-Pugh class B). Not studied in severe impairment (Child-Pugh class C).

Elderly

Age has no clinically relevant effects on Cl.

Children

Not studied.

Gender

Gender has no clinically relevant effects on Cl.

Race

Race has no clinically relevant effects on Cl.

Indications and Usage

Treatment of advanced renal cell carcinoma after failure of 1 prior systemic therapy.

Contraindications

None well documented.

Dosage and Administration

Adults

PO 5 mg twice daily initially. Patients who tolerate this dosage for at least 2 consecutive weeks with no adverse reactions greater than grade 2, are normotensive, and are not receiving antihypertensive medication may have their dosage increased to 7 mg twice daily, and further to 10 mg twice daily using the same criterion.

Dosage adjustment

If a dosage reduction from 5 mg twice daily is required because of adverse reactions, the recommended dosage is 3 mg twice daily. If an additional dose reduction is required, the recommended dosage is 2 mg twice daily.

Concomitant therapy
Strong CYP3A4/5 inhibitors

The concomitant use of strong CYP3A4/5 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of axitinib by approximately half is recommended. The subsequent doses can be increased or decreased based on individual safety and tolerability. If coadministration of the strong inhibitor is discontinued, the axitinib dose should be returned (after 3 to 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.

CYP3A4/5 inducers

Avoid the concomitant use of strong CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John's wort). Moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided if possible.

Hepatic Function Impairment

Decrease the starting dose by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). Subsequent doses may be increased or decreased based on individual safety and tolerability.

General Advice

  • Administer each dose approximately 12 h apart with or without food. Swallow whole with a glass of water.
  • If the patient vomits or if a dose is missed, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Grapefruit or grapefruit juice

May increase axitinib plasma concentrations and should be avoided.

Moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin)

Axitinib plasma concentration may be reduced. Avoid coadministration if possible.

Strong CYP3A4/5 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifamycins [eg, rifampin], St. John's wort)

Coadministration will reduce axitinib plasma concentration. Avoid coadministration.

Strong CYP3A4/5 inhibitors (eg, clarithromycin, HIV protease inhibitors [eg, ritonavir], itraconazole, ketoconazole, nefazodone, telithromycin, voriconazole)

Avoid coadministration because of the risk of increased axitinib plasma concentration. If coadministration cannot be avoided, reduce the axitinib dosage.

Adverse Reactions

Cardiovascular

Hypertension (40%); deep vein thrombosis, transient ischemic attack (1%).

CNS

Fatigue (39%); asthenia (21%); headache (14%); dizziness (9%).

Dermatologic

Rash (13%); dry skin (10%); pruritus (7%); alopecia (4%); erythema (2%).

EENT

Dysphonia (31%); dysgeusia (11%); tinnitus (3%); retinal vein occlusion/thrombosis (1%).

GI

Diarrhea (55%); nausea (32%); vomiting (24%); constipation (20%); stomatitis (15%); abdominal pain (14%); dyspepsia (10%); upper abdominal pain (8%); hemorrhoids (4%); rectal hemorrhage (2%).

Genitourinary

Proteinuria (11%); hematuria (3%).

Hematologic-Lymphatic

Anemia (4%); polycythemia (1%).

Lab Tests

Creatinine increased (55%); bicarbonate decreased (44%); Hgb decreased (35%); absolute lymphocytes decreased (33%); alkaline phosphatase increased (30%); lipase increased (27%); amylase increased (25%); ALT increased (22%); AST increased (20%); platelets decreased (15%); WBC decreased (11%); Hgb increased (9%).

Metabolic-Nutritional

Hypocalcemia (39%); decreased appetite (34%); hyperglycemia (28%); weight decreased (25%); hypothyroidism (19%); hypernatremia (17%); hyperkalemia, hypoalbuminemia (15%); hyponatremia, hypophosphatemia (13%); hypoglycemia (11%); dehydration (6%).

Musculoskeletal

Arthralgia (15%); pain in extremity (13%); myalgia (7%).

Respiratory

Cough, dyspnea (15%); epistaxis (6%); hemoptysis, pulmonary embolism (2%).

Miscellaneous

Palmar-plantar erythrodysesthesia syndrome (27%); mucosal inflammation (15%).

Precautions

Monitor

Monitor for hypertension. Monitor for symptoms of GI perforation or fistula periodically during treatment. Monitor ALT, AST, bilirubin, and thyroid function, and for proteinuria before initiation of, and periodically throughout, treatment.


Pregnancy

Category D . Advise women of childbearing potential to avoid becoming pregnant.

Lactation

Undetermined.

Children

Safety and efficacy not studied.

Renal Function

Use with caution in patients with ESRD (CrCl less than 15 mL/min).

Hepatic Function

Adjust dose in patients with moderate hepatic impairment. Axitinib has not been studied in patients with severe hepatic impairment.

GI effects

GI perforation or fistula may occur.

Hemorrhage

Hemorrhage, including fatal cases, has been reported. If any bleeding requires medical intervention, temporarily interrupt axitinib treatment.

Hepatic effects

ALT elevations have been reported.

Hypertension

Hypertension has been reported; BP increases were observed as early as 4 days after initiation. Hypertensive crisis was seen in less than 1% of patients. BP should be well controlled before initiating axitinib.

Proteinuria

Has been reported; reduce dose or temporarily interrupt therapy.

Reversible posterior leukoencephalopathy syndrome

Has been reported; discontinue therapy in patients developing reversible posterior leukoencephalopathy syndrome.

Thromboembolic events

Arterial and venous thromboembolic events, including deaths, have been reported. Use with caution in patients at risk of thromboembolic events.

Thyroid dysfunction

Hyper- and hypothyroidism have been reported.

Wound healing

Stop treatment at least 24 h prior to scheduled surgery. Base the decision to resume treatment on clinical judgement and adequate wound healing.

Overdosage

Symptoms

Dizziness, fatal hemoptysis, hypertension, seizures associated with hypertension.

Patient Information

  • Advise patients that hypertension may develop during treatment and that BP should be monitored regularly.
  • Advise patients that arterial and venous thromboembolic events have been observed during treatment and to inform their health care provider if they experience symptoms suggestive of thromboembolic events.
  • Advise patients that axitinib may increase the risk of bleeding and to promptly inform their health care provider of any bleeding episodes.
  • Advise patients that GI disorders, such as diarrhea, nausea, vomiting, and constipation, may develop during treatment and to seek immediate medical attention if they experience severe or persistent abdominal pain.
  • Advise patients that abnormal thyroid function may develop during treatment and to inform their health care provider if symptoms of abnormal thyroid function occur.
  • Advise patients to inform their health care provider if they have an unhealed wound or if they have a surgery scheduled.
  • Advise patients to inform their health care provider if they have symptoms suggestive of reversible posterior leukoencephalopathy syndrome (eg, headache, seizure, lethargy, confusion, blindness, other visual disturbances).
  • Advise patients that axitinib may cause birth defects or fetal loss and that they should not become pregnant during treatment. Counsel patients to use effective birth control during treatment. Advise female patients not to breast-feed during therapy.
  • Advise patients to inform their health care provider of all concomitant medications, vitamins, or dietary and herbal supplements.

Copyright © 2009 Wolters Kluwer Health.

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