Votrient
Effect on liver function
Cases of liver failure (including fatal cases) have been reported with the use of pazopanib. In clinical studies of pazopanib, increases in transaminase activity (ALT, AST) and bilirubin concentrations were observed. In most cases, there was an isolated increase in ALT and AST activity, not accompanied by a simultaneous increase in alkaline phosphatase activity or bilirubin concentration. In patients over 60 years of age, the risk of ALT elevations greater than three times the ULN may increase. Patients carrying the HLA-B57:01 allele also had an increased risk of pazopanib-induced ALT elevation (19% of patients with the HLA-B57:01 allele versus 10% without). It is necessary to monitor liver function in patients taking pazopanib, regardless of their genotype and age. In the vast majority of cases, increases in transaminase activity of any grade were observed during the first 18 weeks of pazopanib therapy. Severity is based on the National Cancer Institute's AE CTC classification.
It is necessary to monitor the activity of liver enzymes before using pazopanib and at 3, 5, 7 and 9 weeks of therapy, then at 3 and 4 months of therapy and as clinically indicated. Periodic monitoring should be carried out after 4 months of therapy. The following guidelines apply to patients with baseline total bilirubin concentrations ≤1.5xULN and ALT and AST activities ≤2xULN.
- Patients with an isolated increase in ALT activity above the ULN of 3-8 times can continue taking pazopanib, and liver function tests should be monitored weekly until ALT activity decreases to grade 1 toxicity or to the baseline value.
- Patients with an increase in ALT activity greater than 8 times the ULN should interrupt pazopanib until ALT activity decreases to the 8th grade of toxicity or to the baseline value. If the potential benefit of resuming pazopanib outweighs the risk of hepatotoxicity, pazopanib may be reinstituted at a dose reduced to 400 mg once daily with weekly monitoring of liver function tests for 8 weeks. During subsequent doses of pazopanib, if ALT levels rise again to more than three times the ULN, pazopanib should be completely discontinued.
- In patients with an increase in ALT activity more than three times the ULN and a simultaneous increase in bilirubin concentration more than two times the ULN, pazopanib should be completely discontinued. The patient should be observed until ALT activity decreases to grade 1 toxicity or to the baseline value. Pazopanib is a UGT1A1 inhibitor. Mild indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome. In patients with only mild indirect hyperbilirubinemia, with Gilbert's syndrome or suspected of having it, with an increase in ALT activity more than three times the ULN, the drug should be used in the same way as in patients with an isolated increase in ALT activity. Concomitant use of pazopanib and simvastatin increases the risk of increased ALT activity (see section "Interaction with other drugs") and requires special caution and close monitoring.
There are no additional recommendations for dose adjustments during treatment based on the results of liver tests in patients with pre-existing liver dysfunction.
Arterial hypertension
Increases in blood pressure (BP) and cases of hypertensive crisis were observed during clinical trials of pazopanib. Before using pazopanib, baseline blood pressure should be determined. No later than one week after the start of treatment, as well as throughout treatment with pazopanib, blood pressure should be monitored and, if necessary, antihypertensive therapy should be carried out, while a dose reduction or interruption in taking pazopanib should be clinically justified (see sections “Method of administration and dosage” and “ Side effect").
Arterial hypertension (systolic pressure ≥150 mmHg or diastolic pressure ≥100 mmHg) occurs early in the course of treatment (in approximately 40% of cases by day 9 and in approximately 90% during the first 18 weeks). If signs of a hypertensive crisis appear or in cases of severe arterial hypertension or persistently elevated blood pressure values that are resistant to antihypertensive agents and pazopanib dose reduction, pazopanib should be discontinued.
Reversible posterior encephalopathy syndrome (RPES)/reversible leukoencephalopathy syndrome (LEPS)
POSES/reversible PEPS has been reported with pazopanib.
POSES/reversible PEPS presents with the following symptoms: headache, hypertension, seizures, drowsiness, confusion, blindness, other visual impairment and neurological impairment. Fatal cases have been reported. Pazopanib should be discontinued in patients with developing PRES/reversible PEPS.
Interstitial lung disease (ILD)/pneumonitis
When using pazopanib, the development of IBL with possible death was noted. Monitor patients for pulmonary symptoms suggestive of IPD/pneumonitis and discontinue pazopanib in patients who develop IPD or pneumonitis.
Cardiac dysfunction
The following cardiac dysfunctions were reported during clinical trials of pazopanib: chronic heart failure and decreased left ventricular ejection fraction (LVEF).
Patients should be closely monitored for clinical signs or symptoms of congestive heart failure. In patients at risk of developing cardiac dysfunction, it is recommended that baseline LVEF be determined, as well as regular repeat LVEF measurements.
Prolongation of the
QT and torsades pointes
During clinical trials of pazopanib, cases of prolongation of the QT interval and torsades de pointes were observed (see section "Side effects " ) .
Pazopanib should be used with caution in patients with a history of QT prolongation, those taking antiarrhythmic and other drugs that prolong the QT interval, and in patients with cardiac disease. It is recommended to carry out initial and subsequent periodic monitoring of the electrocardiogram and electrolyte levels (calcium, magnesium, potassium) when using pazopanib.
Arterial thrombosis
During clinical trials of pazopanib, cases of myocardial infarction, angina pectoris, ischemic stroke and transient cerebral ischemia were reported (see section "Side effects"). Fatal cases have been reported.
The drug should be used with caution in patients with an increased risk of arterial thrombosis or with a history of arterial thrombosis. Pazopanib has not been studied in patients who have experienced these events within the previous 6 months. Therefore, the decision to use pazopanib should be made individually based on an assessment of the risk-benefit ratio.
Thrombotic microangiopathy
During clinical trials of pazopanib, both as monotherapy and in combination with bevacizumab or topotecan, cases of thrombotic microangiopathy were reported (see section "Side effects").
Pazopanib should be discontinued if thrombotic microangiopathy develops. After discontinuation of drug therapy, resolution of the symptoms of thrombotic microangiopathy was noted. Pazopanib is not indicated for use in combination with other anticancer drugs.
Bleeding
During clinical trials of pazopanib, cases of bleeding were reported (see section "Side effects"), including death. Pazopanib should be administered with caution to patients at high risk of bleeding.
Perforation and fistula formation of the gastrointestinal tract
During clinical trials of pazopanib, cases of gastrointestinal perforation (GIT) and fistula formation were observed (see section "Side effects"). Fatal cases have been reported. Therefore, pazopanib should be administered with caution to patients at risk of gastrointestinal perforation and fistula formation.
Wound healing
The effect of pazopanib on wound healing has not been studied. Because VEGF inhibitors may impair wound healing, pazopanib should be discontinued at least 7 days before elective surgery.
The decision to restart pazopanib treatment after surgery should be made based on clinical assessment of the adequacy of postoperative wound healing. Pazopanib should be discontinued in patients with wound dehiscence.
Hypothyroidism
During clinical trials of pazopanib, cases of hypothyroidism were observed (see section "Side effects"). It is recommended to carry out preventive monitoring of thyroid function.
Proteinuria
During clinical trials of pazopanib, cases of proteinuria were observed (see section "Side effects"). Periodic urine testing is recommended during treatment with pazopanib to monitor for the occurrence of proteinuria. If nephrotic syndrome develops, pazopanib should be discontinued.
Pneumothorax
Cases of pneumothorax were observed in clinical trials of pazopanib for advanced STS. Patients receiving pazopanib treatment should be closely monitored for signs and symptoms of pneumothorax.
Contraception
Patients with preserved reproductive potential should use reliable methods of contraception during treatment with pazopanib and for two weeks after discontinuation of pazopanib therapy.
During sexual intercourse with men, incl. with a history of vasectomy receiving pazopanib treatment, and their sexual partners (pregnant women, women at risk of pregnancy, or women with preserved reproductive potential) should use a condom during the entire period of treatment of the man, as well as for 2 weeks after administration last dose of the drug.
Release form, composition and packaging
Pink, capsule-shaped, film-coated tablets with “GS JT” engraved on one side.
One tablet contains:
active substance: pazopanib hydrochloride 216.7 mg, which corresponds to the content of pazopanib 200 mg;
excipients: sodium carboxymethyl starch - 21.2 mg, magnesium stearate - 2.1 mg, povidone K30 - 16 mg, microcrystalline cellulose - 64.1 mg;
composition of the film shell: opadry pink YS-1-14762-A - 9.6 mg (hypromellose - 5.66 mg, titanium dioxide - 2.98 mg, macrogol 400 - 0.77 mg, polysorbate 80 - 0.1 mg, iron dye red oxide - 0.09 mg).
30 pcs. — bottles made of high-density polyethylene (1) — cardboard packs. 90 pcs. — bottles made of high-density polyethylene (1) — cardboard packs.
White film-coated tablets, capsule-shaped, with “GS UHL” engraved on one side.
One tablet contains:
active substance: pazopanib hydrochloride 433.4 mg, which corresponds to the content of pazopanib 400 mg;
excipients: sodium carboxymethyl starch - 42.4 mg, magnesium stearate - 4.2 mg, povidone K30 - 32 mg, microcrystalline cellulose - 128.1 mg;
composition of the film shell: opadry white YS-1-7706-G - 19.2 mg (hypromellose - 11.47 mg, titanium dioxide - 6 mg, macrogol 400 - 1.54 mg, polysorbate 80 - 0.19 mg).
30 pcs. — bottles made of high-density polyethylene (1) — cardboard packs. 60 pcs. — bottles made of high-density polyethylene (1) — cardboard packs.
Drug interactions
Inducers or inhibitors of the CYP3A4 isoenzyme
Based on data from in vitro studies, it can be assumed that the oxidative metabolism of pazopanib in human liver microsomes occurs mainly with the participation of the CYP3A4 isoenzyme, with a minor contribution of CYP1A2 and CYP2C8. Thus, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
Inhibitors of the isoenzyme CYP3A4, P-gp and BCRP
Pazopanib is a substrate for CYP3A4, P-gp and BCRP.
Co-administration of pazopanib (400 mg 1 time/day) with a potent inhibitor of the CYP3A4 and P-gp isoenzyme, ketoconazole (400 mg 1 time/day) sequentially for 5 days led to a 66% and 45% increase in mean AUC values (0 -24) and Cmax of pazopanib, respectively, compared with the use of pazopanib without concomitant drugs (400 mg 1 time / day for 7 days). With increasing doses in the range from 50 mg to 2000 mg of the drug, the Cmax and AUC values of pazopanib increased less than proportionally to the dose. Thus, in most patients, after reducing the dose of pazopanib to 400 mg 1 time / day in the presence of potent inhibitors of the CYP3A4 isoenzyme, exposure values similar to those observed after administration of pazopanib without concomitant drugs at a dose of 800 mg 1 time / day are observed. However, in some patients, the magnitude of systemic exposure to pazopanib may be greater than that observed after administration of pazopanib without concomitant medications at a dose of 800 mg.
Co-administration of pazopanib with other strong CYP3A4 inhibitors (such as itraconazole, clarithromycin, atazanavir, indinavir, nefozadone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) may result in increased pazopanib concentrations. Grapefruit juice may also increase pazopanib concentrations.
Administration of 1500 mg of lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp and BCRP, with 800 mg of pazopanib resulted in an approximately 50-60% increase in the mean AUC(0-24) and Cmax values of pazopanib compared with the use of pazopanib alone per dose. 800 mg. Co-administration of pazopanib with inhibitors of the isoenzyme CYP3A4, P-gp and BCRP (for example, lapatinib) leads to increased plasma concentrations of pazopanib. Concomitant use with potent P-gp or BCRP inhibitors may alter the exposure and distribution of pazopanib, incl. number of distribution in the central nervous system.
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If a clinically acceptable alternative to a strong CYP3A4 inhibitor is not available, the dose of pazopanib should be reduced to 400 mg/day for
the entire period of use of concomitant therapy. If drug-related adverse events occur, further dose reduction may be considered.
Concomitant use of the drug with potent P-gp inhibitors should be avoided, or alternative drugs that have no or minimal inhibitory effects on P-gp should be used.
Inducers of the CYP3A4 isoenzyme
Inducers of the CYP3A4 isoenzyme, such as rifampicin, may reduce the plasma concentrations of pazopanib. Concomitant use with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, incl. distribution in the central nervous system. It is recommended to choose alternative drugs that have no or minimal inhibitory activity against the CYP3A4 isoenzyme.
Effect of pazopanib on cytochrome P450 substrates
In in vitro studies of human liver microsomes, pazopanib was shown to inhibit CYP1A2, 3A4, 2B6, 2C8, 2C9, 2C19 and 2E1. The ability to induce CYP3A4 in humans has been demonstrated in in vitro studies using the human pregnane X receptor (PXR). In studies of the pharmacological properties of pazopanib, where the drug was used at a dose of 800 mg 1 time / day, 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 resulted in an approximately 30% increase in the mean AUC and Cmax of midazolam (CYP3A4 substrate) and a 33-64% increase in the ratio of dextromethorphan to dextrorphan concentrations in urine after oral dextromethorphan (CYP2D6 substrate).
Co-administration of pazopanib at a dose of 800 mg once a day and paclitaxel at a dose of 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once a week led, on average, to an increase in the AUC and Cmax of paclitaxel by 26% and 31%, respectively.
Concomitant use of pazopanib with substrates of CYP3A4, 2D6, 2C8 isoenzymes with a narrow therapeutic index is not recommended.
Effect of pazopanib on other enzymes and transport proteins
In vitro studies also showed 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 concentrations of drugs that are primarily cleared by UGT1A1 and OATP1B1.
Concomitant use of pazopanib and simvastatin
Concomitant use of pazopanib and simvastatin increases the incidence of increased ALT activity. In the pooled study population
During pazopanib monotherapy, ALT elevations >3×ULN were reported in 126 of 895 (14%) patients not taking a statin and in 11 of 41 (27%) patients taking concomitant simvastatin (p = 0.038). If ALT elevations occur in a patient taking simvastatin concomitantly, follow dosing recommendations for pazopanib and discontinue simvastatin. There are insufficient data to assess the risk of concomitant use of alternative statins and pazopanib.
Effect of food intake on the pharmacokinetics of paz opanib
Taking pazopanib with a saturated or low-fat meal results in an approximately two-fold increase in drug AUC and Cmax.
Medicines that increase gastric pH
Concomitant use of pazopanib and esomeprazole reduces the bioavailability of pazopanib by approximately 40% (AUC and Cmax). The simultaneous use of pazopanib with drugs that increase gastric pH should be avoided. If concomitant use of a proton pump inhibitor (PPI) is necessary, it is recommended to take a dose of pazopanib without meals, 1 time/day in the evening, simultaneously with the PPI. If concomitant use of an H2-receptor antagonist is necessary, pazopanib should be taken without meals at least 2 hours before or at least 10 hours after dosing with the H2-receptor antagonist. Pazopanib should be taken at least 1 hour before or 2 hours after short-acting antacids. Recommendations for the simultaneous use of PPIs and H2 receptor antagonists are based on the physiological characteristics of the human body.
Dosage
The recommended dose of Votrient is 800 mg orally once a day. Votrient should be taken at least 1 hour before or 2 hours after meals. The tablets should be swallowed whole without breaking their integrity (do not break or chew). Missed doses should not be made up if less than 12 hours are left before the next dose.
Dose selection
Depending on individual tolerance, the daily dose of the drug can be reduced or increased in increments of 200 mg, while the maximum daily dose should not exceed 800 mg.
Special patient groups
The safety and effectiveness of the drug in children have not been established.
No adjustments to the dosage regimen or frequency of administration are required in patients over 65 years of age.
Due to the low rate of renal excretion of pazopanib and its metabolites, renal failure does not have a clinically significant effect on the pharmacokinetics of pazopanib, therefore, no dosage adjustment is required in patients with creatinine clearance ≥30 ml/min. There is no experience with the use of Votrient in patients with severe renal impairment or in patients on peritoneal dialysis or hemodialysis, and therefore the use of Votrient in such patients is not recommended.
The safety and pharmacokinetics of pazopanib in patients with pre-existing liver dysfunction have not been fully established. Patients with mild liver dysfunction, as determined by ALT and bilirubin values, do not require dose adjustment. In patients with moderate hepatic impairment, the Votrient dose should be reduced to 200 mg/day. There are insufficient data on the use of pazopanib in patients with severe hepatic impairment (total bilirubin concentration >3 x ULN at any ALT level), and therefore the use of Votrient in such patients is not recommended.
Overdose
In clinical studies, pazopanib was used in doses up to 2000 mg.
Symptoms: Dose-limiting toxicity (grade 3 fatigue) and grade 3 hypertension were observed in 1 of 3 patients taking 2000 mg
and 1000 mg pazopanib per day, respectively. It is possible that the adverse reactions described above may intensify.
Treatment: symptomatic therapy. Due to the high degree of binding of pazopanib to plasma proteins, its elimination during hemodialysis is negligible.
Side effects
Infectious and parasitic diseases
: infections (with or without neutropenia), gum infections.
Benign, malignant and unspecified neoplasms
(including cysts and polyps): pain in neoplasms.
From the hematopoietic system
: neutropenia, thrombocytopenia, leukopenia.
From the endocrine system
: hypothyroidism, increased activity of thyroid-stimulating hormones in the blood, decreased concentration of glucose in the blood.
From the nervous system:
dizziness, insomnia, hemorrhagic stroke, hypoesthesia, peripheral sensory neuropathy, paresthesia, lethargy, weakness, drowsiness, dysgeusia (taste disorder), cerebrovascular accident, ischemic stroke, transient ischemic attack (transient cerebrovascular accident), reversible posterior encephalopathy syndrome.
From the side of the heart
: cardiac dysfunction (such as decreased left ventricular ejection fraction and chronic heart failure), bradycardia (asymptomatic), myocardial infarction, myocardial ischemia, QT prolongation, cardiac dysfunction.
From the side of blood vessels:
arterial hypertension, epistaxis, hematuria, pulmonary hemorrhage, venous thromboembolic complications, gastrointestinal bleeding, esophageal bleeding, cerebral hemorrhage, retroperitoneal bleeding, rectal bleeding, oral bleeding, hemorrhoidal bleeding, anal bleeding, hot flashes, hypertensive crisis, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome).
From the respiratory system
: cough, dysphonia, dyspnea (shortness of breath), daymothorax, rhinorrhea, pain in the oropharynx, hiccups, hemoptysis, pulmonary embolism, bronchial bleeding.
Metabolic disorders
: anorexia, weight loss, dyspepsia, decreased appetite, dehydration.
From the digestive system
: abdominal pain, diarrhea, flatulence, ulcerative stomatitis, frequent bowel movements, hematemesis, hematochesis, ileal perforation, gastric or intestinal perforation, melena, pancreatitis, peritonitis, formation of gastric and/or intestinal fistulas, external abdominal fistula, increased activity lipase, nausea, upper gastrointestinal bleeding, gastrointestinal bleeding.
Contraindications
- severe liver failure (due to insufficient data);
- severe renal failure (due to insufficient data);
- children's age (due to insufficient data);
- pregnancy;
- period of breastfeeding;
- hypersensitivity to pazopanib or any other component of the drug.
Use with caution in patients with mild to moderate hepatic impairment; gastrointestinal diseases; diseases of the heart
vascular system (including arterial hypertension, prolongation of the QT interval, a history of ventricular tachycardia of the “pirouette” type, in patients taking antiarrhythmic drugs and drugs that prolong the QT interval); cerebrovascular diseases; arterial thrombosis; dysfunction of the thyroid gland; in patients at increased risk of bleeding.
