Votrient - instructions for use, doses, side effects, contraindications

Active substancePazopanibPazopanib

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Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet, film-coated, contains:

Name of components	Quantity, mg / tablet
Name of components	200 mg	400 mg
*Core tablet:*
Active substance:
Pazopanib hydrochloride	216,7	433,4
(in terms of pazopanib)	200,0	400,0
Excipients:
Sodium carboxymethyl starch	21,2	42,4
Magnesium stearate	2,1	4,2
Povidone To 30	16,0	32,0
Microcrystalline cellulose	64,1	128,1
Film sheath
Opadrai® Pink YS-1-14762-A	9,6	-
Opadry® white YS-1-7706-G	-	19,2

Code of opedraj	Components	Amount, mg
Opadrai® Pink YS- 1-14762-A	Hypromellose	5,66
	Titanium dioxide	2,98
	Macrogol-400	0,77
	Polysorbate 80	0,10
	Iron Oxide Red Dye Oxide	0,09
Opadry® white YS-1 7706-G	Hypromellose	11,47
	Titanium dioxide	6,00
	Macrogol-400	1,54
	Polysorbate 80	0,19

Description:

Tablets with a dosage of 200 mg: capsular tablets, covered with a film membrane of pink color. On one side of the tablet there is an engraving "GS JT".

Tablets with a dosage of 400 mg: capsular tablets, film-coated white color. On one side of the tablet there is an engraving "GS UHL".

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E Protein kinase inhibitors

L.01.X.E.11 Pazopanib

Pharmacodynamics:

Mechanism of action

Pazopanib is a potent inhibitor of many tyrosine kinases for oral administration, including tyrosine kinases of endothelial growth factor receptors (VEGFR) -1, 2, 3, platelet-derived growth factor receptors (PDGFR)-aelfa and beta, fibroblast growth factor receptors (FGFR) -1 and -3, the stem cell factor receptor (Kit), as well as T-cell kinase, induced by interleukin 2 (Itk), leukocyte-specific protein-tyrosine kinase (Lck) and macrophage colony-stimulating factor receptor tyrosine kinase (c-Fms). In vitro pazopanib inhibits ligand-induced autophosphorylation VEGFR-2, Kit and PDGFR-p. In vivo pazopanib inhibits VEGF-induced phosphorylation VEGFR-2 in lung tissues in animals, angiogenesis in animals, and the growth of some human tumor xenografts in animals. The values of inhibitory concentration in 50% (IC₅₀) in the binding of pazopanib to receptors of endothelial vascular growth factor, platelet growth factor and stem cell factor are 10, 30, 47, 71, 84 and 74 nmol / L, respectively.

Pharmacokinetics:

Suction

The maximum concentration (C_m_Oh) pazopanib, on average, is achieved 2-4 hours after ingestion.Daily intake leads to a 1-, 2-, 3-, 4-fold increase in the area under the pharmacokinetic curve "concentration-time" (AUC). With daily intake of 800 mg of zazopanib values AUC and C_m_Oh were 1.037 h x μg / ml and 58.1 μg / ml (equivalent to 132 μmol / l), respectively. Significant increase AUC and C_m_Oh It was not observed with an increase in the dose of pazopanib more than 800 mg.

Systemic exposure of pazopanib increased with admission with food. The use of pazopanib with high and low fat foods results in approximately 2-fold increase AUC and C_m_Oh. In this way, pazopanib should be taken at least 1 hour before or 2 hours after ingestion (see section "Method of administration and dose").

The use of 400 mg of pazopanib in the form of a crumbled tablet causes an increase AUC_(0-₇₂₎ and C_m_Oh approximately 2 times and causes a decrease in t_max (time to reach the maximum concentration in the blood plasma) by approximately 1.5 hours compared with the use as a whole tablet.

Bioavailability and the degree of absorption of pazopanib by oral intake increases with the intake of a crumbled tablet compared to the whole tablet. In connection with the above, pazopanib tablets should not be milled (see.See section "Dosing and Administration").

Distribution

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

Data in vitro allow us to assume that pazopanib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Metabolism

Research in vitro showed that the metabolism of pazopanib is primarily mediated by isoenzyme CYP3A4, and also to an insignificant degree by isoenzymes CYP1A2 and CYP2C8.

Excretion

Pasopanib is slowly excreted with an average half-life (t_1/2) 30.9 hours after admission at the recommended dose of 800 mg. Excretion is carried out mainly through the intestine, and only less than 4% of the accepted dose is excreted by the kidneys.

Pharmacokinetics in special cases

Patients with impaired renal function

The excretion of pazopanib does not depend on the clearance of creatinine (CK) (30-150 ml / min).

It is not expected that the systemic exposure of pazopanib will change in patients with QC ≥ 30 ml / min, and therefore no dose adjustment is required in this category.

Patients with impaired hepatic function

In patients with impairedliver function of mild degree (bilirubin concentration within the norm with increasing alanine aminotransferase (ALT) activity of any degree or increase in bilirubin concentration is less than 1.5 times higher than the upper limit of norm (VGN) irrespective of ALT activity) after single administration of pazopanib at 800 mg dose once a day the average values of pharmacokinetic parameters (C_m_Oh 30.9 μg / ml, (12.5-17.3 μg / ml) and AUQ_(0-24₎ 841.8 μg x h / ml (600.4-1078 μg h / ml)) are comparable with the mean values in patients with normal liver function (C_m_Oh 49.4 μg / ml (17.1-85.7 μg / m) and AUC_(0-24₎ 888.2 μg x h / ml (345.5-1482 μg x h / ml)).

The maximum tolerated dose of pazopanib in patients with moderate impairment of liver function (an increase in bilirubin concentration from one and a half to three times higher than that of ALT, was 200 mg once daily. Mean values of C_m_Oh (22.4 μg / ml (6.4-32.9 μg / ml)) and AUC_(0-24₎ (350.0 μg x h / ml (131.8-487.7 μg h / ml)) after taking 200 mg of pazopanib once a day in patients with moderate impairment of liver function were approximately 45% and 39% with average values in patients with normal liver function after taking the drug at a dose of 800 mg once a day.There is insufficient data on the use of pazopanib in patients with severe hepatic dysfunction (the concentration of total bilirubin is more than three times higher than ULN, regardless of the activity of ALT), and therefore the use in patients of this category is not recommended (see the section "Contraindications") .

Indications:

Treatment of advanced renal cell carcinoma (RCC).

Treatment of common soft tissue sarcoma (SMT) (except for gastrointestinal stromal tumors and liposarcomas) in patients who previously received chemotherapy.

Contraindications:

- Hypersensitivity to pazopanibu or any other component of the drug;

- severe liver dysfunction (due to insufficient data);

- severe renal dysfunction (due to insufficient data);

- simultaneous use with other antitumor drugs;

- pregnancy and the period of breastfeeding;

- children's age (due to insufficient data).

Carefully:

Use with caution in patients with impaired liver function of mild to moderate severity; diseases of the gastrointestinal tract; diseases of the cardiovascular system (including arterial hypertension, lengthening of the interval QT, ventricular tachycardia of the "pirouette" type in the anamnesis, in patients taking antiarrhythmic drugs and drugs that extend the interval QT); cerebrovascular diseases; arterial thrombosis; disorders of thyroid function; in patients with an increased risk of bleeding, as well as in patients carrying an allele HLA-B*57:01 (see section "Special instructions").

Pregnancy and lactation:

Contraindicated the use of drug Votrient during pregnancy and during breastfeeding.

In studies in animals, reproductive toxicity has been detected. If the drug is used during pregnancy or when pregnancy occurs while taking the drug, the patient should be warned about the potential risk to the fetus. There is no data on the use of the drug in pregnancy in humans. Patients with reproductive potential should use reliable contraceptive methods during treatment with pazopanib and within two weeks after discontinuation of therapy.

It is not known whether the pazopanib in breast milk. It is necessary to stop breastfeeding during the period of treatment with pazopanib.

Dosing and Administration:

The recommended dose of Votrient is 800 mg orally once a day. The drug Vocrient should be taken at least one hour before or two hours after eating. Tablets should be swallowed whole, without violating their integrity (do not break, do not chew).

If a dose is missed, the missed dose should be taken only if there are more than 12 hours left until the next scheduled appointment.

Dose selection

Depending on the individual tolerability, the daily dose of the drug can be reduced or increased in 200 mg increments, with the maximum daily dose not exceeding 800 mg.

Special patient groups

Elderly patients

Correction of the dosing regimen and frequency of admission in patients over the age of 65 is not required.

Patients with impaired renal function

Due to the low degree of excretion of pazopanib and its metabolites by the kidneys, renal dysfunction does not clinically significantly affect the pharmacokinetics of pazopanib, therefore correction of the dosing regimen in patients with CK ≥ 30 mL / min is not required.

The experience of using pazopanib in patients with impaired renal function of a serious degree or in patients on peritoneal dialysis or hemodialysis is absent,in connection with which the use of pazopanib in such patients is contraindicated.

Patients with impaired hepatic function

The safety of the use and pharmacokinetics of pazopanib in patients with already existing violations of the liver function is not fully established. Patients with a mild liver function disorder (determined by ALT activity and bilirubin concentrations) do not need dose adjustment.

In patients with impaired liver function of the average degree, a dose of pazopanib should be reduced to 200 mg per day.

Data on the use of pazopanib in patients with impaired liver function, accompanied by an increase in the concentration of total bilirubin more than three times higher than ULN (with any activity of ALT) is not enough, and therefore the use of pazopanib in such patients is contraindicated.

Side effects:

Below are the undesirable reactions (HP) that occurred when the drug was used in clinical trials, indicating the frequency of their occurrence (Table 1). HP is grouped according to the classification of organs and systems of organs MedDRA.

Frequency of occurrence is defined as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000, including individual cases).

Table 1

	RCC	CMT
Infectious and parasitic diseases
Infections (with or without neutropenia)¹	Infrequently	Infrequently
Gum Infections	Infrequently	Often
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Pain in the neoplasm	Infrequently	Often
Violations of the blood and lymphatic system
Neutropenia	Often	Often
Thrombocytopenia	Often	Often
Leukopenia	Often	Often
Polycythemia	Infrequently
Disorders from the endocrine system
Hypothyroidism¹	Often	Often
Increased activity of thyroid-stimulating hormones in the blood	Often	♦
Reducing the concentration of glucose in the blood	Infrequently	♦
Disorders from the metabolism and nutrition
Anorexia	Often	Often
Weight loss	Often	Often
Decreased appetite	Often	Often
Hypophosphatemia	Often	♦
Dehydration	Often	Often
Hypomagnesemia	Infrequently	Infrequently
Disorders of the psyche
Insomnia	Often	Often
Disturbances from the nervous system
Dizziness	Often	Often
Hypesesia	Infrequently	♦
Peripheral sensory neuropathy	Often	Often
Paresthesia	Often	Infrequently
Inhibition	Often	♦
Drowsiness	Infrequently	Infrequently
Dysgeusia (a disorder of taste)	Often²	Often
Headache	Often	Often
Ischemic stroke¹	Infrequently	Infrequently
Transient ischemic attack¹	Infrequently	♦
Syndrome of reversible posterior encephalopathy¹	Rarely	Infrequently
Disturbances on the part of the organ of sight
Blurred vision	Often	Often
Lacquer bleaching	Infrequently	♦
Retinal detachment / rupture	Infrequently	Infrequently
Heart Disease
Violations of the cardiac activity (reduction of the fraction of the ejection of the left ventricle, chronic heart failure, limited cardiomyopathy)¹	Infrequently	Often
Bradycardia	Infrequently⁴	Often⁴
Myocardial infarction¹	Infrequently	Infrequently
Myocardial ischemia¹	Infrequently	♦
Interval lengthening QT¹	Infrequently	Infrequently
Ventricular tachycardia of the "pirouette" type (torsade de pointes)¹	Infrequently	♦
Infringements from cocof
Hemorrhage in the brain¹	Infrequently	Infrequently
Nose bleed	Often	Often
Gastrointestinal bleeding¹	Infrequently	Infrequently
Bleeding from the esophagus	Infrequently	Infrequently
Hematuria	Often	Infrequently
Arterial hypertension¹	Often	Often
Hyperemia	Often	Often
Pulmonary haemorrhage¹	Infrequently	Often
Venous thromboembolic complications (deep vein thrombosis, pulmonary embolism (including fatal) and thrombosis)	Often (2%)	Often (5%)
Hemorrhage	Infrequently	Infrequently
Bleeding from the upper gastrointestinal tract	Infrequently	Infrequently
Retroperitoneal bleeding	Infrequently	Infrequently
Rectal bleeding	Infrequently	Infrequently
Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome)¹	Rarely	Infrequently
Bleeding from the mouth	Infrequently	Often
Hemorrhoidal hemorrhage	Infrequently	♦
Anal bleeding	Infrequently	Often
Bronchial bleeding	♦	Infrequently
Bleeding from the urinary tract	Infrequently	♦
"Tides"	Often	Often
Hypertensive crisis	Infrequently	♦
Disturbances from the respiratory system, chest and mediastinal organs
Cough	♦	Often
Dysphonia	Often	Often
Dispno (shortness of breath)	Often	Often
Pneumothorax	Infrequently	Often
Rhinorrhea	Infrequently	Infrequently
Pain in the oropharynx	♦	Infrequently
Hiccups	♦	Often
Hemoptysis	Often	Infrequently
Interstitial lung disease / pneumonitis¹	Rarely	Rarely
Disorders from the gastrointestinal tract
Flatulence	Often	Often
Bloating	Often	Often
Ulcerative stomatitis	Often	♦
Frequent bowel movement	Infrequently	♦
Vomiting with blood	Infrequently	♦
Hematocheia	Infrequently	♦
Perforation colon	Infrequently	♦
Perforation of the ileum	Infrequently	Infrequently
Melena	Infrequently	Infrequently
Pancreatitis	Infrequently	Infrequently
Peritonitis	Infrequently	Infrequently
Pain in the abdomen (including in epigastrium and along the bowel)	Often	Often
Diarrhea	Often	Often
Dyspepsia	Often	Often
Perforation of the stomach or intestine¹	Infrequently	♦
Formation of gastric and / or intestinal fistula¹	Infrequently	Infrequently
External ventral fistula	Infrequently	Infrequently
Increased lipase activity	Often⁵	♦
Nausea	Often	Often
Stomatitis	Often	Often
Vomiting	Often	Often
Dryness of the oral mucosa	Often	Often
Disturbances from the liver and bile ducts
Hepatotoxicity	Often	♦
Jaundice	Infrequently	♦
Drug loss liver	Infrequently	♦
Liver failure	Infrequently	♦
Impaired liver function¹	Often	Infrequently
Disturbances from the skin and subcutaneous tissues
Skin lesions	Infrequently	Often³
Alopecia	Often	Often
Exfoliation of the skin	Infrequently	♦
Generalized itching	Infrequently	♦
Dryness of the skin	Often	Often
Exfoliative rash	♦	Often
Hair color change	Often	Often
The defeat of nails	Infrequently	Often
Palmar-plantar erythrodysesthesia (palmar-plantar syndrome)	Often	Infrequently
Plantar erythema	Infrequently	♦
Ulcers of the skin	♦	Infrequently
Photosensitivity	Infrequently	Infrequently
Hyperhidrosis	Often	Often
Rash	Often	Infrequently
Vesicular rash	Infrequently	♦
Papular rash	Infrequently	Infrequently
Erythematous rash	Infrequently	♦
Generalized rash	Infrequently	♦
Macular rash	Infrequently	♦
Itching rash	Infrequently	♦
Itching	Often	Often
Erythema	Often	Often
Depigmentation of the skin	Often	Often
Hypopigmentation of the skin	Often	Often
Disorders from the kidneys and urinary tract
Proteinuria¹	Often	Infrequently
Disturbances from musculoskeletal and connective tissue
Musculoskeletal pain	Infrequently	Often
Muscle spasm	Often	Often
Arthralgia	Often	Infrequently
Myalgia	Often	Often
Violations of the genitals and mammary gland
Menorrhagia	Infrequently	Infrequently
Metrorrhagia	Infrequently	♦
Vaginal bleeding	Infrequently	Infrequently
Laboratory and toolsMr.data
Increased ALT activity¹	Often	Often
Increase in activity of aspartate aminotransferase (ACT)¹	Often	Often
Hyperbilirubinemia¹	Often	Infrequently
Cholesterol change in blood	♦	Often
Increase in the concentration of creatinine in the blood	Often	♦
Increase of amylase activity	Often	♦
Increase in the concentration of urea in the blood	Often	♦
Hypoalbuminemia	♦	Often
Increased activity gamma-glutamyltranspeptidase	Often	Often
Change in activity of thyroid hormones	Infrequently	♦
General disorders and disorders at the site of administration
Inflammation of the mucosa	Often	Infrequently
Edema	Often⁶	Often⁷
Asthenia	Often	Infrequently
Chest pain¹	Often	Often
Chills	Infrequently	Often
Increased fatigue	Often	Often

♦ during the registration clinical trials, the association of the undesirable phenomenon with the use of pazopanib has not been established;

¹- for details, see "Special instructions";

²- agevzia (loss of taste sensitivity), hypogevia (lowering of taste sensitivity);

³ - in most cases, palmar-plantar erythrodysesthesia (palmar-plantar syndrome);

⁴- bradycardia is determined based on the heart rate (less than 60 beats per minute). Bradycardia with clinical manifestations is less common, and its frequency is based on reports of the dazhopanib safety databases.

⁵- for the indication of RCC, the frequency of occurrence is based on data obtained from additional studies;

⁶- peripheral edema, local edema, edema of the eyes, face;

⁷- peripheral edema, puffiness of the eyelids.

Neutropenia, thrombocytopenia and palmar-plantar erythrodysesthesia (palmar-plantar syndrome) were more common in patients of East Asian origin.

Table 2 shows the deviations of the laboratory indicators that occurred in ≥15% of patients with RCC who were taking pazopanib in clinical trials. The degree of deviation is based on the classification of general criteria for the terminology of adverse events (CACAE) of the National Cancer Institute.

table 2

Options	Pazopanib (N=290)			Placebo (N=145)
	All degree,%	Degree 3,%	Degree 4,%	All degree,%	Degree 3,%	Degree 4,%
Hematological
Leukopenia	37	0	0	6	0	0
Neutropenia	34	1	<1	6	0	0
Thrombocytopenia	32	<1	<1	5	0	<1
Lymphocytopenia	31	4	<1	24	1	0
Biochemical
Increased ALT activity	53	10	2	22	1	0
Increase activity ACT	53	7	<1	19	<1	0
Hyperglycaemia	41	<1	0	33	1	0
Increase in the concentration of total bilirubin	36	3	<1	10	1	<1
Hypophosphatemia	34	4	0	11	0	0
Hypocalcemia	33	1	1	26	1	<1
Hyponatremia	31	4	1	24	4	1
Hyperkalemia	27	4	<1	23	5	0
Hypercreatinemia	26	0	<1	25	<1	0
Hypomagnesemia	26	<1	1	14	0	0
Hypoglycaemia	17	0	<1	3	0	0

Table 3 shows the deviations of the laboratory indicators that occurred in ≥15% of patients with SMT who received pazopanib in clinical trials. The degree of deviation is based on the classification of the STAAE of the National Cancer Institute.

Table 3

Options	Pazopanib (N = 240)			Placebo (N = 123)
Options	All stefines, %	Degree 3, %	Degree 4, %	All stefines, %	Degree 3, %	Degree 4,%
Hematological
Leukopenia	44	1	0	15	0	0
Neutropenia	33	4	0	7	0	0
Thrombocytosinging	36	2>	<1	6	0	0
Lymphocytesinging	43	10	0	36	9	2
Anemia	27	5	2	23	<1	<1
Biochemical
Increase activity alkaline phosphatases (AF)	32	3	0	23	<1	0
Increase ALT activity	46	8	2	18	2	<1
Increase activity ACT	51	5		22	2	0
Hypoalbuminemia	34	<1	0	21	0	0
Hyperglycaemia	45	<1	0	35	2	0
Increase concentrations of total bilirubin	29	1	0	7	2	0
Hyponatremia	31	4	0	20	3	0
Hypokalemia	16	1	0	11	0	0

Overdose:

In clinical trials pazopanib was used in doses up to 2000 mg.

Symptoms

Dose-limiting toxicity (increased fatigue of grade 3) and grade 3 arterial hypertension were observed in 1 of 3 patients who took 2000 mg and 1000 mg of pazopanib per day, respectively.It is possible to enhance the above-described undesirable phenomena.

Treatment

Symptomatic.

Only a small part of the pazopanib can be excreted by hemodialysis, as the high degree of its binding to blood plasma proteins.

Interaction:

Inductors or inhibitors of the cytochrome P450 system (isoenzyme CYP3A4)

Based on the research data in vitro it can be assumed that the oxidative metabolism of pazopanib in microsomes of the human liver proceeds mainly with the participation of the isoenzyme CYP3A4, with insignificant participation of isoenzymes CYP1A2 and CYP2C8. Thus, inhibitors and inducers of isoenzyme CYP3A4 can alter the metabolism of pazopanib.

Inhibitor inhibitors CYP3A4, P-gp and BCRP

Pzopanib is a substrate for isoenzyme CYP3A4, P-gp and BCRP.

The simultaneous use of pazopanib (400 mg once daily) with a potent inhibitor of isoenzyme CYP3A4 and P-gp, ketoconazole (400 mg once daily) successively for 5 days resulted in an increase in the mean values AUC_(0-24) and C_m_Oh pazopanib by 66% and 45% respectively, compared with the use of pazopanib without concomitant medications (400 mg once a day for 7 days). With an increase in the dose in the range from 50 mg to 2000 mg of the C_m_Oh and AUC pazopanib increased to a lesser extent than proportionally to the dose. Thus, in most patients after a dose reduction of pazopanib to 400 mg once daily in the presence of potent inhibitors of isoenzyme CYP3A4 systemic exposure of pazopanib corresponded to that when using pazopanib in a dose of 800 mg once a day without concomitant use of concomitant medications. However, in some patients, the magnitude of the systemic exposure of pazopanib can increase compared to that when administered alone at a dose of 800 mg.

The simultaneous use of pazopanib with other potent inhibitors of isoenzyme CYP3A4 (such as itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) can lead to an increased concentration of pazopanib. When taking the drug with grapefruit juice, there may also be an increase in the concentration of pazopanib.

The use of 1500 mg of lapatinib, a substrate and a weak isoenzyme inhibitor CYP3A4, P-gp and BCRP, simultaneously with 800 mg of pazopanib leads to an increase in the mean values AUC_(0-24) and FROM_m_Oh the latter by approximately 50-60% compared with a single application of pazopanib in a dose of 800 mg. Simultaneous use of pazopanib with isozyme inhibitors CYP3A4, P-gp and BCRP (eg, lapatinib) leads to an increase in the concentration of pazopanib in the blood plasma. Simultaneous application with powerful inhibitors P-gp or BCRP can alter the exposure and distribution of the pazopanib, including distribution in the central nervous system (CNS). It should avoid simultaneous use of the drug with potent inhibitors P-gp or BCRP, or use alternative drugs that do not have this effect, or have a minimal inhibitory effect on P-gp or BCRP.

It should avoid simultaneous use of pazopanib with a potent inhibitor of isoenzyme CYP3A4. If a clinically acceptable alternative to a potent inhibitor of isoenzyme CYP3A4 not available, the dose of pazopanib should be reduced to 400 mg per day for the entire period of simultaneous therapy (see section "Special instructions"). In the event of the development of adverse events related to drugs, the possibility of further dose reduction may be considered.

Inductors of isoenzyme CYP3A4

Inductors of isoenzyme CYP3A4, eg rifampicin, can reduce the concentration of pazopanib in the blood plasma. Simultaneous use of pazopanib with powerful inducers P-gp or BCRP can change the exposure and distribution of the pazopanib, including distribution in the central nervous system. It is recommended to use alternative drugs that do not have this effect or have minimal inhibitory activity with respect to the isoenzyme CYP3A4.

Effect of pazopanib on substrates of the cytochrome P450 system

In studies in vitro it was shown that pazopanib inhibits isoenzymes of cytochrome 1A2, 3A4, 2B6, 2C8, 2C9, 2C19 and 2E1. In studies of the pharmacological properties of pazopanib, where the drug was used at a dose of 800 mg once a day, it was shown that pazopanib has no clinically significant effect on the pharmacokinetics of caffeine (substrate isoenzyme CYP1A2), warfarin (substrate isoenzyme CYP2C9) or omeprazole (substrate isoenzyme CYP2C19) in patients with malignant neoplasms.

Pazopanib led to an increase in average values AUC and C_m_Oh midazolam (substrate isoenzyme CYP3A4) by about 30% and a 33-64% increase in the ratio of the concentrations of dextromethorphan and dextrorphan in the urine after ingestion of dextromethorphan (substrate isoenzyme CYP2D6).

Simultaneous application of 800 mg of pazopanib once a day and paclitaxel 80 mg / m²(substrate of isoenzymes CYP3A4 and CYP2C8) once a week resulted, on average, in an increase AUC and C_m_Oh paclitaxel by 26% and 31%, respectively.

Simultaneous use of pazopanib with isozyme substrates CYP3A4, 2D6, 2S8 with a narrow therapeutic range is not recommended.

Effect of pazopanib on other enzymes and transport proteins

Research in vitro showed that pazopanib is a potent inhibitor UGT1A1 and OATP1B1 with IC₅₀ 1.2 μM and 0.79 μM, respectively. Pazopanib can increase the concentration of drugs, the removal of which is carried out mainly with the participation of UGT1A1 and OATP1B1.

The simultaneous use of pazopanib and simvastatin

Simultaneous use of pazopanib and simvastatin increases the frequency of increase in ALT activity (27% vs. 14%). If the patient receiving simvastatin at the same time with pazopanib, ALT activity increases, recommendations for dosage of pazopanib should be followed and abolished simvastatin. Data for assessing the risk of concurrent use of alternative statins and pazopanib is not enough.

Effect of food intake on the pharmacokinetics of pazopanib

Taking pazopanib along with saturated or poor fats with food results in a roughly two-fold increase AUC and C_m_Oh pazopanib.

Drugs that increase the pH of gastric juice

The simultaneous use of pazopanib and esomeprazole reduces the bioavailability of pazopanib by approximately 40% (AUC and C_m_Oh). It should avoid the simultaneous use of pazopanib with medicines that increase the pH of gastric juice. If simultaneous use of proton pump inhibitors (PPIs) is required, it is recommended to take a dose of pazopanib outside meals, once a day in the evening, simultaneously with PPI. If it is necessary to simultaneously apply antagonists H₂-receptors, pazopanib should not be taken during meals, at least 2 hours before or at least 10 hours after taking antagonist H₂receptors. Pazopanib should be taken at least 1 hour before or 2 hours after the use of short-acting antacids. Recommendations for the simultaneous use of PPIs and antagonists H₂-receptors are based on the physiological characteristics of the human body.

Special instructions:

Effects on liver function

When using pazopanib, cases of hepatic insufficiency (including fatal cases). In clinical studies of pazopanib, an increase in the activity of transaminases (ALT, ACT) and bilirubin concentrations. In most cases there was an isolated increase in ALT activity and ACT, not accompanied by a simultaneous increase in the activity of alkaline phosphatase or bilirubin concentration. In patients older than 60 years, the risk of increased ALT activity, which is three times higher than UGN, may increase. Patients bearing an allele HLA-B57:01, There was also an increased risk of pazopanib increase in ALT activity (19% of patients with allele HLA-B57:01 against 10% without it). It is necessary to monitor liver function in patients taking pazopanib, regardless of their genotype and age. In the vast majority of cases, an increase in the activity of transaminases of any degree was noted during the first 18 weeks of therapy with pazopanib. The degree of severity is based on the CTC classification of the National Cancer Institute.

It is necessary to monitor the activity of liver enzymes before the use of pazopanib and at 3, 5, 7 and 9 weeks of therapy, then at 3 and 4 months of therapy and according to clinical indications.Periodic monitoring should be performed after 4 months of therapy. The following guidelines apply to patients with baseline total bilirubin ≤1.5xVGN, as well as ALT and ACT ≤2хVGN.

- Patients with an isolated increase in ALT activity above IHV 3-8 times may continue taking pazopanib, and weekly monitoring of liver function parameters should be performed before the ALT activity decreases to the first toxicity level or to the initial value.

- Patients with increased ALT activity more than 8 times with respect to IGN, the use of pazopanib should be discontinued before the ALT activity decreases before the Voi toxicity level or to the initial value. If the potential benefit of resuming pazopanib intake exceeds the risk of developing hepatotoxicity, the use of pazopanib can be resumed at a dose reduced to 400 mg once a day, under weekly monitoring of liver function indicators for 8 weeks. With subsequent doses of pazopanib in the case of a second increase in ALT activity more than three times the VGN pazopanib should be completely abolished.

- In patients with an increase in ALT activity more than three times the relative to IGN, and a simultaneous increase in the bilirubin concentration is more than twice that of IGN pazopanib should be completely abolished. The patient should be monitored until the ALT activity decreases to the first toxicity level or to the initial value. Pazopanib is an inhibitor UGT1A1. In patients with Gilbert's syndrome, indirect (unconjugated) mild hyperbilirubinemia may occur. In patients with only mild hyperbilirubinemia, with Gilbert's syndrome or suspected of having it, with an increase in activity ALT more than three times the IGN drug should be used in the same way as in patients with an isolated increase in ALT activity. Simultaneous use of pazopanib and simvastatin increases the risk increase ALT activity (see section "Interaction with other medicines ") and requires special care and careful observation.

Additional recommendations for dose adjustment in the course of treatment based on the results of liver tests in patients with an already present impaired hepatic function are absent.

Arterial hypertension

Clinical studies of pazopanib showed an increase blood pressure (BP) and cases of hypertensive crisis.Before using pazopanib, determine the baseline level of blood pressure. Not later than one week after the start of treatment, and also throughout the treatment with pazopanib, monitor blood pressure and, if necessary, carry out antihypertensive therapy, while a dose reduction or a break in taking pazopanib should be clinically justified (see sections "Method application and dose "and" Side effect ").

Arterial hypertension (systolic pressure ≥150 mm Hg or diastolic pressure ≥100 mm Hg. ) occurs at the beginning of the course of treatment (approximately 40% of cases by the 9th day and approximately 90% - during the first 18 weeks). In the case of the appearance of signs of hypertensive crisis or in the case of severe arterial hypertension or permanently elevated values of blood pressure resistant to antihypertensive drugs and a lower dose of pazopanib, pazopanib should be canceled.

Syndrome of reversible posterior encephalopathy (SOSE) / reversible leukoencephalopathic syndrome (LEPS)

With the use of pazopanib, the occurrence of SOSE / reversible LEPS was reported.

SOPE / reversible LEPS manifest themselves following symptoms: headache, arterial hypertension, seizures, drowsiness, confusion, blindness, other visual impairment and neurological disorders. Cases of death were reported. Pazopanib should be discontinued in patients with developing SOSE / reversible LEPS.

Interstitial lung disease (IBL) / pneumonitis

With the use of pazopanib, development of an ILC with a possible lethal outcome. Patients should be monitored for pulmonary symptoms that indicate IBL / pneumonitis, and discontinue the use of pazopanib in patients with developing IBL or pneumonitis.

Heart Dysfunction

In the clinical studies of pazopanib, the following cardiac dysfunctions were noted: chronic heart failure and a reduction in the left ventricular ejection fraction (LVEF).

Patients should be monitored carefully to identify clinical signs or symptoms of congestive heart failure. In patients at risk of developing cardiac dysfunction, it is recommended to determine the initial LVEF, and also to conduct regular repeated measurements of LVEF.

Interval lengthening QT and ventricular tachycardia such as "pirouette" (torsade de pointes)

In clinical trials of pazopanib, cases of lengthening of the interval QT and ventricular tachycardia of the "pirouette" type (see the "Side effect" section).

In patients with lengthening interval QT in the history of taking antiarrhythmic and other drugs that extend the interval QT, as well as in patients with heart disease it is recommended to apply pazopanib carefully. It is recommended to conduct initial and subsequent periodic monitoring of the electrocardiogram and the content of electrolytes (calcium, magnesium, potassium) with the use of pazopanib.

Arterial thrombosis

In clinical trials of pazopanib, cases of myocardial infarction, angina pectoris, ischemic stroke, and transient ischemia of the brain were reported (see "Side effect"). Cases of death were reported.

It should be used with caution in patients with an increased risk of arterial thrombosis or with an arterial thrombosis in the anamnesis. Pazopanib It was not studied in patients who experienced these phenomena during the previous 6 months. Thus, the decision to use pazopanib should be taken individually based on an assessment of the risk-benefit ratio.

Thrombotic microangiopathy

In clinical trials of pazopanib, both monotherapy and in combination with bevacizumab or topotecan, cases of thrombotic microangiopathy have been reported (see "Side effect").

Pazopanib should be discontinued in the case of thrombotic development microangiopathy. After the abolition of therapy with the drug, the resolution of thrombotic symptoms microangiopathy. Pazopanib is not indicated for use in combination with other antitumor drugs.

Bleeding

In the course of clinical studies of pazopanib, there have been recorded cases of bleeding (see " action "), including those with a fatal outcome.People with a high risk of bleeding pazopanib should be appoint with caution.

Perforation and fistula formation of the gastrointestinal tract

During clinical studies of pazopanib cases perforation of the gastrointestinal tract (GIT) and fistula formation (see section "Side effect"). Cases of death were reported. Concerning pazopanib should be administered with caution to patients at risk perforation of the gastrointestinal tract and fistula formation.

Healing of wounds

The effect of pazopanib on wound healing has not been studied. Since inhibitors VEGF can worsen wound healing, pazopanib should be canceled at least 7 days before the planned operational interference.

The decision to resume treatment pazopanib following surgical intervention should be taken on the basis of clinical assessment of the adequacy of healing postoperative wound. Pazopanib should be discarded in patients with a discrepancy in the edges of the wound.

Hypothyroidism

In clinical trials pazopanib observed cases hypothyroidism (see section "Side effect"). It is recommended to carry out prophylactic control of thyroid function.

Proteinuria

In clinical trials pazopanib marked cases the emergence of proteinuria (see section "Side effect"). Recommended conduct periodic analysis of urine during treatment with pazopanib for the appearance of proteinuria. In case of development of a nephrotic syndrome pazopanib should be canceled.

Pneumothorax

In clinical studies of the use of pazopanib in the prevalent CMT cases of pneumothorax have been observed. Patients receiving treatment pazopanib, should be carefully Observe the appearance of signs and symptoms of pneumothorax.

Contraception

Patients with preserved reproductive potential should use reliable contraceptive methods during treatment with pazopanib and within two weeks after discontinuation of therapy pazopanibom.

At sexual contacts to men, incl. with a history of vasectomy treated with pazopanib and their sexual partners (pregnant women, women likely to have pregnancy, or women with preserved reproductive potential), it is necessary to use a condom the entire time of the treatment of a man, and also within 2 weeks after taking the last dose of the drug.

Effect on the ability to drive transp. cf. and fur:

The influence of pazopanib on the ability to drive vehicles has not been studied. Given the pharmacological properties of the drug, no impact on activities of this kind is expected. The general condition of the patient and the side effect profile of the drug should be taken into account.

Form release / dosage:

The film-coated tablets are 200 mg and 400 mg.

Packaging:

Dosage of 200 mg: 30 or 90 tablets per bottle from PE high density, ukuporenny a cover made of polypropylene with protection against opening by children and film from polyethylene, covered with foil.

Dosage of 400 mg: 30 or 60 tablets per bottle from high-density PE, ukuporenny polypropylene cover with protection from opening by children and film from polyethylene, covered with foil.

The bottle with instructions for use is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008805/10

Date of registration:27.08.2010 / 22.11.2016

Expiration Date:Unlimited

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

GLAXO OPERATIONS UK, Limited United Kingdom

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp26.03.2017

Illustrated instructions

Instructions

Votrient (Votrient)