Votrient
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF VOTRIENT™ (VOTRIENT™)
Composition:
Active substance: pazopanib;
1 tablet contains 200 mg or 400 mg of pazopanib (as pazopanib hydrochloride);
Excipients: magnesium stearate, microcrystalline cellulose, povidone K30, sodium starch glycolate (type A); coating Opadry White YS-1-7706-G (for 400 mg tablet): hypromellose, polyethylene glycol 400, polysorbate 80, titanium dioxide (E 171); coating Opadry Pink YS-1-14762-A (for 200 mg tablet): hypromellose, red iron oxide (E 172), polyethylene glycol 400, polysorbate 80, titanium dioxide (E 171).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
400 mg tablets: white film-coated tablet, capsule-shaped, with imprint GS UHL on one side;
200 mg tablets: pink film-coated tablet, capsule-shaped, with imprint GS JT on one side.
Pharmacotherapeutic group. Antineoplastic agents, protein kinase inhibitors, other protein kinase inhibitors.
ATC code L01E X03.
Pharmacological Properties
Pharmacodynamics
Votrient™ is an oral, potent multi-targeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α and -β, and stem cell factor receptor (c-KIT), with respective IC50 values of 10, 30, 47, 71, 84, and 74 nmol/mL. In preclinical experimental studies, pazopanib dose-dependently inhibited ligand-induced autophosphorylation of VEGFR-2, c-Kit, and PDGFR-β in cells. In in vivo studies, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in animal lungs, angiogenesis in animals across various experimental models, and growth of multiple human tumor xenografts in animals.
Pharmacogenomics
In a pharmacogenetic meta-analysis of data from 31 clinical trials of pazopanib administered as monotherapy or in combination with other agents, ALT levels exceeding 5 times the upper limit of normal (ULN) (Grade 3) were observed in 19% of patients carrying the HLA-B*57:01 allele and in 10% of patients without this allele. Among the 2235 patients included in these clinical trials, 133 carried the HLA-B*57:01 allele (see section "Special Warnings and Precautions for Use").
Pharmacokinetics
Absorption
Following a single 800 mg oral dose of pazopanib in patients with solid tumors, a plasma Cmax of approximately 19 ± 13 µg/mL is reached on average at 3.5 hours (range: 1.0–11.9 hours), and the AUC(0–∞) is approximately 650 ± 500 µg×h/mL. Daily administration of the drug results in a 1.23- to 4-fold increase in AUC(0–T). Increasing the Votrient™ dose beyond 800 mg does not result in a corresponding increase in AUC or Cmax.
Systemic exposure to pazopanib increases when administered with food. Administration of Votrient™ with either high- or low-fat meals approximately doubles its AUC and Cmax. Therefore, Votrient™ should be administered at least 1 hour before or 2 hours after a meal (see section "Dosage and Administration").
Administration of one crushed 400 mg tablet of pazopanib increased AUC(0–72) by 46% and Cmax approximately 2-fold, while reducing tmax by approximately 2 hours, compared to administration of an intact tablet. These data indicate that the bioavailability and extent of absorption of pazopanib following oral administration increase after administration of a crushed tablet compared to an intact tablet. Due to this potential increase in drug absorption, Votrient™ tablets should not be crushed (see section "Dosage and Administration").
Distribution
In vivo, pazopanib is more than 99% bound to human plasma proteins across the concentration range of 10–100 µg/mL, independent of drug concentration. In vitro studies have shown that pazopanib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Metabolism
In vitro studies have demonstrated that pazopanib metabolism is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.
Elimination
Pazopanib is slowly eliminated from the body, with a mean elimination half-life of 30.9 hours after administration of the recommended 800 mg dose. The drug is predominantly excreted in feces, with renal excretion accounting for less than 4% of the administered dose.
Clinical characteristics.
Indications.
Treatment of locally advanced and/or metastatic renal cell carcinoma (RCC).
Treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy, except for patients with gastrointestinal stromal tumor or liposarcoma.
Contraindications.
Hypersensitivity to any component of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Medicinal products that inhibit or induce cytochrome P450 3A4 enzymes.
In vitro data suggest that oxidative metabolism of pazopanib in human liver microsomes is predominantly mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter pazopanib metabolism.
Inhibitors of CYP3A4, P-gp, BCRP: Pazopanib is a substrate for CYP3A4, P-gp, and BCRP.
Concomitant administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp inhibitor ketoconazole (400 mg once daily) for 5 consecutive days increased mean AUC(0-24) and Cmax of pazopanib by 66% and 45%, respectively, compared to pazopanib (400 mg once daily for 7 days) administered alone. Increases in AUC and Cmax of pazopanib are less than proportional to dose increases within the range of 50 mg to 2000 mg. Therefore, reducing the pazopanib dose to 400 mg once daily in the presence of a strong CYP3A4 inhibitor will result in systemic exposure to pazopanib similar to that observed after administration of 800 mg pazopanib once daily alone in most patients. However, in some patients, systemic exposure to pazopanib will be higher than that observed with 800 mg pazopanib administered alone.
Concomitant use of Votrient™ with other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice may also lead to increased plasma concentrations of pazopanib. Concomitant use with potent inhibitors of P-gp or BCRP may also alter pazopanib exposure and distribution, including distribution into compartments of the central nervous system.
Administration of 1500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, BCRP, and P-gp, together with 800 mg Votrient™ resulted in approximately 50–60% increases in AUC(0-24) and Cmax of pazopanib compared to administration of 800 mg Votrient™ alone. Concomitant use of Votrient™ with a CYP3A4, BCRP, and P-gp inhibitor such as lapatinib leads to increased plasma concentrations of pazopanib.
Concomitant use of pazopanib with strong CYP3A4 inhibitors should be avoided. If there is no clinically acceptable alternative to a strong CYP3A4 inhibitor, the pazopanib dose should be reduced to 400 mg daily during concomitant use (see section "Special instructions for use"). If adverse reactions related to the medicinal product occur, further dose reduction of the medicinal product should be considered.
Combination of pazopanib with strong inhibitors of P-gp or BCRP should be avoided, or in such cases, alternative concomitant medicinal products with no or minimal inhibitory potential toward P-gp or BCRP are recommended.
Inducers of CYP3A4, P-gp, BCRP
Inducers of CYP3A4, such as rifampicin, may reduce pazopanib plasma concentrations. Concomitant use of pazopanib with potent inducers of P-gp or BCRP may alter pazopanib exposure and distribution, including distribution into compartments of the central nervous system. Alternative concomitant medicinal products with no or minimal enzyme-inducing activity are recommended.
Effect of Votrient™ on other medicinal products
In vitro studies using human liver microsomes have shown that pazopanib inhibits CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. In vitro studies quantifying human pregnane X receptor (PXR) demonstrated the potential of the drug to induce human CYP3A4. Clinical pharmacology studies in which Votrient™ was administered at 800 mg once daily showed that Votrient™ had no clinically significant effect on the pharmacokinetics of caffeine (a marker substrate for CYP1A2), warfarin (a marker substrate for CYP2C9), or omeprazole (a marker substrate for CYP2C19) in oncology patients. Votrient™ caused an increase of approximately 30% in the mean AUC and Cmax of midazolam (a marker substrate for CYP3A4), as well as a 33–64% increase in the urinary concentration ratio of dextromethorphan to its active metabolite dextrorphan after oral administration of dextromethorphan (a marker substrate for CYP2D6). Combined administration of Votrient™ 800 mg once daily and weekly paclitaxel (a substrate of CYP3A4 and CYP2C8) at 80 mg/m² once weekly resulted in mean increases of 26% and 31% in AUC and Cmax of paclitaxel, respectively.
Pazopanib should be used with caution when administered concomitantly with other oral substrates of BCRP and P-gp, due to its inhibitory effect on these proteins.
In vitro studies also demonstrated that pazopanib is a potential inhibitor of the transport proteins UGT1A1 and OATP1B1. Pazopanib may increase concentrations of medicinal products that are primarily eliminated via UGT1A1 and OATP1B1.
Concomitant use of Votrient™ and simvastatin
Concomitant use of Votrient™ and simvastatin increases the frequency of ALT elevation. In clinical trials of Votrient™ monotherapy, ALT elevations greater than 3 times the ULN were observed in 126 of 895 patients (14%) who were not taking statins, compared to 11 of 41 patients (27%) who were concomitantly taking simvastatin. If a patient taking simvastatin as a concomitant medication develops elevated ALT levels, dosing recommendations for Votrient™ should be followed and simvastatin should be discontinued (see section "Special instructions for use"). Votrient™ should be used with caution with other statins, as data assessing the risk for such combinations are limited.
Effect of food on Votrient™
Administration of Votrient™ with food, either high- or low-fat, results in approximately a two-fold increase in AUC and Cmax. Therefore, Votrient™ should be administered at least 1 hour before or at least 2 hours after a meal (see section "Dosage and administration").
Medicinal products affecting gastric pH
Concomitant administration of pazopanib with esomeprazole reduces pazopanib bioavailability by approximately 40% (AUC and Cmax). Therefore, concomitant use of pazopanib with medicinal products that increase gastric pH should be avoided. If concomitant use with a proton pump inhibitor is necessary, the recommended approach is to take the pazopanib dose once daily in the evening without food, together with the proton pump inhibitor. If concomitant use with an H2-receptor antagonist is necessary, the pazopanib dose should be taken without food at least 2 hours before or 10 hours after administration of the H2-receptor antagonist. Pazopanib should be taken at least 1 hour before or 2 hours after administration of short-acting antacids.
Special precautions.
Hepatic effects.
Cases of hepatic failure (including fatal cases) have been reported with the use of Votrient™. In clinical trials with Votrient™, elevations in serum levels of transaminases (ALT, aspartate aminotransferase [AST]) and bilirubin were observed during treatment (see section "Adverse reactions"). In most cases, isolated increases in ALT and AST levels were reported without concomitant elevation of alkaline phosphatase or bilirubin levels. Patients over 60 years of age have a higher risk of moderate (ALT > 3 ULN) or marked (ALT > 8 ULN) elevation of ALT. Patients who are carriers of the HLA-B*57:01 allele also have an increased risk of ALT elevation associated with Votrient™ use. Liver function should be monitored in all patients receiving Votrient™ treatment regardless of genotype or age.
Serum levels of liver enzymes should be determined before initiating Votrient™ therapy and at weeks 3, 5, 7, and 9 of treatment. Subsequently, monitoring should be performed at months 3 and 4 of treatment and additionally as clinically indicated. After 4 months of therapy, periodic monitoring of liver enzyme levels should continue based on clinical need.
For patients with baseline (pre-treatment) total bilirubin levels ≤ 1.5 ULN and AST and ALT ≤ 2 ULN, the following recommendations apply.
Patients with isolated ALT elevation between 3 ULN and 8 ULN may continue Votrient™ treatment provided weekly monitoring of liver function is performed until ALT levels decrease to Grade 1 or return to baseline.
Patients with ALT > 8 ULN should discontinue Votrient™ until this parameter returns to Grade 1 or baseline levels. If the potential benefits of reinitiating Votrient™ are considered to outweigh the risk of hepatotoxicity, treatment may be restarted at a reduced dose (400 mg once daily), with weekly determination of serum liver enzyme levels for 8 weeks (see section "Dosage and administration"). If ALT elevation > 3 ULN recurs after reinitiation of Votrient™, the drug should be permanently discontinued.
If ALT elevation > 3 ULN occurs concurrently with bilirubin elevation > 2 ULN, Votrient™ should be permanently discontinued. These patients require ongoing monitoring of these parameters until they return to Grade 1 or baseline values. Pazopanib is an inhibitor of UGT1A1. In patients with Gilbert's syndrome, mild indirect (unconjugated) hyperbilirubinemia may develop during treatment with this drug. Management of patients who have only mild indirect hyperbilirubinemia, previously diagnosed or suspected Gilbert's syndrome, and ALT elevation > 3 ULN should follow the recommendations provided for isolated ALT elevation.
Concomitant use of Votrient™ and simvastatin increases the risk of ALT elevation (see section "Interaction with other medicinal products and other forms of interaction") and should be used cautiously with careful monitoring.
In addition to recommendations that patients with minor liver test abnormalities (defined as ALT elevation with normal bilirubin or bilirubin elevation up to 1.5 times ULN regardless of ALT level) should receive 800 mg Votrient™ once daily and patients with moderate hepatic impairment (bilirubin levels exceeding 1.5–3 times ULN regardless of ALT level) should have their initial dose reduced to 200 mg daily, no further dose modification recommendations based on liver test results have been established for patients with pre-existing hepatic impairment. Pazopanib is not recommended for patients with severe hepatic dysfunction (total bilirubin more than 3 times ULN regardless of ALT level) (see section "Dosage and administration").
Arterial hypertension.
Cases of arterial hypertension, including hypertensive crises, were observed during clinical trials of pazopanib. Blood pressure should be well controlled before initiating pazopanib therapy. Blood pressure should be monitored early in treatment (within one week of starting Votrient™) and then at intervals necessary to ensure adequate blood pressure control, with prompt initiation of standard antihypertensive therapy, dose reduction, or treatment interruption as clinically indicated (see sections "Dosage and administration" and "Adverse reactions"). Arterial hypertension (systolic blood pressure ≥ 150 mm Hg or diastolic ≥ 100 mm Hg) during Votrient™ treatment develops early (in approximately 40% of cases by day 9, in approximately 90% of cases within the first 18 weeks). Votrient™ should be discontinued if signs of hypertensive crisis occur or if arterial hypertension is severe and persists despite antihypertensive therapy and dose reduction of Votrient™.
Posterior reversible encephalopathy syndrome / posterior reversible leukoencephalopathy.
Cases of posterior reversible encephalopathy syndrome / posterior reversible leukoencephalopathy have been reported during Votrient™ use. This syndrome may present with headache, arterial hypertension, seizures, lethargy, confusion, blindness, and other visual and neurological disturbances and may be fatal. If this syndrome occurs, Votrient™ treatment should be permanently discontinued.
Interstitial lung disease (ILD)/pneumonitis
Cases of ILD, which may be fatal, have been reported with pazopanib (see section "Adverse reactions"). Close monitoring for signs and symptoms suggestive of ILD/pneumonitis is required, and pazopanib treatment should be discontinued in patients diagnosed with ILD or pneumonitis.
Cardiac function impairment / heart failure
The benefit-risk ratio of pazopanib treatment should be evaluated before initiating therapy in patients with a history of cardiac dysfunction. The safety and pharmacokinetics of pazopanib in patients with moderate or severe heart failure or with left ventricular ejection fraction below normal have not been studied.
Cases of cardiac dysfunction, including congestive heart failure and decreased left ventricular ejection fraction, were observed in clinical trials with pazopanib. In a randomized clinical trial comparing pazopanib to sunitinib in patients with renal cell carcinoma, cardiac dysfunction was observed in 13% (47/362) of patients in the pazopanib group compared to 11% (42/369) in the sunitinib group. Congestive heart failure was observed in 0.5% of patients in each group. Congestive heart failure occurred in 3 of 240 patients (1%) in phase III clinical trials in patients with soft tissue sarcoma. In this study, decreased left ventricular ejection fraction in subjects who had measurements at baseline and during treatment was observed in 11% (15/140) in the group receiving Votrient™ compared to 3% (1/39) in the placebo group.
Risk factors
13 of 15 subjects in the pazopanib group during the phase III study in soft tissue sarcoma (STS) had concomitant hypertension, which may have exacerbated cardiac dysfunction in at-risk patients due to increased cardiac afterload. 99% of patients (243/246) enrolled in the phase III STS study, including 15 subjects, received anthracyclines. Prior anthracycline therapy may be a risk factor for cardiac dysfunction.
Outcomes
4 of 15 subjects fully recovered (within 5% of baseline), and 5 partially recovered (within normal range but > 5% below baseline). One subject did not recover, and data were unavailable for the other 5 subjects.
Treatment
In patients with significant decrease in left ventricular ejection fraction (LVEF), interruption and/or dose reduction of pazopanib should be combined with treatment of hypertension (if present, see hypertension warning above) as clinically indicated.
QT interval prolongation and polymorphic ventricular tachycardia (torsade de pointes).
Cases of QT interval prolongation and development of torsade de pointes during Votrient™ administration were reported in clinical studies (see section "Adverse reactions"). Votrient™ should be used with caution in patients with a history of QT prolongation, those taking antiarrhythmic drugs or other medicinal products that may potentially prolong the QT interval, or those with significant cardiovascular disease. Electrocardiograms are recommended before starting treatment and periodically during therapy, and electrolyte levels (calcium, magnesium, potassium) should be maintained within normal ranges.
Arterial thrombosis.
Cases of myocardial infarction, myocardial ischemia, angina pectoris, ischemic stroke, and transient ischemic attacks were observed during clinical studies of Votrient™ (see section "Adverse reactions"). Fatal outcomes occurred as a result of these complications. Votrient™ should be used with caution in patients with increased risk of thrombotic events or with a history of such events. Pazopanib has not been studied for treatment of patients who experienced thrombotic events within the previous 6 months. The decision to initiate treatment with this drug should be based on an individual benefit-risk assessment for each patient.
Venous thromboembolism.
Cases of venous thromboembolism, including venous thrombosis and fatal cases of pulmonary embolism, were observed during clinical studies of Votrient™. The frequency of these events was higher in the soft tissue sarcoma group (5%) compared to the renal cell carcinoma group (2%).
Thrombotic microangiopathy.
Cases of thrombotic microangiopathy were reported during clinical trials of Votrient™ monotherapy, in combination with bevacizumab, and in combination with topotecan (see section "Adverse reactions"). If thrombotic microangiopathy occurs, Votrient™ treatment should be permanently discontinued. Reversal of thrombotic microangiopathy effects has been observed after discontinuation of Votrient™. Votrient™ is not indicated for use in combination with other medicinal products.
Hemorrhagic complications.
Cases of hemorrhagic complications during Votrient™ administration were reported in clinical studies (see section "Adverse reactions"). Fatal outcomes occurred as a result of hemorrhagic complications. Votrient™ has not been studied in patients with a history of hemoptysis, intracranial hemorrhage, or clinically significant gastrointestinal bleeding within the previous 6 months. Votrient™ should be used with caution in patients at significant risk of hemorrhagic events.
Aneurysms and arterial dissections
Use of VEGF inhibitors in patients with or without arterial hypertension may promote the formation of aneurysms and/or arterial dissections. This risk should be carefully considered before administering pazopanib to patients with risk factors such as arterial hypertension or a history of aneurysm.
Gastrointestinal tract (GI) perforations and fistulae.
Cases of GI perforations and fistula formation during Votrient™ administration were reported in clinical studies (see section "Adverse reactions"). Fatal outcomes occurred after perforations. Votrient™ should be used with caution in patients at risk of GI perforations and fistula formation.
Wound healing.
Studies evaluating the effect of Votrient™ on wound healing are lacking. Since vascular endothelial growth factor inhibitors may impair wound healing, Votrient™ therapy should be discontinued at least 7 days prior to planned surgical intervention. The decision to resume Votrient™ therapy should be based on clinical assessment indicating adequate surgical wound healing. Votrient™ should be discontinued in patients with open wounds.
Hypothyroidism.
Cases of hypothyroidism during Votrient™ administration were reported in clinical studies (see section "Adverse reactions"). Proactive monitoring of thyroid function is recommended.
Proteinuria.
Cases of proteinuria during Votrient™ administration were reported in clinical studies (see section "Adverse reactions"). Urinalysis is recommended before starting treatment and periodically during therapy, with monitoring for possible worsening of pre-existing proteinuria. Votrient™ should be discontinued if nephrotic syndrome develops.
Tumor lysis syndrome (TLS)
TLS, including fatal cases, has been associated with pazopanib use (see section "Adverse reactions"). Patients at increased risk of TLS include those with rapidly growing tumors, high tumor burden, impaired renal function, or dehydration. Preventive measures such as treatment of elevated uric acid levels and intravenous hydration should be considered before initiating Votrient™. High-risk patients should be closely monitored and managed as clinically indicated.
Pneumothorax.
Cases of pneumothorax were reported in clinical trials involving patients with advanced soft tissue sarcoma (see section "Adverse reactions"). Patients receiving pazopanib should be carefully evaluated for signs and symptoms of pneumothorax.
Infections.
Cases of serious infections (with or without neutropenia), sometimes fatal, have been reported.
Combination with other systemic antineoplastic agents.
Clinical trials evaluating Votrient™ in combination with pemetrexed, lapatinib, and pembrolizumab were terminated early due to concerns about excessive toxicity and/or mortality. A safe and effective combination dosing regimen was not established. Votrient™ is not indicated for use in combination with these agents.
Juvenile toxicity in animals.
Due to its mechanism of action, Votrient™ may significantly affect organ development and maturation during early postnatal life; therefore, Votrient™ should not be administered to children under 2 years of age.
Pregnancy.
Preclinical studies in animals showed reproductive toxicity of the drug. If Votrient™ is used during pregnancy or if a patient becomes pregnant while receiving this drug, the patient must be informed of the potential hazard to the fetus. Women of reproductive potential should be advised to avoid pregnancy during treatment with pazopanib and for 2 weeks after discontinuation (see section "Use during pregnancy or breastfeeding").
Interactions.
Concomitant use with strong inhibitors of CYP3A4, P-gp, or BCRP should be avoided due to the risk of increased pazopanib exposure (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to using alternative medicinal products with no or minimal CYP3A4, P-gp, or BCRP inhibition potential.
Concomitant use with inducers of CYP3A4 should be avoided due to the risk of reduced pazopanib exposure (see section "Interaction with other medicinal products and other forms of interaction").
Cases of hyperglycemia have been observed with concomitant use of ketoconazole.
Pazopanib should be used with caution with substrates of UGT1A1 (e.g., irinotecan), as pazopanib is an inhibitor of UGT1A1 (see section "Interaction with other medicinal products and other forms of interaction").
Grapefruit juice should be avoided during pazopanib treatment.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg)/film-coated tablet, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding.
Fertility.
Votrient™ may impair fertility in both men and women. Animal studies showed reduced fertility in female animals.
Pregnancy.
There are currently no convincing evidence-based data on the use of Votrient™ in pregnant women. Experimental animal studies demonstrated reproductive toxicity of the drug. The potential risk to humans remains unknown. Votrient™ should not be used during pregnancy except when the potential benefit outweighs the risk. If Votrient™ is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient must be informed of the potential hazard to the fetus.
To prevent pregnancy during pazopanib therapy, women of reproductive potential should be advised to use effective contraceptive methods during pazopanib treatment and for 2 weeks after discontinuation of pazopanib.
Male patients (including those who have undergone vasectomy) should use condoms during sexual intercourse during pazopanib treatment and for at least 2 weeks after the last dose of pazopanib to avoid potential effects of the drug on partners who are pregnant or women of reproductive potential.
Breastfeeding period.
The safety of Votrient™ use during breastfeeding has not been established. It is not known whether pazopanib is excreted in human breast milk; therefore, breastfeeding must be discontinued during Votrient™ treatment.
Ability to affect reaction speed when driving vehicles or operating machinery.
No studies have been conducted on the effect of Votrient™ on the ability to drive or operate machinery. Given the pharmacological properties of pazopanib, its adverse effect on such activities is unlikely. When assessing a patient's ability to perform tasks requiring decision-making, motor, and cognitive skills, the patient's clinical status and the adverse reaction profile of Votrient™ should be considered.
Method of Administration and Dosage
Treatment with Votrient™ should only be prescribed by a physician experienced in the use of anticancer agents.
The recommended dose of Votrient™ for the treatment of renal cell carcinoma and soft tissue sarcoma is 800 mg orally once daily. Treatment should continue until disease progression or until unacceptable toxicity occurs.
Votrient™ should be taken on an empty stomach (at least one hour before or two hours after a meal) (see section "Pharmacokinetics").
Votrient™ tablets should be swallowed whole with water, without chewing or crushing, to ensure that the tablet remains intact (see section "Pharmacokinetics").
If a dose is missed, it should not be taken if less than 12 hours remain before the next scheduled dose.
Dosage Modifications
To manage adverse reactions or in cases of increased individual sensitivity to the drug, dosage adjustments may be necessary. Dose modifications—either increases or reductions—should be made in 200 mg increments, based on individual tolerability, to allow appropriate monitoring of adverse reactions. The dose of Votrient™ should not exceed 800 mg.
Special Patient Populations
Renal Impairment
Experience with Votrient™ in patients with severe renal impairment or those undergoing peritoneal dialysis or hemodialysis is lacking; therefore, Votrient™ is not recommended in these patients. Renal impairment is not expected to have a clinically significant effect on the pharmacokinetics of pazopanib, given the low renal excretion of pazopanib and its metabolites. Dose adjustment is not required in patients with a creatinine clearance ≥ 30 mL/min (see section "Pharmacokinetics").
Hepatic Impairment
The safety and pharmacokinetic profile of pazopanib in patients with pre-existing hepatic impairment have not been fully studied (see section "Special Warnings and Precautions for Use").
All patients should undergo liver function tests before starting and during treatment with pazopanib. Pazopanib should be used with caution in patients with mild to moderate hepatic impairment, and close monitoring of tolerability is recommended.
For patients with minor abnormalities in liver function tests—defined as elevated ALT levels with normal bilirubin levels, or elevated bilirubin levels up to 1.5 times the upper limit of normal (ULN) regardless of ALT levels—the recommended dose is 800 mg once daily.
In patients with moderate hepatic dysfunction (total bilirubin levels 1.5 to 3 times the ULN, regardless of ALT levels), the dose of Votrient™ should be reduced to 200 mg once daily. There is insufficient data on the use of Votrient™ in patients with severe hepatic impairment (total bilirubin more than 3 times the ULN, regardless of ALT levels); therefore, Votrient™ is not recommended in these patients.
Elderly Patients
Patients aged 65 years and older do not require dose, frequency, or route of administration adjustments.
Pediatric Population
The safety and efficacy of Votrient™ in children have not been established (see section "Special Warnings and Precautions for Use").
Overdose
Doses of Votrient™ up to 2000 mg have been studied in clinical trials. Grade 3 fatigue (dose-limiting toxicity) was observed in 1 of 3 patients receiving 2000 mg daily, and grade 3 hypertension was observed in 1 of 3 patients receiving 1000 mg daily.
Symptoms and Signs
Experience with Votrient™ overdose is limited to date.
Treatment
There is no specific antidote for pazopanib overdose. Standard supportive measures should be implemented based on clinical presentation. Hemodialysis is unlikely to enhance pazopanib elimination, as the drug is minimally excreted renally and is highly protein-bound.
Adverse reactions.
The pooled data from the main study in patients with RCC (VEG105192, n=290), the expanded study (VEG107769, n=71), the phase II supportive study (VEG102616, n=225), and the randomized open-label phase III non-inferiority study with parallel groups (VEG108844, n=557) were analyzed as part of the overall safety and tolerability assessment of pazopanib (total n=1149) in patients with RCC.
The pooled data from the main study in patients with soft tissue sarcoma (STS) (VEG110727, n=369) and the phase II supportive study (VEG20002, n=142) were analyzed as part of the overall safety and tolerability assessment of pazopanib (total safety population n=382) in patients with STS.
The most clinically significant serious adverse reactions identified in studies in patients with RCC or STS were transient ischemic attack, ischemic stroke, myocardial ischemia, myocardial infarction, cerebral infarction, cardiac dysfunction, gastrointestinal (GI) perforation and fistulae, QT interval prolongation, torsades de pointes ventricular tachycardia, and pulmonary, GI, and intracranial hemorrhage. All these adverse reactions occurred in <1% of patients receiving treatment. Other important serious adverse reactions identified in studies in patients with STS included venous thromboembolic events, left ventricular dysfunction, and pneumothorax.
Fatal events considered possibly related to pazopanib included GI hemorrhage, pulmonary hemorrhage/hemoptysis, hepatic function test abnormalities, intestinal perforation, and ischemic stroke.
The most common adverse reactions (occurring in at least 10% of patients), of any grade, reported in clinical trials in patients with RCC and STS were: diarrhea, hair color changes, skin hypopigmentation, exfoliative rash, hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased, pain, increased alanine aminotransferase and aspartate aminotransferase levels.
The adverse reactions listed below are presented according to the MedDRA organ system class terminology. The following frequency categories were used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), and not known (cannot be estimated from the available data).
Categories were defined based on the absolute frequency of adverse reactions observed in clinical trials. Post-marketing safety and tolerability data from all pazopanib clinical trials and spontaneous reports were also evaluated. Within each organ system class, adverse reactions with similar frequencies are listed in descending order of severity.
Treatment-related adverse reactions reported in studies in patients with RCC (n=1149) or during post-marketing use
| System Organ Class |
Frequency (all grades) |
Adverse Reactions |
All Grades n (%) |
Grade 3 n (%) |
Grade 4 n (%) |
| Infections and Infestations |
common |
Infections (with or without neutropenia)† |
frequency unknown |
frequency unknown |
frequency unknown |
| uncommon |
Gingival infection |
1 (< 1 %) |
0 |
0 |
|
| Infectious peritonitis |
1 (< 1 %) |
0 |
0 |
||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
uncommon |
Tumour pain |
1 (< 1 %) |
1 (< 1 %) |
0 |
| Blood and lymphatic system disorders |
common |
Thrombocytopenia |
80 (7 %) |
10 (< 1 %) |
5 (< 1 %) |
| Neutropenia |
79 (7 %) |
20 (2 %) |
4 (< 1 %) |
||
| Leukopenia |
63 (5 %) |
5 (< 1 %) |
0 |
||
| uncommon |
Increased red blood cell count |
6 (0.03 %) |
1 |
0 |
|
| rare |
Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)† |
frequency unknown |
frequency unknown |
frequency unknown |
|
| Endocrine disorders |
common |
Hypothyroidism |
83 (7 %) |
1 (< 1 %) |
0 |
| Metabolism and nutrition disorders |
very common |
Decreased appetiteд |
317 (28 %) |
14 (1 %) |
0 |
| common |
Hypophosphatemia |
21 (2 %) |
7 (< 1 %) |
0 |
|
| Dehydration |
16 (1 %) |
5 (< 1 %) |
0 |
||
| uncommon |
Hypomagnesemia |
10 (< 1 %) |
0 |
0 |
|
| frequency unknown |
Tumour lysis syndrome* |
frequency unknown |
frequency unknown |
frequency unknown |
|
| Psychiatric disorders |
common |
Insomnia |
30 (3 %) |
0 |
0 |
| Nervous system disorders |
very common |
Dysgeusiaу |
254 (22 %) |
1 (< 1 %) |
0 |
| Headache |
122 (11 %) |
11 (< 1 %) |
0 |
||
| common |
Dizziness |
55 (5 %) |
3 (< 1 %) |
1 (< 1 %) |
|
| Lethargy |
30 (3 %) |
3 (< 1 %) |
0 |
||
| Paraesthesia |
20 (2 %) |
2 (< 1 %) |
0 |
||
| Peripheral sensory neuropathy |
17 (1 %) |
0 |
0 |
||
| uncommon |
Hypoesthesia |
8 (< 1 %) |
0 |
0 |
|
| Transient ischaemic attack |
7 (< 1 %) |
4 (< 1 %) |
0 |
||
| Somnolence |
3 (< 1 %) |
1 (< 1 %) |
0 |
||
| Acute cerebrovascular accident |
2 (< 1 %) |
1 (< 1 %) |
1 (< 1 %) |
||
| Ischaemic stroke |
2 (< 1 %) |
0 |
1 (< 1 %) |
||
| rare |
Reversible posterior encephalopathy syndrome/posterior reversible leukoencephalopathy syndrome† |
frequency unknown |
frequency unknown |
frequency unknown |
|
| Eye disorders |
common |
Blurred vision |
19 (2 %) |
1 (< 1 %) |
0 |
| uncommon |
Retinal detachment† |
1 (< 1 %) |
1 (< 1 %) |
0 |
|
| Retinal tear† |
1 (< 1 %) |
1 (< 1 %) |
0 |
||
| Discoloration of eyelashes |
4 (< 1 %) |
0 |
0 |
||
| Cardiac disorders |
uncommon |
Bradycardia |
6 (< 1 %) |
0 |
0 |
| Myocardial infarction |
5 (< 1 %) |
1 (< 1 %) |
4 (< 1 %) |
||
| Cardiac dysfunctionе |
4 (< 1 %) |
1 (< 1 %) |
0 |
||
| Myocardial ischaemia |
3 (< 1 %) |
1 (< 1 %) |
0 |
||
| Vascular disorders |
very common |
Arterial hypertension |
473 (41 %) |
115 (10 %) |
1 (< 1 %) |
| common |
Flushing |
16 (1 %) |
0 |
0 |
|
| Venous thromboembolic eventж |
13 (1 %) |
6 (< 1 %) |
7 (< 1 %) |
||
| Facial flushing |
12 (1 %) |
0 |
0 |
||
| uncommon |
Hypertensive crisis |
6 (< 1 %) |
0 |
2 (< 1 %) |
|
| Haemorrhage |
1 (< 1 %) |
0 |
0 |
||
| rare |
Arterial aneurysms and dissections |
Frequency unknown |
Frequency unknown |
Frequency unknown |
|
| Respiratory, thoracic and mediastinal disorders |
common |
Nosebleed |
50 (4 %) |
1 (< 1 %) |
0 |
| Dysphonia |
48 (4 %) |
0 |
0 |
||
| Dyspnoea |
42 (4 %) |
8 (< 1 %) |
1 (< 1 %) |
||
| Haemoptysis |
15 (1 %) |
1 (< 1 %) |
0 |
||
| uncommon |
Rhinorrhoea |
8 (< 1 %) |
0 |
0 |
|
| Pulmonary haemorrhage |
2 (< 1 %) |
0 |
0 |
||
| Pneumothorax |
1 (< 1 %) |
0 |
0 |
||
| rare |
Interstitial lung disease/pneumonitis† |
frequency unknown |
frequency unknown |
frequency unknown |
|
| Gastrointestinal disorders |
Very common |
Diarrhoea |
614 (53 %) |
65 (6 %) |
2 (< 1 %) |
| Nausea |
386 (34 %) |
14 (1 %) |
0 |
||
| Vomiting |
225 (20 %) |
18 (2 %) |
1 (< 1 %) |
||
| Stomach painа |
139 (12 %) |
15 (1 %) |
0 |
||
| common |
Stomatitis |
96 (8 %) |
4 (< 1 %) |
0 |
|
| Dyspepsia |
83 (7 %) |
2 (< 1 %) |
0 |
||
| Flatulence |
43 (4 %) |
0 |
0 |
||
| Abdominal distension |
36 (3 %) |
2 (< 1 %) |
0 |
||
| Mouth ulceration |
28 (2 %) |
3 (< 1 %) |
0 |
||
| Dry mouth |
27 (2 %) |
0 |
0 |
||
| uncommon |
Pancreatitis |
8 (< 1 %) |
4 (< 1 %) |
0 |
|
| Rectal haemorrhage |
8 (< 1 %) |
2 (< 1 %) |
0 |
||
| Fresh blood in stool |
6 (< 1 %) |
0 |
0 |
||
| Gastrointestinal haemorrhage |
4 (< 1 %) |
2 (< 1 %) |
0 |
||
| Melena |
4 (< 1 %) |
1(< 1 %) |
0 |
||
| Increased frequency of defecation |
3 (< 1 %) |
0 |
0 |
||
| Rectal haemorrhage |
2 (< 1 %) |
0 |
0 |
||
| Colon perforation |
2 (< 1 %) |
1 (< 1 %) |
0 |
||
| Oral haemorrhage |
2 (< 1 %) |
0 |
0 |
||
| Upper gastrointestinal haemorrhage |
2 (< 1 %) |
1 (< 1 %) |
0 |
||
| External intestinal fistula |
1 (< 1 %) |
0 |
0 |
||
| Haematemesis |
1 (< 1 %) |
0 |
0 |
||
| Haemorrhoidal haemorrhage |
1 (< 1 %) |
0 |
0 |
||
| Ileal perforation |
1 (< 1 %) |
0 |
1 (< 1 %) |
||
| Oesophageal haemorrhage |
1 (< 1 %) |
0 |
0 |
||
| Retroperitoneal haemorrhage |
1 (< 1 %) |
0 |
0 |
||
| Hepatobiliary disorders |
common |
Hyperbilirubinaemia |
38 (3 %) |
2 (< 1 %) |
1 (< 1 %) |
| Liver function test abnormalities |
29 (3 %) |
13 (1 %) |
2 (< 1 %) |
||
| Hepatotoxicity |
18 (2 %) |
11(< 1 %) |
2 (< 1 %) |
||
| uncommon |
Jaundice |
3 (< 1 %) |
1 (< 1 %) |
0 |
|
| Drug-induced liver injury |
2 (< 1 %) |
2 (< 1 %) |
0 |
||
| Hepatic failure† |
1 (< 1 %) |
0 |
1 (< 1 %) |
||
| Skin and subcutaneous tissue disorders |
Very common |
Change in hair colour |
404 (35 %) |
1 (< 1 %) |
0 |
| Palmar-plantar erythrodysesthesia syndrome |
206 (18 %) |
39 (3 %) |
0 |
||
| Alopecia |
130 (11 %) |
0 |
0 |
||
| Rash |
129 (11 %) |
7 (< 1 %) |
0 |
||
| common |
Hypopigmentation of the skin |
52 (5 %) |
0 |
0 |
|
| Dry skin |
50 (4 %) |
0 |
0 |
||
| Pruritus |
29 (3 %) |
0 |
0 |
||
| Erythema |
25 (2 %) |
0 |
0 |
||
| Depigmentation of the skin |
20 (2 %) |
0 |
0 |
||
| Hyperhidrosis |
17 (1 %) |
0 |
0 |
||
| uncommon |
Nail disorders |
11 (< 1 %) |
0 |
0 |
|
| Peeling skin |
10 (< 1 %) |
0 |
0 |
||
| Photosensitivity reaction |
7 (< 1 %) |
0 |
0 |
||
| Erythematous rash |
6 (< 1 %) |
0 |
0 |
||
| Skin lesion |
5 (< 1 %) |
0 |
0 |
||
| Macular rash |
4 (< 1 %) |
0 |
0 |
||
| Rash with pruritus |
3 (< 1 %) |
0 |
0 |
||
| Bullous rash |
3 (< 1 %) |
0 |
0 |
||
| Generalised pruritus |
2 (< 1 %) |
1 (< 1 %) |
0 |
||
| Generalised rash |
2 (< 1 %) |
0 |
0 |
||
| Papular rash |
2 (< 1 %) |
0 |
0 |
||
| Plantar erythema |
1 (< 1 %) |
0 |
0 |
||
| Skin ulcer† |
frequency unknown |
frequency unknown |
frequency unknown |
||
| Musculoskeletal and connective tissue disorders |
common |
Arthralgia |
48 (4 %) |
8 (< 1 %) |
0 |
| Myalgia |
35 (3 %) |
2 (< 1 %) |
0 |
||
| Muscle spasms |
25 (2 %) |
0 |
0 |
||
| uncommon |
Musculoskeletal pain |
9 (< 1 %) |
1 (< 1 %) |
0 |
|
| Renal and urinary disorders |
Very common |
Proteinuria |
135 (12 %) |
32 (3 %) |
0 |
| uncommon |
Urinary tract haemorrhage |
1 (< 1 %) |
0 |
0 |
|
| Reproductive system and breast disorders |
uncommon |
Menorrhagia |
3 (< 1 %) |
0 |
0 |
| Vaginal haemorrhage |
3 (< 1 %) |
0 |
0 |
||
| Metrorrhagia |
1 (< 1 %) |
0 |
0 |
||
| General disorders and administration site conditions |
Very common |
Fatigue |
415 (36 %) |
65 (6 %) |
1 (< 1 %) |
| common |
Mucosal inflammation |
86 (7 %) |
5 (< 1 %) |
0 |
|
| Asthenia |
82 (7 %) |
20 (2 %) |
1 (< 1 %) |
||
| Oedemab |
72 (6 %) |
1 (< 1 %) |
0 |
||
| Chest pain |
18 (2 %) |
2 (< 1 %) |
0 |
||
| uncommon |
Chills |
4 (<1 %) |
0 |
0 |
|
| Mucosal disorder |
1 (<1 %) |
0 |
0 |
||
| Investigations |
Very common |
Increased alanine aminotransferase levels |
246 (21 %) |
84 (7 %) |
14 (1 %) |
| Increased aspartate aminotransferase levels |
211 (18 %) |
51 (4 %) |
10 (< 1 %) |
||
| common |
Decreased body weight |
96 (8 %) |
7 (< 1 %) |
0 |
|
| Increased blood bilirubin levels |
61 (5 %) |
6 (< 1 %) |
1 (< 1 %) |
||
| Increased blood creatinine levels |
55 (5 %) |
3 (< 1 %) |
0 |
||
| Increased lipase levels |
51 (4 %) |
21 (2 %) |
7 (< 1 %) |
||
| Decreased white blood cell countг |
51 (4 %) |
3 (< 1 %) |
0 |
||
| Increased blood thyroid-stimulating hormone levels |
36 (3 %) |
0 |
0 |
||
| Increased amylase levels |
35 (3 %) |
7 (< 1 %) |
0 |
||
| Increased gamma-glutamyltransferase levels |
31 (3 %) |
9 (< 1 %) |
4 (< 1 %) |
||
| Increased blood pressure |
15 (1 %) |
2 (< 1 %) |
0 |
||
| Increased blood urea levels |
12 (1 %) |
1 (< 1 %) |
0 |
||
| Liver function abnormalities |
12 (1 %) |
6 (< 1 %) |
1 (< 1 %) |
||
| uncommon |
Increased liver enzyme levels |
11 (< 1 %) |
4 (< 1 %) |
3 (< 1 %) |
|
| Increased blood glucose levels |
7 (< 1 %) |
0 |
1 (< 1 %) |
||
| QT interval prolongation on electrocardiogram |
7 (< 1 %) |
2 (< 1 %) |
0 |
||
| Increased transaminase levels |
7 (< 1 %) |
1 (< 1 %) |
0 |
||
| Thyroid function test abnormalities |
3 (< 1 %) |
0 |
0 |
||
| Increased diastolic blood pressure |
2 (< 1 %) |
0 |
0 |
||
| Increased systolic blood pressure |
1 (< 1 %) |
0 |
0 |
||
| †Adverse reactions related to treatment that were reported during post-marketing use (spontaneous reports and serious adverse reactions reported in all pazopanib clinical trials). * Treatment-related adverse reactions reported only during the post-marketing period. Frequency cannot be estimated from available data. The following terms were combined: aStomach pain, upper abdominal pain, and lower abdominal pain. bOedema, peripheral oedema, eye oedema, localized oedema, and facial oedema. cDysgeusia, ageusia, and hypogeusia. dDecreased appetite and anorexia. eCardiac dysfunction, left ventricular dysfunction, heart failure, and restrictive cardiomyopathy. fVenous thromboembolic event, deep vein thrombosis, pulmonary embolism, and pulmonary thrombosis. |
|||||
Neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia syndrome were more frequently observed in patients of East Asian origin.
Treatment-related adverse reactions reported in studies in patients with advanced/metastatic breast cancer (n=382)
| System Organ Class |
Frequency (all grades) |
Adverse Reactions |
All Grades n (%) |
Grade 3 n (%) |
Grade 4 n (%) |
|
| Infections and infestations |
common |
Gingival infection |
4 (1 %) |
0 |
0 |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Very common |
Tumour pain |
121 (32%) |
32 (8 %) |
0 |
|
| Blood and lymphatic system disorders |
Very common |
Leukopenia |
106 (44%) |
3 (1 %) |
0 |
|
| Thrombocytopenia |
86 (36 %) |
7 (3 %) |
2 (< 1 %) |
|||
| Neutropenia |
79 (33 %) |
10 (4 %) |
0 |
|||
| uncommon |
Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome) |
1 (< 1 %) |
1 (< 1 %) |
0 |
||
| Endocrine disorders |
common |
Hypothyroidism |
18 (5 %) |
0 |
0 |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
108 (28%) |
12 (3 %) |
0 |
|
| Hypoalbuminemia |
81 (34 %) |
2 (< 1 %) |
0 |
|||
| common |
Dehydration |
4 ( 1%) |
2 (1%) |
0 |
||
| uncommon |
Hypomagnesemia |
1 (< 1 %) |
0 |
0 |
||
| frequency unknown |
Tumour lysis syndrome* |
frequency unknown |
frequency unknown |
frequency unknown |
||
| Psychiatric disorders |
common |
Insomnia |
5 (1 %) |
1 (< 1 %) |
0 |
|
| Nervous system disorders |
Very common |
Dysgeusia |
79 (21%) |
0 |
0 |
|
| Headache |
54 (14%) |
2 (<1%) |
0 |
|||
| common |
Peripheral sensory neuropathy |
30 (8%) |
1 (<1%) |
0 |
||
| Dizziness |
15 (4 %) |
0 |
0 |
|||
| uncommon |
Somnolence |
3 (< 1 %) |
0 |
0 |
||
| Paresthesia |
1 (< 1 %) |
0 |
0 |
|||
| Cerebral infarction |
1 (< 1 %) |
0 |
1 (< 1 %) |
|||
| Eye disorders |
common |
Blurred vision |
15 (4 %) |
0 |
0 |
|
| Cardiac disorders |
common |
Cardiac dysfunction |
21 (5 %) |
3 (< 1 %) |
1 (< 1 %) |
|
| Left ventricular dysfunction |
13 (3 %) |
3 (< 1 %) |
0 |
|||
| Bradycardia |
4 (1 %) |
0 |
0 |
|||
| uncommon |
Myocardial infarction |
1 (< 1 %) |
0 |
0 |
||
| Vascular disorders |
very common |
Hypertension |
152 (40%) |
26 (7 %) |
0 |
|
| common |
Venous thromboembolic events |
13 (3 %) |
4 (1 %) |
5 (1 %) |
||
| Flushing |
12 (3 %) |
0 |
0 |
|||
| Facial flushing |
4 (1 %) |
0 |
0 |
|||
| uncommon |
Haemorrhage |
2 (< 1 %) |
1 (< 1 %) |
0 |
||
| unknown |
Arterial aneurysms and dissections |
Frequency unknown |
Frequency unknown |
Frequency unknown |
||
| Respiratory, thoracic and mediastinal disorders |
common |
Nosebleed |
22 (6 %) |
0 |
0 |
|
| Dysphonia |
20 (5 %) |
0 |
0 |
|||
| Dyspnoea |
14 (4 %) |
3 (< 1 %) |
0 |
|||
| Cough |
12 (3 %) |
0 |
0 |
|||
| Pneumothorax |
7 (2 %) |
2 (< 1 %) |
1 (< 1 %) |
|||
| Hiccough |
4 (1 %) |
0 |
0 |
|||
| Pulmonary haemorrhage |
4 (1 %) |
1 (< 1 %) |
0 |
|||
| uncommon |
Oropharyngeal pain |
3 (< 1 %) |
0 |
0 |
||
| Haemoptysis in bronchi |
2 (< 1 %) |
0 |
0 |
|||
| Rhinorrhoea |
1 (< 1 %) |
0 |
0 |
|||
| Haemoptysis |
1 (< 1 %) |
0 |
0 |
|||
| rare |
Interstitial lung disease/pneumonitis† |
frequency unknown |
frequency unknown |
frequency unknown |
||
| Gastrointestinal disorders |
very common |
Diarrhoea |
174 (46%) |
17 (4 %) |
0 |
|
| Nausea |
167 (44%) |
8 (2 %) |
0 |
|||
| Vomiting |
96 (25 %) |
7 (2 %) |
0 |
|||
| Abdominal pain |
55 (14 %) |
4 (1 %) |
0 |
|||
| Stomatitis |
41 (11 %) |
1 (< 1 %) |
0 |
|||
| common |
Abdominal distension |
16 (4 %) |
2 (1 %) |
0 |
||
| Dry mouth |
14 (4 %) |
0 |
0 |
|||
| Dyspepsia |
12 (3 %) |
0 |
0 |
|||
| Oral haemorrhage |
5 (1 %) |
0 |
0 |
|||
| Flatulence |
5 (1 %) |
0 |
0 |
|||
| Anal haemorrhage |
4 (1 %) |
0 |
0 |
|||
| uncommon |
Gastrointestinal haemorrhage |
2 (< 1 %) |
0 |
0 |
||
| Rectal haemorrhage |
2 (< 1 %) |
0 |
0 |
|||
| External intestinal fistula |
1 (< 1 %) |
1 (< 1 %) |
0 |
|||
| Gastric haemorrhage |
1 (< 1 %) |
0 |
0 |
|||
| Melena |
2 (< 1 %) |
0 |
0 |
|||
| Oesophageal haemorrhage |
1 (< 1 %) |
0 |
1 (< 1 %) |
|||
| Peritonitis |
1 (< 1 %) |
0 |
0 |
|||
| Retroperitoneal haemorrhage |
1 (< 1 %) |
0 |
0 |
|||
| Upper gastrointestinal haemorrhage |
1 (< 1 %) |
1 (< 1 %) |
0 |
|||
| Ileal perforation |
1 (< 1 %) |
0 |
1 (< 1 %) |
|||
| Hepatobiliary disorders |
uncommon |
Liver function test abnormalities |
2 (< 1 %) |
0 |
1 (< 1 %) |
|
| frequency unknown |
Liver failure* |
frequency unknown |
frequency unknown |
frequency unknown |
||
| Skin and subcutaneous tissue disorders |
Very common |
Change in hair colour |
93 (24 %) |
0 |
0 |
|
| Hypopigmentation of skin |
80 (21 %) |
0 |
0 |
|||
| Exfoliative rash |
52 (14 %) |
2 (< 1 %) |
0 |
|||
| common |
Alopecia |
30 (8 %) |
0 |
0 |
||
| Skin lesions |
26 (7 %) |
4 (1 %) |
0 |
|||
| Dry skin |
21 (5 %) |
0 |
0 |
|||
| Hyperhidrosis |
18 (5 %) |
0 |
0 |
|||
| Nail disorders |
13 (3 %) |
0 |
0 |
|||
| Pruritus |
11 (3 %) |
0 |
0 |
|||
| Erythema |
4 (1 %) |
0 |
0 |
|||
| uncommon |
Skin ulcers |
3 (< 1 %) |
1 (< 1 %) |
0 |
||
| Rash |
1 (< 1 %) |
0 |
0 |
|||
| Papular rash |
1 (< 1 %) |
0 |
0 |
|||
| Photosensitivity reaction |
1 (< 1 %) |
0 |
0 |
|||
| Palmar-plantar erythrodysaesthesia syndrome |
2 (< 1 %) |
0 |
0 |
|||
| Musculoskeletal and connective tissue disorders |
common |
Musculoskeletal pain |
35 (9 %) |
2 (< 1 %) |
0 |
|
| Myalgia |
28 (7 %) |
2 (< 1 %) |
0 |
|||
| Muscle spasms |
8 (2 %) |
0 |
0 |
|||
| uncommon |
Arthralgia |
2 (< 1 %) |
0 |
0 |
||
| Renal and urinary disorders |
uncommon |
Proteinuria |
2 (< 1 %) |
0 |
0 |
|
| Reproductive system and breast disorders |
uncommon |
Vaginal haemorrhage |
3 (< 1 %) |
0 |
0 |
|
| Menorrhagia |
1 (< 1 %) |
0 |
0 |
|||
| General disorders and administration site conditions |
very common |
Fatigue |
178 (47%) |
34 (9 %) |
1 (< 1 %) |
|
| common |
Swelling |
18 (5 %) |
1 (< 1 %) |
0 |
||
| Chest pain |
12 (3 %) |
4 (1 %) |
0 |
|||
| Chills |
10 (3 %) |
0 |
0 |
|||
| uncommon |
Mucosal inflammation |
1 (< 1 %) |
0 |
0 |
||
| Asthenia |
1 (< 1 %) |
0 |
0 |
|||
| Investigations |
very common |
Decreased body weight |
86 (23 %) |
5 (1 %) |
0 |
|
| common |
Disorders identified during ENT examination |
29 (8 %) |
4 (1 %) |
0 |
||
| Increased alanine aminotransferase levels |
8 (2 %) |
4 (1 %) |
2 (< 1 %) |
|||
| Blood cholesterol level abnormalities |
6 (2 %) |
0 |
0 |
|||
| Increased aspartate aminotransferase levels |
5 (1 %) |
2 (< 1 %) |
2 (< 1 %) |
|||
| Increased gamma-glutamyltransferase levels |
4 (1 %) |
0 |
3 (< 1 %) |
|||
| uncommon |
Increased blood bilirubin levels |
2 (< 1 %) |
0 |
0 |
||
| Aspartate aminotransferase level change |
2 (< 1 %) |
0 |
2 (< 1 %) |
|||
| Alanine aminotransferase level change |
1 (< 1 %) |
0 |
1 (< 1 %) |
|||
| Decreased platelet count |
1 (< 1 %) |
0 |
1 (< 1 %) |
|||
| QT interval prolongation on electrocardiogram |
2 (< 1 %) |
1 (< 1 %) |
0 |
|||
| † Treatment-related adverse reactions that were reported during post-marketing use (spontaneous reports and serious adverse reactions recorded in all pazopanib clinical trials). * Treatment-related adverse reactions reported only during the post-marketing period. Frequency cannot be estimated from available data. The following terms were combined: aAbdominal pain, upper abdominal pain, and gastrointestinal pain. bSwelling, peripheral swelling, and eyelid swelling. cMost of these cases were described as palmar-plantar erythrodysesthesia syndrome. dVenous thromboembolic events include deep vein thrombosis, pulmonary embolism, and pulmonary thrombosis. eMost of these cases were described as mucositis. fFrequency is based on laboratory values from study VEG110727 (N=240). They were reported less frequently as adverse events by investigators than indicated by laboratory data. gCardiac dysfunction terms include left ventricular dysfunction, heart failure, and restrictive cardiomyopathy. hFrequency is based on adverse events reported by investigators. Laboratory test abnormalities were reported by investigators less frequently than indicated by laboratory data. |
||||||
In patients of East Asian origin, neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia syndrome were observed more frequently.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system (automated pharmacovigilance information system).
Shelf life. 3 years.
Storage conditions.
Store the medicinal product below 30 °C. Keep out of reach and sight of children.
Packaging.
30 tablets in an opaque high-density polyethylene white bottle with a child-resistant polypropylene cap. One bottle per cardboard box.
Prescription status. Prescription only.
Manufacturers.
- Batch release:
Glaxo Wellcome S.A., Spain;
- Batch release:
Novartis Pharmaceutical Manufacturing LLC, Slovenia.
Manufacturers' addresses and locations of their business operations.
- Avda. Extremadura, 3, Pol. Ind. Allendeduero, Aranda de Duero, Burgos, 09400, Spain;
- Verovskova Ulica 57, Ljubljana, 1000, Slovenia.