pazopanib (Rx)

Brand and Other Names:Votrient
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 200mg
  • 400mg

Advanced Renal Cell Carcinoma

Indicated for advanced renal cell carcinoma (RCC)

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

Continue until disease progression or unacceptable toxicity

Soft Tissue Sarcomas

Indicated for advanced soft tissue sarcoma (STS) who have received prior chemotherapy

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

Continue until disease progression or unacceptable toxicity

Dosage Modification

Dose reductions for adverse reactions

  • RCC
    • First dose reduction: 400 mg PO qDay
    • Second dose reduction: 200 mg PO qDay
    • Unable to tolerate second reduction: Permanently discontinue
  • STS
    • First dose reduction: 600 mg PO qDay
    • Second dose reduction: 400 mg PO qDay
    • Unable to tolerate second reduction: Permanently discontinue

Hepatic toxicity

  • Isolated ALT elevations (3-8x ULN): Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline
  • Isolated ALT elevations >8x
    • Withhold until improvement to Grade 1 or baseline
    • If potential benefit for resuming treatment is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg PO qDay and measure serum liver tests weekly for 8 weeks
    • Permanently discontinue if ALT elevations >3x ULN recur despite dose reduction(s)
  • ALT elevations >3x ULN AND bilirubin elevations >2x ULN
    • Permanently discontinue and continue to monitor until resolution
    • Manage per recommendations for isolated ALT elevations in patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations >3x ULN

Left ventricular systolic dysfunction

  • Symptomatic or Grade 3: Withhold until improvement to Grade <3; resume treatment based on medical judgement
  • Grade 4: Permanently discontinue

Hemorrhagic events

  • Grade 2: Withhold until improvement to Grade ≤1; resume at reduced dose
  • Grade 2 recurs after dose interruption and reduction, Grade 3 or 4: Permanently discontinue

Venous thromboembolic events

  • Grade 3: Withhold and resume at same dose if managed with appropriate therapy for at least 1 week
  • Grade 4: Permanently discontinue

Gastrointestinal fistula

  • Grade 2 or 3: Withhold and resume based on medical judgement
  • Grade 4: Permanently discontinue

Hypertension

  • Grade 2 or 3: Reduce dose (see above) and initiate or adjust antihypertensive therapy
  • Grade 3 recurs despite dose reduction(s) and adjustment of antihypertensive therapy, Grade 4 or hypertensive crisis: Permanently discontinue

Proteinuria

  • 24-hr urine protein ≥3 grams
    • Withhold until improvement to Grade ≤1; resume at a reduced dose (see above)
    • Permanently discontinue if 24-hr urine protein ≥3 grams does not improve or recurs despite dose reductions
  • Confirmed nephrotic syndrome
    • Permanently discontinue

Permanently discontinue if these adverse reactions occur at any grade

  • Arterial thromboembolic events
  • Thrombotic microangiopathy
  • Gastrointestinal perforation
  • Gastrointestinal fistula
  • Interstitial lung disease (ILD)/pneumonitis
  • Posterior reversible encephalopathy syndrome (PRES)

CYP3A4 inhibitors or inducers

  • Strong CYP3A4 inhibitors
    • Avoid coadministration; use an alternative with no or minimal potential to inhibit CYP3A4
    • If coadministration is warranted, decrease pazopanib dose to 400 mg/day; further dose reduction may be needed if adverse effects occur
  • Strong CYP3A4 inducers
    • Avoid coadministration; use alternant medication with no or minimal potential to induce CYP3A4
    • Pazopanib not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers

Gastric acid-reducing agents

  • Avoid coadministration
  • If use cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists; separate short-acting antacid and pazopanib dosing by several hours

Renal impairment

  • All severities: No dosage adjustment required

Hepatic impairment

  • Mild (bilirubin <1.5x ULN and any ALT): No dosage adjustment necessary
  • Moderate (bilirubin ≥1.5-3x ULN and any ALT): Reduce dose to 200 mg PO qDay
  • Severe (bilirubin >3x ULN and any ALT): Not recommended

Dosing Considerations

Limitation of use

  • Efficacy not demonstrated in adipocytic soft tissue sarcoma or gastrointestinal stromal tumors

Ovarian Cancer (Orphan)

Orphan designation for treatment of ovarian cancer

Orphan sponsor

  • Novartis Pharmaceuticals Corp; One Health Plaza, 337/B17.5F; East Hanover, New Jersey 07936

Hereditary Hemorrhagic Telangiectasia (Orphan)

Orphan designation for treatment of hereditary hemorrhagic telangiectasia

Sponsor

  • HHT Foundation International (d/b/a Cure HHT); 8 Henderson Hill Ct; Monkton, Maryland 21111

Safety and efficacy not established; not indicated for use in pediatric patients

Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development, particularly in children younger than 2 years

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Interactions

Interaction Checker

and pazopanib

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10% (RCC)

            All grades

            • ALT/AST increased (53%)
            • Diarrhea (52%)
            • Glucose increased (41%)
            • Hypertension (40%)
            • Hair color changes (38%)
            • Leukopenia (37%)
            • Total bilirubin increased (36%)
            • Phosphorous decreased (34%)
            • Neutropenia (34%)
            • Thrombocytopenia (32%)
            • Lymphocytopenia (31%)
            • Sodium decreased (31%)
            • Magnesium decreased (26%)
            • Nausea (26%)
            • Anorexia (22%)
            • Vomiting (21%)
            • Fatigue (19%)
            • Glucose decreased (17%)
            • Asthenia (14%)
            • Abdominal pain (11%)

            >10% (STS)

            All grades

            • Fatigue (65%)
            • Diarrhea (59%)
            • Nausea (56%)
            • AST increased (51%)
            • Weight decreased (48%)
            • ALT increased (46%)
            • Glucose increased (45%)
            • Leukopenia (44%)
            • Lymphocytopenia (43%)
            • Hypertension (42%)
            • Appetite decreased (40%)
            • Hair color changes (39%)
            • Thrombocytopenia (36%)
            • Albumin decreased (34%)
            • Neutropenia (33%)
            • Vomiting (33%)
            • Alkaline phosphatase increased (32%)
            • Sodium decreased (31%)
            • Total bilirubin increased (29%)
            • Tumor pain (29%)
            • Dysgeusia (28%)
            • Headache (23%)
            • Musculoskeletal pain (23%)
            • Myalgia (23%)
            • Gastrointestinal pain (23%)
            • Dyspnea (20%)
            • Exfoliative rash (18%)
            • Cough (17%)
            • Potassium increased (16%)
            • Peripheral edema (14%)
            • Mucositis (12%)
            • Alopecia (12%)
            • Dizziness (11%)
            • Skin disorder (11%)
            • Skin hypopigmentation (11%)
            • Stomatitis (11%)

            Grade 3-4

            • Fatigue (1-13%)

            1-10% (RCC)

            All grades

            • Headache (10%)
            • Proteinuria (9%)
            • Weight decreased (9%)
            • Rash (8%)
            • Alopecia (8%)
            • Dysgeusia (8%)
            • Palmoplantar erythrodysesthesia (6%)
            • Chest pain (5%)
            • Dyspepsia (5%)
            • Dysphonia (4%)
            • Skin depigmentation (3%)
            • Facial edema (1%)

            Grade 3-4

            • ALT increased (2-10%)
            • AST increased (≤7%)
            • Hypertension (4%)
            • Phosphorus decreased (4%)
            • Sodium decreased (1-4%)
            • Asthenia (3%)
            • Diarrhea (≤3%)
            • Total bilirubin increased (≤3%)
            • Anorexia (2%)
            • Vomiting (≤2%)
            • Abdominal pain (2%)
            • Magnesium decreased (≤1%)
            • Neutropenia (≤1%)

            1-10% (STS)

            All grades

            • Chest pain (10%)
            • Insomnia (9%)
            • Hypothyroidism (8%)
            • Dysphonia (8%)
            • Epistaxis (8%)
            • LVEF dysfunction (8%)
            • Dyspepsia (7%)
            • Dry skin (6%)
            • Chills (5%)
            • Vision blurred (5%)
            • Nail disorder (5%)

            Grade 3-4

            • Lymphocytopenia (10%)
            • Tumor pain (8%)
            • ALT increased (8%)
            • Hypertension (7%)
            • Appetite decreased (6%)
            • Diarrhea (5%)
            • Dyspnea (≤5%)
            • AST increased (5%)
            • Weight decreased (4%)
            • Neutropenia (4 %)
            • Sodium decreased (4%)
            • Thrombocytopenia (3%)
            • Alkaline phosphatase increased (3%)
            • Nausea (3%)
            • Vomiting (3%)
            • Gastrointestinal pain (3%)
            • Musculoskeletal pain (2%)
            • Myalgia (2%)
            • Peripheral edema (2%)
            • Mucositis (2%)
            • Skin disorder (2%)
            • Stomatitis (2%)
            • Dizziness (1%)
            • Headache (1%)
            • Albumin decreased (1%)
            • Total bilirubin increased (1%)
            • Potassium increased (1%)
            • Leukopenia (1%)

            <1% (RCC)

            Grade 3-4

            • Hair color changes
            • Nausea
            • Glucose increased
            • Glucose decreased
            • Thrombocytopenia

            <1% (STS)

            Grade 3-4

            • Exfoliative rash
            • Cough
            • Skin hypopigmentation
            • Glucose increased

            Postmarketing Reports

            Polycythemia

            Retinal detachment/tear

            Pancreatitis

            TLS (including fatal cases)

            Arterial (including aortic) aneurysms, dissections, and rupture

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            Severe and fatal hepatotoxicity observed in clinical trials

            Patients aged >65 years are at greater risk for hepatotoxicity

            Monitor liver tests at baseline; at Weeks 3, 5, 7, and 9; at Month 3 and Month 4; and then periodically as clinically indicated

            Increase to weekly monitoring for patients with elevated ALT until ALT returns to Grade 1 or baseline

            Withhold dose and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity

            Contraindications

            None

            Cautions

            Hepatotoxicity, manifested as increases in ALT, AST, and bilirubin, occurred (see Black Box Warnings)

            Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome; manage elevation in ALT >3x ULN per dosing recommendations in such patients

            Fatal hemorrhage, fatal arterial thromboembolic events, and cerebral/intracranial hemorrhage have occurred

            Has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, patients who have had an arterial thromboembolic event within the previous 6 months, or clinically significant gastrointestinal hemorrhage in the past 6 months

            Venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE) reported; monitor for signs and symptoms of VTE and PE

            Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), occurred in clinical trials

            Gastrointestinal perforation or fistula has been reported; monitor for signs and symptoms of gastrointestinal perforation or fistula; withhold in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement; permanently discontinue in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula

            ILD/pneumonitis and PRES, which can be fatal, has been reported

            Hypothyroidism has occurred; monitor thyroid tests at baseline, during treatment and as clinically indicated and manage appropriately

            Proteinuria has been reported; perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hr urine protein as clinically indicated

            Cases of TLS, including fatal cases, have been reported

            Can cause fetal harm when administered to a pregnant woman

            Serious infections (with or without neutropenia), some with fatal outcome, reported; monitor for signs and symptoms and treat active infection promptly; interrupt or discontinue therapy

            Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development

            Not indicated for combination therapy; safe and effective combination dose has not been established

            Impaired wound healing

            • Impaired wound healing complications can occur; may have the potential to adversely affect wound healing
            • Withhold dose at least 1 week prior to elective surgery
            • Do not administer for at least 2 weeks following major surgery and until adequate wound healing
            • Safety of resuming therapy after resolution of wound healing complications has not been established

            Hypertension

            • Hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥ 100 mmHg) and hypertensive crisis were observed
            • Do not initiate in patients with uncontrolled hypertension
            • Optimize blood pressure before initiating treatment
            • Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate
            • Withhold and then reduce pazopanib dose or permanently discontinue based on severity of hypertension

            Cardiac dysfunction

            • Cardiac dysfunction, including decreased LVEF and congestive heart failure, occurred
            • Monitor blood pressure and manage appropriately
            • Monitor for clinical signs or symptoms of congestive heart failure
            • Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction, including previous anthracycline exposure
            • Withhold or permanently discontinue based on severity of cardiac dysfunction

            QT prolongation

            • QT prolongation and Torsades de Pointes occurred
            • Monitor patients who are at significant risk of developing QTc prolongation, including patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease
            • Monitor ECG and electrolytes (eg, calcium, magnesium, potassium) at baseline and as clinically indicated. Correct electrolyte imbalances before initiating and during treatment

            Drug interaction overview

            Pazopanib is CYP3A4, P-gp, and BCRP substrate; moderate CYP3A4, CYP2D6, and CYP2C8 inhibitor

            • Strong CYP3A4 inhibitors
              • Avoid coadministration
              • Strong CYP3A4 inhibitors increases pazopanib concentrations
              • If unable to avoid, adjust pazopanib dose
            • Strong CYP3A4 inducers
              • Avoid coadministration
              • Strong CYP3A4 inducers may decrease plasma pazopanib concentrations
            • Transporters
              • Avoid coadministration
              • Strong inhibitors of P-gp or BCRP may increase pazopanib concentrations
              • Consider selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP
            • CYP3A4, CYP2D6, or CYP2C8 substrates with narrow therapeutic use
              • Not recommended
              • Coadministration with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 may inhibit the metabolism of these products and increase the risk for toxicities
            • Gastric acid-reducing agents
              • Avoid use
              • Coadministration with esomeprazole, a PPI, decreased the exposure of pazopanib
            • Simvastatin
              • Coadministration of simvastatin increases the risk of ALT elevations
              • Insufficient data are available to assess the risk of concomitant use of alternative statins with pazopanib
            • Drugs that prolong the QT interval
              • Avoid coadministration
              • Therapy is associated with QTc interval prolongation
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            Pregnancy & Lactation

            Pregnancy

            Based on animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females

            No data available on use in pregnant females to evaluate drug-associated risk

            Verify pregnancy status of females of reproductive potential before starting treatment

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 2 weeks after last dose
            • Males (including those who have had vasectomies) with female partners of reproductive potential: Use condoms during treatment and for at least 2 weeks after last dose

            Infertility

            • Based on findings from animal studies, fertility may be impaired in females and males of reproductive potential while receiving treatment

            Animal studies

            • Oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg

            Lactation

            No data available on the drug presence or its metabolites in human milk or the effects on the breastfed infant or milk production

            Advise females not to breastfeed during treatment and for 2 weeks after last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Multikinase inhibitor (including VEGF & PDGF receptor tyrosine kinases) some of which are implicated in tumor growth, angiogenesis, & metastasis

            Absorption

            Peak Plasma Time: 2-4 hr

            Peak Plasma Concentration: 58.1 mcg/mL

            AUC: 1,037 hr•mcg/mL

            Cmax and AUC increased 2-fold with food; also increased if table crushed

            Distribution

            Protein Bound: >99%

            Pgp substrate

            Metabolism

            Metabolized by CYP3A4 (major), CYP1A2 and CYP2C8 (minor)

            Elimination

            Half-Life: 30.9 hr

            Excretion: Feces (Primarily); urine (<4%)

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            Administration

            Oral Administration

            Take without food at least 1 hr ac or 2 hr pc

            Do not crush or chew (increases bioavailability and absorption rate, with possible increased toxicity)

            Food also increases bioavailability, possibly resulting in increased toxicity

            Storage

            Store at room temperature between 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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