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AXITINIB

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Axitinib, a tyrosine kinase inhibitor, is an antineoplastic agent indicated to treat advanced renal cell carcinoma after failure of one prior systemic therapy.

Specific Substances

    1) N-Methyl-2-({3-[(1E)-2-(pyridin-2-yl)ethenyl]-1H-indazol-6-yl}sulfanyl)benzamide
    2) AG-013736
    3) CAS 319460-85-0
    1.2.1) MOLECULAR FORMULA
    1) C22-H18-N4-O-S (Prod Info INLYTA(R) oral tablets, 2012)

Available Forms Sources

    A) FORMS
    1) Axitinib is available as 1 mg and 5 mg film-coated tablets (Prod Info INLYTA(R) oral tablets, 2012).
    B) USES
    1) Axitinib is approved for use in patients with advanced renal cell carcinoma who were refractory to one prior systemic therapy (Prod Info INLYTA(R) oral tablets, 2012).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Axitinib is indicated to treat advanced renal cell carcinoma after failure of one prior systemic therapy.
    B) PHARMACOLOGY: Axitinib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3) implicated in angiogenesis and tumor growth leading to cancer progression.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include diarrhea (55%), hypertension (40%), fatigue (39%), decreased appetite (34%), nausea (32%), dysphonia (31%), hand-foot syndrome (27%), decreased weight (25%), vomiting (24%), asthenia (21%), and constipation (20%).
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include, hypothyroidism, cough, mucosal inflammation, arthralgia, stomatitis, dyspnea, abdominal pain, headache, rash, proteinuria, dysgeusia, dry skin, dyspepsia, pruritus, alopecia, and erythema.
    E) WITH POISONING/EXPOSURE
    1) Dizziness, hypertension, seizures associated with hypertension, and fatal hemoptysis occurred in patients who received axitinib orally at doses up to 20 mg twice daily during clinical trials.
    0.2.20) REPRODUCTIVE
    A) Axitinib is classified as pregnancy category D. Although there are no adequate and well-controlled studies of axitinib use in pregnant women, it is believed that axitinib may cause fetal harm based on its mechanism of action. In mice, post-implantation loss occurred at doses of at least 15 mg/kg/dose administered twice daily, and embryofetal toxicities, including cleft palate and skeletal ossification variation, have occurred at twice daily administration of 1.5 mg/kg/dose and at least 0.5 mg/kg/dose, respectively.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes and thyroid function tests.
    C) Monitor complete blood count (CBC) including differential and platelet count. Monitor for bleeding; monitor for clinical evidence of thromboembolic events.
    D) Monitor vital signs. Severe hypertension has been reported with therapeutic use and in overdose.
    E) Monitor urinalysis. Proteinuria has been reported with therapeutic use.
    F) Serum axitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding (greater than 99%).
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions, symptomatic patients and those ingesting more than 2 extra doses, should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with severe hypertension or bleeding should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult with a medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected axitinib overdose, the possibility of multi-drug involvement should be considered.
    I) PHARMACOKINETICS
    1) Based on a pooled analysis of data from 17 trials, the mean absolute bioavailability of axitinib is 58% following a single 5 mg oral dose. Greater than 99% plasma protein bound. Primarily metabolized via cytochrome P450 3A4/5 (CYP3A4/5). Following a single 5 mg oral dose of radiolabeled axitinib, approximately 23% of radioactivity was recovered in the urine (no unchanged drug) and approximately 41% of radioactivity was recovered in the feces (12% of which was unchanged drug). Half-life ranges from 2.5 to 6.1 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension, or hemorrhagic and thromboembolic events.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Oral axitinib doses up to 20 mg twice daily have resulted in dizziness, hypertension, seizures associated with hypertension, and fatal hemoptysis.
    B) THERAPEUTIC DOSE: ADULT: The recommended starting dose is 5 mg orally twice daily. If tolerated, the dose may be increased up to a MAXIMUM dose of 10 mg orally twice daily. PEDIATRIC: Safety and efficacy have not been established.

Summary Of Exposure

    A) USES: Axitinib is indicated to treat advanced renal cell carcinoma after failure of one prior systemic therapy.
    B) PHARMACOLOGY: Axitinib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3) implicated in angiogenesis and tumor growth leading to cancer progression.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include diarrhea (55%), hypertension (40%), fatigue (39%), decreased appetite (34%), nausea (32%), dysphonia (31%), hand-foot syndrome (27%), decreased weight (25%), vomiting (24%), asthenia (21%), and constipation (20%).
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include, hypothyroidism, cough, mucosal inflammation, arthralgia, stomatitis, dyspnea, abdominal pain, headache, rash, proteinuria, dysgeusia, dry skin, dyspepsia, pruritus, alopecia, and erythema.
    E) WITH POISONING/EXPOSURE
    1) Dizziness, hypertension, seizures associated with hypertension, and fatal hemoptysis occurred in patients who received axitinib orally at doses up to 20 mg twice daily during clinical trials.

Heent

    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dysphonia was reported in 31% of patients who received axitinib (n=359) compared with 14% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hypertension (all grades) was reported in 40% of patients who received axitinib (n=359) compared with 29% of patients who received sorafenib (n=355). Grade 3/4 hypertension was reported in 16% of axitinib-treated patients compared with 11% of sorafenib-treated patients. Onset of hypertension occurred at a median of one month after treatment initiation, although blood pressure increases have occurred as early as 4 days after initiation. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib. Discontinuation of treatment due to hypertension was reported in less than 1% (1 of 359) of axitinib-treated patients and 0% of sorafenib-treated patients (Prod Info INLYTA(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) During clinical trials, hypertension was reported in patients who received initial axitinib doses of 10 to 20 mg orally twice daily (2 to 4 times greater than the recommended starting dose of 5 mg orally twice daily) (Prod Info INLYTA(R) oral tablets, 2012).
    B) HYPERTENSIVE CRISIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hypertensive crisis was reported in less than 1% (2 of 359) of patients who received axitinib compared with 0% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, pulmonary embolism was reported in 2% of patients who received axitinib (n=359) for a median of 6.4 months. Fatal pulmonary embolism was reported one axitinib-treated patient and none in the sorafenib-treated patients (Prod Info INLYTA(R) oral tablets, 2012).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dyspnea (all grades) was reported in 15% of patients who received axitinib (n=359) compared with 12% of patients who received sorafenib (n=355). Grade 3/4 dyspnea was reported in 3% of axitinib-treated patients and in 3% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, cough (all grades) was reported in 15% of patients who received axitinib (n=359) compared with 17% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    D) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hemoptysis was reported in 2% of patients who received axitinib (n=359) for a median of 6.4 months (Prod Info INLYTA(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) During clinical trials, fatal hemoptysis was reported in patients who received axitinib starting doses of 10 to 20 mg orally twice daily (2 to 4 times greater than the recommended starting dose of 5 mg orally twice daily) (Prod Info INLYTA(R) oral tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in less than 1% of patients who received axitinib (n=359) for a median of 6.4 months. In other clinical trials, 2 additional cases of RPLS were reported with axitinib (Prod Info INLYTA(R) oral tablets, 2012).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, asthenia (all grades) was reported in 21% of patients who received axitinib (n=359) compared with 14% of patients who received sorafenib (n=355). Grade 3/4 asthenia was reported in 5% of axitinib-treated patients compared with 3% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dizziness was reported in 9% of patients who received axitinib (n=359) for a median of 6.4 months (Prod Info INLYTA(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Dizziness was reported in a patient who inadvertently received, during a clinical trial, axitinib at an oral dose of 20 mg twice daily for 4 days (2 times greater than the maximum dose of 10 mg orally twice daily) (Prod Info INLYTA(R) oral tablets, 2012).
    D) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, fatal cerebrovascular accident was reported in less than 1% (1 of 359) of patients who received axitinib compared with 0% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    E) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, fatigue (all grades) was reported in 39% of patients who received axitinib (n=359) compared with 32% of patients who received sorafenib (n=355). Grade 3/4 fatigue was reported in 11% of axitinib-treated patients compared with 5% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    F) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, headache (all grades) was reported in 14% of patients who received axitinib (n=359) compared with 11% of patients who received sorafenib (n=355). Grade 3/4 headache was reported in 1% of axitinib-treated patients compared with 0% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    G) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures associated with hypertension occurred in patients who received axitinib at starting doses of 10 to 20 mg orally twice daily (2 to 4 times greater than the recommended starting dose of 5 mg orally twice daily) (Prod Info INLYTA(R) oral tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, nausea (all grades) was reported in 32% of patients who received axitinib (n=359) compared with 22% of patients who received sorafenib (n=355). Grade 3/4 nausea was reported in 3% of axitinib-treated patients compared with 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    b) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, vomiting (all grades) was reported in 24% of patients who received axitinib (n=359) compared with 17% of patients who received sorafenib (n=355). Grade 3/4 vomiting was reported in 3% of axitinib-treated patients compared with 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, diarrhea (all grades) was reported in 55% of patients who received axitinib (n=359) compared with 53% of patients who received sorafenib (n=355). Grade 3/4 diarrhea was reported in 11% of axitinib-treated patients compared with 7% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    C) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, gastrointestinal perforation was reported in less than 1% (1 of 359) of axitinib-treated patient compared with 0% of sorafenib-treated patients (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    b) In clinical trials, gastrointestinal perforation was reported in 1% (5 of 715) of patients who received axitinib for advanced renal cell carcinoma, with one case resulting in death (Prod Info INLYTA(R) oral tablets, 2012).
    D) GASTROINTESTINAL FISTULA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, gastrointestinal fistulas were reported in 1% (4 of 715) of patients who received axitinib for advanced renal cell carcinoma (Prod Info INLYTA(R) oral tablets, 2012).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, decreased appetite (all grades) was reported in 34% of patients who received axitinib (n=359) compared with 29% of patients who received sorafenib (n=355). Grade 3/4 decreased appetite was reported in 5% of axitinib-treated patients compared with 4% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, constipation (all grades) was reported in 20% of patients who received axitinib (n=359) and in 20% of patients who received sorafenib (n=355). Grade 3/4 constipation was reported in 1% of axitinib-treated patients and in 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    G) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, mucosal inflammation (all grades) was reported in 15% of patients who received axitinib (n=359) compared with 12% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    H) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, stomatitis (all grades) was reported in 15% of patients who received axitinib (n=359) compared with 12% of patients who received sorafenib (n=355). Grade 3/4 stomatitis was reported in 1% of axitinib-treated patients and in less than 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    I) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dyspepsia (all grades) was reported in 10% of patients who received axitinib (n=359) compared with 2% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    J) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, abdominal pain (all grades) was reported in 14% of patients who received axitinib (n=359) compared with 11% of patients who received sorafenib (n=355). Grade 3/4 abdominal pain was reported in 2% of axitinib-treated patients and in 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    K) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dysgeusia (all grades) was reported in 11% of patients who received axitinib (n=359) compared with 8% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In clinical trials, ALT elevations (all grades) were reported in 22% of patients who received axitinib (n=331) and 22% of patients who received sorafenib (n=313). Grade 3/4 ALT elevations were reported in less than 1% of axitinib-treated patients compared with 2% of sorafenib-treated patients (Prod Info INLYTA(R) oral tablets, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, proteinuria (all grades) was reported in 11% of patients who received axitinib (n=359) compared with 7% of patients who received sorafenib (n=355). Grade 3 proteinuria was reported in 3% of axitinib-treated patients compared with 2% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hemorrhagic events (all grades) were reported in 16% (58 of 359) of patients who received axitinib compared with 18% (64 of 355) of patients who received sorafenib. Grade 3/4 hemorrhagic events were reported in 1% (3 of 359) of axitinib-treated patients (eg, cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) compared with 3% (11 of 355) of sorafenib-treated patients. Fatal hemorrhage was reported in 1 axitinib-treated patient (gastric hemorrhage) and 3 sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    B) ARTERIAL THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, arterial thrombotic events (grade 3/4) were reported in 1% (4 of 359) of patients who received axitinib and 1% (4 of 355) of patients who received sorafenib for a median of 6.4 months and 5 months, respectively. Some arterial thrombotic events resulted in death (Prod Info INLYTA(R) oral tablets, 2012).
    b) In clinical trials, arterial thromboembolic events (eg, TIA, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 2% (17 of 715) of patients who received axitinib for advanced renal cell carcinoma. Two deaths secondary to cerebrovascular accident were reported in this trial (Prod Info INLYTA(R) oral tablets, 2012).
    C) VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, venous thromboembolic events (all grades) were reported in 3% (11 of 359) of patients who received axitinib compared with 1% (2 of 355) of patients who received sorafenib. Grade 3/4 venous thromboembolic events (eg, pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) were reported in 3% (9 of 359) of axitinib-treated patients compared with 1% (2 of 355) of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    b) In clinical trials, venous thromboembolic events were reported in 3% (22 of 715) of patients who received axitinib for advanced renal cell carcinoma. Two deaths secondary to pulmonary embolism were reported in this trial (Prod Info INLYTA(R) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, palmar-plantar erythrodysesthesia (hand-foot) syndrome (all grades) was reported in 27% of patients who received axitinib (n=359) compared with 51% of patients who received sorafenib (n=355). Grade 3/4 palmar-plantar erythrodysesthesia syndrome was reported in 5% of axitinib-treated patients compared with 16% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, alopecia (all grades) was reported in 4% of patients who received axitinib (n=359) compared with 32% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, rash (all grades) was reported in 13% of patients who received axitinib (n=359) compared with 32% of patients who received sorafenib (n=355). Grade 3/4 rash was reported in less than 1% of axitinib-treated patients compared with 4% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    D) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, dry skin (all grades) was reported in 10% of patients who received axitinib (n=359) compared with 11% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    E) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, pruritus (all grades) was reported in 7% of patients who received axitinib (n=359) compared with 12% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    F) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, erythema (all grades) was reported in 2% of patients who received axitinib (n=359) compared with 10% of patients who received sorafenib (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, arthralgia (all grades) was reported in 15% of patients who received axitinib (n=359) compared with 11% of patients who received sorafenib (n=355). Grade 3/4 arthralgia was reported in 2% of axitinib-treated patients compared with 1% of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hypothyroidism was reported in 19% of axitinib-treated patients (n=359) compared with 8% of sorafenib-treated patients (n=355). The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).
    B) HYPERTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label, multicenter study of advanced renal cell carcinoma treatment, hyperthyroidism was reported in 1% (4 of 359) of axitinib-treated patients and 1% (4 of 355) of sorafenib-treated patients. The median duration of therapy was 6.4 months with axitinib and 5 months with sorafenib (Prod Info INLYTA(R) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Axitinib is classified as pregnancy category D. Although there are no adequate and well-controlled studies of axitinib use in pregnant women, it is believed that axitinib may cause fetal harm based on its mechanism of action. In mice, post-implantation loss occurred at doses of at least 15 mg/kg/dose administered twice daily, and embryofetal toxicities, including cleft palate and skeletal ossification variation, have occurred at twice daily administration of 1.5 mg/kg/dose and at least 0.5 mg/kg/dose, respectively.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE: The embryofetal toxicities of malformation (cleft palate) and variation in skeletal ossification were noted in mice administered oral axitinib twice daily during the period of organogenesis at a non-maternally toxic dose of 1.5 mg/kg/dose (approximately 0.5 times the exposure at the recommended human starting dose) and greater than or equal to 0.5 mg/kg/dose (approximately 0.15 times the exposure at the recommended starting dose), respectively (Prod Info INLYTA(R) oral tablets, 2014)
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Axitinib is classified as pregnancy category D. There are no adequate and well-controlled studies of axitinib in pregnant women. Animal studies indicate that axitinib causes fetal harm when administered during pregnancy. Therefore, women of childbearing potential should be cautioned against becoming pregnant while undergoing treatment with axitinib. If a patient does become pregnant during treatment or if this drug is used during pregnancy, advise the patient of the potential consequences to the fetus (Prod Info INLYTA(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) MICE: In animal studies, oral axitinib increased post-implantation loss at doses greater than or equal to 15 mg/kg/dose (approximately 10 times the systemic exposure at the recommended human starting dose) administered twice daily to mice before mating and through the first week of pregnancy (Prod Info INLYTA(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether axitinib is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined. Because of the potential for toxicity in a nursing infant, either breastfeeding or axitinib should be discontinued, considering the need for treatment of the mother (Prod Info INLYTA(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Although axitinib did not appear to affect mating or fertility rate in male mice given doses up to 50 mg/kg/dose twice daily (approximately 57 times the AUC of patients at the recommended starting dose) for at least 70 days, repeat-dose toxicology studies did show abnormal findings in the male reproductive tract of the testes/epididymis (decreased organ weight, atrophy or deterioration, reduced sperm density and count, decreased numbers of germinal cells, hypospermia or abnormal sperm forms) when male mice were given axitinib at doses of at least 15 mg/kg orally twice daily (approximately 7 times the AUC of patients at the recommended starting dose). Abnormal reproductive tract findings were also noted in dogs who received at least 1.5 mg/kg/dose orally twice daily (approximately 0.1 times the AUC in patients at the recommended starting dose) (Prod Info INLYTA(R) oral tablets, 2014).
    2) Reduced fertility and embryonic viability were noted in female mice who received at least 15 mg/kg/dose orally twice daily (approximately 10 times the AUC of patients at the recommended starting dose) for at least 15 days. In female mice and dogs, abnormal findings of the reproductive tract (delayed sexual maturity, decreased uterine weights and uterine atrophy, and reduced or absent corpora lutea) were observed following administration of axitinib at doses of at least 5 mg/kg (approximately 1.5 times or 0.3 times the AUC, respectively) (Prod Info INLYTA(R) oral tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, carcinogenicity studies have not been conducted (Prod Info INLYTA(R) oral tablets, 2012).

Genotoxicity

    A) Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay; however, it was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay, nor was it clastogenic in the in vitro human lymphocyte chromosome aberration assay (Prod Info INLYTA(R) oral tablets, 2012).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes and thyroid function tests.
    C) Monitor complete blood count (CBC) including differential and platelet count. Monitor for bleeding; monitor for clinical evidence of thromboembolic events.
    D) Monitor vital signs. Severe hypertension has been reported with therapeutic use and in overdose.
    E) Monitor urinalysis. Proteinuria has been reported with therapeutic use.
    F) Serum axitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe hypertension or bleeding should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with a medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions, those who are symptomatic and those ingesting more than 2 extra doses, should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes and thyroid function tests.
    C) Monitor complete blood count (CBC) including differential and platelet count. Monitor for bleeding; monitor for clinical evidence of thromboembolic events.
    D) Monitor vital signs. Severe hypertension has been reported with therapeutic use and in overdose.
    E) Monitor urinalysis. Proteinuria has been reported with therapeutic use.
    F) Serum axitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no specific antidote.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    2) Monitor liver enzymes and thyroid function tests.
    3) Monitor complete blood count (CBC) including differential and platelet count. Monitor for bleeding; monitor for clinical evidence of thromboembolic events.
    4) Monitor vital signs. Severe hypertension has been reported with therapeutic use and in overdose.
    5) Monitor urinalysis; proteinuria has been reported with therapeutic use.
    6) Serum axitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    16) LABETALOL
    a) INTRAVENOUS INDICATIONS
    1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.
    b) ADULT DOSE
    1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
    2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).
    c) PEDIATRIC DOSE
    1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).
    d) ADVERSE REACTIONS
    1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).
    e) PRECAUTIONS
    1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
    2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).
    f) MONITORING PARAMETER
    1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective due to high protein binding (greater than 99%).

Summary

    A) TOXICITY: A specific toxic dose has not been established. Oral axitinib doses up to 20 mg twice daily have resulted in dizziness, hypertension, seizures associated with hypertension, and fatal hemoptysis.
    B) THERAPEUTIC DOSE: ADULT: The recommended starting dose is 5 mg orally twice daily. If tolerated, the dose may be increased up to a MAXIMUM dose of 10 mg orally twice daily. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended starting dose is 5 mg orally twice daily. If tolerated, the dose may be increased up to a MAXIMUM dose of 10 mg orally twice daily (Prod Info INLYTA(R) oral tablets, 2012).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info INLYTA(R) oral tablets, 2012).

Maximum Tolerated Exposure

    A) A patient experienced dizziness after inadvertently receiving axitinib at a dose of 20 mg orally twice daily for 4 days during a clinical trial (Prod Info INLYTA(R) oral tablets, 2012).
    B) Patients enrolled in an axitinib clinical dose finding study experienced hypertension, seizures associated with hypertension, and fatal hemoptysis after receiving initial axitinib doses of 10 to 20 mg orally twice daily (Prod Info INLYTA(R) oral tablets, 2012).

Pharmacologic Mechanism

    A) Axitinib is a kinase inhibitor shown to inhibit the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3) implicated in angiogenesis and tumor growth leading to cancer progression (Prod Info INLYTA(R) oral tablets, 2012).

Physical Characteristics

    A) Axitinib is a white to light yellow powder that is soluble (greater than 0.2 mcg/mL) in aqueous media over a pH range of 1.1 to 7.8 (Prod Info INLYTA(R) oral tablets, 2012).

Molecular Weight

    A) 386.47 Daltons (Prod Info INLYTA(R) oral tablets, 2012)

General Bibliography

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    4) Deal JE , Barratt TM , & Dillon MJ : Management of hypertensive emergencies. Arch Dis Child 1992; 67(9):1089-1092.
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