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Pazopanib

Pronunciation: paz-OH-pa-nib
Class: Tyrosine kinase inhibitor

Trade Names

Votrient
- Tablets 200 mg

Pharmacology

Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)–1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)–alpha and PDGFR-beta, fibroblast growth factor receptor (FGFR)–1 and FGFR-3, cytokine receptor, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein receptor tyrosine kinase.

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Pharmacokinetics

Absorption

T max is 2 to 4 h. Crushing the tablet increases C max 2-fold and decreases T max by 2 h. Administration with high- or low-fat meals increases AUC and C max 2-fold.

Distribution

Protein binding is greater than 99%.

Metabolism

Metabolized by CYP3A4 with minor contribution from CYP1A2 and CYP2C8.

Elimination

Mean half-life is 30.9 h. Eliminated primarily in the feces, with renal elimination accounting for less than 4% of a dose.

Special Populations

Renal Function Impairment

No data are available in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. Renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib.

Hepatic Function Impairment

Cl was decreased by 50% in patients with moderate hepatic impairment. No data are available in patients with mild or severe hepatic impairment.

Indications and Usage

Treatment of advanced renal cell carcinoma.

Contraindications

Standard considerations.

Dosage and Administration

Advanced Renal Cell Carcinoma
Adults

PO 800 mg once daily without food (max, 800 mg daily).

Dosage adjustment

Initial dose reduction should be 400 mg, and additional dose increases or decreases should be in 200 mg increments based on individual tolerability (max, 800 mg daily).

Isolated ALT elevation 3 to 8 times ULN

Continue treatment and monitor liver function weekly until ALT returns to grade 1 or baseline.

Isolated ALT elevation greater than 8 times ULN

Interrupt treatment until ALT returns to grade 1 or baseline. Consider restarting pazopanib at no more than 400 mg once daily and measure liver function weekly for 8 wk. If ALT elevation of more than 3 times ULN recurs, permanently discontinue pazopanib.

ALT elevation greater than 3 times ULN and bilirubin elevation greater than 2 times ULN

Permanently discontinue pazopanib and monitor patient until resolution.

Hepatic function impairment

Decrease dose to 200 mg in patients with moderated hepatic impairment. Not recommended in patients with severe hepatic impairment.

General Advice

  • Administer once daily without food 1 h before or 2 h after a meal.
  • Caution patient not to chew, crush, or break tablets.
  • If a dose is missed, it should not be taken if it is less than 12 h until the next dose.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Agents with a narrow therapeutic index metabolized by CYP3A4 (eg, cyclosporine), CYP2C8, or CYP2D6

Plasma concentrations of these agents may be elevated by pazopanib, increasing the pharmacologic effects and risk of adverse reactions. Coadministration is not recommended.

Drugs that prolong the QT interval (eg, antiarrhythmic agents)

Additive QT interval prolongation may occur, increasing the risk of cardiac arrhythmias, including torsades de pointes. Coadminister with caution. Monitor patients for QT prolongation.

Grapefruit juice

Pazopanib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Lapatinib

Pazopanib AUC and C max are increased approximately 50% to 60%, respectively, compared with taking pazopanib alone. Observe the patient for adverse reactions. Reduce the pazopanib dose as needed.

Midazolam

Coadministration of midazolam and pazopanib increases the midazolam AUC and C max by approximately 30%. Observe the response of the patient. If an interaction is suspected, adjust the midazolam dose as needed.

Paclitaxel

Coadministration of pazopanib and paclitaxel may increase the paclitaxel AUC and C max . Observe the response of the patient. If an interaction is suspected, adjust the paclitaxel dose as needed.

Strong CYP3A4 inducers (eg, rifampin)

Pazopanib plasma concentrations may be reduced, decreasing the efficacy. Avoid coadministration. Do not give pazopanib to patients who cannot avoid long-term use of strong CYP3A4 inducers.

Strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, ritonavir)

Pazopanib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration. If coadministration cannot be avoided, reduce the pazopanib dosage to 400 mg once daily. Observe the patient for adverse reactions and further reduce the pazopanib dose if needed.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (47%); MI/ischemia (2%); QT prolongation (less than 2%); transient ischemic attack (TIA) (1%); cerebral/intracranial hemorrhage, cerebral vascular accident (CVA), torsades de pointes (less than 1%).

CNS

Fatigue (19%); asthenia (14%); headache (10%).

Dermatologic

Alopecia, rash (8%); skin depigmentation (3%).

EENT

Epistaxis (2%).

GI

Diarrhea (52%); nausea (26%); anorexia (22%); vomiting (21%); abdominal pain (11%); dysgeusia (8%); dyspepsia (5%); rectal hemorrhage (1%).

Genitourinary

Proteinuria (9%); hematuria (4%)

Hematologic-Lymphatic

Leukopenia (37%); neutropenia (34%); thrombocytopenia (32%); lymphocytopenia (31%).

Lab Tests

ALT increased, AST increased (53%); glucose increased (41%); total bilirubin increased (36%); phosphorus decreased (34%); sodium decreased (31%); elevated TSH, lipase increased (27%); magnesium decreased (26%); ALT greater than 3 times ULN (18%); glucose decreased (17%); ALT greater than 10 times ULN (4%); ALT greater than 3 times ULN and bilirubin greater than 2 times ULN (2%).

Metabolic-Nutritional

Hypothyroidism (7%).

Respiratory

Hemoptysis (2%).

Miscellaneous

Hair color changes (38%); hemorrhage (13%); weight decreased (9%); palmar-plantar erythrodysesthesia (6%); chest pain (5%); facial edema, fatal hemorrhage, GI perforation or fistula (1%).

Precautions

Warnings

Severe and fatal hepatoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended (see Administration and Dosage).


Monitor

Monitor serum liver tests before initiation of therapy and at least once every 4 wk for at least the first 4 months of therapy or as indicated. Periodically monitor serum liver tests thereafter. Baseline and periodic monitoring of ECG and maintenance of electrolytes within the healthy range should be performed. Monitor for symptoms of GI perforation or fistula. Monitor for development of hypertension. Monitor thyroid function tests. Perform a baseline and periodic urinalysis during therapy.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

The greater sensitivity of some older individuals cannot be ruled out.

Hepatic Function

Dose adjustment necessary in patients with moderate hepatic impairment. Pazopanib has not been studied in patients with severe hepatic impairment; use is not recommended.

CV

MI, angina, ischemic stroke, and TIA occurred in clinical studies. These events were sometimes fatal. Use with caution in patients at risk for these events or who have a history of these events. Avoid use in patients that have had any of these events in the past 6 mo.

GI effects

GI perforation, sometimes fatal, and fistula have been reported.

Hemorrhage

Fatal hemorrhage has occurred. Avoid use in patients with a history of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 mo.

Hypertension

Treatment-emergent hypertension has been reported, usually early in the course of therapy. May require dosage reduction of pazopanib if not controlled with antihypertensives.

Hypothyroidism

May occur.

Proteinuria

Has been reported. Discontinue pazopanib in patients with grade 4 proteinuria.

QT prolongation and torsades de pointes

May occur. Use with caution in patients with a history of QT prolongation, relevant preexisting cardiac disease, and those taking medications that may prolong the QT interval.

Wound healing

Temporarily interrupt therapy at least 7 days prior to surgical procedures. Discontinue in patients with wound dehiscence.

Overdosage

Symptoms

Dose-limiting toxicity (grade 3 fatigue) and grade 3 hypertension have been reported with dosages up to 2,000 mg/day.

Patient Information

  • Instruct patients to read the Medication Guide before starting pazopanib therapy and to reread it with each refill.
  • Instruct patients to take the prescribed dose without food 1 h before or 2 h after a meal.
  • Instruct patients that if a dose is missed, it should not be taken if it is less than 12 h until the next dose.
  • Inform patients that therapy with pazopanib may result in hepatobiliary laboratory abnormalities. Serum liver tests (ALT, AST, bilirubin) should be monitored prior to initiation of therapy and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated.
  • Inform patients that they should report any of the following signs and symptoms of liver problems to their health care provider right away: yellowing of the skin or the whites of the eyes, dark urine, unusual tiredness, right upper stomach pain.
  • Inform patients that GI adverse reactions such as diarrhea, nausea, and vomiting have been reported with pazopanib. Advise patients on management of diarrhea and instruct them to notify their health care provider if moderate to severe diarrhea occurs.
  • Advise women of childbearing potential of the potential hazard to the fetus and to avoid becoming pregnant.
  • Advise patients to inform their health care providers of all concomitant medications, vitamins, or dietary and herbal supplements.
  • Advise patient that depigmentation of the hair or skin may occur during treatment with pazopanib.

Copyright © 2009 Wolters Kluwer Health.

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