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PAZOPANIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pazopanib is a tyrosine kinase inhibitor.

Specific Substances

    1) Pazopanib hydrochloride
    2) GW-786034B
    3) CAS 444731-52-6 (pazopanib)
    4) CAS 635702-64-6 (pazopanib hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C21-H23-N7-O2-S (Prod Info VOTRIENT(R) oral tablets, 2009)

Available Forms Sources

    A) FORMS
    1) Pazopanib is available as 200 mg tablets (Prod Info VOTRIENT(R) oral tablets, 2015).
    B) USES
    1) Pazopanib is indicated for the treatment of advanced renal cell carcinoma and soft tissue sarcoma (Prod Info VOTRIENT(R) oral tablets, 2015).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Indicated for the treatment of advanced renal cell carcinoma.
    B) PHARMACOLOGY: Inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptors alpha and beta, fibroblast growth factor receptors 1 and 3, cytokine receptor, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein receptor tyrosine kinase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration include: bone marrow suppression (i.e., leukopenia, neutropenia, and thrombocytopenia), hypertension, hair depigmentation, nausea, vomiting, diarrhea, and anorexia.
    2) RARE: QT prolongation, torsades de pointes, hemorrhagic events (i.e., pulmonary, gastrointestinal, genitourinary, and cerebral hemorrhage), and severe hepatotoxicity, with fatalities, have been rarely reported with pazopanib therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: fatigue and hypertension were reported in patients receiving 2,000 mg daily and 1,000 mg daily, respectively.
    2) SEVERE POISONING: Severe toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses, and may include myelosuppression, nausea, vomiting, diarrhea, hypertension, and possibly QTc prolongation, bleeding and hepatotoxicity.
    0.2.20) REPRODUCTIVE
    A) Pazopanib is classified as FDA pregnancy category D. Pazopanib may result in fetal harm when used during pregnancy. Advise women to avoid pregnancy during pazopanib treatment. If pregnancy occurs, apprise patient of potential for fetal harm. In animal studies, there was evidence of teratogenicity, embryotoxicity, fetotoxicity, and spontaneous abortion in animals exposed to pazopanib. It is not known whether pazopanib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. Discontinue nursing or discontinue treatment, taking into account the importance of the drug to the mother.

Laboratory Monitoring

    A) Monitor vital signs and liver enzymes after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor serial CBC with differential and platelet counts.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat severe hypertension with nitroprusside as the preferred agent; nitroglycerin or phentolamine as alternatives. QT prolongation and torsades de pointes have been reported with therapeutic doses and may occur following overdose. Treat torsades de pointes with IV magnesium sulfate and correct electrolyte abnormalities; use overdrive pacing. Hemorrhagic events (i.e., pulmonary, gastrointestinal, and genitourinary) have been observed. Myelosuppression has been reported. For severe neutropenia, administer colony stimulating factor (e.g., filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to maintain his or her airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if the airway is protected.
    D) ANTIDOTE
    1) None.
    E) HYPERTENSIVE EPISODE
    1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside is preferred, with nitroglycerin or phentolamine as alternatives.
    F) TORSADES DE POINTES
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium and/or atrial overdrive pacing. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULT: 2 g IV over 1 to 2 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    G) MYELOSUPPRESSION
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/meter(2)/day IV over 4 hours. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding (greater than 99%).
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions (or a single extra dose) can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions 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 demonstrating severe fluid and electrolyte imbalance, cardiovascular instability, or severe hepatotoxicity should be admitted.
    4) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected pazopanib overdose, the possibility of multi-drug involvement should be considered.
    K) PHARMACOKINETICS
    1) Protein binding is greater than 99%. Elimination is primarily via feces; less than 4% of a dose is excreted renally. Mean half-life, following oral administration of 800 mg, is 30.9 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause myelosuppression (e.g, sorafenib), elevated liver enzymes (e.g., alcohol, acetaminophen), or QT interval prolongation.

Range Of Toxicity

    A) A toxic dose has not been established. Grade 3 fatigue and grade 3 hypertension were reported in patients receiving pazopanib orally at doses of 2,000 mg daily and 1,000 mg daily, respectively.
    B) THERAPEUTIC DOSE: The recommended dose is 800 mg orally once daily.

Clinical Effects

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypertension (systolic of 150 mmHg or greater or diastolic of 100 mmHg or greater) was reported in 47% of renal cell carcinoma patients who received pazopanib therapy during clinical trials. Hypertension occurred within the first 18 weeks of treatment in 88% of patients (Prod Info VOTRIENT(R) oral tablets, 2009).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, epistaxis was reported in 2% of patients who received pazopanib hydrochloride (n=290), and was one of the most commonly reported hemorrhagic events associated with pazopanib therapy (Prod Info VOTRIENT(R) oral tablets, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension (systolic of 150 mmHg or greater or diastolic of 100 mmHg or greater) was reported in 47% of renal cell carcinoma patients who received pazopanib therapy during clinical trials. Hypertension occurred within the first 18 weeks of treatment in 88% of patients (Prod Info VOTRIENT(R) oral tablets, 2009).
    b) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, hypertension (all grades) was reported in 40% (115/290) of patients who received pazopanib hydrochloride compared with 10% (15/145) of patients who received placebo. Grade 3 and grade 4 hypertension were reported in 4% (13/290) and 0%, respectively, of patients who received pazopanib compared with less than 1% (1/145) and 0%, respectively, of patients who received placebo. Less than 1% (2 of 290) of patients who received pazopanib permanently discontinued treatment due to hypertension.(Prod Info VOTRIENT(R) oral tablets, 2009).
    c) In the overall safety population for renal cell carcinoma, 1 patient who received pazopanib hydrochloride (n=586) experienced a hypertensive crisis (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, chest pain (all grades) was reported in 5% of patients who received pazopanib hydrochloride (n=290) compared with 1% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, myocardial infarction/ischemia was reported in 2% of patients who received pazopanib hydrochloride (n=290) compared with 0% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) During clinical studies of renal cell carcinoma therapy, QT prolongation of 500 msec or greater was identified on routine ECG monitoring in less than 2% of patients who received pazopanib hydrochloride (n=558). Post-baseline QTc values of between 500 and 549 msec were identified in 1% of patients who received pazopanib hydrochloride (n=290) compared with 0% of patients who received placebo (n=145) during the randomized clinical trial (Prod Info VOTRIENT(R) oral tablets, 2009).
    E) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) During monotherapy studies, torsades de pointes occurred in 2 of 977 renal cell carcinoma patients following administration of pazopanib hydrochloride (Prod Info VOTRIENT(R) oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, hemoptysis was reported in 2% of patients who received pazopanib hydrochloride (n=290), and was one of the most commonly reported hemorrhagic events associated with pazopanib therapy (Prod Info VOTRIENT(R) oral tablets, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, asthenia (all grades) was reported in 14% of patients who received pazopanib hydrochloride (n=290) compared with 8% of patients who received placebo (n=145). Grade 3 and grade 4 asthenia were reported in 3% and 0%, respectively, of patients who received pazopanib compared with 0% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, headache (all grades) was reported in 10% of patients who received pazopanib hydrochloride (n=290) compared with 5% of patients who received placebo (n=145). Grade 3 and grade 4 headache were not observed in either group (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, fatigue (all grades) was reported in 19% of patients who received pazopanib hydrochloride (n=290) compared with 8% of patients who received placebo (n=145). Grade 3 and grade 4 fatigue were reported in 2% and 0%, respectively, of patients who received pazopanib compared with 1% and 1%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Cerebral/intracranial hemorrhage was reported in 2 of 586 patients treated with pazopanib during clinical trials (Prod Info VOTRIENT(R) oral tablets, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, nausea (all grades) was reported in 26% of patients who received pazopanib hydrochloride (n=290) compared with 9% of patients who received placebo (n=145). Grade 3 and grade 4 nausea were reported in less than 1% and 0%, respectively, of patients who received pazopanib compared with 0% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    b) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, vomiting (all grades) was reported in 21% of patients who received pazopanib hydrochloride (n=290) compared with 8% of patients who received placebo (n=145). Grade 3 and grade 4 vomiting were reported in 2% and less than 1%, respectively, of patients who received pazopanib compared with 2% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, diarrhea (all grades) was reported in 52% of patients who received pazopanib hydrochloride (n=290) compared with 9% of patients who received placebo (n=145). Grade 3 and grade 4 diarrhea were reported in 3% and less than 1%, respectively, of patients who received pazopanib compared with less than 1% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, abdominal pain (all grades) was reported in 11% of patients who received pazopanib hydrochloride (n=290) compared with 1% of patients who received placebo (n=145). Grade 3 and grade 4 abdominal pain were reported in 2% and 0%, respectively, of patients who received pazopanib compared with 0% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, anorexia (all grades) was reported in 22% of patients who received pazopanib hydrochloride (n=290) compared with 10% of patients who received placebo (n=145). Grade 3 and grade 4 anorexia were reported in 2% and 0%, respectively, of patients who received pazopanib compared with less than 1% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    E) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical study of renal cell carcinoma treatment, increases in lipase values were reported in 27% of patients who received pazopanib hydrochloride (n=181). Serum lipase elevations were reported in 10 patients (4%) who received pazopanib hydrochloride, with grade 3 elevations reported in 6 patients and grade 4 elevations reported in 1 patient (Prod Info VOTRIENT(R) oral tablets, 2009).
    b) In clinical renal cell carcinoma studies, clinical pancreatitis was reported in 4 of 586 patients who received pazopanib hydrochloride therapy (Prod Info VOTRIENT(R) oral tablets, 2009).
    F) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, dysgeusia (all grades) was reported in 8% of patients who received pazopanib hydrochloride (n=290) compared with less than 1% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    G) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) Among clinical renal cell carcinoma studies, gastrointestinal perforation or fistula was reported in 5 of 586 patients who received pazopanib therapy. Perforation resulted in fatalities in 2 patients (Prod Info VOTRIENT(R) oral tablets, 2009).
    H) RECTAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, rectal hemorrhage was reported in 1% of patients who received pazopanib hydrochloride (n=290), and was one of the most commonly reported hemorrhagic events associated with pazopanib therapy (Prod Info VOTRIENT(R) oral tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, increased ALT (all grades) was reported in 53% of patients who received pazopanib hydrochloride (n=290) compared with 22% of patients who received placebo (n=145). Grade 3 and grade 4 ALT increases were reported in 10% and 2%, respectively, of patients who received pazopanib compared with 1% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    b) In a controlled clinical study of renal cell carcinoma treatment, ALT greater than 3 times the ULN was reported in 18% of patients who received pazopanib hydrochloride compared with 3% of patients who received placebo. In addition, ALT greater than 10 times the ULN was reported in 4% of patients who received pazopanib hydrochloride compared with less than 1% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    c) ALT greater than 3 times and 8 times the ULN were reported in 14% and 4%, respectively, of patients who received pazopanib (n=977) among all monotherapy studies (Prod Info VOTRIENT(R) oral tablets, 2009).
    d) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, increased AST (all grades) was reported in 53% of patients who received pazopanib hydrochloride (n=290) compared with 19% of patients who received placebo (n=145). Grade 3 and grade 4 AST increases were reported in 7% and less than 1%, respectively, of patients who received pazopanib compared with less than 1% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    e) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, increased total bilirubin (all grades) was reported in 36% of patients who received pazopanib hydrochloride (n=290) compared with 10% of patients who received placebo (n=145). Grade 3 and grade 4 increased total bilirubin were reported in 3% and less than 1%, respectively, of patients who received pazopanib compared with 1% and less than 1%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    f) Concurrent elevations in ALT greater than 3 times the ULN and bilirubin greater than 2 times the ULN, regardless of alkaline phosphatase levels, were reported in 13 of 977 patients who received pazopanib hydrochloride among all monotherapy studies. Two of the patients died due to disease progression and hepatic failure (Prod Info VOTRIENT(R) oral tablets, 2009).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma (RCC) treatment, proteinuria (all grades) was reported in 9% of patients who received pazopanib hydrochloride (n=290) compared with 0% of patients who received placebo (n=145), and led to pazopanib discontinuation in 2 patients. Among clinical RCC studies, proteinuria was reported in 8% of patients who received pazopanib therapy (n=586), with grade 3 and grade 4 proteinuria reported in 5 patients and 1 patient, respectively (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, hematuria was reported in 4% of patients who received pazopanib hydrochloride (n=290), and was one of the most commonly reported hemorrhagic events associated with pazopanib therapy (Prod Info VOTRIENT(R) oral tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, leukopenia (all grades) was reported in 37% of patients who received pazopanib hydrochloride (n=290) compared with 6% of patients who received placebo (n=145). Grade 3 and grade 4 leukopenia were not observed in either group (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, neutropenia (all grades) was reported in 34% of patients who received pazopanib hydrochloride (n=290) compared with 6% of patients who received placebo (n=145). Grade 3 and grade 4 neutropenia were reported in 1% and less than 1%, respectively, of patients who received pazopanib compared with 0% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, thrombocytopenia (all grades) was reported in 32% of patients who received pazopanib hydrochloride (n=290) compared with 5% of patients who received placebo (n=145). Grade 3 and grade 4 thrombocytopenia were reported in less than 1% and less than 1%, respectively, of patients who received pazopanib compared with 0% and less than 1%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, lymphocytopenia (all grades) was reported in 31% of patients who received pazopanib hydrochloride (n=290) compared with 24% of patients who received placebo (n=145). Grade 3 and grade 4 lymphocytopenia were reported in 4% and less than 1%, respectively, of patients who received pazopanib compared with 1% and 0%, respectively, of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    E) HEMORRHAGE OF BLOOD VESSEL
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, at least 1 hemorrhagic event was reported in 13% of patients who received pazopanib hydrochloride (n=290) compared with 5% of patients who received placebo (n=145). Serious hemorrhagic events (i.e., pulmonary, gastrointestinal, and genitourinary hemorrhage) were reported in 9 of the 37 pazopanib-treated patients. Death due to hemorrhage occurred in 4 pazopanib-treated patients compared with none of the placebo-treated patients (Prod Info VOTRIENT(R) oral tablets, 2009).
    b) Among clinical renal cell carcinoma studies, hemorrhagic events (all grades) were reported in 16% of patients who received pazopanib therapy (n=586), with grade 3 to 5 hemorrhagic events reported in 2% of patients. Fatalities due to hemorrhagic events occurred in 5 of 586 patients who received pazopanib (Prod Info VOTRIENT(R) oral tablets, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HAIR COLOR CHANGE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, hair color changes (all grades) were reported in 38% of patients who received pazopanib hydrochloride (n=290) compared with 3% of patients who received placebo (n=145). Grade 3 and grade 4 hair color changes were reported in less than 1% and 0%, respectively, of patients who received pazopanib compared with 0% of patients who received placebo (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, alopecia (all grades) was reported in 8% of patients who received pazopanib hydrochloride (n=290) compared with less than 1% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, rash (all grades) was reported in 8% of patients who received pazopanib hydrochloride (n=290) compared with 3% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) ACRAL ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, palmar-plantar erythrodysesthesia (all grades) was reported in 6% of patients who received pazopanib hydrochloride (n=290) compared with less than 1% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) INCREASED GLUCOSE LEVEL
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, increased serum glucose concentration (all grades) was reported in 41% of patients who received pazopanib hydrochloride (n=290) compared with 33% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    B) DECREASED GLUCOSE LEVEL
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, decreased serum glucose concentration was reported in 17% of patients who received pazopanib hydrochloride (n=290) compared with 3% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).
    C) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma (RCC) treatment, hypothyroidism was reported in 7% of patients who received pazopanib hydrochloride (n=290) compared with 0% of patients who received placebo (n=145). Among clinical RCC studies, hypothyroidism was reported in 4% of patients who received pazopanib therapy (n=586). TSH increases from normal at baseline to above normal range at post-baseline visits occurred in 27% of pazopanib-treated patients compared with 5% of placebo-treated patients (Prod Info VOTRIENT(R) oral tablets, 2009).
    D) WEIGHT DECREASED
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blinded, controlled study of renal cell carcinoma treatment, weight decreased (all grades) was reported in 9% of patients who received pazopanib hydrochloride (n=290) compared with 3% of patients who received placebo (n=145) (Prod Info VOTRIENT(R) oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Pazopanib is classified as FDA pregnancy category D. Pazopanib may result in fetal harm when used during pregnancy. Advise women to avoid pregnancy during pazopanib treatment. If pregnancy occurs, apprise patient of potential for fetal harm. In animal studies, there was evidence of teratogenicity, embryotoxicity, fetotoxicity, and spontaneous abortion in animals exposed to pazopanib. It is not known whether pazopanib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. Discontinue nursing or discontinue treatment, taking into account the importance of the drug to the mother.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, there was evidence of teratogenicity, embryotoxicity, fetotoxicity, and spontaneous abortion following exposure to pazopanib. Cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, reduced fetal body weight, and embryolethality were reported at pazopanib doses approximately 0.1 times the human exposure based on AUC (Prod Info VOTRIENT(R) oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified pazopanib as FDA pregnancy category D (Prod Info VOTRIENT(R) oral tablets, 2016).
    2) Pazopanib may result in fetal harm when used during pregnancy. Although there are no adequate and well-controlled studies of pazopanib use during pregnancy, the drug is expected to result in adverse reproductive effects based on its mechanism of action. Advise women to avoid pregnancy during pazopanib treatment. If pregnancy occurs, apprise patient of potential for fetal harm (Prod Info VOTRIENT(R) oral tablets, 2016).
    B) CONTRACEPTION
    1) Advise women of childbearing potential to use effective contraception during treatment and for at least 2 weeks after the last treatment dose (Prod Info VOTRIENT(R) oral tablets, 2016).
    C) ANIMAL STUDIES
    1) In animal studies, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was reported at doses approximately 0.007 times the human exposure. Severe maternal body weight loss and 100% litter loss were also reported at doses 0.02 times the human exposure. Reduced fetal weight was reported at doses of 3 mg/kg/day or greater (AUC not calculated) (Prod Info VOTRIENT(R) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether pazopanib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. Discontinue nursing or discontinue treatment, taking into account the importance of the drug to the mother (Prod Info VOTRIENT(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Reduced fertility, including preimplantation loss and early resorptions, were reported in female animals who received pazopanib at doses approximately 0.4 times the human exposure. Total litter resorption also occurred following doses approximately 0.8 times the human exposure. In males, following 15 weeks of dosing, decreased sperm production rates and testicular sperm concentrations occurred at doses of 3 mg/kg/day or greater, decreased epididymal sperm concentrations occurred at doses approximately 0.35 times the human exposure, and decreased sperm motility occurred at doses of 100 mg/kg/day or greater. Decreased testicular and epididymal weights, atrophy and degeneration of the testes, and epididymal cribiform change, hypospermia, and aspermia were also observed in males at doses approximately 0.35 times the human exposure during a 6-month study (Prod Info VOTRIENT(R) oral tablets, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) Administration of pazopanib at doses approximately 1.4 times the human exposure for 2 years in CD-1 mice did not result in an increased incidence of neoplasms. Duodenal adenocarcinoma was observed in male and female Sprague-Dawley rats following administration of pazopanib at doses approximately 0.3 times the human exposure for 2 years (Prod Info VOTRIENT(R) oral tablets, 2016).

Genotoxicity

    A) Pazopanib was not mutagenic according to the microbial mutagenesis (Ames) assay. Pazopanib was also not clastogenic in the in vitro cytogenetic assay, using primary human lymphocytes, and in the in vivo rat micronucleus assay (Prod Info VOTRIENT(R) oral tablets, 2016).

Summary Of Exposure

    A) USES: Indicated for the treatment of advanced renal cell carcinoma.
    B) PHARMACOLOGY: Inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptors alpha and beta, fibroblast growth factor receptors 1 and 3, cytokine receptor, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein receptor tyrosine kinase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration include: bone marrow suppression (i.e., leukopenia, neutropenia, and thrombocytopenia), hypertension, hair depigmentation, nausea, vomiting, diarrhea, and anorexia.
    2) RARE: QT prolongation, torsades de pointes, hemorrhagic events (i.e., pulmonary, gastrointestinal, genitourinary, and cerebral hemorrhage), and severe hepatotoxicity, with fatalities, have been rarely reported with pazopanib therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: fatigue and hypertension were reported in patients receiving 2,000 mg daily and 1,000 mg daily, respectively.
    2) SEVERE POISONING: Severe toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses, and may include myelosuppression, nausea, vomiting, diarrhea, hypertension, and possibly QTc prolongation, bleeding and hepatotoxicity.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzymes after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor serial CBC with differential and platelet counts.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Treatment

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 demonstrating severe fluid and electrolyte imbalance, cardiovascular instability, or severe hepatotoxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions (or a single extra dose) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a 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 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 vital signs and liver enzymes after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor serial CBC with differential and platelet counts.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and liver enzymes after significant overdose.
    2) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    3) Monitor serial CBC with differential and platelet counts.
    4) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    C) HYPERTENSIVE DISORDER
    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).
    D) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    E) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective due to high protein binding (greater than 99%) (Prod Info VOTRIENT(R) oral tablets, 2009).

Range Of Toxicity

Summary

    A) A toxic dose has not been established. Grade 3 fatigue and grade 3 hypertension were reported in patients receiving pazopanib orally at doses of 2,000 mg daily and 1,000 mg daily, respectively.
    B) THERAPEUTIC DOSE: The recommended dose is 800 mg orally once daily.

Therapeutic Dose

    7.2.1) ADULT
    A) 800 mg orally once daily, either 1 hour before or 2 hours after food (Prod Info VOTRIENT(R) oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info VOTRIENT(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) Grade 3 fatigue and grade 3 hypertension were reported in patients receiving pazopanib orally at doses of 2,000 mg daily and 1,000 mg daily, respectively (Prod Info VOTRIENT(R) oral tablets, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pazopanib is a multiple tyrosine kinase inhibitor, including inhibition of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-alpha and -beta, fibroblast growth factor receptor (FGFR) -1 and -3, cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit and PDGFR-beta receptors. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice (Prod Info VOTRIENT(R) oral tablets, 2009).

Physicochemical

Physical Characteristics

    A) Pazopanib hydrochloride is a white to yellow solid that is slightly soluble at pH 1 and insoluble above pH 4 in aqueous media (Prod Info VOTRIENT(R) oral tablets, 2009).

Molecular Weight

    A) 473.99 (Prod Info VOTRIENT(R) oral tablets, 2009)

References

General Bibliography

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    2) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    3) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
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    8) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
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    26) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
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    28) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    29) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    30) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    31) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    32) Product Information: VOTRIENT(R) oral tablets, pazopanib oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2014.
    33) Product Information: VOTRIENT(R) oral tablets, pazopanib oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2015.
    34) Product Information: VOTRIENT(R) oral tablets, pazopanib oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2016.
    35) Product Information: VOTRIENT(R) oral tablets, pazopanib oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2009.
    36) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
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    42) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
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