Вотриент
Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain
Code of automatic telephone exchange: L01XE11
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Tablets, film coated pink color, kapsulovidny, with the engraving "GS JT" on one party.
Active ingredient: a pazopaniba a hydrochloride of 216.7 mg that corresponds to the maintenance of a pazopanib of 200 mg
Excipients: sodium carboxymethylstarch - 21.2 mg, magnesium stearate - 2.1 mg, K30 povidone - 16 mg, cellulose microcrystallic - 64.1 mg.
Structure of a film cover: опадрай® pink YS-1-14762-A - 9.6 mg (a gipromelloza - 5.66 mg, titanium dioxide - 2.98 mg, a macrogoal of 400 - 0.77 mg, polysorbate of 80 - 0.1 mg, dye ferrous oxide red - 0.09 mg).
Pharmacological properties:
Antineoplastic drug, tyrosinekinase inhibitor for intake. Вотриент actively influences many receptors targets.
Пазопаниб contacts receptors of the endothelial growth factor of vessels allocated from growth factor thrombocytes and a receptor of a factor of stem cells, at the same time values of the inhibiting concentration in 50% (IC50) make 10, 30, 47, 71, 84 and 74 nmol/l respectively.
Пазопаниб tyrosinekinases of a receptor of endothelial growth factors-1, 2, 3 (VEGFR-1, VEGFR-2, VEGFR-3), a receptor of a growth factor of thrombocytes the alpha and a beta (PDGFR-α and PDGFR-β), a receptor of a growth factor of fibroblasts-1 and-3 (FGFR-1,-3), a receptor of cytokine (Kit), a receptor interleykina-2, the induced by a kinase of T-cells (Itk), leykotsitspetsifichesky a protein tyrosinekinase (Lck) and transmembrane glycoprotein receptor of a tyrosinekinase is inhibitor of a set of tyrosinekinases, including (with-Fms). In vitro пазопаниб inhibits a ligand - the induced autophosphorylation of VEGFR-2, Kit and PDGFR-β. In vivo пазопаниб inhibits the VEGF induced phosphorylation of VEGFR-2, angiogenesis and growth of some human tumoral heterografts at mice.
Increase in the ABP at equilibrium concentration of a pazopanib was observed.
Pharmacokinetics. Absorption
Пазопаниб it is soaked up, reaching Cmax, on average, in 2-4 h after intake. Daily reception brings to 1-, 2-, 3, to 4-fold increase in AUC. At daily reception of 800 mg of a pazopanib AUC and Cmax value made 1.037 ч×мкг/мл and 58.1 mkg/ml (132 microns are equivalent), respectively. Essential increase in AUC and Cmax was not observed at increase in a dose of a pazopanib more than 800 mg.
System exposure of a pazopanib increased at reception with food. Purpose of a pazopanib with food with the high and low content of fat leads approximately to 2-fold increase in AUC and Cmax. Thus, пазопаниб it is necessary to take, at least, for 1 h to or in 2 h after meal.
Purpose of 400 mg of a pazopanib in the form of the crumbed tablet causes increase in AUC(0-72) and Smakhpriblizitelno twice and causes Tmax reduction approximately for 1.5 hours in comparison with purpose of the whole tablet. These results show that bioavailability and extent of absorption of a pazopanib at oral administration increases at reception of the crumbed tablet in comparison with the whole tablet. Therefore because of such possibility of the increased influence of a tablet of a pazopanib it is not necessary to crush.
Distribution
Linkng of a pazopanib with proteins of a blood plasma of in vivo made more than 99% regardless of concentration in the range of 10-100 mkg/ml.
These in vitro allow to assume what пазопаниб is substrate for the R-glycoprotein (P-gp) and protein of resistance of a breast cancer (BCRP).
Metabolism
The researches in vitro showed that metabolism of a pazopanib is mediated preferential by CYP3A4 isoenzyme, and also in insignificant degree of CYP1A2 and CYP2C8.
Removal
Пазопаниб it is removed slowly with average T1/2 30.9 value of the h after reception in the recommended dose of 800 mg. Removal is carried out, generally by intestines, at the same time only less than 4% of the accepted dose are removed by kidneys.
Pharmacokinetics at special groups of patients
Patients with a renal failure
Removal of a pazopanib does not depend on clearance of creatinine (30–150 ml/min.). The renal failure should not influence system influence of a pazopanib therefore ≥ 30 ml/min. of dose adjustment are not required to patients with clearance of creatinine.
Patients with an abnormal liver function
At patients to an easy abnormal liver function (normal concentration of bilirubin at increase in activity of alaninaminotranspherase (ALT) of any degree or increase in concentration of bilirubin to 1,5 × the upper bound of norm (UBN), irrespective of the ALT level) after a single dose of a pazopanib of 800 mg once a day average values (mkg/ml Cmax30,9, an interval of 12,5-47,3 and AUC (0-24)841,8 mkg × h/ml, an interval 600,4–1078) are comparable to average values at patients with normal function of a liver (mkg/ml Cmax49,4, an interval of 17,1-85,7 and AUC (0-24)888,2 mkg × h/ml, an interval 345,5–1482).
The maximum tolerable dose of a pazopanib at patients with a moderate abnormal liver function (increase in concentration of bilirubin> 1,5 × to 3 × VGN, irrespective of the ALT level) made 200 mg once a day. Average Cmax values (22,4 mkg/ml, an interval 6,4–32,9) and AUC(0-24)(350,0 of mkg × h/ml, an interval 131,8–487,7) after reception of 200 mg of a pazopanib once a day at patients with a moderate abnormal liver function made about 45% and 39%, respectively, of average values at patients with normal function of a liver after administration of drug in a dose of 800 mg once a day. There are not enough data on patients with a heavy abnormal liver function (concentration of the general bilirubin> 3 × VGN, irrespective of the ALT level) therefore it is not recommended to apply пазопаниб at these patients.
Indications to use:
— treatment of widespread nephrocellular cancer;
— treatment of widespread sarcoma of soft tissues (except gastrointestinal stromal tumors and a liposarcoma) at the patients who were earlier receiving chemotherapy.
Route of administration and doses:
The recommended dose of drug of Votriyent makes 800 mg in 1 times / Votriyent should take not less than for 1 h to or in 2 h after meal. Tablets should be swallowed entirely, without breaking their integrity (not to break, not to chew). The passed doses should not be filled if before reception of the next dose there were less than 12 h.
Selection of a dose
Depending on individual portability the daily dose of drug can be reduced or increased with a step of 200 mg, at the same time the maximum daily dose should not exceed 800 mg.
Special groups of patients
Safety and efficiency of use of drug for children are not established.
Corrections of the mode of dosing and frequency of reception at patients are aged more senior than 65 years it is not required.
Due to low extent of removal of a pazopanib and its metabolites kidneys, the renal failure has no clinically significant influence on pharmacokinetics of a pazopanib therefore with KK of ≥30 ml/min. correction of the mode of dosing is not required from patients. Experience of use of Votriyent for patients with a renal failure of heavy degree or at the patients who are on peritoneal dialysis or a hemodialysis no therefore Votriyent's use for such patients is not recommended.
Safety of use and pharmacokinetics of a pazopanib at patients with already available abnormal liver functions are completely not established. To patients with the easy abnormal liver function established on ALT values and bilirubin, dose adjustment is not required. At patients with a liver failure of moderate severity it is necessary to lower Votriyent's dose to 200 mg / Data on use of a pazopanib for patients with a heavy liver failure (concentration of the general bilirubin> 3×ВГН at any ALT level) insufficiently therefore Votriyent's use for such patients is not recommended.
Features of use:
Influence on function of a liver
At Votriyent's use cases of development of a liver failure (increase in activity of ALT, nuclear heating plant and concentration of bilirubin), including cases with a lethal outcome are noted. The isolated increase in activity of ALT and ACT which was not followed by simultaneous increase in activity of ShchF or concentration of bilirubin was in most cases noted.
It is necessary to carry out monitoring of activity of liver enzymes before Votriyent's appointment and, at least, 1 time in 4 weeks or is more often (according to clinical indications) within, at least, first 4 months of treatment. Periodic monitoring should be carried out also after the first 4 months. These instructions concern patients with reference values of the general bilirubin ≤ 1.5×ВГН, and also values of activity of ALT and ACT ≤ 2×ВГН.
Patients with the isolated increase in activity of ALT above VGN by 3-8 times can continue Votriyent's reception, at the same time it is necessary to monitorirovat weekly indicators of function of a liver until activity of ALT does not decrease to 1 degree of toxicity or to a reference value.
Patients with increase in activity of ALT> 8×ВГН should interrupt Votriyent's reception before decrease of the activity of ALT to 1 degree of toxicity or to a reference value. If the potential advantage of resuming of reception of Votriyent exceeds risk of development of a hepatotoxic, then Votriyent's reception can be resumed in the reduced dose to 400 mg of 1 times / under weekly control of indicators of function of a liver within 8 weeks. At the subsequent receptions of Votriyent, in case of repeated increase in activity of ALT> 3×ВГН, Votriyent should be cancelled completely.
Patients with increase have activities of ALT> 3×ВГН and simultaneous increase in concentration of bilirubin> 2×ВГН Votriyent should be cancelled completely. Patients have to be under observation of the doctor before decrease of the activity of ALT to the 1st degree of toxicity or to a reference value. Пазопаниб is UGT1A1 inhibitor. Patients with Gilbert's syndrome can have an indirect (not conjugated) hyperbilirubinemia of easy degree. To the patients only with an indirect hyperbilirubinemia of easy degree having Gilbert's syndrome or with suspicion on its existence, with increase in activity of ALT> 3×ВГН drug is appointed also as to patients with the isolated increase in activity of ALT.
Simultaneous use of a pazopanib and simvastatin increases risk of increase in activity of ALT and demands extra care and careful observation.
With a moderate abnormal liver function it is recommended to patients to reduce an initial dose of a pazopanib to 200 mg / Additional recommendations about dose adjustment in the course of treatment on the basis of results of hepatic tests at patients with already available abnormal liver function are absent.
Arterial hypertension
At treatment pazopaniby increase in the ABP and cases of hypertensive crisis were observed. Before purpose of a pazopanib it is necessary to achieve adequate control of the ABP. No later than 1 week after an initiation of treatment pazopaniby it is necessary to carry out monitoring of the ABP and, if necessary, to carry out hypotensive therapy, at the same time the dose decline or a break in reception of a pazopanib have to be clinically proved.
Arterial hypertension (systolic pressure ≥ 150 mm hg or diastolic pressure ≥ 100 mm hg) arises at the beginning of a course of treatment (approximately in 40% of cases by 9th day and in 90% of cases within the first 18 weeks). In case of symptoms of hypertensive crisis or in case of heavy arterial hypertension or constantly increased ABP values (140/90 mm. hg), resistant to antihypertensives and a dose decline of a pazopanib, пазопаниб it is necessary to cancel.
Syndrome of Reversible Back Encephalopathy (SRBE) / reversible leykoentsefalopatichesky syndrome (LEPS)
At use of a pazopanib it was reported about emergence of SOZE/LEPS. SOZE/LEPS is shown by the following symptoms: headache, arterial hypertension, spasms, drowsiness, confusion of consciousness, blindness, other vision disorders and neurologic disturbances. It was reported about cases with a lethal outcome. Пазопаниб it is necessary to cancel at patients with SOZE/LEPS.
Dysfunctions of heart
During clinical trials the following dysfunctions of heart were registered: chronic heart failure; decrease in the fraction of emission of a left ventricle (FELV). Chronic heart failure was noted at 3 of 240 patients (1.0%) in the 3rd phase of clinical trial of SMT. In these clinical trials decrease in FVLZh at the patients undergoing inspection after an initial investigation phase was noted in 11% of cases (16/142) in the group receiving пазопаниб in comparison with 5% (2/40) - in group of placebo. 14 of 16 patients in the group receiving пазопаниб suffered from the accompanying arterial hypertension which could promote deterioration in cordial function at predisposed patients (for example, receiving earlier therapy by anthracycline antibiotics) due to increase in an afterload.
It is necessary to carry out monitoring and timely correction of arterial pressure using a combination of anti-hypertensive therapy and selection of a dose of a pazopanib (cancellation and repeated purpose of therapy already in a smaller dose, proceeding from a clinical situation). It is necessary to reveal carefully at patients clinical signs of congestive heart failure. At patients with risk of development of disturbance of cordial activity it is recommended to define initial FVLZh, and also to take regular repeated measurements of FVLZh.
Lengthening of an interval of QT and ventricular tachycardia like "pirouette"
At use of a pazopanib cases of lengthening of an interval of QT and ventricular tachycardia like "pirouette" were noted.
At the patients having lengthening of an interval of QT in the anamnesis, accepting the antiarrhytmic and other drugs extending QT interval and also at patients with heart diseases which can be complicated by disturbances of a rhythm it is recommended to apply пазопаниб in the conditions of periodic control of an ECG and concentration of electrolytes (calcium, magnesium, potassium).
Arterial thrombosis
Cases of a myocardial infarction, stenocardia, ischemic stroke and passing ischemia of a brain are registered. It was reported about cases with a lethal outcome.
Пазопаниб it has to be appointed with care to patients with the increased risk of developing of arterial thrombosis or with arterial thrombosis in the anamnesis. Пазопаниб it was not studied at patients at whom these events were observed within the previous 6 months. Thus, the decision on purpose of a pazopanib should be made individually on the basis of ratio assessment risk/advantage.
Venous tromboembolic episodes
During clinical trials cases of venous tromboembolic episodes, including venous thrombosis and a fatal embolism of a pulmonary artery were registered. Frequency of development of these events was higher in population with SMT (5%) in comparison with population with PKR (2%).
Trombotichesky mikroangiopatiya
During clinical trials of a pazopanib (where пазопаниб it was used as monotherapy, in a combination with bevatsizumaby and in a combination with topotekany) cases of a trombotichesky mikroangiopatiya were registered.
Пазопаниб it is necessary to cancel at patients with a trombotichesky mikroangiopatiya.
Recovery of effects of a trombotichesky mikroangiopatiya was observed after drug withdrawal.
Bleedings
Because at use of a pazopanib cases of bleedings are registered (including with a lethal outcome), to patients at whom pneumorrhagia episodes were noted, it is necessary to appoint intracranial or gastrointestinal bleedings Votriyent within the last 6 months with care.
Perforation and formation of fistulas of a GIT
Cases of perforation of a GIT and formation of fistulas were noted. It was reported about cases with a lethal outcome. In this regard Votriyent should appoint with care to patients with the increased risk of perforation of a GIT and formation of fistulas.
Healing of wounds
Researches of influence of a pazopanib on healing of wounds were not conducted.
As VEGFR inhibitors can worsen healing of wounds, пазопаниб it is necessary to cancel at least in 7 days before a planned operative measure.
The decision on treatment resuming the pazopaniby ambassador of operation should be made on the basis of clinical assessment of adequacy of healing of a postoperative wound. Вотриент it is necessary to cancel at patients with discrepancy of edges of a wound.
Hypothyroidism
Preventive monitoring of function of a thyroid gland is recommended.
Proteinuria
Against the background of therapy pazopaniby cases of emergence of a proteinuria are noted. Periodic monitoring of dynamics of a proteinuria at such patients is recommended. In case of development of a renal syndrome пазопаниб it is necessary to cancel.
Infections
There are messages on serious infections (with a neytroneniya or without it), in certain cases with a lethal outcome.
Combination to other types of system antineoplastic therapy
Clinical trials of use of a pazopanib in combination with pemetreksedy (not small-celled cancer of a lung) and lapatiniby (cancer of a neck of uterus) were stopped ahead of schedule in connection with growth of toxic manifestations and/or mortality. In this regard it was not succeeded to establish a safe and effective dose at use of these combinations. Now пазопаниб it is not shown for use in combination with other antineoplastic drugs.
Interactions
It is necessary to avoid simultaneous use with powerful inhibitors of an isoenzyme CYP3A4 or P-gp in connection with risk of increase in exposure to a pazopanib. It is recommended to consider the possibility of simultaneous use of a pazopanib with alternative medicines which either do not influence, or exert the minimum impact on an isoenzyme of CYP3A4 or P-gp.
Pheumothorax
In clinical trials of use of a pazopanib at widespread sarcoma of soft tissues pheumothorax cases were observed. The patients receiving treatment pazopaniby should be observed carefully concerning emergence of signs and symptoms of pheumothorax.
Reproductive toxicity
Preclinical trials on animals showed reproductive toxicity. The patient needs to explain potential risk for a fruit. Women of childbearing age are recommended to avoid approach of pregnancy during treatment pazopaniby.
Use in pediatrics
As the mechanism of action of a pazopanib can promote development of the expressed growth disorder and maturing of bodies during early post-natal development (according to preclinical trials), пазопаниб children under 2 years should not appoint.
Influence on ability to driving of motor transport and to control of mechanisms
Influence of a pazopanib on ability to manage motor transport was not studied. Considering pharmacological properties of drug, influence on activity such it is not expected. It is necessary to take the general condition of the patient and a profile of side effect of drug into account.
Side effects:
Safety of a pazopanib at treatment of the widespread nephrocellular cancer (NC) was estimated during the randomized, double blind person, placebo - a controlled multicenter research. Patients with widespread and/or metastatic PKR were randomizirovana on 2 groups receiving пазопаниб in a dose of 800 mg of 1 time / (n=290) and placebo (n=145).
Safety of a pazopanib at treatment of the sarcoma of soft tissues (SST) was estimated during the randomized, double blind person, placebo - a controlled multicenter research. The patients from widespread SMT (n=369) who were receiving earlier therapy by anthracyclines or not subject to therapy by anthracyclines were randomizirovana in 2 groups receiving пазопаниб in a dose of 800 mg of 1 time / (n=246) and placebo (n=123).
Undesirable reactions are listed in table 1 according to defeat of bodies and systems of bodies and occurrence frequency. Frequency of occurrence is defined by the following образом:очень often (≥1/10), is frequent (≥1/100 and <1/10), infrequently (≥1/1 000 and <1/100), is rare (≥1/10 000 and <1/1 000), is very rare (<1/10 000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug and data of post-registration observation, including spontaneous messages on clinical cases; reports on serious undesirable reactions during the current researches; the researches of clinical pharmacology and eksplorativny researches estimating use of drug according to indications unregistered currently.
Table 1.
Side reactions Extended Sarcoma of soft tissues
nephrocellular
cancer
Infectious and parasitic diseases
Infections (with or without
neutropenias) infrequently infrequently
Infections of gums • often
The high-quality, malignant and not specified new growths
(including cysts and polyps)
Pains in new growths • very often
From system of a hemopoiesis
Neutropenia often very often
Thrombocytopenia often very often
Leukopenia often very often
From endocrine system
Hypothyroidism often often
Increase in activity
thyritropic hormones
in blood it is frequent •
Decrease in concentration
glucose in blood infrequently •
From a nervous system
Dizziness is often very frequent
Sleeplessness • often
Hemorrhagic stroke infrequently •
Hypesthesia infrequently •
Peripheral touch
neuropathy infrequently often
Paresthesia often infrequently
Block often •
Weakness often infrequently
Drowsiness often •
Dysgeusia
(disorder of taste) it is often very frequent
Headache very often very often
Disturbance of brain
blood circulations infrequently •
Ischemic stroke infrequently infrequently
Tranzitorny ischemic
attack (passing disturbance
cerebral circulation) * it is frequent •
Syndrome of reversible back
encephalopathies it is seldom rare
From heart
Disturbances of cordial
activity (such, as
decrease in fraction of emission
left ventricle and chronic
heart failure) infrequently often
Bradycardia (proceeds
asymptomatically) very often very often
Myocardial infarction infrequently often
Myocardium ischemia often •
Lengthening of an interval of QT often often
Ventricular tachycardia
pirouette type (torsade de
pointes) * infrequently •
Dysfunction of heart it is infrequently frequent
From vessels
Hemorrhage in a brain infrequently infrequently
Nasal bleeding is often frequent
Gastrointestinal
bleeding infrequently infrequently
Esophageal bleeding infrequently infrequently
Hamaturia often infrequently
Arterial hypertension very often very often
Pulmonary bleeding infrequently often
Venous thromboembolic
complications infrequently often
Retroperitoneal bleeding infrequently infrequently
Rectal bleeding infrequently infrequently
Trombotichesky mikroangiopatiya
(including trombotichesky
Werlhof's disease and
gemolitiko-uraemic syndrome) it is seldom rare
Bleeding from an oral cavity is infrequently frequent
Hemorrhoidal bleeding infrequently •
Proctal bleeding • often
Inflows often often
Hypertensive crisis infrequently •
From respiratory system
Cough • very often
Dysphonia often often
Диспноэ (asthma) • very often
Pheumothorax • often
Rhinorrhea • infrequently
Pains in a stomatopharynx • infrequently
Hiccups • often
Pneumorrhagia infrequently infrequently
Pulmonary embolism infrequently •
Bronchial bleeding • infrequently
Disturbances from a metabolism
Anorexia very often very often
Decrease in body weight often very often
The loss of appetite is very often very frequent
Dehydration • often
From the alimentary system
Meteorism often often
Stomacace infrequently •
Frequent bowel emptying infrequently •
Hematemesis infrequently •
Gematokhezis infrequently •
Perforation of an ileal gut infrequently infrequently
Melena infrequently infrequently
Pancreatitis infrequently infrequently
Peritonitis infrequently infrequently
Bleeding from upper
departments of gastrointestinal
path infrequently infrequently
Gastrointestinal bleeding infrequently infrequently
Abdominal pain very often very often
Anorexia very often very often
Diarrhea very often very often
Dyspepsia often often
Perforation of a stomach or intestines * infrequently •
Formation of gastric
and/or intestinal fistulas infrequently infrequently
Outside belly fistula infrequently infrequently
Increase in activity of a lipase *** is frequent •
Nausea very often very often
Stomatitis often very often
Vomiting very often very often
Dryness of a mucous membrane of an oral cavity • often
From a liver and biliary tract
Hepatotoxic infrequently •
Jaundice infrequently •
Liver failure infrequently •
Hepatitis infrequently •
Increase in activity of ALT is very often frequent
Increase in activity of nuclear heating plant is very often frequent
The abnormal liver function is frequent infrequently
Hyperbilirubinemia often infrequently
From skin and hypodermic cellulose
Skin inflammation • often
Alopecia often very often
Skin exfoliation infrequently •
Generalized itch infrequently •
Xeroderma often often
Exfoliative rash • very often
Depigmentation of a hair very often very often
Decolouration of eyelashes infrequently •
Damage of nails • often
Palmarno-plantarnaya eritrodizesteziya
(a palmar and bottom syndrome) it is often very frequent
Bottom erythema infrequently •
Skin ulcers • infrequently
Photosensitivity infrequently infrequently
Hyperhidrosis often often
Rash often infrequently
Vesicular rash infrequently •
Papular rash infrequently infrequently
Erythematic rash infrequently •
Generalized rash infrequently •
Macular rash infrequently •
Pruritic rash infrequently •
Itch often infrequently
Erythema often often
Hyperemia infrequently often
Depigmentation of skin often very often
Hypoxanthopathy often very often
From an urinary system
Proteinuria often infrequently
From a musculoskeletal system
Skeletal and muscular pain &am
Interaction with other medicines:
Inductors or inhibitors of an isoenzyme CYP3A4
On the basis of these researches in vitro it is possible to believe that oxidizing metabolism of a pazopanib in microsomes of a liver of the person proceeds, generally with the participation of CYP3A4 isoenzyme, with an insignificant contribution of CYP1A2 and CYP2C8. Thus, inhibitors and inductors of an isoenzyme CYP3A4 can change metabolism of a pazopanib.
Inhibitors of an isoenzyme CYP3A4, P-gp and BCRP
Пазопаниб is substrate for an isoenzyme of CYP3A4, P-gp and BCRP.
Simultaneous use of a pazopanib (400 mg of 1 times/) with powerful inhibitor of an isoenzyme CYP3A4 and R-gp, ketokonazoly (400 mg of 1 times/) consistently within 5 days led to 66% and 45% increase in average values of AUC(0-24) and Cmax of a pazopanib, respectively, in comparison with use of a pazopanib without the accompanying drugs (400 mg of 1 times / within 7 days). At increase in a dose increased in the range from 50 mg to 2000 mg of drug of the size Cmax and AUC of a pazopanib to a lesser extent, than in proportion to a dose. Thus, at most of patients after a dose decline of a pazopanib to 400 mg of 1 times / in the presence of powerful inhibitors of an isoenzyme CYP3A4 the exposure sizes similar to that as after introduction of a pazopanib without the accompanying drugs in a dose of 800 mg of 1 times / However at some patients the size of system exposure to a pazopanib at the same time can be more considerable, than the pazopaniba observed after introduction without the accompanying drugs in a dose of 800 mg are observed.
Combined use of a pazopanib with other powerful inhibitors of an isoenzyme CYP3A4 (such as итраконазол, кларитромицин, атазанавир, индинавир, нефозадон, нелфинавир, ритонавир, саквинавир, телитромицин and вориконазол) can lead to increase in concentration of a pazopanib. Grapefruit juice can also increase concentration of a pazopanib.
Use of 1500 mg of lapatiniba-substrate and weak inhibitor of an isoenzyme CYP3A4, P-gp and BCRP - from 800 mg of a pazopanib leads to increase approximately at 50–60% of average sizes of AUC(0-24) and Cmax of a pazopanib in comparison with use of one pazopanib in a dose of 800 mg. Combined use of a pazopanib with inhibitors of an isoenzyme CYP3A4, P-gp and BCRP (for example, лапатиниб) leads to increase in concentration of a pazopanib in plasma. Simultaneous use with powerful P-gp or BCRP inhibitors can change exposure and distribution of a pazopanib, including number distribution in TsNS.
It is necessary to avoid simultaneous use of a pazopanib with powerful inhibitor of an isoenzyme CYP3A4. If clinically acceptable alternative to powerful inhibitor of an isoenzyme of CYP3A4 is not available, the dose of a pazopanib has to be lowered to 400 mg / for the entire period of use of the accompanying therapy. In case of development of the undesirable phenomena connected with medicines the possibility of a further dose decline can be considered.
It is necessary to avoid combined use of drug with powerful P-gp inhibitors, or to use the alternative drugs which are not possessing or possessing the minimum inhibiting effect on P-gp.
CYP3A4 isoenzyme inductors
CYP3A4 isoenzyme inductors, for example rifampicin, can reduce plasma concentration of a pazopanib. Simultaneous use with powerful P-gp or BCRP inductors can change exposure and distribution of a pazopanib, including distribution in TsNS. The choice of the alternative drugs which are not possessing or having the minimum inhibiting activity concerning CYP3A4 isoenzyme is recommended.
Influence of a pazopanib on P450 cytochrome substrates
In the researches in vitro of microsomes of a liver of the person it was proved what пазопаниб inhibits isoenzymes of CYP1A2, 3A4, 2B6, 2C8, 2C9, 2C19 and 2E1. Ability to induction of an isoenzyme of CYP3A4 at the person was shown in the researches in vitro with use of a human H-receptor of pregnane (PXR). In researches of pharmacological properties of a pazopanib where drug was used in a dose of 800 mg of 1 times/, it was shown what пазопаниб has no clinically significant influence on caffeine pharmacokinetics (CYP1A2 substrate), warfarin (CYP2C9 substrate) or an omeprazol (CYP2C19 substrate) at patients with malignant new growths.
Пазопаниб led to increase in average AUC and Cmax values of midazolam (CYP3A4 substrate) approximately for 30% and to increase for 33-64% of a ratio of concentration of dextromethorphan and a dekstrorfan in urine after dextromethorphan intake (CYP2D6 substrate).
Combined use of a pazopanib in a dose of 800 mg of 1 time(s) of a paklitaksel in a dose led 80 mg/sq.m (CYP3A4 and CYP2C8 substrate), on average, to increase in AUC and Cmax of a paklitaksel by 26% and 31% respectively once a week.
Simultaneous use of a pazopanib with substrates of isoenzymes CYP3A4, 2D6, 2C8 with a narrow therapeutic range is not recommended.
Influence of a pazopanib on other enzymes and transport proteins
The researches in vitro also showed what пазопаниб is powerful UGT1A1 and OATP1B1 inhibitor with an overwhelming dose (IC50) of 1.2 microns and 0.79 microns respectively.
Пазопаниб can increase concentration of medicines which removal is carried out generally with the participation of UGT1A1 and OATP1B1.
Simultaneous use of a pazopanib and simvastatin
Simultaneous use of a pazopanib and simvastatin increases the frequency of increase in activity of ALT. In the integrated population of the patients participating in researches at monotherapy pazopaniby about increase in activity of ALT> 3×ВГН it was reported at 126 of 895 (14%) patients who did not accept statins, and at 11 of 41 (27%) the patients who were at the same time accepting симвастатин (р = 0.038). If at the patient who is at the same time accepting симвастатин activity of ALT increases, it is necessary to implement recommendations about dosing of a pazopanib and to cancel симвастатин. The alternative statines given for assessment of risk of simultaneous use and a pazopanib are not enough.
Influence of meal on pharmacokinetics of a pazopanib
Reception of a pazopanib together with food saturated or poor in fats leads to approximately double increase in AUC and Cmax of drug.
Medicines which raise рН a gastric juice
Simultaneous use of a pazopanib and esomeprazole reduces bioavailability of a pazopanib approximately by 40% (AUC and Cmax). It is necessary to avoid simultaneous use of a pazopanib with medicines which raise рН a gastric juice. In need of simultaneous use of the inhibitor of a proton pomp (IPP) it is recommended to accept a dose of a pazopanib out of meal, 1 time / evening, along with IPP. In need of simultaneous use of the antagonist of H2 receptors, пазопаниб it is necessary to take out of meal, at least, for 2 h to or, at least, in 10 h after reception of the antagonist of H2 receptors. Пазопаниб it is necessary to take, at least, for 1 h to or in 2 h after use of antacids of short action. Recommendations about simultaneous use of IPP and antagonists of H2 receptors are based on physiological features of a human body.
Contraindications:
— a heavy liver failure (in connection with insufficiency of data);
— a heavy renal failure (in connection with insufficiency of data);
— children's age (in connection with insufficiency of data);
— pregnancy;
— breastfeeding period;
— hypersensitivity to a pazopanib or any other component of drug.
With care it is necessary to apply at patients with a liver failure easy and moderate severity; gastrointestinal diseases; diseases of cardiovascular system (including arterial hypertension, lengthening of an interval of QT, ventricular tachycardia like "pirouette" in the anamnesis, at the patients accepting the antiarrhytmic means and drugs extending QT interval); cerebrovascular diseases; arterial fibrinferments; dysfunctions of a thyroid gland; at patients from group of the increased risk of bleedings.
Use of drug VOTRIENT at pregnancy and feeding by a breast
Drug is contraindicated at pregnancy and in the period of a lactation (breastfeeding).
Use at abnormal liver functions
Safety of use and pharmacokinetics of a pazopanib at patients with already available abnormal liver functions are completely not established. To patients with the easy abnormal liver function established on ALT values and bilirubin, dose adjustment is not required. At patients with a liver failure of moderate severity it is necessary to lower Votriyent's dose to 200 mg / Data on use of a pazopanib for patients with a heavy liver failure (concentration of the general bilirubin> 3×ВГН at any ALT level) insufficiently therefore Votriyent's use for such patients is not recommended.
Use at renal failures
Due to low extent of removal of a pazopanib and its metabolites kidneys, the renal failure has no clinically significant influence on pharmacokinetics of a pazopanib therefore with KK of ≥30 ml/min. correction of the mode of dosing is not required from patients.
Experience of use of Votriyent for patients with a renal failure of heavy degree or at the patients who are on peritoneal dialysis or a hemodialysis no therefore Votriyent's use for such patients is not recommended.
Use for elderly patients
Corrections of the mode of dosing and frequency of reception at patients are aged more senior than 65 years it is not required.
Use for children
Safety and efficiency of use of drug for children are not established.
Overdose:
In clinical trials пазопаниб it was applied in doses to 2000 mg.
Symptoms: dozolimitiruyushchy toxicity (increased fatigue 3 degrees) and arterial hypertension 3 degrees were observed at 1 of 3 patients who accepted 2000 mg and 1000 mg of a pazopanib a day, respectively. Strengthening of the side reactions described above is possible.
Treatment: performing symptomatic therapy. Owing to high extent of linkng of a pazopanib with proteins of plasma its removal at a hemodialysis is insignificant.
Storage conditions:
Drug should be stored the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 2 years.
Issue conditions:
According to the recipe
Packaging:
30 - bottles from polyethylene of high density (1) - packs cardboard.
90 - bottles from polyethylene of high density (1) - packs cardboard.
