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Pazopanib

Medically reviewed by Drugs.com. Last updated on Jun 14, 2020.

Pronunciation

(paz OH pa nib)

Index Terms

  • GW786034
  • Pazopanib HCl
  • Pazopanib Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Votrient: 200 mg

Brand Names: U.S.

  • Votrient

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Pazopanib is a tyrosine kinase (multikinase) inhibitor; limits tumor growth via inhibition of angiogenesis by inhibiting cell surface vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-alpha and -beta), fibroblast growth factor receptor (FGFR-1 and -3), cytokine receptor (cKIT), interleukin-2 receptor inducible T-cell kinase, lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).

Metabolism

Hepatic; primarily via CYP3A4, minor metabolism via CYP1A2 and CYP2C8

Excretion

Feces (primarily); urine (<4%)

Time to Peak

Plasma: 2 to 4 hours

Half-Life Elimination

~31 hours

Protein Binding

>99%

Special Populations: Hepatic Function Impairment

The median steady state Cmax and AUC in patients with moderate impairment (total bilirubin 1.5 to 3 times ULN and any ALT) administered a 200 mg dose were ~43% and ~29%, respectively, of the median values following administration of an 800 mg dose in patients with normal hepatic function. The median steady state Cmax and AUC in patients with severe impairment (total bilirubin >3 times ULN and any ALT) administered a 200 mg dose were ~18% and ~15%, respectively, of the median values after administration of an 800 mg dose in patients with normal hepatic function.

Use: Labeled Indications

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma in adults.

Soft tissue sarcoma, advanced: Treatment of advanced soft tissue sarcoma in adults who have received prior chemotherapy.

Limitations of use: The efficacy of pazopanib for the treatment of adipocytic soft tissue sarcoma or gastrointestinal stromal tumors (GIST) has not been demonstrated.

Off Label Uses

Desmoid tumors (progressive)

Data from a multicenter, open-label, randomized phase 2 study support the use of pazopanib in the treatment of progressive desmoid tumors [Toulmonde 2019].

Thyroid cancer (advanced, differentiated)

Data from a phase 2 study support the use of pazopanib in the treatment of advanced differentiated thyroid cancer [Bible 2010], [Bible 2014].

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to pazopanib or any component of the formulation; use in pediatric patients <2 years of age (due to the antiangiogenic effects)

Dosing: Adult

Note: Withhold pazopanib treatment for at least 1 week prior to elective surgery; do not administer pazopanib for at least 2 weeks after major surgery and until adequate wound healing.

Desmoid tumors, progressive (off-label use): Oral: 800 mg once daily until disease progression or unacceptable toxicity for up to a maximum of 1 year (Toulmonde 2019).

Renal cell carcinoma, advanced: Oral: 800 mg once daily until disease progression or unacceptable toxicity (Sternberg 2010).

Soft tissue sarcoma, advanced: Oral: 800 mg once daily until disease progression or unacceptable toxicity (Van Der Graaf 2012).

Thyroid cancer, advanced differentiated (off-label use): Oral: 800 mg once daily until disease progression or unacceptable toxicity (Bible 2010; Bible 2014).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult Drug Interactions database for more information.

Missed doses: If a dose is missed, do not take if less than 12 hours until the next dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended Pazopanib Dose Reduction Levels for Adverse Reactions

Dose reduction level

Renal cell carcinoma

Soft tissue sarcoma

Usual (initial) dose

800 mg once daily

800 mg once daily

First reduction

400 mg once daily

600 mg once daily

Second reduction

200 mg once daily

400 mg once daily

Permanently discontinue pazopanib if unable to tolerate the second dose reduction.

Recommended Pazopanib Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Pazopanib dosage modification

Cardiotoxicity: Left ventricular systolic dysfunction

Symptomatic or grade 3

Withhold pazopanib until improvement to < grade 3; resume pazopanib treatment based on clinical judgement.

Grade 4

Permanently discontinue pazopanib.

GI perforation

Any grade

Permanently discontinue pazopanib.

GI fistula

Grade 2 or 3

Withhold pazopanib and resume based on clinical judgement.

Grade 4

Permanently discontinue pazopanib.

Hemorrhagic events

Grade 2

Withhold pazopanib until improvement to ≤ grade 1; then resume pazopanib at a reduced dose. Discontinue pazopanib permanently if grade 2 hemorrhage recurs after pazopanib treatment interruption and dose reduction.

Grade 3 or 4

Permanently discontinue pazopanib.

Hypertension

Grade 2 or 3

Reduce pazopanib dose and initiate or adjust antihypertensive therapy. Permanently discontinue pazopanib if hypertension remains at grade 3 despite pazopanib dose reduction and adjustment of antihypertensive therapy.

Grade 4 or hypertensive crisis

Permanently discontinue pazopanib.

Hypothyroidism

n/a

Manage hypothyroidism as appropriate.

Infection

Serious

Institute appropriate anti-infective therapy promptly and consider pazopanib interruption or discontinuation.

Posterior reversible encephalopathy syndrome

Any grade

Permanently discontinue pazopanib.

Pulmonary toxicity: Interstitial lung disease

Any grade

Permanently discontinue pazopanib.

Thrombosis: Arterial thrombotic events

Any grade

Permanently discontinue pazopanib.

Thrombosis: Venous thrombotic events

Grade 3

Withhold pazopanib; resume pazopanib at the same dose if managed with appropriate therapy for at least 1 week.

Grade 4

Permanently discontinue pazopanib.

Thrombotic microangiopathy

Any grade

Permanently discontinue pazopanib.

Administration

Oral: Administer on an empty stomach, 1 hour before or 2 hours after a meal. Swallow tablets whole; do not crush (rate of absorption may be increased; may affect systemic exposure).

If concurrent use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacids in place of proton pump inhibitors and H2-receptor antagonists; separate pazopanib administration from short-acting antacids by several hours.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Antacids: May decrease the serum concentration of PAZOPanib. Management: Avoid the use of antacids in combination with pazopanib whenever possible. Separate doses by several hours if antacid treatment is considered necessary. The impact of dose separation has not been investigated. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCRP/ABCG2 Inhibitors: May increase the serum concentration of PAZOPanib. Avoid combination

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of PAZOPanib. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of PAZOPanib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of PAZOPanib. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required if adverse reactions occur. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of PAZOPanib. Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Histamine H2 Receptor Antagonists: May decrease the serum concentration of PAZOPanib. Management: Avoid the use of histamine H2-antagonists in combination with pazopanib. Strategies to minimize the expected interaction between these agents (eg, dose separation) have not been investigated. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Avoid combination

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of PAZOPanib. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of PAZOPanib. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Repaglinide: CYP2C8 Inhibitors (Weak) may increase the serum concentration of Repaglinide. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Sacituzumab Govitecan: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be increased. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simvastatin: May enhance the adverse/toxic effect of PAZOPanib. Specifically, the risk for ALT/AST elevations may be increased. Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Tolvaptan: May increase the serum concentration of BCRP/ABCG2 Substrates. Management: Avoid concomitant use of BCRP/ABCG2 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the BCRP/ABCG2 substrate would be expected to increase with combined use. Consider therapy modification

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vinflunine: PAZOPanib may enhance the adverse/toxic effect of Vinflunine. Monitor therapy

Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (40% to 42%; early in treatment), bradycardia (2% to 19%), peripheral edema (STS: 14%), cardiac insufficiency (11% to 13%)

Central nervous system: Fatigue (19%; STS: 65%), tumor pain (STS: 29%), headache (10%; STS: 23%), dizziness (11%)

Dermatologic: Hair discoloration (38% to 39%), exfoliative dermatitis (STS: 18%), alopecia (8% to 12%), dermatological disease (STS: 11%), hypopigmentation (STS, skin: 11%), palmar-plantar erythrodysesthesia (6% to 11%)

Endocrine & metabolic: Weight loss (9%, STS: 48%), increased serum glucose (41% to 45%), increased thyroid-stimulating hormone (TSH), decreased serum albumin (STS: 34%), decreased serum phosphate (34%), decreased serum sodium (31%), decreased serum magnesium (26%), decreased serum glucose (17%), increased serum potassium (STS: 16%)

Gastrointestinal: Diarrhea (52% to 59%), nausea (26%, STS: 56%), decreased appetite (STS: 40%), anorexia (22%), vomiting (21%, STS: 33%), dysgeusia (8%, STS: 28%), increased serum lipase (27%), gastrointestinal pain (STS: 23%), abdominal pain (11%), mucositis (STS: 12%), stomatitis (STS: 11%)

Hematologic & oncologic: Leukopenia (37% to 44%; STS, grade 3: 1%), lymphocytopenia (31%; grades 3/4: ≤4%; STS: 43%, grade 3: 10%), thrombocytopenia (32% to 36%; grades 3/4: ≤6%; grade 4: ≤1%), neutropenia (33% to 34%; grades 3/4 [in patients of East Asian descent]: 12%; grades 3/4 [in patients of non-East Asian descent]: ≤4%), hemorrhage (13% to 22%, including pulmonary, gastrointestinal, and genitourinary, grade 4: 1%, including intracranial, subarachnoid, and peritoneal)

Hepatic: Increased serum AST (51% to 53%), increased serum ALT (4% to 53%), increased serum bilirubin (29% to 36%), increased serum alkaline phosphatase (STS: 32%)

Neuromuscular & skeletal: Musculoskeletal pain (STS: 23%), myalgia (STS: 23%), weakness (14%)

Respiratory: Dyspnea (STS: 20%), cough (STS: 17%)

Miscellaneous: Tumor pain (29%)

1% to 10%:

Cardiovascular: Chest pain (5% to 10%; STS: grade 3: 2%), left ventricular systolic dysfunction (STS: 8%), venous thrombosis (STS: 5%), ischemia (≤2%), myocardial infarction (≤2%), prolonged QT interval on ECG (2%), facial edema (RCC: 1%), transient ischemic attacks (RCC: 1%)

Central nervous system: Insomnia (STS: 9%), voice disorder (4% to 8%), chills (STS: 5%)

Dermatologic: Skin rash (RCC: 8%), skin depigmentation (RCC: 3%), xeroderma (STS: 6%), nail disease (STS: 5%)

Endocrine & metabolic: Hypothyroidism (4% to 8%)

Gastrointestinal: Dyspepsia (5% to 7%), anal hemorrhage (STS: 2%), gastrointestinal fistula (≤1%), gastrointestinal perforation (≤1%)

Genitourinary: Proteinuria (1% to 9%), hematuria (RCC: 4%)

Hematologic & oncologic: Oral hemorrhage (STS: 3%), rectal hemorrhage (RCC: 1%)

Ophthalmic: Blurred vision (STS: 5%)

Respiratory: Epistaxis (2% to 8%), pneumothorax (≤3%), hemoptysis (RCC: 2%)

Frequency not defined:

Cardiovascular: Decreased left ventricular ejection fraction, hypertensive crisis

Central nervous system: Reversible posterior leukoencephalopathy syndrome

Hematologic & oncologic: Hemolytic-uremic syndrome, neutropenic infection, thrombotic thrombocytopenic purpura

Hepatic: Hepatotoxicity, severe hepatotoxicity

Infection: Serious infection

Neuromuscular & skeletal: Arthralgia (RCC), muscle spasm (RCC)

<1%, postmarketing, and/or case reports: Cardiac disease, cardiac failure, cerebral hemorrhage, cerebrovascular accident, interstitial pneumonitis, nephrotic syndrome, pancreatitis, polycythemia, retinal changes (tear), retinal detachment, torsades de pointes

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiotoxicity: Cardiac dysfunction (including decreased left ventricular ejection fraction [LVEF] and heart failure) have been reported with pazopanib, in studies both with and without routine on-study LVEF monitoring. Myocardial dysfunction, defined as symptoms of cardiac dysfunction, or ≥15% absolute decline in LVEF (from baseline), or a decline in LVEF of ≥10% (from baseline) that is also below the lower limit of normal, has also been reported. Most patients with pazopanib-related myocardial dysfunction had concurrent hypertension, which may have exacerbated cardiac dysfunction in patients at risk (eg, prior anthracycline therapy) possibly by increasing cardiac afterload; monitor BP and manage as appropriate. If indicated, initiate appropriate antihypertensive treatment to reduce the risk for cardiotoxicity (ASCO [Armenian 2017]). Monitor for clinical signs/symptoms of heart failure. Evaluate LVEF at baseline and periodically in patients at risk of cardiac dysfunction (including prior anthracycline exposure). Depending on the severity of cardiac dysfunction, withhold or permanently discontinue pazopanib.

• GI perforation/fistula: Perforation and fistula (including fatal events) have been reported with pazopanib (rare). Monitor for signs/symptoms of GI perforation and fistula. Withhold pazopanib for grade 2 or 3 GI fistula (resume based on clinical judgement). Permanently discontinue pazopanib for GI perforation or grade 4 GI fistula.

• Hand-foot skin reaction: Hand-foot skin reaction (HFSR) observed with tyrosine kinase inhibitors (TKIs) is distinct from hand-foot syndrome (palmar-plantar erythrodysesthesia) associated with traditional chemotherapy agents. HFSR due to TKIs is localized with defined hyperkeratotic lesions; symptoms include burning, dysesthesia, paresthesia, or tingling of the palms/soles, and generally occur within the first 2 to 4 weeks of treatment. Pressure and flexor areas may develop blisters (callus-like), dry/cracked skin, edema, erythema, desquamation, or hyperkeratosis. The incidence of HFSR is lower with pazopanib (compared to other tyrosine kinase inhibitors). Examine skin at baseline (remove calluses with pedicure prior to treatment) and with each visit; apply an emollient based moisturizer twice daily during treatment. If HFSR develops, consider changing moisturizer to a urea-based product; topical steroids may be utilized for the anti-inflammatory effect; avoid excessive friction or pressure to affected areas and avoid restrictive footwear. Temporary dose reduction or treatment interruption may be necessary (Appleby 2011).

• Hemorrhage: Hemorrhagic events (including fatal events) have been reported. The most common events were hematuria, epistaxis, hemoptysis, anal/rectal hemorrhage, and mouth hemorrhage. Serious hemorrhagic events included pulmonary, GI, and genitourinary hemorrhage; cerebral/intracranial hemorrhage have been observed rarely. Patients with a history of hemoptysis, cerebral hemorrhage or clinically significant GI hemorrhage within 6 months were excluded from clinical trials. Depending on the hemorrhage severity, withhold (and resume at a reduced dose) or permanently discontinue pazopanib.

• Hepatotoxicity: [US Boxed Warning]: Severe and fatal hepatotoxicity (transaminase and bilirubin elevations) has been observed with pazopanib. Monitor hepatic function and interrupt treatment, reduce dose, or discontinue as recommended. Among clinical trials, ALT elevations of >3 to >10 times ULN have occurred; concurrent elevation in ALT > 3 times ULN and bilirubin >2 times ULN in the absence of significant alkaline phosphatase >3 times ULN has also been reported. Deaths due to hepatic failure have been described (rare). Monitor LFTs at baseline; at weeks 3, 5, 7, and 9; at months 3 and 4; then periodically as clinically indicated. If ALT elevation occurs, increase to weekly monitoring until ALT returns to grade 1 or baseline. Transaminase elevations usually occur early in the treatment course, with most elevations (any grade) occurring within the first 18 weeks. Based on the hepatotoxicity severity, withhold pazopanib (and resume at reduced dose with continued weekly monitoring for 8 weeks) or permanently discontinue pazopanib with weekly monitoring until resolution. Dosage reduction is recommended for preexisting moderate hepatic impairment; use is not recommended in patients with preexisting severe hepatic impairment. Mild indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert syndrome (pazopanib is a UGT1A1 inhibitor); for patients with known Gilbert syndrome (only a mild indirect bilirubin elevation) and ALT >3 times ULN, follow the dosage modification recommendations for isolated ALT elevations. Patients >65 years of age are at a higher risk for hepatotoxicity. Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations; insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib.

• Hypertension: Pazopanib may cause and/or worsen hypertension (systolic BP ≥150 mm Hg or diastolic BP ≥100 mm Hg); hypertensive crisis has been observed. Approximately 40% of patients experienced hypertension; grade 3 hypertension occurred in some patients. Most cases occurred within the initial 18 weeks of pazopanib treatment, while ~40% of cases occurred by day 9. A small percentage of patients required permanent pazopanib discontinuation due to hypertension. Optimize blood pressure prior to pazopanib initiation; do not initiate pazopanib in patients with uncontrolled hypertension. Monitor BP as clinically indicated and initiate/adjust antihypertensives as clinically indicated. Based on the hypertension severity, withhold pazopanib (and then reduce the dose) or permanently discontinue pazopanib.

• Infections: Serious, including fatal, infections (with and without neutropenia) have been reported; monitor for signs and symptoms of infection. Initiate appropriate anti-infection therapy and consider temporary pazopanib treatment interruption or discontinuation for serious infections.

• Ocular toxicity: Cases of retinal detachment/tear have been reported with pazopanib.

• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported (rarely) with pazopanib; may be fatal. PRES is a neurological disorder, which may present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension may also be present. Confirm PRES diagnosis with MRI. Permanently discontinue pazopanib in patients who develop PRES.

• Proteinuria: Proteinuria has been reported with pazopanib. Nephrotic syndrome has been observed rarely. Obtain baseline and periodic urinalysis during treatment and follow up with 24-hour urine protein when clinically indicated. Withhold pazopanib (and resume at a reduced dose) or permanently discontinue based on the severity of proteinuria. Permanently discontinue pazopanib for nephrotic syndrome.

• Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis has been reported with pazopanib; may be fatal. Monitor for pulmonary symptoms which could indicate ILD/pneumonitis; permanently discontinue pazopanib if ILD or pneumonitis develop.

• QTc prolongation: QTc prolongation (≥500 msec), including torsades de pointes, has been observed with pazopanib (based on routine ECG monitoring). Monitor patients who are at significant risk of developing QTc prolongation, including patients with a history of QT prolongation, patients taking antiarrhythmics or other medications known to prolong the QT interval, or those with relevant preexisting cardiac disease. Obtain baseline and periodic ECGs; monitor (at baseline and as clinically indicated) and correct electrolyte (potassium, calcium, and magnesium) abnormalities prior to and during pazopanib treatment.

• Skin depigmentation: Depigmentation of the hair or skin may occur during pazopanib treatment.

• Thromboembolic events: Arterial thromboembolic events, including myocardial infarction, ischemia, cerebrovascular accident, or transient ischemic attack have been observed with pazopanib; some events were fatal. Patients who had an arterial thromboembolic event within the previous 6 months were excluded from clinical trials. Permanently discontinue pazopanib for arterial thromboembolic events. Venous thromboembolic events (VTEs), including venous thrombosis and pulmonary embolus (PE; some fatal) have occurred with pazopanib. Monitor for signs and symptoms of VTE and PE. Based on severity of the venous thromboembolic event, withhold pazopanib and then resume at same dose or permanently discontinue.

• Thrombotic microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed with pazopanib (as monotherapy or in combination with other anticancer agents). TMA typically occurs within 90 days of pazopanib initiation. Monitor for signs/symptoms of TMA; if TMA occurs, permanently discontinue pazopanib (and manage as clinically indicated). Improvement of TMA occurred after pazopanib was discontinued.

• Thyroid disorders: Hypothyroidism has been reported with pazopanib. Hypothyroidism was confirmed in studies based on a simultaneous rise of TSH and decline of T4. Monitor thyroid tests at baseline, during pazopanib treatment, and as clinically indicated. Manage hypothyroidism as appropriate.

• Tumor lysis syndrome: Cases of tumor lysis syndrome (TLS) have been reported with pazopanib (some fatal). Patients with rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration may be at higher risk for TLS. Monitor patients at risk closely and consider prophylactic treatment.

• Wound healing complications: Vascular endothelial growth factor receptor inhibitors are associated with impaired wound healing; therefore, pazopanib may affect wound healing. Withhold pazopanib treatment at least 1 week prior to elective surgery; do not administer pazopanib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming pazopanib treatment after resolution of wound healing complications has not been established.

Concurrent drug therapy issues:

• Combination therapy: Increased toxicity and mortality has been observed in trials evaluating concurrent use of pazopanib with other anticancer agents (pemetrexed, lapatinib)

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• East Asian patients: In an analysis of pooled clinical trials, grade 3 and 4 neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) were more frequently observed in patients of East Asian descent, compared to patients of non-East Asian descent.

• Elderly: Patients ≥65 years of age experienced increased incidences of grade 3 or 4 fatigue, hypertension, decreased appetite, and transaminase elevations and are at increased risk for hepatotoxicity (compared to younger patients).

• Pediatric: Based on the mechanism of action, organ growth and maturation may be affected during early postnatal development. May potentially cause serious adverse effects on organ development, particularly in children <2 years of age. Pazopanib is not approved for use in pediatric patients.

• Pharmacogenomic variation: A pooled analysis of TA repeat polymorphism of UGT1A1 showed a statistically significant increase of hyperbilirubinemia in patients with the (TA)7/TA7 genotype (UGT1A1*28/*28), relative to the (TA)6/(TA)6 and (TA6/(TA)7 genotypes. In a large pooled analysis, grade 2 and 3 ALT elevations (ALT >3 to <20 times ULN) were observed more frequently in patients carrying the HLA-B*57:01 allele versus noncarriers.

Monitoring Parameters

Monitor LFTs (ALT, AST, bilirubin) at baseline; at weeks 3, 5, 7, and 9; at months 3 and 4; then periodically as clinically indicated; if ALT elevation occurs, increase to weekly monitoring until ALT returns to grade 1 or baseline. Monitor serum electrolytes (eg, calcium, magnesium, potassium) at baseline and as clinically indicated; urinalysis for proteinuria at baseline and periodically during treatment (follow up with 24-hour urine protein when clinically indicated); thyroid function (TSH and T4 at baseline and TSH every 6 to 8 weeks during treatment [Appleby 2011]); verify pregnancy status (in females of reproductive potential) prior to therapy initiation. Monitor BP as clinically indicated. Monitor patients who are at significant risk of developing QT prolongation with baseline and periodic ECGs. Evaluate left ventricular ejection fraction (LVEF) at baseline and periodically in patients at risk of cardiac dysfunction. Monitor for clinical signs/symptoms of heart failure, signs/symptoms of GI perforation or fistula, hand-foot skin reaction, hemorrhage, hepatotoxicity, infection, interstitial lung disease/pneumonitis, posterior reversible encephalopathy syndrome, thromboembolic events (VTE and PE), thrombotic microangiopathy, tumor lysis syndrome, and/or wound healing complications. Monitor adherence.

Reproductive Considerations

Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after the last pazopanib dose. Male patients (including vasectomized patients) with female partners of reproductive potential should use condoms during treatment and for at least 2 weeks after the last pazopanib dose.

Transient amenorrhea has been described in a patient on pazopanib monotherapy; normal menses resumed 2 months after pazopanib treatment was discontinued (De Sanctis 2019).

Pregnancy Considerations

Based on data from animal reproduction studies and the mechanism of action, in utero exposure to pazopanib may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat kidney cancer.

• It is used to treat soft tissue sarcoma.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling dizzy, tired or weak

• Headache

• Upset stomach

• Throwing up

• Diarrhea

• Stomach pain

• Not hungry

• Change in taste

• Mouth irritation

• Mouth sores

• Skin discoloration

• Hair discoloration

• Hair loss

• Muscle pain

• Bone pain

• Weight loss

• Trouble sleeping

• Nail changes

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes

• Bleeding like throwing up blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Low thyroid level like constipation; trouble handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up

• Swelling, warmth, numbness, change of color, or pain in a leg or arm

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome like bruising or bleeding; feeling tired or weak; dark urine or yellow skin; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other; trouble speaking or thinking, or change in balance; or fever

• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; not able to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish

• High blood pressure like severe headache or dizziness, passing out, or vision changes

• Chest pain

• Unable to pass urine

• Change in amount of urine passed

• Redness or irritation of palms or soles of feet

• Swelling of belly

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.