Votrient - Instructions For The Use Of Tablets, Reviews, Price, Analogues

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Votrient

Votrient: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. Use in childhood
11. 11. In case of impaired renal function
12. 12. For violations of liver function
13. 13. Use in the elderly
14. 14. Drug interactions
15. 15. Analogs
16. 16. Terms and conditions of storage
17. 17. Terms of dispensing from pharmacies
18. 18. Reviews
19. 19. Price in pharmacies

Latin name: Votrient

ATX code: L01XE11

Active ingredient: pazopanib (pazopanib)

Manufacturer: Glaxo Operations UK (Great Britain)

Description and photo update: 2019-26-08

Prices in pharmacies: from 95,900 rubles.

Buy

Votrient is an oral anticancer drug, tyrosine kinase inhibitor.

Release form and composition

Votrient is available in film-coated tablets:

• 200 mg: pink, capsule-shaped, engraved on one side GS JT (30 pcs. Or 90 pcs. In polyethylene bottles, sealed with a childproof cap covered with plastic wrap and foil, 1 bottle in a cardboard box);
• 400 mg: white, capsule-shaped, engraved on one side GS UHL (30 pcs. Or 60 pcs. In polyethylene bottles, sealed with a childproof cap covered with plastic wrap and foil, in a cardboard box 1 bottle).

1 tablet contains:

• active substance: pazopanib hydrochloride - 216.7 or 433.4 mg (in terms of pazopanib - 200 or 400 mg);
• auxiliary components: magnesium stearate, sodium carboxymethyl starch, povidone K30, microcrystalline cellulose;
• film coating (200/400 mg): Opadry pink YS-1-14762-A (titanium dioxide, hypromellose, polysorbate 80, macrogol 4000, dye iron oxide red) / Opadry white YS-1-7706-G (titanium dioxide, hypromellose, polysorbate 80, macrogol 4000).

Pharmacological properties

Pharmacodynamics

The active component of Votrient is pazopanib, a tyrosine kinase inhibitor, an antitumor agent that actively affects many target receptors. Pazopanib is able to bind to receptors for vascular endothelial growth factor isolated from platelet-derived growth factor, and a receptor for stem cell factor. The inhibitory concentration values of 50% (IC ₅₀) are 10, 30, 47, 71, 84 and 74 nmol / L, respectively.

Pazopanib inhibits many tyrosine kinases, including the tyrosine kinases of the interleukin-2 receptor induced by T-cell kinase (Itk), fibroblast growth factor receptor-1 and -3 (FGFR-1, -3), platelet growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cytokine receptor (Kit), endothelial growth factor receptor-1, -2 and -3 (VEGFR-1, -2 and -3), transmembrane glycoprotein tyrosine kinase receptor (c-Fms) and leukocyte-specific protein tyrosine kinase (Lck).

In vitro, pazopanib inhibits ligand-induced autophosphorylation of VEGFR-2, PDGFR-β and Kit, in vivo VEGF-induced phosphorylation of VEGFR-2, angiogenesis, and the growth of some human tumor xenografts in mice.

At equilibrium concentrations of pazopanib, an increase in blood pressure was observed.

Pharmacokinetics

After taking Votrient internally, pazopanib is absorbed in the gastrointestinal tract. The maximum concentration (C _max) reaches an average of 2-4 hours. With daily administration of the drug, there is a 1-, 2-, 3-, 4-fold increase in the area under the concentration-time curve (AUC). When pazopanib was taken daily at a dose of 800 mg, the C _max and AUC values were 58.1 μg / ml (equivalent to 132 μM) and 1.037 h × μg / ml, respectively. With an increase in the dose of more than 800 mg, a significant increase in C _max and AUC was not observed.

Systemic exposure increased when pazopanib was taken with food. In the case of taking the drug with food (both low and high in fat), an approximately twofold increase in C _max and AUC is noted. In this regard, it is recommended to take Votrient at least 1 hour before meals or 2 hours after meals.

If you take 400 mg of pazopanib in the form of a crushed tablet, there is an increase in C _max and AUC _(0-72) approximately twice, as well as a decrease in the time to reach the maximum concentration (T _max) by about 1.5 hours compared to taking the tablet without violating the integrity of the shell … According to these studies, the absorption and bioavailability of pazopanib are increased when the tablet is crushed. Therefore, Votrient tablets should not be crushed.

In vivo, the connection of pazopanib with blood plasma proteins was> 99%, regardless of the concentration in the blood (10–100 μg / ml).

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

Pazopanib is metabolized mainly with the participation of the isoenzyme CYP3A4, to a small extent - CYP2C8 and CYP1A2.

Pazopanib is excreted slowly from the body. After taking a dose of 800 mg, the average elimination half-life (T _1/2) is 30.9 hours. The main route of elimination is through the intestines. No more than 4% of the dose received is excreted by the kidneys.

Withdrawal of pazopanib does not depend on creatinine clearance (CC 30–150 ml / min), therefore, impaired renal function should not affect the systemic effect of the drug, and accordingly, dose adjustment of Votrient for patients with CC ≥ 30 ml / min is not required.

With mild hepatic dysfunction [normal concentration of bilirubin with any increase in alanine aminotransferase (ALT) activity, or an increase in bilirubin concentration up to 1.5 × ULN (upper limit of normal) at any level of ALT] after a single dose of 800 mg once a day average pharmacokinetic the values of pazopanib (C _max - 30.9 μg / ml, interval - 12.5–47.3 and AUC _(0-24) - 841.8 μg × h / ml, interval - 600.4–1078) are approximately comparable to average similar parameters in patients with normal hepatic function (C _max - 49.4 μg / ml, interval - 17.1-85.7 and AUC _(0-24) - 888.2 μg × h / ml, interval - 345, 5-1482).

The maximum tolerated dose of pazopanib in patients with moderate hepatic dysfunction (increased bilirubin concentration> 1.5 × to 3 × VGN regardless of ALT level) is 200 mg once a day. After taking Votrient at a dose of 200 mg once a day in patients with moderate renal impairment, the mean AUC _(0-24) (350 μg × h / ml, interval - 131.8-487.7) and C _max (22, 4 μg / ml, interval - 6.4–32.9) were, respectively, approximately 39% and 45% of the average similar parameters in patients with normal renal function after taking Votrient at a dose of 800 mg once a day.

There are insufficient data on the pharmacokinetic parameters of pazopanib in patients with severe hepatic impairment (total bilirubin concentration> 3 × ULN at any ALT level), therefore Votrient is not recommended for this category of patients.

Indications for use

According to the instructions, Votrient is used to treat the following diseases:

• advanced renal cell carcinoma;
• common sarcoma of soft tissues (with the exception of gastrointestinal stromal tumors and liposarcoma) in patients who received chemotherapy earlier.

Contraindications

Absolute:

• severe renal / hepatic impairment (insufficient data on the efficacy and safety of pazopanib);
• the period of pregnancy and lactation (breastfeeding);
• children's age (insufficient data on the efficacy and safety of using pazopanib);
• hypersensitivity to the active ingredient or excipients of the drug.

Votrient tablets are taken with caution (relative contraindications) for mild and moderate hepatic insufficiency, diseases of the gastrointestinal tract (GIT), cerebrovascular diseases, arterial thrombosis, thyroid dysfunction, increased risk of bleeding, diseases of the cardiovascular system (including including arterial hypertension, prolongation of the QT interval, a history of ventricular tachycardia such as pirouette, as well as in patients taking antiarrhythmic drugs and drugs that prolong the QT interval).

Instructions for the use of Votrient: method and dosage

Votrient tablets are taken orally, swallowing whole, without breaking or chewing, observing the interval with food intake - at least 1 hour before and 2 hours after meals.

Recommended dosing regimen: 800 mg once a day; missed doses should not be replenished if less than 12 hours remain until the next dose.

Depending on individual tolerance, the daily dose of Votrient may be reduced or increased in increments of 200 mg to select the optimal dose, while the maximum daily dose should not exceed 800 mg.

Patients over 65 years of age do not require dose and frequency adjustment.

Due to the insignificant excretion of pazopanib and its metabolites by the kidneys, renal failure does not have a clinically significant effect on the pharmacokinetics of the drug. Therefore, if creatinine clearance (CC) is ≥ 30 ml / min, no adjustment of the Votrient dosage regimen is required. The experience of using the drug in severe renal failure and in patients on hemo- or peritoneal dialysis is absent, it is not recommended to use it in such groups of patients.

In case of impaired liver function, the safety of use and the pharmacokinetics of pazopanib have not been fully determined. Mild hepatic impairment, established by alanine aminotransferase (ALT) and bilirubin indications, does not require dose adjustment of Votrient. In patients with moderate hepatic impairment, the dose of Votrient should be reduced to 200 mg per day. There is insufficient information on the treatment with pazopanib in patients with severely impaired liver function [with a total bilirubin concentration 3 times higher than the upper limit of normal (ULN), regardless of the ALT level], therefore, the use of the drug in this category of patients is not recommended.

Side effects

Adverse events from organs and systems according to clinical studies and post-marketing studies of the action of Votrient (very often - ≥ 1/10; often - ≥ 1/100 and <1/10; infrequently - ≥ 1/1000 and <1/100):

• gastrointestinal tract (GIT): very often - nausea / vomiting, diarrhea, abdominal pain, anorexia; often - dyspepsia; infrequently - formation of fistulas, perforation of the gastrointestinal tract;
• endocrine system: often - hypothyroidism;
• hematopoietic and lymphatic systems: very often - neutropenia, leukopenia, thrombocytopenia, lymphocytopenia;
• nervous system: very often - headache; often - dysgeusia, transient cerebrovascular accident (transient ischemic attack); infrequently - ischemic stroke;
• cardiovascular system (CVS): very often - increased blood pressure (BP); often - prolongation of the QT interval, myocardial ischemia; infrequently - pirouette-type arrhythmias, myocardial infarction and cardiac disorders, including chronic heart failure (CHF) and decreased left ventricular ejection fraction;
• bleeding: often - hematuria, epistaxis; infrequently - gastrointestinal bleeding, pulmonary hemorrhage, cerebral hemorrhage;
• liver and biliary tract: very often - increased activity of liver enzymes ALT and ACT (aspartate aminotransferase), hyperbilirubinemia; often - liver failure;
• kidneys and urinary tract: very often - increased serum creatinine concentration; often - proteinuria;
• skin and subcutaneous fat: very often - hair depigmentation; often - hair loss (alopecia), rash, skin depigmentation, palmar-plantar syndrome (palmar-plantar erythrodysesthesia);
• laboratory indicators: very often - an increase or decrease in serum glucose concentration, a decrease in the level of phosphorus, sodium, calcium, magnesium, an increase in the level of potassium and lipase activity;
• other reactions: very often - asthenia, increased fatigue; often - weight loss, chest pain.

Overdose

Symptoms of an overdose of pazopanib are dose-limiting grade 3 arterial hypertension and toxicity / increased fatigue of grade 3, observed in a third of patients who took 1000 mg and 2000 mg of pazopanib per day, respectively, with a possible further increase in the above-described adverse reactions.

Therapy of the condition is symptomatic, since pazopanib can be excreted only through hemodialysis, but to a small extent (due to its high level of binding to blood plasma proteins).

special instructions

Effect of Votrient on liver function

As a result of the use of pazopanib, cases of liver dysfunction were recorded with an increase in the concentration of bilirubin and the activity of ALT, AST, up to a lethal outcome. In most episodes, there was an isolated increase in ALT and ACT activity only, without a simultaneous increase in bilirubin concentration or alkaline phosphatase activity.

Before the appointment of Votrient and at least once every 4 weeks or more often (according to clinical indications), the activity of hepatic enzymes should be monitored for at least 4 months at the beginning of treatment; in the future, periodic monitoring is also required. These recommendations should be followed by patients with baseline values of total bilirubin exceeding the ULN by no more than 1.5 times and the activity of ALT and ACT exceeding the ULN by 2 times or less.

Recommendations for the correction of therapy with changes in the activity of liver enzymes:

• an isolated increase in the activity of only ALT 3–8 times higher than VGN: therapy with pazopanib can be continued provided that the liver function indicators are monitored weekly until the ALT activity is reduced to grade I toxicity or to the initial value;
• isolated increase in ALT activity> 8 VGN: therapy should be interrupted until ALT activity is reduced to grade I toxicity or to its initial value; if the potential benefit of resuming pazopanib is exceeded over the risk of hepatotoxicity, treatment can be resumed with a dose reduction to 400 mg per day with the condition of weekly monitoring of liver function indicators for 8 weeks; with a repeated increase in ALT activity> 3 VGN due to continued therapy with pazopanib, it should be canceled completely;
• an increase in ALT activity> 3 VGN and a simultaneous increase in the concentration of bilirubin> 2 VGN: pazopanib should be canceled completely.

Taking pazopanib in combination with simvastatin increases the risk of increased ALT activity and requires extreme caution and close monitoring.

For patients with pre-existing mild hepatic impairment, Votrient is prescribed at a dose of 800 mg / day, and for patients with moderate hepatic impairment, the initial dose of pazopanib is reduced to 200 mg / day; no other recommendations for additional dose adjustment have been developed at present.

Effect of Votrient on other conditions / diseases

• arterial hypertension: an increase in blood pressure is possible (up to a hypertensive crisis), therefore, before taking pazopanib, it is necessary to ensure adequate blood pressure control and then monitor pressure and, if necessary, antihypertensive therapy. An increase in systolic pressure of more than 150 mm. rt. Art. or diastolic - more than 100 mm. rt. Art. at the beginning of the course of therapy is observed in 39% of cases on day 9 and in 88% of cases during the first 18 weeks. In case of resistant hypertension (despite the ongoing antihypertensive treatment), the dose of pazopanib is reduced, and in severe arterial hypertension, insensitive to antihypertensive drugs, or in the event of symptoms of a hypertensive crisis, Votrient is discontinued;
• prolongation of the QT interval, ventricular tachycardia: in patients with a history of prolongation of the QT interval and ventricular tachycardia of the pirouette type, taking antiarrhythmic and other drugs to prolong the QT interval, in patients with cardiac pathologies that may be aggravated by arrhythmias, pazopanib is recommended in conditions of periodic monitoring of the electrocardiogram (ECG) and the concentration of electrolytes (magnesium, calcium, potassium);
• arterial thrombosis: there is evidence of myocardial infarction, angina pectoris, ischemic stroke and transient cerebral ischemia (up to death) during Votrient therapy; pazopanib should be used with caution in patients with an increased risk of arterial thrombosis or with a history of arterial thrombosis, and only after a careful assessment of the ratio of the benefits of drug therapy with the likelihood of such side effects;
• bleeding: since the use of Votrient has been observed cases of bleeding (up to death), patients with episodes of hemoptysis, intracranial or gastrointestinal bleeding during the last 6 months are prescribed pazopanib with caution;
• fistula formation, perforation of the gastrointestinal tract: cases with a fatal outcome due to gastrointestinal tract perforation and the formation of fistulas have been reported, and therefore, patients with a tendency to adverse reactions from the gastrointestinal tract should be prescribed pazopanib with caution;
• wound healing: there have been no special studies on the effect of pazopanib on wound healing, but given the ability of inhibitors of vascular endothelial growth factor receptors (VEGFR) to impair healing, pazopanib should be discontinued at least 1 week before the planned surgery; resumption of therapy after surgery begins based on an assessment of the adequacy of postoperative wound healing; in case of divergence of the wound edges, pazopanib is stopped;
• hypothyroidism: it is recommended to conduct a preventive study of thyroid function;
• proteinuria: during therapy with Votrient, there have been cases of proteinuria, therefore, the presence of protein in the urine should be periodically checked, and if renal syndrome develops, stop taking it

Influence on the ability to drive vehicles and complex mechanisms

These indicators have not been studied, but given the pharmacological properties of Votrient, this kind of effect is not expected. However, when driving vehicles and performing other potentially hazardous types of work, it is required to take into account the side effect profile of pazopanib and the general condition of the patient.

Application during pregnancy and lactation

Votrient is contraindicated for women who are carrying a child or breastfeeding.

Pediatric use

Due to the lack of data on the safety and effectiveness of pazopanib in children, Votrient is not used in pediatrics.

With impaired renal function

The clearance of creatinine does not affect the elimination of pazopanib, therefore, patients with CC ≥ 30 ml / min do not need to adjust the dosage regimen of Votrient.

The experience of using the drug in patients with severe renal failure and patients on hemodialysis or peritoneal dialysis is absent. In this regard, Votrient is not recommended for this category of patients.

For violations of liver function

The pharmacokinetics of pazopanib and the safety of its use in the presence of concomitant liver dysfunction have not been fully established. For mild hepatic dysfunctions determined by bilirubin and ALT values, dose adjustment is not required. In case of moderate hepatic insufficiency, the daily dose of Votrient is reduced to 200 mg.

Information on the use of the drug in severe hepatic impairment (total bilirubin concentration> 3 × ULN at any ALT level) is insufficient. In this regard, Votrient is not recommended to be prescribed to such patients.

Use in the elderly

There is no need to adjust the dosage regimen of Votrient in elderly patients (over 65 years).

Drug interactions

Due to the high pharmacological activity of pazopanib, only the attending physician can give recommendations on the combined use of Votrient with other medicinal substances / preparations.

Taking grapefruit juice can lead to an increase in the concentration of pazopanib, and food saturated or low in fat increases the AUC and C _max values of the drug by about 2 times.

Possible interaction reactions with the simultaneous use of Votrient with other drugs / agents:

• drugs that increase the pH of gastric juice: the bioavailability of pazopanib (AUC and C _max) is reduced by about 40%, so the combined use of drugs should be avoided. If concomitant administration of a proton pump inhibitor (PPI) is necessary, it is recommended to take pazopanib 1 time per day together with PPI outside meals. If at the same time it is necessary to prescribe an antagonist of H ₂ -receptors, you should take pazopanib outside meals at least 2 hours before taking the antagonist of H ₂ -receptors or 10 hours after taking it. When used together with short-acting antacids, pazopanib should be taken at least 1 hour before taking them or 2 hours after;
• simvastatin: the frequency of increased ALT activity increases. If this happens, simvastatin should be discontinued and the recommendations for dosing of pazopanib should be followed. There are insufficient data to assess the risk of concomitant use of alternative statins with pazopanib;
• drugs, the elimination of which is carried out mainly with the participation of UGT1A1 and OATP1B1: an increase in their concentration is possible;
• cytochrome P ₄₅₀ substrates: with the simultaneous use of caffeine (CYP1A2 substrate), omeprazole (CYP2C19 substrate), warfarin (CYP2C9 substrate), no significant drug interactions were noted, midazolam (CYP3A4 substrate) - an increase in its average C _max and AUC values by about 30% is observed, dextromethorphan (CYP2D6 substrate) - the ratio of dextromethorphan and dextrorphan concentrations in urine increases by 33–64%, paclitaxel (CYP3A4 and CYP2C8 substrate) - C _max and AUC values increase by 31% and 26%, respectively. The simultaneous use of Votrient with substrates of isoenzymes CYP3A4, CYP 2D6, CYP 2C8, which have a narrow therapeutic range, is not recommended;
• inducers and inhibitors of the CYP3A4 isoenzyme: a change in the metabolism of pazopanib is possible;
• inducers of the CYP3A4 isoenzyme (for example, rifampicin): a decrease in the plasma concentration of pazopanib is possible;
• powerful P-gp or BCRP inducers: it is possible to change the exposure and distribution of pazopanib, including in the central nervous system. It is recommended to choose alternative drugs without or with minimal activity against the isoenzyme CYP3A4;
• inhibitors of isoenzyme CYP3A4, P-gp and BCRP: AUC and C _max values are significantly increasedpazopaniba. After reducing the daily dose of pazopanib to 400 mg while taking a potent inhibitor of the isoenzyme CYP3A4 and P-gp ketoconazole in most patients, the exposure values are similar to those in patients taking only pazopanib at a daily dose of 800 mg. However, in some patients, the value of systemic exposure to pazopanib may be more significant than in patients receiving only pazopanib at a dose of 800 mg once a day. The combined use of other potent inhibitors of the CYP3A4 isoenzyme (such as indinavir, clarithromycin, telithromycin, nelfinavir, atazanavir, voriconazole, ritonavir, nefazodone, itraconazole, saquinavir) can lead to an increase in the concentration of pazopanib. In this regard, it is recommended to avoid the simultaneous use of Votrient and potent CYP3A4 inhibitors. If an acceptable alternative to a potent CYP3A4 inhibitor is not available, the daily dose of pazopanib should be reduced to 400 mg. If side effects occur, further reduction in the dose of Votrient should be considered. The concomitant administration of potent P-gp inhibitors should be avoided or alternative drugs with no or minimal inhibitory effect on P-gp should be used.

Analogs

Votrient's analogs are the following drugs belonging to the same pharmacological group (protein tyrosine kinase inhibitor, antineoplastic agent): Albitinib, Afinitor, Bosulif, Vargatef, Genfatinib, Glemihib, Giotrif, Gistamel, Gleevec, Dazatinib-native, Jaklivib, Ibmagli Kaprelsa, Mekinist, Neopax, Sprysel, Tyverb, Tarceva, Torizel, Erlotinib, etc.

Terms and conditions of storage

Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Shelf life is 2 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Votrient

Considering the indications for which the drug is used, there are practically no reviews of Votrient on forums and specialized medical sites. In some reports, relatives of patients write both about the high efficacy of this antitumor agent (which is manifested by a decrease in the size of the tumor and pain syndrome), and about the lack of effect. The very high cost of Votrient is noted, which, in the absence of a free prescription, is too expensive for many patients.

Price for Votrient in pharmacies

Average prices of Votrient: 200 mg coated tablets - 105,000-108,000 rubles. per pack of 90 pieces, 400 mg each - 88,900–122,900 rubles. per pack of 60 pcs.

Votrient: prices in online pharmacies

Drug name Price Pharmacy

Votrient 400 mg film-coated tablets 60 pcs. RUB 95,900 Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!