Amezopan (Tablets) Instructions for Use

Marketing Authorization Holder

Amedart LLC (Russia)

ATC Code

L01EX03 (Pazopanib)

Active Substance

Pazopanib (Rec.INN registered by WHO)

Dosage Forms

	Amezopan	Film-coated tablets, 200 mg: 10, 30 or 60 pcs.
		Film-coated tablets, 400 mg: 10, 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, biconvex.

Excipients: microcrystalline cellulose 102 – 64.1 mg, sodium carboxymethyl starch – 21.2 mg, povidone K30 – 16 mg, magnesium stearate – 2.1 mg.

Film coating composition Opadry^® AMB II white 88A180040 (polyvinyl alcohol (E1203) – 37%, talc – (E553b) – 31%, titanium dioxide (E171) – 25%, glycerol monocaprylocaprate (type 1) – 4%, sodium lauryl sulfate – 3%) (colorcon) – 9.6 mg.

10 pcs. – high-density polyethylene jars (1) – cardboard packs.
30 pcs. – high-density polyethylene jars (1) – cardboard packs.
60 pcs. – high-density polyethylene jars (1) – cardboard packs.

Film-coated tablets white or almost white, oval, biconvex.

Excipients: microcrystalline cellulose 102 – 128.1 mg, sodium carboxymethyl starch – 42.4 mg, povidone K30 – 32 mg, magnesium stearate – 4.2 mg.

Film coating composition Opadry^® AMB II white 88A180040 (polyvinyl alcohol (E1203) – 37%, talc – (E553b) – 31%, titanium dioxide (E171) – 25%, glycerol monocaprylocaprate (type 1) – 4%, sodium lauryl sulfate – 3%) (colorcon) – 19.2 mg.

10 pcs. – high-density polyethylene jars (1) – cardboard packs.
30 pcs. – high-density polyethylene jars (1) – cardboard packs.
60 pcs. – high-density polyethylene jars (1) – cardboard packs.

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 vascular endothelial growth factor receptors, platelet-derived growth factor, and 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 kinase 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 growth of certain human tumor xenografts in mice.

An increase in blood pressure was observed upon reaching 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. Thus, 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 at the recommended dose of 800 mg. Elimination occurs mainly through 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 previously treated with chemotherapy.

ICD codes

Dosage Regimen

Take orally once daily.

The recommended dose is 800 mg.

Administer at least 1 hour before or 2 hours after a meal.

Do not exceed the maximum daily dose of 800 mg.

Adjust the dose based on individual tolerance.

Reduce or increase the dose in 200 mg increments.

The minimum daily dose is 400 mg.

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

Monitor liver function tests before treatment initiation and at least every 4 weeks for the first 4 months.

Discontinue treatment if ALT increases > 8 × ULN.

Resume at a reduced dose of 400 mg daily only if benefit outweighs risk, with weekly liver function monitoring for 8 weeks.

Permanently discontinue if ALT re-elevates > 3 × ULN upon rechallenge.

Permanently discontinue if ALT > 3 × ULN occurs concurrently with bilirubin > 2 × ULN.

Control blood pressure before starting therapy.

Monitor blood pressure within 1 week of initiation and regularly thereafter.

Manage hypertension with antihypertensive therapy; consider dose reduction for resistant hypertension.

Discontinue for severe, treatment-resistant hypertension or hypertensive crisis.

Discontinue at least 7 days prior to elective surgery.

Withhold therapy in patients with wound dehiscence.

Avoid concomitant use with potent CYP3A4 inhibitors.

If co-administration with a potent CYP3A4 inhibitor is unavoidable, consider a pazopanib dose reduction.

Avoid concomitant use with strong CYP3A4 inducers.

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.

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, AST activity; frequent – dyspepsia, increased lipase activity, liver dysfunction, hyperbilirubinemia; infrequent – gastric or intestinal perforation, formation of gastric and/or intestinal fistulas.

From the skin and subcutaneous tissue : very common – alopecia, exfoliative rash, hair depigmentation, skin depigmentation, palmar-plantar erythrodysesthesia (hand-foot syndrome); frequent – dry skin, nail lesions, 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 insufficiency, severe renal failure; 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

It is necessary to monitor liver enzyme activity before starting treatment with pazopanib and at least once every 4 weeks or more often (according to clinical indications) for at least the first 4 months of treatment. Periodic monitoring should also be carried out after the first 4 months. These instructions apply to patients with baseline total bilirubin values ≤ 1.5 × ULN, as well as ALT and AST activity values ≤ 2 × ULN.

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

In patients with increased ALT activity > 3 × ULN and simultaneous increase in bilirubin concentration > 2 × ULN, Pazopanib should be completely 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. Blood pressure should be monitored no later than 1 week after starting pazopanib 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 course of treatment (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 drugs, or if signs of a hypertensive crisis appear, Pazopanib should be discontinued.

It is necessary to monitor and timely correct blood pressure using a combination of antihypertensive therapy and selection of the pazopanib dose (discontinuation and re-prescription of therapy at a lower dose, based on the clinical situation). Patients should be carefully screened for clinical signs of congestive heart failure. In patients at risk of developing cardiac dysfunction, baseline LVEF should be determined and regular repeated LVEF measurements should be performed.

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 arrhythmias, it is recommended to use Pazopanib under ECG control 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 elective 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.

Preventive 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.

Pazopanib is currently 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 primarily 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 an increase in pazopanib concentration.

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

Use 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 with the use of pazopanib alone at a dose of 800 mg. Concomitant use of pazopanib with inhibitors of the CYP3A4 isoenzyme, Pgp and BCRP (for example, lapatinib) leads to an increase in the plasma concentration of pazopanib.

Thus, concomitant use of pazopanib with potent inhibitors of the CYP3A4 isoenzyme should be avoided, or alternative drugs that do not have or have minimal inhibitory effect on the CYP3A4 isoenzyme should be used. If such combinations are necessary, the possibility of reducing the dose of pazopanib should be considered.

Inducers of the CYP3A4 isoenzyme, for example rifampicin, may reduce the plasma concentration of pazopanib. It is recommended to choose alternative drugs that do not have or have minimal inhibitory activity against the CYP3A4 isoenzyme.

In vitro studies of 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 studies of the pharmacological properties 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 malignant neoplasms.

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 ratio of dextromethorphan and dextrorphan concentrations in urine after oral administration of dextromethorphan (CYP2D6 substrate).

Concomitant use of pazopanib at a dose of 800 mg once daily and paclitaxel at a dose of 80 mg/m² (substrate of CYP3A4 and CYP2C8) once a week 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 dose (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 the pooled population of patients participating in monotherapy studies with pazopanib, increased ALT activity >3 x ULN was reported in 126 of 895 (14%) patients who did not take a statin, and in 11 of 41 (27%) patients simultaneously taking simvastatin (p = 0.038). If a patient taking simvastatin concomitantly has increased ALT activity, the dosing recommendations for pazopanib 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 25°C (77°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.