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Votrient

Pronunciation

Generic Name: Pazopanib Hydrochloride
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide monohydrochloride
Molecular Formula: C21H23N7O2S
CAS Number: 635702-64-6

Warning(s)

REMS:

FDA approved a REMS for pazopanib to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.1 2

Uses for Votrient

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma.1 2

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Votrient Dosage and Administration

General

  • BP should be adequately controlled prior to initiating therapy.1 (See Hypertension under Cautions.)

  • A risk management program (Risk Evaluation and Mitigation Strategy, REMS) has been developed to inform patients of the serious risks associated with pazopanib and the need for laboratory monitoring during therapy.2 6 A medication guide must be provided to the patient with each prescription.2 6

Administration

Oral Administration

Administer orally without food (i.e., ≥1 hour before or 2 hours after a meal).1

Swallow tablets whole and do not crush; crushing tablets increases rate of absorption and systemic exposure.1

Dosage

Available as pazopanib hydrochloride; dosage expressed in terms of pazopanib.1

Adults

Renal Cell Carcinoma
Oral

800 mg once daily.1 Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.3 In principal efficacy study, therapy was continued for a median of 7.4 months.1

Dosage Modification
Oral

In general, when dosage modification is required, reduce dosage by 400 mg daily initially; adjust subsequent dosage in increments or decrements of 200 mg daily, depending on individual patient tolerability.1

Hepatotoxicity
Table 1. Recommended Dosage Modification for Hepatotoxicity1

ALT and/or Bilirubin Concentrations

Recommended Action

Serum ALT concentration 3–8 times ULN

Continue pazopanib; monitor liver function weekly until serum ALT concentration returns to grade 1 or baseline

Serum ALT concentration >8 times ULN

Interrupt therapy until serum ALT concentration returns to grade 1 or baseline; if benefit outweighs risk, reinitiate pazopanib at a reduced dosage of ≤400 mg once daily; following reinitiation, monitor liver function weekly for 8 weeks; if serum ALT concentration rises to >3 times ULN, discontinue pazopanib permanently

Serum ALT concentration >3 times ULN and mild, indirect (unconjugated) hyperbilirubinemia in patients with Gilbert's syndrome

Manage per recommendations for patients with isolated ALT elevations

Serum ALT concentration >3 times ULN and serum bilirubin concentration >2 times ULN

Discontinue pazopanib permanently; monitor liver function until hepatotoxicity resolves

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use with potent inhibitors or inducers of CYP3A4 may alter plasma concentrations of pazopanib.1 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, reduce pazopanib dosage to 400 mg once daily.1 This dosage is predicted to adjust the AUC of pazopanib to the range observed without CYP3A4 inhibitors; no clinical data with use of this dosage in patients concomitantly receiving potent CYP3A4 inhibitors.1 Further dosage reductions may be required if adverse effects occur during therapy.1

Avoid concomitant use with a potent CYP3A4 inducer.1

Prescribing Limits

Adults

Renal Cell Carcinoma
Oral

Maximum 800 mg daily.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration ≤1.5 times ULN and any concentration of ALT15 ): No dosage adjustment required.18

Moderate hepatic impairment (total bilirubin concentration >1.5 times but ≤3 times ULN and any concentration of ALT15 ): Reduce dosage to 200 mg once daily.1

Severe hepatic impairment (total bilirubin concentration >3 times ULN and any concentration of ALT): Avoid use. 1

Renal Impairment

Dosage adjustment not required.1

Cautions for Votrient

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Hepatic Effects

Severe or fatal hepatotoxicity, manifested as increases in concentrations of aminotransferases (ALT, AST) and bilirubin, reported.1 Most (92.5%) cases of aminotransferase elevations (of any grade) occurred during first 18 weeks of therapy.1

Because pazopanib inhibits UGT1A1 (an enzyme that catalyzes the glucuronidation of bilirubin for elimination), mild elevations in indirect (unconjugated) bilirubin may occur in patients with deficient glucuronidation of bilirubin (i.e., Gilbert's syndrome).1 8

Perform liver function tests prior to initiation of therapy, at least once every 4 weeks for at least the first 4 months or as clinically indicated, and periodically thereafter.1

If hepatotoxicity occurs, interrupt therapy, reduce dosage, or discontinue pazopanib permanently.1 (See Hepatotoxicity under Dosage and Administration.)

Other Warnings and Precautions

QT Interval Prolongation and Torsades de Pointes

Prolongation of QT interval and torsades de pointes reported.1

Use with caution in patients with history of QT interval prolongation, patients receiving antiarrhythmic agents or other drugs known to cause prolongation of the QT interval, and patients with relevant preexisting cardiac disease.1

Monitor ECG prior to initiation of pazopanib and periodically during therapy; maintain serum electrolytes (e.g., calcium, magnesium, potassium) within normal range.1

Hemorrhage

Hemorrhage, sometimes severe or fatal, reported.1 Most common hemorrhagic events reported include hematuria, epistaxis, hemoptysis, and rectal hemorrhage; severe hemorrhagic events reported include pulmonary, GI, GU, and cerebral/intracranial hemorrhage.1

Not evaluated in patients with history of hemoptysis or patients with cerebral or GI hemorrhage within the past 6 months; avoid use in such patients.1

Thromboembolism

Arterial thromboembolic events (e.g., myocardial infarction/ischemia, angina, cerebrovascular accident, TIA, ischemic stroke), sometimes severe or fatal, reported.1

Use with caution in patients who are at increased risk or who have a history of arterial thromboembolic events.1 Not evaluated in patients with history of an arterial thromboembolic event within the past 6 months; avoid use in such patients.1

GI Effects

GI perforation or fistula, sometimes fatal, reported.1

Use with caution in patients at increased risk for GI perforation or fistula formation.1

Monitor for manifestations of GI perforation or fistula formation during therapy.1

Hypertension

Hypertension (SBP ≥150 mm Hg or DBP ≥100 mm Hg) reported.1 Most (88%) cases occurred during first 18 weeks of therapy.1 Majority of cases were managed with antihypertensive therapy or by reduction in pazopanib dosage.1 Hypertensive crisis reported rarely.1

Monitor BP and treat hypertension with standard antihypertensive therapy as needed.1 If hypertension persists despite use of antihypertensive therapy, reduce pazopanib dosage1 (i.e., by 400 mg daily initially, then by 200 mg daily, depending on individual patient tolerability).15 If hypertension is severe or persists despite use of antihypertensive therapy and pazopanib dosage reduction, discontinue pazopanib.1

Wound-healing Complications

Effect on wound healing not established.1

Inhibitors of vascular endothelial growth factor receptor (VEGFR), including pazopanib, may impair wound healing; discontinue pazopanib ≥7 days prior to scheduled surgery.1 Decision to resume therapy should be based on clinical assessment of adequacy of wound healing.1

Discontinue pazopanib if wound dehiscence occurs.1

Hypothyroidism

Hypothyroidism reported.1

Proactive monitoring of thyroid function tests is recommended.1

Proteinuria

Proteinuria reported.1

Perform urinalysis prior to initiation of pazopanib and periodically during therapy; discontinue pazopanib if grade 4 proteinuria occurs.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, fetotoxicity, and abortifacient effects demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Adequate Patient Evaluation and Monitoring

Monitor liver function tests, ECG, electrolytes, BP, and urinalysis prior to initiation of pazopanib and periodically during therapy.1 Proactive monitoring of thyroid function tests is recommended.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether pazopanib is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger patients, but increased sensitivity cannot be ruled out.1 Patients >60 years of age may be at greater risk of hepatotoxicity (i.e., serum ALT concentration >3 times ULN).1

Hepatic Impairment

Decreased pazopanib clearance in patients with moderate hepatic impairment (total serum bilirubin concentration >1.5 times but ≤3 times ULN and any concentration of ALT15 ); dosage reduction necessary.1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Safety and pharmacokinetics not established in patients with severe hepatic impairment; use not recommended.1

Renal Impairment

Renal impairment unlikely to affect pharmacokinetics (e.g., exposure) of pazopanib; no dosage adjustment necessary in patients with renal impairment.1 (See Special Populations under Pharmacokinetics.)

Pharmacokinetic profile not established in patients with severe renal impairment (Clcr <30 mL/minute) or in patients undergoing peritoneal dialysis or hemodialysis.1

Common Adverse Effects

Diarrhea,1 hypertension,1 hair color changes (depigmentation),1 nausea,1 anorexia,1 vomiting,1 fatigue,1 asthenia,1 abdominal pain,1 headache.1

Laboratory abnormalities: Increased ALT,1 AST,1 and bilirubin1 concentrations; increased or decreased glucose concentrations;1 cytopenias (leukopenia,1 neutropenia,1 thrombocytopenia,1 lymphocytopenia1 ); decreased sodium,1 magnesium,1 and phosphorus1 concentrations.

Interactions for Votrient

Metabolized principally by CYP3A4 and, to a lesser extent, by CYP isoenzymes 1A2 and 2C8.1

Weak inhibitor of CYP isoenzymes 3A4, 2C8, and 2D6, but has no effect on CYP isoenzymes 1A2, 2C9 and 2C19; may induce CYP3A4.1

Inhibits glucuronidation by UGT1A1; also inhibits organic anion transport protein (OATP) 1B1.1

Substrate of P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Pharmacokinetic interaction (increased peak plasma concentrations and AUC of pazopanib).1 Avoid concomitant use with a potent CYP3A4 inhibitor; if concomitant therapy cannot be avoided, reduce pazopanib dosage.1 (See Specific Drugs and Foods under Interactions and also see Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.)

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentration of pazopanib).1 Avoid concomitant use and consider selecting an alternative agent with minimal or no enzyme induction potential; if long-term use of a potent CYP3A4 inducer is required, do not initiate pazopanib therapy.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 3A4, 2D6, or 2C8: Pharmacokinetic interaction (increased exposure to substrate).1 Avoid concomitant use with substrates of CYP isoenzymes 3A4, 2D6, or 2C8 that have a narrow therapeutic index.1

Substrates of CYP isoenzymes 1A2, 2C9, or 2C19: No clinically relevant pharmacokinetic interaction.1

Drugs Transported by Organic Anion Transport Protein (OATP)

Potential pharmacokinetic interaction (increased plasma concentration of drugs transported by OATP1B1).1

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)

Potential pharmacokinetic interaction (increased plasma concentration of drugs metabolized by UGT1A1).1

Drugs that Prolong the QT Interval

Risk of prolonged QT interval and torsades de pointes.1 Use concomitantly with caution.1 (See QT Interval Prolongation and Torsades de Pointes under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antiarrhythmic agents

Use concomitantly with caution1 (see QT Interval Prolongation and Torsades de Pointes under Cautions)

Caffeine

No clinically relevant pharmacokinetic interaction1

Clarithromycin

Possible increased plasma pazopanib concentrations1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce pazopanib dosage to 400 mg once daily; further dosage reductions may be required if adverse effects occur1

Dextromethorphan

Increased urine concentrations of dextromethorphan and dextrorphan1

Grapefruit or grapefruit juice

Possible increased plasma pazopanib concentrations1

Avoid concomitant use1

Ketoconazole

Increased peak plasma concentrations and AUC of pazopanib following concomitant use with pazopanib ophthalmic solution1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce pazopanib dosage to 400 mg once daily; further dosage reductions may be required if adverse effects occur1

Lapatinib

Increased peak plasma concentrations and AUC of pazopanib1

Midazolam

Increased peak plasma concentrations and AUC of midazolam1

Omeprazole

No clinically relevant pharmacokinetic interaction1

Paclitaxel

Increased peak plasma concentrations and AUC of paclitaxel 1

Rifampin

Possible decreased plasma pazopanib concentrations1

Avoid concomitant use; select an alternative agent with minimal or no enzyme induction potential1

If long-term use of a potent CYP3A4 inducer is required, do not initiate pazopanib therapy1

Ritonavir

Possible increased plasma pazopanib concentrations1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce pazopanib dosage to 400 mg once daily; further dosage reductions may be required if adverse effects occur1

Warfarin

No clinically relevant pharmacokinetic interaction1

Votrient Pharmacokinetics

Absorption

Bioavailability

Incompletely absorbed from GI tract, with reported bioavailabilities of 14–39%.18

Following oral administration, peak plasma concentrations are attained within 2–4 hours.1

Administration of a single 400-mg crushed tablet increased peak plasma concentrations by twofold and AUC by 46% and decreased time to peak plasma concentrations by approximately 2 hours.1

Food

Food increases peak plasma concentrations and AUC by approximately twofold.1

Distribution

Extent

Not known whether pazopanib is distributed into human milk.1

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4 and, to a lesser extent, by CYP1A2 and CYP2C8.1 Metabolites account for <10% of administered dose.2 18

Elimination Route

Excreted principally in feces (approximately 82%) and, to a lesser extent, in urine (<4%).1

Hemodialysis not expected to enhance elimination because pazopanib is highly bound to plasma proteins and is not substantially excreted renally.1

Half-life

Approximately 30.9 hours.1

Special Populations

Clearance is reduced by 50% in patients with moderate hepatic impairment (total serum bilirubin concentration >1.5 times but ≤3 times ULN15 ).1 (See Hepatic Impairment under Dosage and Administration.)

Clcr (within the range of 30–150 mL/minute) does not substantially affect pazopanib clearance.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple receptor tyrosine kinases (RTKs), which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1 2 4 10 12 13

  • Inhibits signal transduction pathways involving multiple receptor tyrosine kinases, principally vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factors (PDGFR-α, PDGFR-β), and stem cell factor receptor (i.e., c-kit).7 12 17 18

  • Has modest inhibitory effects on fibroblast growth factor receptors (i.e., FGFR1, FGFR3), transmembrane glycoprotein receptor tyrosine kinase (c-Fms), leukocyte-specific protein tyrosine kinase (Lck), and interleukin-2 receptor inducible T-cell kinase (Itk).7 12

  • Shown to inhibit angiogenesis in a mouse model and the growth of some human tumor xenografts in mice.1 12

  • Appears to be as potent as sorafenib and sunitinib against VEGFR (i.e., VEGFR-1, VEGFR-2, VEGFR-3) and less potent than sunitinib against fms-like tyrosine kinase 3 (Flt-3).7 13 Differences in potencies against non-VEGF receptors may account for variabilities in non-VEGFR-related (“off-target”) adverse effects observed with pazopanib (e.g., hepatotoxicity, lower incidence of palmar-plantar erythrodysesthesia [hand-foot syndrome] and rash compared with sorafenib or sunitinib [based on indirect cross-study comparison], lower incidence of and less severe myelosuppression compared with sunitinib [based on indirect cross-study comparison]).4 11 13

  • Inhibits UGT1A1, an enzyme that catalyzes the glucuronidation of bilirubin for elimination.1 Patients who are homozygous for the UGT1A1*28 allele (characterized by a mutation in the promoter region of the UGT1A1 gene) have reduced expression of UGT1A1, which may manifest as mild hyperbilirubinemia (i.e., Gilbert's syndrome).1 16 Mild elevations of indirect (unconjugated) bilirubin concentrations may occur in patients with Gilbert's syndrome receiving pazopanib.1

Advice to Patients

  • Pazopanib medication guide must be provided to patient each time the drug is dispensed;2 6 importance of patient reading the medication guide prior to initiating pazopanib therapy and each time the prescription is refilled.1

  • Importance of taking pazopanib without food (i.e., ≥1 hour before or 2 hours after a meal).1 Importance of swallowing tablets whole and not crushing the tablets.1 Avoid grapefruit or grapefruit juice while taking the drug.1

  • If a dose is missed by <12 hours, take it as soon as it is remembered, and take the next dose at the regularly scheduled time.1 Do not take more than one dose at a time.1

  • Risk of adverse hepatic effects.1 Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusual fatigue, unusual darkening of urine, nausea, vomiting, loss of appetite, right-upper quadrant pain, easy bruising).1

  • Risk of adverse cardiovascular effects.1 Importance of monitoring BP regularly during therapy.1 Importance of immediately reporting irregular or fast heart beat, fainting, or manifestations of a heart attack or stroke (e.g., chest pain or pressure; pain in arms, back, neck, or jaw; shortness of breath; numbness or weakness on one side of body; trouble talking; headache; dizziness).1

  • Risk of bleeding.1 Importance of promptly informing clinicians of any unusual bleeding, bruising, or wounds that do not heal.1 15

  • Risk of adverse GI effects (e.g., diarrhea, nausea, vomiting, GI perforation).1 Importance of understanding measures to manage mild diarrhea and of notifying clinician if moderate or severe diarrhea occurs.1 Importance of immediately reporting any manifestations of GI perforation (e.g., abdominal pain or swelling, vomiting blood, black sticky stools).1

  • Risk of depigmentation of hair and skin.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease, hepatic impairment).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pazopanib Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg (of pazopanib)

Votrient

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Votrient (pazopanib hydrochloride) tablets prescribing information. Research Triangle Park, NC: 2010 Apr.

2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 24-465: Summary review. From FDA website. Accessed 2010 Mar 8.

3. Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010; 28:1061-8. [PubMed 20100962]

4. Limvorasak S, Posadas EM. Pazopanib: therapeutic developments. Expert Opin Pharmacother. 2009; 10:3091-102. [PubMed 19954277]

5. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ). From ClinicalTrials.gov registry. Accessed 2010 Mar 19.

6. Food and Drug Administration. Votrient (pazopanib) tablets. Risk Evaluation and Mitigation Strategy (REMS) document. Rockville, MD; 2010 Mar 8. From FDA website.

7. Kumar R, Crouthamel MC, Rominger DH et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer. 2009; 101:1717-23. [PubMed 19844230]

8. Reck B, Xue Z, Huang L et al. Polymorphisms in the UGT1A locus are associated with hyperbilirubinemia in pazopanib treated patients. Abstract 2231 (presented at the 59th Annual ASHG meeting). Honolulu, HI: 2009 Oct 21.

10. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs. 2008; 9:1324-35. [PubMed 19037839]

11. Hutson TE, Davis ID, Machiels JP et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010; 28:475-80. [PubMed 20008644]

12. Kumar R, Knick VB, Rudolph SK et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007; 6:2012-21. [PubMed 17620431]

13. Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. 2010; doi:10.1016/j.ctrv.2010.01.003.

15. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

16. Strassburg CP. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics. 2008; 9:703-15. [PubMed 18518849]

17. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 24-465: Medical review(s). From FDA website. Accessed 2010 May 25.

18. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 24-465: Clinical pharmacology and biopharmaceutics review(s). From FDA website. Accessed 2010 May 25.

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