Composition, form of production and packaging
Hard gelatin capsules, size 3, opaque, white, with a black inscription "568" and a white inscription on a black background "100 mg", the contents of capsules - powder from white to light orange.
vorinostat 100 mg
Excipients: microcrystalline cellulose - 44.33 mg, croscarmellose sodium - 4.5 mg, magnesium stearate - 1.17 mg.
The composition of the shell capsules: titanium dioxide (E171) - 2.9079%, gelatin - up to 100%.
Ink composition: Opacode Black S-1-17822 (shellac glaze 45% ethanol 44.5%, ferric oxide black oxide 23.4%, butanol 16.6%, isopropanol 12.5%, propylene glycol 2%, ammonium hydroxide 28% -1%) or Opacode Black S-1-17823 (shellac glaze 45% ethanol 44.5% iron oxide black 23.4% butanol 2.2% isopropanol 26.9% propylene glycol - 2%, ammonium hydroxide 28% - 1%).
120 pcs. - bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
Antitumor drug, histone deacetylase inhibitor. Vorinostat is a potent inhibitor of histone-deacetylase (HDAC) - HDAC1, HDAC2 and HDAC3 (class I), and HDAC6 (class II) (PC50 <86 nmol / L). These enzymes catalyze the cleavage of the acetyl group from the lysine residues of proteins, incl. histones and transcription factor proteins. The antitumor activity of vorinostat is due to suppression of HDAC activity followed by the accumulation of acetylated proteins, including histones.Acetylation of histones is accompanied by transcriptional activation of genes, incl. tumor suppressor genes, and their expression, in turn, induces cell differentiation or apoptosis and suppression of tumor growth. The concentration of vorinostat necessary for the accumulation of acetylated histones also causes cell cycle arrest, differentiation, or apoptosis of mutated cells.
According to studies on cell cultures, vorinostat induces apoptosis in a wide range of mutated (tumor) cells. On cultures of tumor cells, vorinostat demonstrated additional or synergistic activity when used in conjunction with other types of antitumor therapy, including radiation therapy and chemotherapy by kinase inhibitors, cytotoxic drugs and cell differentiation inducers. In vivo, the antitumor activity of vorinostat is demonstrated on a wide range of cancer models in rodents, including xenograft models of prostate, breast and colon malignant tumors.
After a single oral intake of 400 mg of vorinostat concomitantly with fatty foods in patients with refractory or relapsing advanced cancer, the mean В± standard deviation of AUC, C max and the median (range) of T max were 5.5 В± 1.8 Ојmol / l В· h, 1.2 В± 0.62 Ојmol / l and 4 (2-10) h, respectively. After a single dose of 400 mg at the time of fasting, the mean values вЂ‹вЂ‹of AUC, C max and medians T max were 4.2 В± 1.9 Ојmol / lh, 1.2 В± 0.35 Ојmol / l and 1.5 (0.5-10) h, respectively. Thus, simultaneous reception of vorinostat with fatty food is accompanied by an increase (by 33%) of the intake value and a slight decrease in the rate of absorption (an increase in T max by 2.5 h) compared with the administration of the drug on an empty stomach. In general, it is assumed that these minor deviations of the pharmacokinetic parameters are not of clinical significance.
With repeated administration of vorinostat at a dose of 400 mg simultaneously with food, the values вЂ‹вЂ‹of AUC, C max and medians T max in the equilibrium state were 6.0 В± 2.0 Ојmol / lh, 1.2 В± 0.53 Ојmol / l and 4 (0.5-14) h, respectively.
In the plasma concentration range from 0.5 to 50 Ојg / ml, the binding of vorinostat to plasma proteins is approximately 71%. Vorinostat rapidly penetrates the placental barrier in rats and rabbits when administered at daily doses of 15 mg / kg and 150 mg / kg, respectively (which corresponds to a lower exposure value than in humans according to AUC 0-24 ), with achievement of transplacental equilibrium after about 30 min after administration.
The main ways of metabolism of vorinostat are the reactions of glucuronization and hydrolysis followed by? -oxidation. The plasma concentrations of two metabolites, O-glucuronide vorinostate and 4-anilino-4-oxobutanoic acid, were measured. Both metabolites are pharmacologically inactive. Compared to the vorinostat, in an equilibrium state, the exposure of the v-spinotin O-glucuronide and 4-anilino-4-oxobutanoic acid exceeds the vorinostat exposure by approximately 4 and 13 times, respectively.
The conducted in vitro studies on human liver microsomes indicate a slight biotransformation of the preparation with enzymes of the cytochrome P450 system.
Vorinostat is predominantly metabolized in the liver, in unchanged form, less than 1% of the administered dose is excreted by the kidneys, therefore, renal excretion plays little role in removing the drug from the body. Upon reaching the equilibrium state, two pharmacologically inactive metabolites of vorinostat-O-glucuronide vorinostat in the amount of 16 В± 5.8% of the administered dose of vorinostat and 4-anilino-4-oxobutanoic acid in the amount of 36 В± 8.6% of the administered dose of vorinostate were detected in urine. Thus, the amount of unchanged vorinostat detected in the urine and the two specified metabolites averaged 52 В± 13.3% of the injected dose of vorinostat. T 1/2 vorinostat and its O-glucuronide metabolite was about 2 hours, and T 1/2 of 4-anilino-4-oxobutanoic acid was approximately 11 hours.
Pharmacokinetics in specific patient groups
According to the analysis of a limited amount of data, the sex, race and age of the patients did not have a clinically significant effect on the pharmacokinetic parameters of the vorinostat.
The pharmacokinetic parameters of vorinostat in children and adolescents under the age of 18 have not been studied.
Vorinostat is contraindicated for use in patients with severe hepatic insufficiency and is not recommended for use in patients with moderate liver failure. These recommendations are based on the primary results of ongoing pharmacokinetic studies in patients with mild, moderate (total bilirubin 1.5-3 higher than UGN) and severe (total bilirubin more than 3 times higher than UGN) degree of hepatic insufficiency. These studies suggest that in patients with severe hepatic failure after taking vorinostat, the risk of dose-related toxicity is higher than in patients without hepatic impairment.
In general, the study of vorinostat excludes patients with severe hepatic impairment. However, there are a limited number of patients with moderate degree of hepatic impairment who have been included in clinical studies. There was no clinically significant difference in the development of side effects associated with liver function in patients with a history of hepatic impairment compared to patients without it.
The pharmacokinetic parameters of the drug in patients with renal insufficiency have not been studied. It should be noted that renal excretion is not involved in the excretion of vorinostat from the body.
- Treatment of cutaneous T-cell lymphoma, which progresses, persists or recurs, despite systemic therapy.
The drug is taken orally during a meal. Capsules should be swallowed whole, not opening.
The recommended dose is 400 mg 1 time / day.
In case of intolerance, the dose can be reduced to 300 mg 1 time / day - for 5 consecutive days a week, if necessary.
Treatment is performed until complete control (no signs of further progression) or until signs of unacceptable toxicity appear.
Older patients do not need a dose adjustment.
When taking the drug at a dose of 400 mg 1 time / day the following 4 groups of side effects are most typical: on the part of the digestive system (diarrhea, nausea, anorexia, weight loss, vomiting, constipation, decreased appetite, dry mouth), general reactions (feeling fatigue, chills), from the hematopoiesis system (thrombocytopenia, anemia) and the violation of taste sensations (dysgeusia).
Side effects that occur very often (? 1/10) in patients with cutaneous T-cell lymphoma who received the Zolinza В® preparation at a dose of 400 mg 1 time / day are described below.
On the part of the hematopoiesis system: very often thrombocytopenia, anemia.
From the metabolism: very often - anorexia, a decrease in appetite.
From the digestive system: very often - diarrhea, nausea, dry mouth, vomiting, constipation.
From the skin and subcutaneous tissues: very often - alopecia.
From the musculoskeletal system: very often - muscle spasms.
From the nervous system: very often - dysgeusia.
General reactions: very often - a feeling of fatigue, chills.
Laboratory and instrumental data: very often - weight loss, increased plasma concentration of creatinine.
Of the aforementioned very common side effects of 3-5, the severity was as follows: thrombocytopenia (5.8%), anemia (2.3%), anorexia (2.3%), decreased appetite (1.2%), nausea (3.5%), muscle spasms 2.3%), a feeling of fatigue (2.3%), chills (1.2%), weight loss (1.2%). None of the side effects had 5 degrees of severity.
The profile of adverse events in patients receiving other doses of the drug was similar. When treated with Zolinz В® at doses exceeding 400 mg 1 time / day, the frequency of more pronounced thrombocytopenia, anemia and fatigue increased.
Severe side effects
In clinical studies in patients with cutaneous T-cell lymphoma, the following treatment-related serious side effects (regardless of the dose of the drug) were observed.
Determination of the frequency of adverse reactions: often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100).
Infectious and parasitic diseases: infrequently - streptococcal bacteremia.
From the hemopoietic system: often - thrombocytopenia, anemia.
From the side of metabolism: often - dehydration.
From the cardiovascular system: infrequently - deep vein thrombosis, arterial hypotension.
From the respiratory system: often - embolism of the branches of the pulmonary artery.
From the digestive system: infrequently - diarrhea, gastrointestinal bleeding, nausea, vomiting, ischemia of the liver.
From the nervous system: infrequently - ischemic stroke, syncope.
Common violations: infrequently - pain in the chest, death (unknown etiology), pyrexia.
Discontinuation of treatment
In a subgroup of patients with cutaneous T-cell lymphoma who received ZolinzВ® at a dose of 400 mg 1 time / day, 10.5% prelarized treatment due to the development of side effects caused by the preparation Zolinza В® , in particular, with anemia, angioedema, asthenia, chest pain, deep vein thrombosis, ischemic stroke, lethargy, embolism of the pulmonary arteries, skin manifestations and death.
In a subgroup of patients with cutaneous T-cell lymphoma who received the Zolinza В® preparation at a dose of 400 mg once a day, 10.5% of patients had to lower the dose of Zolinza В® due to side effects, in particular, an increase in plasma creatinine concentration, a decrease in appetite, hypokalemia, leukopenia, neutropenia, thrombocytopenia and vomiting. The average duration before the appearance of the first side effect, which caused a decrease in the dose of the drug, was 42 days (from 17 to 263 days).
Laboratory and instrumental data
Deviations of laboratory parameters were observed in 86 patients who received the drug at a daily dose of 400 mg, and in 1 patient who received the drug at a daily dose of 350 mg.
An increase in plasma glucose concentration was observed in 69% of patients with cutaneous T-cell lymphoma, with pronounced shifts (3 degrees) observed in only 5.8% of patients. The association of hyperglycemia with the treatment is established in 4.7% of patients with cutaneous T-cell lymphoma who received the drug at a daily dose of 400 mg.
Transient, non-expressed increase in plasma creatinine concentration was observed in 47.1% of patients with cutaneous T-cell lymphoma.
Proteinuria was observed in 51.4% of the patients examined. Clinical significance of proteinuria is not established.
Based on the observed cases of dehydration in clinical trials, considered as a serious, treatment-related side effect, patients were recommended to comply with the drinking regime - at least 2 liters of fluid per day to ensure adequate hydration. After the implementation of this recommendation, the frequency of episodes of dehydration decreased.
Side-effects in patients with other (non-cutaneous T-cell lymphoma) diseases
Patients received the drug for solid tumors or other oncohematological (non-cutaneous T-cell lymphoma) diseases as monotherapy or in combination with other antitumor drugs. The treatment-related side effects in this patient population were generally comparable to the side effects profile observed in patients with cutaneous T-cell lymphoma. The incidence of individual side effects in this patient population was higher. Side effects observed only in the population of patients with solid tumors and other oncohematological diseases included: single episodes of visual and hearing impairment, dysphagia, asthenia, abdominal pain, diverticulitis, hyponatremia, non-small cell lung cancer, tumor bleeding, Guillain-Barre syndrome, kidney failure , urinary retention, cough, hemoptysis, episodes of hypertension and vasculitis.
- hypersensitivity to the components of the drug;
- severe degree of hepatic insufficiency;
- children and adolescence under 18;
lactation period (breastfeeding).
With caution: moderate degree of hepatic insufficiency; a thromboembolism in the anamnesis; initial nausea, vomiting and diarrhea (should be eliminated before treatment begins); diabetes mellitus and the risk of developing diabetes.
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical studies of the use of Zolinza В® during pregnancy have not been conducted.
Women of childbearing age should avoid pregnancy during treatment with Zolinz В® . If the need for ZolinzВ® treatment occurs during pregnancy or if pregnancy occurs during treatment, the patient should be aware of the potential harm to the fetus.
There are no data on the isolation of the drug with breast milk. Given that most medicinal products are secreted into breast milk, and that Zolinza В® can cause side effects in an infant, breastfeeding during treatment with the drug is not recommended.
Avoid contact of the contents of the capsule with the skin and mucous membranes. On contact, rinse thoroughly with water.
With the development during the treatment of disorders of the digestive system, including nausea, vomiting and diarrhea, it may be necessary to prescribe antiemetic and anti-diarrheal agents. To prevent dehydration and maintain electrolyte balance, it is recommended to rehydrate and replenish electrolytes. If the patient has nausea, vomiting and diarrhea before starting treatment, they must be eliminated before using ZolinzВ®.
Therapy with Zolinz В® can be accompanied by the development of dose-dependent thrombocytopenia and anemia. If during the treatment with the Zolinz В®preparation there is a significant decrease in the number of platelets and / or hemoglobin levels, the dose of the drug should be reduced or the treatment temporarily discontinued.
According to available data during the treatment, it is possible to develop complications such as pulmonary embolism and deep vein thrombosis. Careful observation of patients, especially with a history of heaviness, is necessary to timely detect symptoms of pulmonary embolism and deep vein thrombosis.
Studies of the use of Zolinza В® in patients with hepatic impairment are limited. Based on these studies, it is not recommended to take the drug in patients with moderate hepatic impairment.
Blood glucose concentrations should be monitored, especially in patients with existing diabetes mellitus or the risk of developing diabetes mellitus. It may be necessary to prescribe a diet and / or hypoglycemic therapy.
Careful monitoring of the parameters of the clinical and biochemical blood test should be carried out, including plasma, glucose and creatinine electrolyte concentrations at least every 2 weeks in the first 2 months of treatment, then monthly.
According to clinical studies, the effectiveness and safety of Zolinza В® in elderly patients (over 65 years old) was comparable to those of younger patients (up to 65 years of age). Correction of dose depending on age is not required.
Use in Pediatrics
Safety and effectiveness of the drug in children have not been studied.
Impact on the ability to drive vehicles and manage mechanisms
There is no evidence to suggest a possible negative impact of Zolinz В® on the ability to drive vehicles or complex mechanisms.
Special information on the treatment of an overdose of Zolinza В® is not available. The following maximum daily doses of the drug were studied in the clinical studies: 600 mg (once a day), 800 mg (400 mg 2 times / day) and 900 mg (300 mg 3 times / day). Patients who received the drug at a dose exceeding the recommended dose in the study (but no more than the maximum dose studied) did not observe any side effects.
The pharmacological effects of the drug may be present after the removal of the blood product (i.e., zero values occur at plasma concentrations of the active vorinostat).
Treatment: In case of overdose should start the standard supportive measures: removing the drug from the gastrointestinal tract nevsosavsheysya, monitoring vital signs and the appointment (if necessary) maintenance therapy. Of dialysis effectiveness data to derive no vorinostat.
Anticoagulants - coumarin derivatives
In simultaneous reception preparation Zolinza В® and coumarin anticoagulants rarely observed in patients elongation of prothrombin time and increase MHO. If necessary, simultaneous drug treatment Zolinza В® and coumarin derivatives recommended careful monitoring of blood coagulation parameters.
Other histone deacetylase inhibitors
should not be prescribed the drug Zolinza В® concurrently with other histone deacetylase inhibitors (particularly with valproic acid) because of the possible summing the characteristic side effects of this class of drugs. With simultaneous drug treatment Zolinza В®valproic acid and observed the development of severe (grade 4) with thrombocytopenia gastrointestinal bleeding and anemia.
Interaction with other drugs
vorinostat suppresses involved in the metabolism of other drugs microsomal CYP isoenzymes of cytochrome only at high concentrations (PC 50> 75 micromol / L).The study of gene expression in human hepatocytes revealed a potential ability to suppress the activity of CYP2C9 and CYP3A4 isozymes vorinostat at concentrations? 10 mol / L, i.e., exceeding pharmacological. Hence, in clinical practice vorinostat effect on the pharmacokinetics of other drugs is expected. Since cytochrome CYP isoenzymes are involved in the metabolic conversion of the drug, the drug is not expected to interact with concomitant administration of vorinostat with drugs that suppress or induce cytochrome isozymes CYP. However, special studies of drug interactions with vorinostat not performed.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 3 years.