Zolinza - instructions for use, dose, side effects, contraindications

Active substanceVorinostatVorinostat

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Zolinza®

capsules inwards

Merck Sharp and Doum B.V. Netherlands

Dosage form: & nbsp capsules

Composition:

For 1 capsule:

Contents of the capsule

Active substance: vorinostat 100.0 mg

Excipients:cellulose microcrystalline 44.33 mg, croscarmellose sodium 4,500 mg, magnesium stearate 1,170 mg.

Capsule shell:

titanium dioxide (E171) 2.9079%, gelatin to 100%.

Ink:

Opacode Black Sl-17822: shellac glaze 45% solution in ethanol 44.5%, iron dye oxide black 23.4%, butanol 16.6%, isopropanol 12.5%, propylene glycol 2.0%, ammonium hydroxide 28% 1.0%. or

Opacode Black S-1-17823: shellac glaze 45% solution in ethanol 44.5%, iron dye oxide black 23.4%, butanol 2.2%, isopropanol 26.9%, propylene glycol 2.0% , ammonium hydroxide 28% 1.0%.

Description:

Hard gelatinous opaque capsules of white color (size 3) with a black inscription "568" and a white inscription on a black background "100 mg". Contents of capsules: powder from white to light orange color.

Pharmacotherapeutic group:Antitumor agent - histone deacetylase inhibitor

ATX: & nbsp

L.01.X.X.38 Vorinostat

Pharmacodynamics:Vorinostat is a potent inhibitor of histone deacetylase (HDAC) - HDAC1, HDAC2 and HDAC3 (Class I), as well as HDAC6 (grade II) (PC₅₀ <86 nmol / l). These enzymes catalyze the cleavage acetyl groups from lysine residues of proteins, including histones and transcription factor proteins.The antitumor activity of vorinostat is due to inhibition of activity HDAC with the subsequent accumulation of acetylated proteins, including histones. Acetylation of histones causes transcriptional activation of genes, including tumor suppressor genes. Their expression, in turn, induces cell differentiation or apoptosis and suppression of tumor growth.The concentration of vorinostat, which causes accumulation of acetylated histones, also causes the arrest of the cell cycle, differentiation or apoptosis of the altered cells.

According to studies on cell cultures vorinostat induces apoptosis in a large number of mutated (tumor) cells. On cultures tumor cells vorinostat demonstrated additional or synergistic activity when used in conjunction with other species antitumor therapy, including radiotherapy and chemotherapy with kinase inhibitors, cytotoxic drugs and inducers differentiation of cells. In vivo vorinostat demonstrated antitumor activity on a wide range of cancer models in rodents,including models of xenografts of malignant tumors of the prostate, breast and large intestine.

Pharmacokinetics:

Suction

After a single oral intake of 400 mg of vorinostat concomitantly with fatty foods in patients with refractory or relapsing advanced tumors, the mean ± standard deviation of the area under the concentration-time curve (AUC), the maximum plasma concentration of the drug (C_max and the median (range) of time to reach the maximum concentration (C_max) were 5.5 ± 1.8 μmol / lhh, 1.2 ± 0.6 μmol / l and 4 (2-10) h, respectively.

After a single oral intake of the drug at a dose of 400 mg on an empty stomach, the average values of AUC, C_max and medians T_max were 4.2 ± 1.9 μmol / l * h, 1.2 ± 0.3 μmol / 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 suction and a slight decrease in the rate of absorption (delay in onset of T_max for 2.5 hours) 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 oral multiple admission of vorinostat at a dose of 400 mg concurrently with food, the values of AUC, C_max and medians T_max in the equilibrium state were 6.0 ± 2.0 μmol / l h, 1.2 ± 0.53 μmol / L and 4 (0.5-14) h, respectively.

Distribution

In the plasma concentration range from 0.5 to 50 μg / ml, about 71% of the vorinostate binds to plasma proteins. Vorinostat quickly passes through 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 AUC₀_-₂₄) with the achievement of transplacental equilibrium approximately 30 minutes after administration.

Metabolism

The main ways of metabolism of vorinostat are the reactions of glucuronization and hydrolysis followed by β-oxidation.

Plasma concentrations of two metabolites were measured - ABOUT-glucuronide vorinostat and 4-anilino-4-oxobutanoic acid. Both metabolites are pharmacologically inactive. In comparison with the vorinostat, in the equilibrium state the exposure ABOUT-glucuronide vorinostat and 4-anilino-4-oxobutanoic acid in the serum exceeds the vorinostat exposure by approximately 4 and 13 times, respectively.In vitro studies on human liver microsomes indicate a slight biotransformation of the preparation with enzymes of the cytochrome P450 system (CYP).

Excretion

Vorinostat mainly metabolized in the liver. Kidneys are excreted unchanged in less than 1% of the administered dose. Consequently, renal excretion has virtually no effect on removing the drug from the body. Upon reaching the equilibrium state in the urine, two pharmacologically inactive metabolites of vorinostat were detected - ABOUT- vorinostat glucuronide in an amount of 16 ± 5.8% of the injected dose of vorinostat and 4-anilino-4-oxobutanoic acid in an amount of 36 ± 8.6% of the administered dose of vorinostat. Thus, the amount of unchanged vorinostat detected in the urine and the two specified metabolites averaged 52 ± 13.3% of the accepted dose of vorinostat. The half-life of vorinostat and ABOUT-glucuronide was about 2.0 hours, and the half-life of 4-anilino-4-oxobutanoic acid was approximately 11 hours.

Pharmacokinetics in specific patient groups

According to a limited data analysis, the sex, race and age of the patients did not have a clinically significant effect on the pharmacokinetic parameters of the vorinostat.

Children

The pharmacokinetic parameters of vorinostat in children and adolescents under the age of 18 have not been studied.

Patients with hepatic insufficiency

Vorinostat is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic insufficiency, the drug should be used with caution. These recommendations are based on pharmacokinetic data in patients with mild (total bilirubin above the upper limit of the norm (> 1.0 = 1.5) or total bilirubin below or equal to the upper limit of the norm and aspartate aminotransferase activity above the upper limit of the norm), mean (total bilirubin in 1,5-3 times above the upper limit of the norm) and severe (total bilirubin more than 3 times the upper limit of the norm) degrees of hepatic insufficiency. These studies suggest that in patients with severe hepatic impairment after taking vorinostat, the risk of dose-related toxicity is higher than in patients without impaired liver function (even with a reduced dose of the drug).

A portable daily dose of vorinostat for patients with mild and moderate hepatic insufficiency is 300 mg and 200 mg, respectively.

In general, patients with severe hepatic impairment were excluded from the study. However, there are a limited number of patients with moderate hepatic impairment who have been included in the 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.

Patients with renal insufficiency

The pharmacokinetic parameters of vorinostat in patients with renal insufficiency have not been studied. It should be noted that renal excretion does not affect the excretion of vorinostat from the body.

Indications:The preparation Zolinza® is indicated for the treatment of cutaneous T-cell lymphoma, which progresses, persists or recurs, despite systemic therapy.

Contraindications:

- Hypersensitivity to any of the components of the drug;

- Severe hepatic insufficiency;

- Children under 18 years;

- Pregnancy and lactation.

Carefully:

- Moderate hepatic impairment;

- Thromboembolism in history;

- Initial nausea, vomiting and diarrhea (should be eliminated before treatment begins);

- Diabetes and the risk of developing diabetes.

Pregnancy and lactation:

Adequately-controlled studies of ZOLINZA® in pregnant women have not been conducted. Women of childbearing age should avoid pregnancy during treatment with ZOLINZA®. If the need for a treatment drug ZOLINZA® occurs during pregnancy or if pregnancy occurs during treatment, the patient should be aware of the potential harm to the fetus of treatment. There are no data on the secretion of the drug in breast milk. Given that the majority of breast milk secreted drugs, and that ZOLINZA® can cause side effects in the infant, breast-feeding during treatment with ZOLINZA® not recommended.

Dosing and Administration:

The drug should be taken orally during meals. Capsules should not be opened, swallowed whole.

The recommended dose of Zolinza® is 400 mg once a day.

In case of intolerance, the dose can be reduced to 300 mg once a day for 5 consecutive days a week.

Treatment is performed until complete control of the disease (no signs of further progression) or until signs of unacceptable toxicity appear.

Age-related dose adjustment in the elderly is not required.

A portable daily dose of vorinostat for patients with mild to moderate hepatic impairment is 300 mg and 200 mg, respectively.

Pediatric Use

The safety and efficacy of ZOLINZA® in children have not been studied.

Application in elderly patients

According to clinical studies, the efficacy and safety of ZOLINZA® in elderly patients (≥65 years) was comparable to those in young (<65 years). No age correction is required.

Side effects:

The safety of Zolinza ® was evaluated in 111 patients with cutaneous T-cell lymphoma in two clinical trials. 86 patients received the drug at a dose of 400 mg once a day. The typical undesirable reactions associated with taking Zolinza® 400 mg once a day can be combined into 4 groups of symptom-complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia,weight loss, vomiting, constipation, decreased appetite), general symptoms (increased fatigue, chills), hematologic disorders (thrombocytopenia, anemia) and a taste disorder (dysgeusia, dry mouth).

Very often (≥1 / 10) adverse reactions (clinical and laboratory) associated with Zolinza® treatment in patients with cutaneous T-cell lymphoma who took the drug at a dose of 400 mg once a day are indicated below.

Violations of the blood and lymphatic system

Very often: thrombocytopenia, anemia.

Disorders from the metabolism and nutrition

Very often: anorexia, decreased appetite.

Disorders from the gastrointestinal tract

Very often: diarrhea, nausea, dry mouth, vomiting, constipation.

Disturbances from the skin and subcutaneous tissues

Very often: alopecia, itchy skin.

Disturbances from musculoskeletal and connective tissue

Very often: muscle spasms.

Disturbances from the nervous system

Very often: dysgeusia, dizziness, headache.

General disorders and disorders at the site of administration

Very often: increased fatigue, chills.

Often: fever

Vascular disorders

Very often: peripheral edema.

Disturbances from the respiratory system, organs thoracic cells andthe mediastinum.

Frequent: cough, upper respiratory tract infections.

Laboratory and instrumental data

Very often: weight loss, increased plasma concentration of creatinine.

Undesirable reactions of 3-5 degrees of severity were observed for the following reactions: thrombocytopenia (5.8%), anemia (2.3%), anorexia (2.3%), decreased appetite (1.2%), nausea 3.5%), muscle spasms (2.3%), fatigue (2.3%), chills (1.2%) and weight loss (1.2%). None of the unwanted reactions had a 5-degree severity.

The profile of adverse reactions in patients receiving other doses of the drug was similar. The frequency of expressed thrombocytopenia, anemia and fatigue was elevated when treated with doses of Zolinzas over 400 mg once a day.

Serious adverse reactions

In clinical studies in patients with cutaneous T-cell lymphoma, the following treatment-related serious adverse reactions (regardless of the dose taken) were observed.

Frequent (≥1 / 100 and <1/10), infrequent (≥ 1/1000 and <1/100).

Infectious and parasitic diseases

Infrequently: streptococcal bacteremia.

Violations of the blood and lymphatic system

Often: thrombocytopenia, anemia.

Disorders from the metabolism and nutrition

Often: dehydration.

Vascular disorders

Infrequent: deep vein thrombosis, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs

Often: embolism of the branches of the pulmonary artery.

Disorders from the gastrointestinal tract

Infrequently: diarrhea, gastrointestinal bleeding, nausea, vomiting.

Disturbances from the liver and bile ducts

Infrequently: liver ischemia.

Disturbances from the nervous system

Infrequent: ischemic stroke, fainting.

General disorders and disorders at the site of administration

Infrequent: chest pain, death (unknown etiology), pyrexia.

Discontinuation of treatment

Of the subgroup of patients with cutaneous T-cell lymphoma who received Zolinza® 400 mg once daily, 10.5% of patients discontinued treatment due to treatment-related adverse reactions, in particular anemia,angioneurotic edema, asthenia, chest pain, deep vein thrombosis, ischemic stroke, lethargy, embolism of the pulmonary artery branches, skin lesion and death.

Dose change

In a subgroup of patients with cutaneous T-cell lymphoma who took Zolinz in the 400 mg regimen once a day, 10.5% of patients required a decrease in the dose of Zolinz® in connection with unwanted reactions, in particular, an increase in plasma creatinine concentration, a decrease in appetite, hypokalemia, leukopenia, neutropenia, thrombocytopenia and vomiting. The average length of time 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 taking the drug at a daily dose of 400 mg, and in one 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 changes (3 degrees) observed in only 5 patients. The association of hyperglycemia with the treatment is established in 4.7% of patients with cutaneous T-cell lymphoma who took 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% (in 38 patients out of 74 patients) of the examined patients. Clinical significance of proteinuria is not established.

Dehydration

Based on the cases of dehydration in clinical trials, considered as a serious, treatment-related adverse reaction, patients were recommended to comply with the drinking regime - at least 2 liters of fluid per day to ensure adequate hydration. After the introduction of the recommendation, the frequency of episodes of dehydration decreased.

Side effect in patients with other oncological (non-cutaneous T-cell lymphoma) diseases

Clinical trials involved patients with solid tumors or other oncohematological diseases (non-cutaneous T-cell lymphoma) who took Zolinza® as a monotherapy or in combination with other antitumor drugs. Treatment-related adverse reactions in this group of patients were generally comparable to the profile of adverse reactions observed in patients with cutaneous T-cell lymphoma.The frequency of individual adverse reactions in the group of patients with non-cutaneous T-cell lymphoma was higher. Unwanted reactions observed only in the group of patients with solid tumors and other oncohematological diseases included single episodes: blurred vision and hearing, dysphagia, asthenia, abdominal pain, diverticulitis, hyponatremia, non-small cell lung cancer, tumor bleeding, Guillain-Barre syndrome, kidney failure , urinary retention, cough, hemoptysis, episodes of high blood pressure and vasculitis.

In some patients during the recovery period after operations on the intestine, there was a violation of the healing process of the anastomosis. In connection with this, care should be taken when using Zolinza ® during the perioperative period if the patient needs an operation on the intestine.

Overdose:

Special information on the treatment of an overdose of ZOLINZA® is not available.

The following maximum daily doses of the drug were tested in clinical trials: 600 mg (once a day), 800 mg (400 mg twice daily) and 900 mg (300 mg three times daily).In patients who exceeded the recommended dose in the study (but did not exceed the maximum tested dose), no side effects were observed.

Pharmacological effects of the drug may be present after removing the drug from the blood (i.e., observed at zero values of the plasma concentration of the active vorinostat). Data on the effectiveness of dialysis vorinostat no.

In case of an overdose, it is necessary to start the standard supporting measures: removal of the non-sucking drug from the gastrointestinal tract, monitoring of vital signs and the appointment (if necessary) of maintenance therapy.

Interaction:

Anticoagulants - coumarin derivatives

With the simultaneous administration of Zolinz® and coumarin anticoagulants, in rare cases, patients experienced prolonged prothrombin time and an increase in INR (the international normalized ratio). If it is necessary to simultaneously treat Zolinz® and coumarin derivatives, careful monitoring of blood clotting parameters is recommended.

Other inhibitors of histone deacetylase

Do not prescribe Zolinz® along with other histone deacetylase inhibitors (in particular, with valproic acid) because of the possible summation of the side effects characteristic of this class of drugs. With simultaneous treatment with Zolinz® and valproic acid, development of severe (4th degree) thrombocytopenia with gastrointestinal bleeding and anemia was observed.

Interaction with other drugs and additional pharmacokinetic data

Vorinostat inhibits microsomal isozymes of the cytochrome CYP system participating in the metabolism of other drugs only in high concentrations (PK50> 75 μmol / L). The study of gene expression in human hepatocytes revealed a potential possibility of inhibiting the activity of CYP2C9 and CYP3A4 isoenzymes by vorinostat at concentrations ≥ 10 μmol / l, i.е. concentrations exceeding pharmacological. Consequently, in clinical practice, the influence of vorinostat on the pharmacokinetics of other drugs is not expected. Since the isoenzymes of the cytochrome CYP system are not involved in the metabolic transformations of the drug,no inter-drug interactions are contemplated with concomitant administration of vorinostat with drugs suppressing or inducing isoenzymes of the CYP cytochrome system. However, formal studies on the study of inter-drug interactions with vorinostat were not conducted.

Research in vitro showed that vorinostat is not a substrate of human P-glycoprotein (P-rn). Besides vorinostat does not have an inhibitory effect on vinblastine transport mediated R-gp (P-gp substrate marker) at concentrations up to 100 μM. In this way, vorinostat it is unlikely to inhibit P-gp in a pharmacologically active concentration of 2 μM (Cmax) in humans.

Special instructions:

Avoid contact of the contents of the capsule with the skin and mucous membranes. On contact, rinse thoroughly with water.

Disturbances from the organs of the gastrointestinal tract

With the development during the treatment of violations of the gastrointestinal tract (GIT), including nausea, vomiting and diarrhea (see section "Side effect"), 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 initial nausea, vomiting and diarrhea, they must be eliminated before starting treatment with Zolinz®.

Changes in hematological parameters

Therapy with Zolinz® can be accompanied by the development of dose-dependent thrombocytopenia and anemia. If a significant reduction in the number of platelets and / or hemoglobin levels occurs during treatment with Zolinz (see "Changes in laboratory parameters"), the dose of the drug should be reduced or the treatment temporarily discontinued.

Vascular disorders

During treatment, it is possible to develop complications such as pulmonary embolism and deep vein thrombosis (see section "Side effect"). Careful observation of patients, especially with a history of heaviness, is necessary to timely detect symptoms of pulmonary embolism and deep vein thrombosis.

Dysfunction of the liver

The study of Zolinz's preparation in 42 patients with other oncological diseases (not cutaneous T-cell lymphoma) and liver failure,it is necessary to take the drug with caution in patients with mild and moderate hepatic impairment (see the section "Pharmacokinetics" and "Contraindications").

Hyperglycaemia

Monitor plasma glucose concentrations, especially in patients with existing diabetes mellitus or the risk of developing diabetes mellitus (see section "Changes in laboratory parameters" and "Pharmacokinetics"). It may be necessary to prescribe a diet and / or hypoglycemic therapy.

Changes in laboratory parameters

Careful monitoring of the parameters of the clinical and biochemical blood test, including plasma electrolyte concentrations (potassium, magnesium, calcium), glucose and creatinine, at least every 2 weeks in the first 2 months of treatment, and subsequently monthly. Hypokalemia and hypomagnesemia should be corrected before starting the Zolinz® drug. It is also necessary to control the potassium and magnesium content of patients with nausea, vomiting, diarrhea, dehydration and cardiovascular disorders.

Effect on the ability to drive transp. cf. and fur:There is no information to suggest a possible negative effect of ZOLINZA® on the ability to drive or complex machinery.

Form release / dosage:

Capsules 100 mg.

Packaging:

For 120 capsules in a bottle of high-density polyethylene, sealed with a protective membrane and closed with a plastic lid with a device against opening the bottle by children.

1 bottle with instructions for use in a cardboard box.

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

Shelf life:

3 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001458

Date of registration:25.01.2012 / 06.02.2017

Expiration Date:Unlimited

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

MERCK SHARP & DOHME, B.V. Netherlands

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp15.10.2017

Illustrated instructions

Instructions

Zolinza® (Zolinza®)