Pazopanib (Tablets) Instructions for Use

ATC Code

L01EX03 (Pazopanib)

Active Substance

Pazopanib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

Antitumor agent, tyrosine kinase inhibitor. It actively affects many target receptors.

Pazopanib binds to receptors for vascular endothelial growth factor, platelet-derived growth factor, and the stem cell factor receptor, with 50% inhibitory concentration (IC₅₀) values of 10, 30, 47, 71, 84, and 74 nmol/L, respectively.

Pazopanib is an inhibitor of multiple tyrosine kinases, including tyrosine kinases of endothelial growth factor receptors-1, 2, 3 (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), fibroblast growth factor receptor-1 and -3 (FGFR-1, -3), cytokine receptor (Kit), interleukin-2 receptor, inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, Pazopanib inhibits ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β. In vivo, Pazopanib inhibits VEGF-induced phosphorylation of VEGFR-2, angiogenesis, and the growth of certain human tumor xenografts in mice.

An increase in blood pressure was observed upon reaching the steady-state concentration (C_ss) of pazopanib.

Pharmacokinetics

Pazopanib is absorbed, reaching C_max on average 2-4 hours after oral administration. Daily administration leads to a 1-, 2-, 3-, 4-fold increase in AUC. With daily administration of 800 mg of pazopanib, the AUC and C_max values were 1,037 h × µg/mL and 58.1 µg/mL (equivalent to 132 µM), respectively. No significant increase in AUC and C_max was observed when the pazopanib dose was increased above 800 mg.

Systemic exposure of pazopanib increased when taken with food. Administration of pazopanib with high-fat and low-fat food leads to an approximately 2-fold increase in AUC and C_max. Therefore, Pazopanib should be taken at least 1 hour before or 2 hours after a meal.

The binding of pazopanib to plasma proteins in vivo was more than 99% regardless of concentration in the range of 10-100 µg/mL.

In vitro data suggest that Pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP).

In vitro studies have shown that the metabolism of pazopanib is mediated primarily by the CYP3A4 isoenzyme, and to a lesser extent by CYP1A2 and CYP2C8.

Pazopanib is eliminated slowly with a mean T_1/2 of 30.9 hours after administration of the recommended dose of 800 mg. Elimination occurs mainly via the intestine, with less than 4% of the administered dose excreted by the kidneys.

Pharmacokinetic data showed that in patients with moderate hepatic impairment, the clearance of pazopanib decreased by approximately 50% compared to patients without hepatic impairment.

Indications

Treatment of advanced renal cell carcinoma; treatment of advanced soft tissue sarcoma (excluding gastrointestinal stromal tumors and liposarcoma) in patients who have previously received chemotherapy.

ICD codes

Dosage Regimen

Administer pazopanib orally as a single daily dose.

The recommended starting dose is 800 mg taken once per day.

Take tablets at least one hour before or two hours after a meal due to increased systemic exposure with food.

Do not exceed the maximum daily dose of 800 mg.

Adjust the dose based on individual tolerance and the management of adverse reactions.

Reduce the dose in 200 mg increments if necessary; the minimum recommended dose is 400 mg daily.

For patients with moderate hepatic impairment, initiate therapy at a reduced dose of 200 mg per day.

Interrupt treatment for specific laboratory abnormalities or severe adverse events, such as elevated liver enzymes.

If therapy is resumed following hepatotoxicity, consider a dose reduction to 400 mg daily with close monitoring.

Permanently discontinue pazopanib for severe liver function impairment or other life-threatening events.

Suspend treatment at least seven days prior to elective surgical procedures.

Adverse Reactions

From the hematopoietic system: frequent – neutropenia, thrombocytopenia.

From the endocrine system: frequent – hypothyroidism.

From the nervous system: very common – dizziness, dysgeusia, headache; frequent – transient ischemic attack (transient cerebrovascular accident); infrequent – ischemic stroke.

From the cardiovascular system: very common – increased blood pressure; frequent – cardiac dysfunction (such as decreased left ventricular ejection fraction and chronic heart failure), myocardial infarction, myocardial ischemia, QT interval prolongation; infrequent – torsades de pointes ventricular tachycardia.

From the respiratory system: very common – cough, dyspnea; frequent – dysphonia, pneumothorax.

From the blood coagulation system: frequent – epistaxis, hematuria, pulmonary hemorrhage, venous thromboembolic complications; infrequent – cerebral hemorrhage, gastrointestinal bleeding, venous thromboembolic complications.

From the digestive system: very common – abdominal pain, anorexia, diarrhea, nausea, stomatitis, vomiting, increased ALT activity, AST activity; frequent – dyspepsia, increased lipase activity, impaired liver function, hyperbilirubinemia; infrequent – gastric or intestinal perforation, formation of gastric and/or intestinal fistulas.

From the skin and subcutaneous tissues: very common – alopecia, exfoliative rash, hair depigmentation, skin depigmentation, palmar-plantar erythrodysesthesia (hand-foot syndrome); frequent – dry skin, nail disorders, rash.

From the urinary system: frequent – proteinuria.

From the musculoskeletal system: very common – bone pain, myalgia.

Other: very common – asthenia, weight loss, chest pain, increased fatigue, peripheral edema; frequent – chills, decreased visual acuity.

Contraindications

Severe hepatic impairment, severe renal impairment; children and adolescents under 18 years of age; pregnancy, lactation (breastfeeding); hypersensitivity to pazopanib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Monitoring of liver enzyme activity should be performed before starting treatment with pazopanib and at least once every 4 weeks or more frequently (based on clinical indications) for at least the first 4 months of treatment. Periodic monitoring should also be performed after the first 4 months. These instructions apply to patients with baseline total bilirubin ≤ 1.5 × ULN and ALT and AST activity ≤ 2 × ULN.

If ALT activity increases to > 8 × ULN, pazopanib should be interrupted until ALT activity decreases to grade 1 toxicity or to the baseline value. If the potential benefit of resuming pazopanib outweighs the risk of hepatotoxicity, pazopanib can be resumed at a reduced dose of 400 mg once daily with weekly monitoring of liver function parameters for 8 weeks. Upon subsequent administration of pazopanib, if ALT activity increases again to > 3 × ULN, pazopanib should be permanently discontinued.

In patients with increased ALT activity > 3 × ULN and concurrent bilirubin concentration > 2 × ULN, Pazopanib should be permanently discontinued.

Concomitant use of pazopanib and simvastatin increases the risk of increased ALT activity and requires special caution and careful monitoring.

In patients with moderate hepatic impairment, it is recommended to reduce the initial dose of pazopanib to 200 mg/day. There are no additional recommendations for dose adjustment during treatment based on liver test results in patients with pre-existing hepatic impairment.

Adequate blood pressure control should be achieved before using pazopanib. No later than 1 week after starting pazopanib treatment, blood pressure should be monitored and, if necessary, antihypertensive therapy should be administered.

Arterial hypertension (systolic pressure ≥ 150 mm Hg or diastolic pressure ≥ 100 mm Hg) occurs at the beginning of the treatment course (in approximately 40% of cases by day 9 and in 90% of cases within the first 18 weeks). In case of resistant arterial hypertension (despite ongoing antihypertensive therapy), the dose of pazopanib can be reduced. In case of severe arterial hypertension resistant to antihypertensive agents, or if signs of a hypertensive crisis appear, Pazopanib should be discontinued.

Monitoring and timely correction of blood pressure using a combination of antihypertensive therapy and pazopanib dose adjustment (discontinuation and re-prescription of therapy at a lower dose, based on the clinical situation) is necessary. Patients should be carefully monitored for clinical signs of congestive heart failure. In patients at risk of developing cardiac dysfunction, it is recommended to determine the baseline LVEF and perform regular repeated LVEF measurements.

In patients with a history of QT interval prolongation, taking antiarrhythmic and other drugs that prolong the QT interval, as well as in patients with heart disease that may be complicated by rhythm disturbances, it is recommended to use Pazopanib with ECG monitoring and electrolyte concentrations (calcium, magnesium, potassium).

Pazopanib should be used with caution in patients with an increased risk of arterial thrombosis or with a history of arterial thrombosis. Thus, the decision to use should be made individually based on a risk/benefit assessment.

Pazopanib should be used with caution in patients who have experienced episodes of hemoptysis, intracranial or gastrointestinal bleeding within the last 6 months.

Use with caution in patients with an increased risk of gastrointestinal perforation and fistula formation.

Since VEGFR inhibitors may impair wound healing, Pazopanib should be discontinued at least 7 days before planned surgery.

The decision to resume treatment with pazopanib after surgery should be based on a clinical assessment of the adequacy of postoperative wound healing. Pazopanib should be discontinued in patients with wound dehiscence.

Prophylactic monitoring of thyroid function is recommended during treatment.

Periodic monitoring of proteinuria dynamics is recommended in such patients during treatment. If nephrotic syndrome develops, Pazopanib should be discontinued.

Currently, Pazopanib is not indicated for use in combination with other antitumor drugs.

Drug Interactions

Based on in vitro data, it is believed that the oxidative metabolism of pazopanib in human liver microsomes occurs mainly with the participation of the CYP3A4 isoenzyme, with a minor contribution from CYP1A2 and CYP2C8. Thus, inhibitors and inducers of the CYP3A4 isoenzyme may alter the metabolism of pazopanib.

Concomitant use of pazopanib with potent inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) may lead to increased concentrations of pazopanib.

Concomitant consumption of grapefruit juice may also increase the concentration of pazopanib.

Administration of 1500 mg of lapatinib – a substrate and weak inhibitor of the CYP3A4 isoenzyme, P-glycoprotein and BCRP – with pazopanib at a dose of 800 mg leads to an increase of approximately 50-60% in the mean AUC_(0-24) and C_max of pazopanib compared to the use of pazopanib alone at a dose of 800 mg. Concomitant use of pazopanib with inhibitors of the CYP3A4 isoenzyme, Pgp and BCRP (e.g., lapatinib) leads to an increase in the plasma concentration of pazopanib.

Therefore, concomitant use of pazopanib with potent inhibitors of the CYP3A4 isoenzyme should be avoided, or alternative drugs that have no or minimal inhibitory effect on the CYP3A4 isoenzyme should be used. If such combinations are necessary, consideration should be given to reducing the dose of pazopanib.

Inducers of the CYP3A4 isoenzyme, for example rifampicin, may decrease the plasma concentration of pazopanib. It is recommended to choose alternative drugs that have no or minimal inhibitory activity against the CYP3A4 isoenzyme.

In vitro studies using human liver microsomes have proven that Pazopanib inhibits the CYP1A2, 3A4, 2B6, 2C8, 2C9, 2C19 and 2E1 isoenzymes. The ability to induce the CYP3A4 isoenzyme in humans was demonstrated in in vitro studies using the human pregnane X receptor (PXR). In pharmacological studies of pazopanib at a dose of 800 mg once daily, it was shown that Pazopanib does not have a clinically significant effect on the pharmacokinetics of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate) or omeprazole (CYP2C19 substrate) in patients with malignancies.

Pazopanib led to an increase in the mean AUC and C_max of midazolam (CYP3A4 substrate) by approximately 30% and an increase of 33-64% in the urinary concentration ratio of dextromethorphan and dextrorphan after oral administration of dextromethorphan (CYP2D6 substrate).

Concomitant administration of pazopanib at a dose of 800 mg once daily and paclitaxel at a dose of 80 mg/m² (CYP3A4 and CYP2C8 substrate) once weekly led, on average, to an increase in the AUC and C_max of paclitaxel by 26% and 31%, respectively.

Concomitant use of pazopanib with substrates of the CYP3A4, 2D6, 2C8 isoenzymes with a narrow therapeutic range is not recommended.

In vitro studies have also shown that Pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 with an inhibitory concentration (IC50) of 1.2 µM and 0.79 µM, respectively.

Pazopanib may increase the concentrations of drugs whose elimination is primarily mediated by UGT1A1 and OATP1B1.

Concomitant use of pazopanib and simvastatin increases the frequency of increased ALT activity. In a pooled population of patients participating in monotherapy studies with pazopanib, increased ALT activity >3 × ULN was reported in 126 out of 895 (14%) patients who did not take a statin, and in 11 out of 41 (27%) patients concomitantly taking simvastatin (p = 0.038). If a patient concomitantly taking simvastatin experiences an increase in ALT activity, the recommendations for pazopanib dosing should be followed and simvastatin should be discontinued. There is insufficient data to assess the risk of concomitant use of alternative statins and pazopanib.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.