- Available:In stock1158
- Availability date:2020-07-30
- Dosage form:Tablets
- In stock:1158 Items
Votrient is an oral agent, a powerful polyarget inhibitor of vascular endothelial growth factor receptors (vegfr) -1, -2 and -3, platelet-derived growth factor receptors (pdgfr) -α and β and stem cell factor receptors (c-kit) for which the ic50 of the drug is 10; thirty; 47; 71; 84 and 74 nmol / ml, respectively. in preclinical experimental studies, pazopanib dose-dependently inhibited ligand-induced autophosphorylation of vegfr-2, c-kit and pdgfr-β receptors in cells. in an in vivo study, pazopanib inhibited vegf-induced vegfr-2 phosphorylation in animal lungs, animal angiogenesis in various experimental models, and the growth of multiple xenografts of human tumor in animals.
Pharmacokinetics Absorption. Pazopanib is absorbed with the median time required to reach Cmax the drug in the blood, 2-4 hours after ingestion. A daily intake of the drug causes an increase in AUC of 1.23-4 times. With an increase in the dose of Votrient over 800 mg, a corresponding increase in AUC and Cmax missing.
Systemic absorption of pazopanib is increased when taken with food. Eating, depending on high or low fat, causes an increase in AUC and Cmax Votrienta about 2 times. Based on this, Votrient should be taken at least 1 hour before or 2 hours after a meal (see APPLICATION).
When taking one crushed tablet of pazopanib 400 mg AUC(0–72) increased by 46%, Cmax - about 2 times, and also Tmax decreased by about 1.5 hours compared with taking a whole tablet of the drug. These data indicate that the bioavailability of pazopanib and its level of absorption after oral administration increase when taking a crushed tablet compared to taking a whole tablet of the drug. Therefore, taking into account such a possible increase in the absorption of the drug, Votrient tablets should not be crushed (see APPLICATION).
Distribution. The binding of pazopanib to plasma proteins in humans in vivo is more than 99%, regardless of the concentration of the drug in the blood within the range of 10–100 μg / ml. In vitro studies have shown that pazopanib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Metabolism. In vitro studies have shown that pazopanib metabolism provides predominantly CYP 3A4 with little involvement of CYP 1A2 and CYP 2C8.
Elimination. Pazopanib is excreted slowly, medium T½ is 30.9 hours after taking the recommended dose of 800 mg. Elimination of the drug occurs mainly with feces, while 4% of the accepted dose is excreted in the urine.
Treatment of locally advanced and / or metastatic renal cell carcinoma (PCC).
Treatment of patients with advanced soft tissue sarcoma who have previously received chemotherapy, with the exception of patients with gastrointestinal stromal tumor or liposarcoma.
The recommended dose of the Votrient preparation for the treatment of patients with PCD and soft tissue sarcoma is 800 mg once a day orally. treatment lasts until disease progresses or intolerable toxicity.
Votrient should be taken between meals (at least 1 hour before or 2 hours after eating) (see Pharmacokinetics).
Votrient should be swallowed without chewing and washed down with water, making sure that the tablet is not broken or crushed (see Pharmacokinetics).
If the next dose is missed, the tablet should not be taken less than 12 hours before the next dose.
Dose modification. In order to control adverse reactions or in case of increased individual sensitivity to the drug, dose modification is possible. Dosing changes - both with increasing and decreasing doses - are carried out in stages, with a step of 200 mg, taking into account the individual tolerance of the drug, to ensure proper control of adverse reactions. The dose of Votrient should not exceed 800 mg.
Special patient groups
Renal failure.To date, there is no experience with the use of the drug in patients with severe renal failure or those on peritoneal dialysis or hemodialysis, therefore, Votrient is not recommended for such patients. Renal failure should not have a clinically significant effect on the pharmacokinetics of pazopanib, taking into account the low level of excretion of pazopanib and its metabolites through the kidneys, and dose adjustment is not required for patients with creatinine clearance ≥30 ml / min (see Pharmacokinetics).
Liver failure. The safety of pazopanib and its pharmacokinetics in patients with hepatic impairment have not been sufficiently studied to date (see SPECIAL INSTRUCTIONS).
Patients with mild hepatic insufficiency, which is determined by the level of aminotransferase (AlAT) and bilirubin, do not need to change the dose (see PHARMACOLOGICAL PROPERTIES).
In patients with moderate liver dysfunction, the dose of Votrient should be reduced to 200 mg / day. To date, there is insufficient data on the use of the drug in patients with severe hepatic insufficiency (total bilirubin is more than 3 times higher than the upper limit of normal (VGN), regardless of the level of ALAT), therefore, the appointment of Votrient is not recommended for such patients.
Elderly patients. Patients over the age of 65 do not need to adjust the dose, frequency and method of taking the drug.
Hypersensitivity to any component of the drug.
The following are adverse reactions in accordance with the classification "system - organ - class" meddra. the following conventions were used to classify by the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10 000 , 1/1000).
Categories are determined based on the absolute incidence of adverse reactions according to clinical studies.
|Organs and systems||Frequency|
|PAC||Soft tissue sarcoma|
|Infections and infestations|
|Infections (with or without neutropenia) *||Infrequently||**|
|From benign neoplasms, malignant and nonspecific (including cysts and polyps)|
|On the part of the blood and lymphatic system|
|Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) *||Rarely||Rarely|
|Metabolic and nutritional disorders|
|Decreased appetite, including anorexia||Often||Often|
|From the nervous system|
|Dysgeusia (including agevzia and hypogevzia)||Often||Often|
|Peripheral Sensory Neuropathy||Infrequently||Often|
|Transient Ischemic Attacks||Infrequently||**|
|Posterior Reverse Encephalopathy / Posterior Reverse Leukoencephalopathy *||Rarely||**|
|On the part of the organ of vision|
|Discoloration of the eyelids||Infrequently||**|
|From the heart|
|Heart dysfunction (left ventricular dysfunction, heart failure, obstructive cardiomyopathy)||Infrequently||Often|
|From the vessels|
|Venous thromboembolic complications (including deep vein thrombosis, pulmonary thrombosis)||Infrequently||Often|
|Flushing (redness of the face)||Infrequently||Often|
|From the respiratory system|
|From the digestive system|
|Frequent bowel movements||Infrequently||**|
|Feces with blood||Infrequently||**|
|Bleeding from the upper gastrointestinal tract||Infrequently||Infrequently|
|On the part of the liver and biliary tract|
|Impaired liver function||Often||Infrequently|
|On the part of the skin and its derivatives|
|Hair color change||Often||Often|
|Palmar-plantar erythrodysesthesia syndrome||Often||Infrequently|
|Hypopigmentation of the skin||Often||Often|
|Violations of the nails||**||Often|
|From the musculoskeletal system and connective tissue|
|Pain in the organs of the musculoskeletal system||**||Often|
|From the kidneys and urinary system|
|Urinary tract bleeding||Infrequently||**|
|From the reproductive system and mammary glands|
|Edema (peripheral edema, eye edema, localized edema and facial edema)||Often||Often|
|Laboratory test data|
|Body weight reduction||Often||Often|
|Changes in the level of cholesterol in the blood||**||Often|
|Increased Blood Creatinine||Often||–|
|Blood bilirubin increase||Often||Often|
|Decreased white blood cell count, including decreased neutrophils and white blood cells||Often||**|
|Decreased blood lipase levels||Often||**|
|Increase in blood pressure||Often||**|
|Thyroid hormone levels||Often||**|
|Increased Gamma Glutamyl Transferase Levels||Often||Often|
|Increased blood urea||Infrequently||**|
|ECG Q-T interval extension||Infrequently||Infrequently|
|Increased blood amylase||Infrequently||**|
|Increased blood glucose||Infrequently||**|
|Increased transaminase levels||Infrequently||**|
|Increased diastolic blood pressure||Infrequently||**|
|Thyroid abnormal tests||Infrequently||**|
|Increased systolic blood pressure||Infrequently||**|
|Abnormal liver function tests||Infrequently||**|
* Side effects according to post-marketing applications.
** Side effects are not considered to be associated with the use of pazopanib in a pilot clinical trial for this indication.
Effect on the liver. There are reports of cases of the development of liver failure (including fatal outcome) with the use of the drug vientent. during clinical trials, against the background of the use of the drug, an increase in the level of transaminases (alat, asat) and bilirubin was noted (see side effects). in most cases, an isolated increase in the levels of alat and asat was recorded without a concomitant increase in the levels of alkaline phosphatase or bilirubin. in the vast majority of cases (90%), an increase in the level of transaminases of any severity developed in the first 18 weeks of using the drug.
It is necessary to determine the levels of hepatic enzymes in blood plasma before treatment with Votrient and at least every 4 weeks during the first 4 months of treatment with the drug, as well as in the presence of clinical indications. In the future, these indicators should also be periodically monitored.
For patients with the initial (before treatment with the drug) level of total bilirubin is ≤1.5 times higher than VGN and AsAT, AlAT ≤2 times higher than VGN, one should adhere to the following recommendations for the use of the drug:
- patients with an isolated increase in ALAT levels in the range from 3 to ≤8 above VGN can continue treatment with Votrient subject to weekly monitoring of liver function until the level of ALAT decreases to I degree or returns to the initial level.
- Patients with ALAT 8 above VGN should stop taking Votrient until the level of this indicator drops to grade I or returns to the initial level. If the potential benefits of re-taking Votrient are regarded as predominant over the risk of developing manifestations of hepatotoxicity of the drug, you can again start Votrient treatment at a low dose (400 mg once a day), while monitoring the level of plasma liver enzymes weekly for 8 weeks (see APPLICATION). If, after repeated use of Votrient, an increase in the level of AlAT 3 above VGN is again noted, it is necessary to permanently cancel the drug.
- If an increase in the level of AlAT 3 above VGN is noted simultaneously with an increase in the level of bilirubin 2 above VGN, it is necessary to permanently cancel Votrient. In such patients, it is necessary to monitor these indicators until they decrease to I degree or return to the original value. Pazopanib is an UGT inhibitor1A1. In patients with Gilberts syndrome, with the use of the drug, mild hyperbilirubinemia due to indirect (unbound) bilirubin may develop. Management of patients only with mild indirect hyperbilirubinemia, previously diagnosed with Gilberts syndrome or in the presence of suspicion of it and an increase in the level of ALAT 3 above VGN should be carried out in accordance with the recommendations given for cases in isolation
Tags: Votrient® [Pazopanib]