Золинза®

General characteristics. Structure:

Active ingredient: 100 mg of a vorinostat in 1 capsule.

Excipients: cellulose microcrystallic, croscarmellose sodium, magnesium stearate.

Structure of a cover of the capsule: titanium dioxide (E171), gelatin.

The structure blackened: опакод black (Opacode Black) S-1-17822 (solution of glaze of shellac of 45% in ethanol - 44.5%, dye ferrous oxide black - 23.4%, butanol - 16.6%, isopropanol - 12.5%, propylene glycol - 2%, ammonium hydroxide of 28% - 1%) or опакод black (Opacode Black) S-1-17823 (solution of glaze of shellac of 45% in ethanol - 44.5%, dye ferrous oxide black - 23.4%, butanol - 2.2%, isopropanol - 26.9%, propylene glycol - 2%, ammonium hydroxide of 28% - 1%).

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug, inhibitor histone-deatsetilazy. Vorinostat is powerful inhibitor a histone-deatsetilaz (HDAC) - HDAC1, HDAC2 and HDAC3 (class I), and also HDAC6 (class II) (PK50 <the 86th nmol/l). These enzymes catalyze eliminating of acetsilt group from the lizinovy remains of proteins, including histones and proteins factors of a transcription. Antineoplastic activity of a vorinostat is caused by suppression of activity of HDAC with the subsequent accumulation of acetylized proteins, including histones. Acetylation of histones is followed by transkriptsionny gene activation, including genes suppressors of tumors, and their expression, in turn, induces a differentiation or apoptosis of cells and suppression of tumoral growth. The concentration of a vorinostat necessary for accumulation of acetylized histones, also causes a stop of a cellular cycle, a differentiation or apoptosis of modified cells.

According to researches on cellular cultures вориностат induces apoptosis with the broad range of modified (tumoral) cells. On cultures of tumor cells вориностат showed additional or synergistic activity when sharing with other types of antineoplastic therapy, including radiation therapy and chemotherapy inhibitors of kinases, cytotoxic drugs and differentiation factors of cells. In vivo is shown antineoplastic activity of a vorinostat on the broad range of models of cancer at rodents, including models of heterografts of malignant tumors of a prostate, mammary gland and large intestine of the person.

Pharmacokinetics. Absorption. After a single dose in a vorinostat in a dose of 400 mg along with greasy food at patients with refractory or recurrent widespread cancer average values ± made a standard deviation of AUC, Cmax and median (range) of Tmax 5.5±1.8 мкмоль/л×ч, 1.2±0.62 µmol/l and 4 (2-10) h respectively. After a single dose in drug in a dose of 400 mg on an empty stomach average values AUC, Cmax and medians of Tmax made 4.2±1.9 мкмоль/л×ч, 1.2±0.35 µmol/l and 1.5 (0.5-10) h respectively. Thus, the concomitant use of a vorinostat with greasy food is followed by increase (for 33%) sizes of absorption and insignificant reduction in the rate of absorption (increase in Tmax at 2.5 h) in comparison with administration of drug on an empty stomach. In general, it is supposed that these insignificant deviations of pharmacokinetic parameters have no clinical value.

At multiple dose in a vorinostat in a dose of 400 mg along with food of value AUC, Cmax and a median of Tmax in an equilibrium state made 6.0±2.0 мкмоль/л×ч, 1.2±0.53 µmol/l and 4 (0.5-14) h respectively.

Distribution. In the range of plasma concentration from 0.5 to 50 mkg/ml linkng of a vorinostat with proteins of plasma makes about 71%. Vorinostat quickly gets through a placental barrier at rats and rabbits at introduction in daily doses of 15 mg/kg and 150 mg/kg respectively (that corresponds to smaller value of exposure, than at the person according to AUC0-24), with achievement of transplacental balance approximately in 30 min. after introduction.

Metabolism. The main ways of metabolism of a vorinostat are reactions of a glyukuronization and hydrolysis with the subsequent β-oxidation.......... Plasma concentration of two metabolites - the O-glucuronide of a vorinostat and 4-anilino-4-oxobutane acid were measured. Both metabolites pharmacological are inactive. In comparison with vorinostaty, in an equilibrium state exposure of the O-glucuronide of a vorinostat and 4-anilino-4-oxobutane acid exceeds exposure of a vorinostat approximately in 4 and 13 times respectively.

The conducted researches in vitro on microsomes of a liver of the person indicate insignificant biotransformation of drug by enzymes of system of P450 cytochrome.

Removal. Vorinostat is preferential metabolized in a liver, in not changed look kidneys remove less than 1% of the entered dose, therefore, renal excretion practically does not play a role in removal of drug from an organism. On reaching an equilibrium state in urine found two pharmacological inactive a metabolite of a vorinostat - the O-glucuronide of a vorinostat in number of 16±5.8% of the entered dose of a vorinostat and 4-anilino-4-oxobutane acid in number of 36 ± 8,6% of the entered dose of a vorinostat. Thus, the quantity found in urine of not changed vorinostat and two specified metabolites averaged 52±13.3% of the entered dose of a vorinostat. T1/2 of a vorinostat and its O-glucuronide of a metabolite made about 2 h, and T1/2 of 4-anilino-4-oxobutane acid made about 11 h.

Pharmacokinetics at special groups of patients. On analysis findings of limited volume of data a floor, race and age of patients did not exert clinically significant impact on pharmacokinetic parameters of a vorinostat.

Pharmacokinetic parameters of a vorinostat at children and teenagers up to 18 years are not studied.

Vorinostat is contraindicated to use for patients with a liver failure of heavy degree and is not recommended for use for patients with a liver failure of moderate degree. These recommendations are based on primary results of the taking place pharmacokinetic researches at patients with easy, moderate (the general bilirubin in 1.5-3 above VGN) and heavy (the general bilirubin is more than 3 times higher than VGN) degrees of a liver failure. These researches assume that at patients with heavy degree of a liver failure after reception of a vorinostat the risk of dozozavisimy toxicity is higher, than at patients without abnormal liver functions.

In general, exclude patients with heavy degree of a liver failure from a research of a vorinostat. However there is a limited number of patients with a liver failure of moderate degree who were included in clinical trials. Clinically significant distinction in development of the side effects connected with function of a liver in patients with hepatic disturbances in the anamnesis in comparison with patients without those is not revealed.

Pharmacokinetic parameters of drug at patients with a renal failure are not studied. It should be noted that renal excretion is not involved in removal of a vorinostat from an organism.

Indications to use:

— treatment of a skin T-cellular lymphoma which progresses persistirut or recurs, despite the carried-out system therapy.

Route of administration and doses:

Drug is accepted inside during food. Capsules should be swallowed entirely, without opening.

The recommended dose makes 400 mg of 1 times/days.

In case of intolerance the dose can be lowered to 300 mg of 1 times/days - within 5 consecutive days a week if it is necessary.

Treatment is carried out to achievement of complete control (lack of signs of further progressing) or before emergence of signs of unacceptable toxicity.

Dose adjustment is not required to patients of advanced age.

Features of use:

Use at pregnancy and feeding by a breast. Adequate and strictly controlled clinical trials of use of the drug Zolinza® at pregnancy were not conducted.

Women of childbearing age should avoid pregnancy during treatment by the drug Zolinza®. If need for treatment by the drug Zolinza® arises at pregnancy or if pregnancy occurs during treatment, the patient has to be informed on potential harm of treatment for a fruit.

There are no data on release of drug with breast milk. Considering that in breast milk the majority of medicines cosecretes and that Zolinza® can cause side effects in the baby, breastfeeding during treatment by drug is not recommended.

Special instructions. It is necessary to avoid contact of contents of the capsule with skin and mucous membranes. At contact carefully to wash away powder water.

At development during therapy of disturbances from the alimentary system, including nausea, vomiting and diarrhea, purpose of antiemetic and antidiarrheal means can be required. For prevention of dehydration and maintenance of electrolytic balance it is recommended to carry out a regidratation and completion of electrolytes. In the presence at the patient of nausea, vomiting and diarrhea prior to treatment they need to be eliminated before drug Zolinza® use.

Therapy by the drug Zolinza® can be followed by development of dozozavisimy thrombocytopenia and anemia. If during treatment decrease in number of thrombocytes and/or level of hemoglobin happens the drug Zolinza® significantly, it is necessary to reduce a dose of drug or to temporarily stop treatment.

According to the available data during treatment development of such complications as an embolism of a pulmonary artery and a deep vein thrombosis is possible. Careful observation of patients, especially with the burdened anamnesis, is necessary for early detection of symptoms of an embolism of a pulmonary artery and a deep vein thrombosis.

Drug use studies of Zolinza® at patients with a liver failure are limited. On the basis of these researches administration of drug at patients with moderate degree of a liver failure is not recommended.

It is necessary to carry out monitoring of concentration of glucose to blood, especially at patients with already available diabetes mellitus or risk of development of a diabetes mellitus. Purpose of a diet and/or hypoglycemic therapy can be required.

It is necessary to carry out careful monitoring of parameters of clinical and biochemical analysis of blood, including concentration of electrolytes of plasma, glucose and creatinine at least 1 time in 2 weeks in the first 2 months of treatment, afterwards - monthly.

According to clinical trials efficiency and safety of the drug Zolinza® at patients of advanced age (65 years are more senior) was comparable with those at more young people (up to 65 years). Dose adjustment depending on age is not required.

Use in pediatrics. Safety and efficiency of drug at children is not studied.

Influence on ability to driving of motor transport and to control of mechanisms. There are no data allowing to assume possible negative influences of the drug Zolinza® on ability to control of motor transport or difficult mechanisms.

Side effects:

At administration of drug in a dose of 400 mg of 1 times/days the following 4 groups of side effects are most characteristic: from the alimentary system (diarrhea, nausea, anorexia, decrease in body weight, vomiting, a lock, a loss of appetite, dryness in a mouth), the general reactions (feeling of fatigue, a fever), from system of a hemopoiesis (thrombocytopenia, anemia) and disturbance of flavoring feelings (dysgeusia).

Side effects which meet very often (≥1/10) at the patients with a skin T-cellular lymphoma receiving the drug Zolinza® in a dose of 400 mg of 1 times/days are described below.

From system of a hemopoiesis: very often - thrombocytopenia, anemia.

From a metabolism: very often - anorexia, a loss of appetite.

From the alimentary system: very often - diarrhea, nausea, dryness in a mouth, vomiting, a lock.

From skin and hypodermic fabrics: very often - an alopecia.

From a musculoskeletal system: very often - muscular spasms.

From a nervous system: very often - a dysgeusia.

General reactions: very often - feeling of fatigue, a fever.

Laboratory and tool data: very often - a body degrowth, increase in plasma concentration of creatinine.

From the listed above very often found side effects the following had 3-5 severity: thrombocytopenia (5.8%), anemia (2.3%), anorexia (2.3%), loss of appetite (1.2%), nausea (3.5%), muscular spasms (2.3%), feeling of fatigue (2.3%), fever (1.2%), decrease in body weight (1.2%). Any of side effects had no 5 severity.

The profile of side effects at the patients receiving other doses of drug was analogous. At treatment by the drug Zolinza® in the doses exceeding 400 mg of 1 times/days frequency more expressed to thrombocytopenia, anemias and feelings of fatigue increased.

Heavy side effects. In clinical trials at patients with a skin T-cellular lymphoma observed the following connected with treatment, serious side effects (irrespective of a drug dose).

Determination of frequency of side reactions: often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100).

Infectious and parasitic diseases: infrequently - streptococcal bacteremia.

From system of a hemopoiesis: often - thrombocytopenia, anemia.

From a metabolism: often - dehydration.

From cardiovascular system: infrequently - a deep vein thrombosis, arterial hypotension.

From respiratory system: often - an embolism of branches of a pulmonary artery.

From the alimentary system: infrequently - diarrhea, gastrointestinal bleedings, nausea, vomiting, liver ischemia.

From a nervous system: infrequently - an ischemic stroke, a syncope.

General disturbances: infrequently - a stethalgia, death (an unknown etiology), a pyrexia.

Treatment termination. In subgroup of the patients with a skin T-cellular lymphoma receiving the drug Zolinza® in a dose of 400 mg of 1 times/days, 10.5% preekratit treatment in connection with development of the side effects caused by the drug Zolinza®, in particular, with anemia, a Quincke's disease, an adynamy, a stethalgia, a deep vein thrombosis, an ischemic stroke, a lethargy, an embolism of branches of a pulmonary artery, skin manifestations and a lethal outcome.

Change of a dose. In subgroup of the patients with a skin T-cellular lymphoma receiving the drug Zolinza® in a dose of 400 mg of 1 times/days at 10.5% of patients it was required to lower a drug Zolinza® dose in connection with side effects, in particular, increase in plasma concentration of creatinine, a loss of appetite, a hypopotassemia, a leukopenia, a neutropenia, thrombocytopenia and vomiting. Average duration before emergence of the first side effect which caused a drug dose decline made 42 days (from 17 to 263 days).

Laboratory and tool data. Deviations of laboratory parameters observed at 86 patients receiving drug in a daily dose of 400 mg and at 1 patient receiving drug in a daily dose of 350 mg.

Increase in plasma concentration of glucose was observed at 69% of patients with a skin T-cellular lymphoma, at the same time the expressed shifts (3 degrees) were noted only at 5.8% of patients. Connection of a hyperglycemia with the carried-out treatment is established at 4.7% of the patients with a skin T-cellular lymphoma receiving drug in a daily dose of 400 mg.

Tranzitornoye, not expressed increase in plasma concentration of creatinine was observed at 47.1% of patients with a skin T-cellular lymphoma.

The proteinuria was observed at 51.4% of the inspected patients. The clinical importance of a proteinuria is not established.

Dehydration. Proceeding from the cases of dehydration observed in clinical trials considered as the serious, connected with treatment side effect, to patients recommended to observe the drinking mode - not less than 2 l of liquid a day for ensuring adequate hydration. After implementation of this recommendation the frequency of episodes of dehydration decreased.

Side effect at patients with others (not a skin T-cellular lymphoma) diseases. Patients received drug concerning solid tumors or others oncohematological (not a skin T-cellular lymphoma) diseases as monotherapy or in a combination with other antineoplastic drugs. The side effects connected with treatment in this population of patients in general were comparable with a profile of the side effects observed at patients with a skin T-cellular lymphoma. Frequency of separate side effects in this population of patients was higher. The side effects observed only in population of patients with solid tumors and other oncohematological diseases included: single episodes of a vision disorder and hearing, a dysphagy, an adynamy, an abdominal pain, a diverticulitis, a hyponatremia, not small-celled cancer of a lung, bleeding from a tumor, a syndrome to Giyena-Barra, a renal failure, an ischuria, cough, a pneumorrhagia, episodes of arterial hypertension and vasculites.

Interaction with other medicines:

Anticoagulants - coumarin derivatives. At a concomitant use of the drug Zolinza® and coumarinic anticoagulants in rare instances at patients observed lengthening of a prothrombin time and increase in MHO. In need of simultaneous treatment the drug Zolinza® and derivatives of coumarin recommend to carry out careful monitoring of parameters of a blood coagulation.

Other inhibitors histone-deatsetilaz. It is not necessary to appoint the drug Zolinza® along with other inhibitors a histone-diatsetilaz (in particular, with valproic acid) in view of possible summing of drugs of side effects, characteristic of this class. At simultaneous treatment by the drug Zolinza® and valproic acid observed development expressed (4 degrees) thrombocytopenia with gastrointestinal bleeding and anemia.

Interaction with other medicines. Vorinostat suppresses the microsomal isoenzymes of system of CYP cytochrome participating in metabolism of other drugs only in high concentration (PK50> of 75 µmol/l). Studying of an expression of genes in hepatocytes of the person revealed potentiality of suppression of activity of isoenzymes of CYP2C9 and CYP3A4 vorinostaty in concentration of ≥10 µmol/l, i.e. exceeding pharmacological. Therefore, in clinical practice influence of a vorinostat on pharmacokinetics of other medicines is not expected. As isoenzymes of system of CYP cytochrome participate in metabolic transformation of drug, medicinal interaction at co-administration of a vorinostat with the drugs suppressing or inducing isoenzymes of system of CYP cytochrome is not expected. However special researches on studying of medicinal interaction with vorinostaty were not conducted.

Contraindications:

— hypersensitivity to drug components;

— heavy degree of a liver failure;

— children's and teenage age up to 18 years;

— pregnancy;

— period of a lactation (breastfeeding).

With care: moderate degree of a liver failure; thromboembolisms in the anamnesis; initial nausea, vomiting and diarrhea (have to be eliminated prior to treatment); diabetes mellitus and risk of development of a diabetes mellitus.

Overdose:

There is no special information on treatment of overdose of the drug Zolinza®. In the conducted clinical trials the following maximum daily doses of drug were studied: 600 mg (1 times/days), 800 mg (on 400 mg of 2 times/days) and 900 mg (on 300 mg of 3 times/days). At patients who received drug in the dose exceeding recommended in a research (but no more maximum studied dose) did not observe any side effects.

Pharmacological effects of drug can be present after removal of drug from blood (i.e. to be observed at zero values of plasma concentration of an active vorinostat).

Treatment: in case of overdose it is necessary to begin the standard supporting actions: removal of not soaked up drug from a GIT, observation of vital signs and appointment (in need of) a maintenance therapy. There are no data on efficiency of dialysis for removal of a vorinostat.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

120 pieces of capsules - bottles (1) - packs cardboard.