Zolinza^® (Capsules) Instructions for Use

Marketing Authorization Holder

Merck Sharp & Dohme, B.V. (Netherlands)

Manufactured By

Patheon Inc. (Canada)

Primary Packaging

MERCK SHARP & DOHME, LLC (USA)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

Contact Information

MSD Pharmaceuticals LLC (Russia)

ATC Code

L01XH01 (Vorinostat)

Active Substance

Vorinostat (Rec.INN registered by WHO)

Dosage Form

Zolinza®

Capsules 100 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 3, opaque, white, with a black inscription “568” and a white inscription on a black background “100 mg”, capsule contents – powder from white to light orange.

Excipients: microcrystalline cellulose – 44.33 mg, croscarmellose sodium – 4.5 mg, magnesium stearate – 1.17 mg.

Capsule shell composition titanium dioxide (E171) – 2.9079%, gelatin – up to 100%.
Ink composition opacode black (Opacode Black) S-1-17822 (shellac glaze solution 45% in ethanol – 44.5%, black iron oxide dye – 23.4%, butanol – 16.6%, isopropanol – 12.5%, propylene glycol – 2%, ammonium hydroxide 28% – 1%) or opacode black (Opacode Black) S-1-17823 (shellac glaze solution 45% in ethanol – 44.5%, black iron oxide dye – 23.4%, butanol – 2.2%, isopropanol – 26.9%, propylene glycol – 2%, ammonium hydroxide 28% – 1%).

120 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents; histone deacetylase (HDAC) inhibitors

Pharmacological Action

Vorinostat is a potent inhibitor of histone deacetylases (HDAC) – HDAC1, HDAC2 and HDAC3 (class I), as well as HDAC6 (class II) (IC₅₀<86 nmol/L). These enzymes catalyze the removal of acetyl groups from lysine residues of proteins, including histones and transcription factor proteins. The antineoplastic activity of vorinostat is due to the inhibition of HDAC activity with subsequent accumulation of acetylated proteins, including histones. Acetylation of histones is accompanied by transcriptional activation of genes, including tumor suppressor genes, and their expression, in turn, induces cell differentiation or apoptosis and suppression of tumor growth. The concentration of vorinostat that causes the accumulation of acetylated histones also causes cell cycle arrest, differentiation, or apoptosis of altered cells.

According to studies on cell cultures, Vorinostat induces apoptosis in a large number of altered (tumor) cells. On tumor cell cultures, Vorinostat demonstrated additional or synergistic activity when used in combination with other types of antineoplastic therapy, including radiation therapy and chemotherapy with kinase inhibitors, cytotoxic drugs, and cell differentiation inducers. In vivo, Vorinostat demonstrated antineoplastic activity in a wide range of rodent cancer models, including models of xenografts of human malignant tumors of the prostate, breast, and colon.

Pharmacokinetics

Absorption

After a single oral dose of 400 mg vorinostat with a high-fat meal in patients with refractory or recurrent advanced tumors, the mean values ± standard deviation of AUC, C_max, and median (range) T_max were 5.5±1.8 µmol/L×h, 1.2±0.62 µmol/L, and 4 (2-10) h, respectively. After a single oral dose of 400 mg on an empty stomach, the mean values of AUC, C_max, and median T_max were 4.2±1.9 µmol/L×h, 1.2±0.35 µmol/L, and 1.5 (0.5-10) h, respectively. Thus, simultaneous administration of vorinostat with a high-fat meal is accompanied by an increase (by 33%) in absorption and a slight decrease in the absorption rate (a delay in T_max by 2.5 h) compared with taking the drug on an empty stomach. In general, it is assumed that these minor deviations in pharmacokinetic parameters are not clinically significant.

With repeated oral administration of vorinostat at a dose of 400 mg with food, the AUC, C_max, and median T_max values at steady 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, the binding of vorinostat to plasma proteins is approximately 71%. Vorinostat rapidly crosses 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 based on AUC_0-24), with transplacental equilibrium reached approximately 30 minutes after administration.

Metabolism

The main pathways of vorinostat metabolism are glucuronidation and hydrolysis reactions followed by β-oxidation. Plasma concentrations of two metabolites were measured – O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid. Both metabolites are pharmacologically inactive. Compared to vorinostat, at steady state, the exposure of O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid in serum exceeds the exposure of vorinostat by approximately 4 and 13 times, respectively.

In vitro studies on human liver microsomes indicate minor biotransformation of the drug by cytochrome P450 system enzymes.

Excretion

Vorinostat is predominantly metabolized in the liver. Less than 1% of the administered dose is excreted unchanged by the kidneys. Therefore, renal excretion has practically no effect on the elimination of the drug from the body. At steady state, two pharmacologically inactive metabolites of vorinostat were detected in the urine – O-glucuronide of vorinostat in the amount of 16±5.8% of the administered vorinostat dose and 4-anilino-4-oxobutanoic acid in the amount of 36±8.6% of the administered vorinostat dose. Thus, the amount of unchanged vorinostat and the two specified metabolites detected in the urine averaged 52±13.3% of the taken vorinostat dose. The T_1/2 of vorinostat and O-glucuronide was about 2 h, and the T_1/2 of 4-anilino-4-oxobutanoic acid was approximately 11 h.

Pharmacokinetics in special patient groups

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

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

Patients with hepatic impairment. Vorinostat is contraindicated in patients with severe hepatic impairment. In patients with mild and moderate hepatic impairment, the drug should be used with caution. These recommendations are based on pharmacokinetic studies in patients with mild (total bilirubin above ULN (>1-1.5) or total bilirubin below or equal to ULN and AST activity above ULN), moderate (total bilirubin 1.5-3 times above ULN) and severe (total bilirubin more than 3 times above ULN) hepatic impairment. These studies suggest that in patients with severe hepatic impairment after taking vorinostat, the risk of dose-dependent toxicity is higher than in patients without liver function impairment (even when taking a reduced dose of the drug). The tolerable daily dose of vorinostat for patients with mild and moderate hepatic impairment is 300 mg and 200 mg, respectively.

In general, patients with severe hepatic impairment were excluded from the vorinostat study. However, there is a limited number of patients with moderate hepatic impairment who were included in clinical studies. No clinically significant difference in the development of side effects associated with liver function was found in patients with a history of hepatic disorders compared to patients without such a history.

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

Indications

• Treatment of cutaneous T-cell lymphoma that progresses, persists, or recurs despite systemic therapy.

ICD codes

Dosage Regimen

The drug should be taken orally with food. Do not open the capsules, swallow them whole.

The recommended dose of Zolinza^® is 400 mg once daily.

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

Treatment is continued until complete control is achieved (no signs of further progression) or until signs of unacceptable toxicity appear.

Elderly patients do not require dose adjustment.

The tolerable daily dose of vorinostat for patients with mild and moderate hepatic impairment is 300 mg and 200 mg, respectively.

Adverse Reactions

The safety of Zolinza^® was evaluated in 111 patients with cutaneous T-cell lymphoma in two clinical studies. 86 patients took the drug at a dose of 400 mg once daily.

Characteristic adverse reactions associated with taking Zolinza^® in the 400 mg once daily regimen can be grouped into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight loss, vomiting, constipation, decreased appetite), general symptoms (increased fatigue, chills), hematological disorders (thrombocytopenia, anemia) and taste disorder (dysgeusia, dry mouth).

Observed very common (≥1/10) adverse reactions (clinical and laboratory) associated with treatment with Zolinza^® in patients with cutaneous T-cell lymphoma taking the drug at a dose of 400 mg once daily are listed below.

From the hematopoietic system very common – thrombocytopenia, anemia.

From the metabolism very common – anorexia, decreased appetite.

From the gastrointestinal tract very common – diarrhea, nausea, dry mouth, vomiting, constipation.

From the skin and subcutaneous tissues very common – alopecia, skin itching.

From the musculoskeletal system very common – muscle spasms.

From the nervous system very common – dysgeusia, dizziness, headache.

From the vascular system very common – peripheral edema.

From the respiratory system common – cough, upper respiratory tract infections.

General reactions very common – increased fatigue, chills; common – increased body temperature.

Laboratory and instrumental data very common – weight loss, increased plasma creatinine concentration.

Adverse reactions of grade 3-5 severity were observed for the following of the above reactions: thrombocytopenia (5.8%), anemia (2.3%), anorexia (2.3%), decreased appetite (1.2%), nausea (3.5%), muscle spasms (2.3%), increased fatigue (2.3%), chills (1.2%), weight loss (1.2%). None of the adverse reactions had grade 5 severity.

The profile of adverse reactions in patients receiving other doses of the drug was similar. The frequency of severe thrombocytopenia, anemia, and fatigue was increased when treated with Zolinza^® at doses exceeding 400 mg once daily.

Serious adverse reactions

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

Definition of frequency categories of adverse reactions: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100).

Infectious and parasitic diseases uncommon – streptococcal bacteremia.

From the hematopoietic system common – thrombocytopenia, anemia.

From the metabolism common – dehydration.

From the cardiovascular system uncommon – deep vein thrombosis, decreased blood pressure.

From the respiratory system common – pulmonary embolism.

From the gastrointestinal tract uncommon – diarrhea, gastrointestinal bleeding, nausea, vomiting.

From the liver and biliary tract uncommon – hepatic ischemia.

From the nervous system uncommon – ischemic stroke, syncope.

General disorders uncommon – chest pain, death (of unknown etiology), pyrexia.

Treatment discontinuation

In the subgroup of patients with cutaneous T-cell lymphoma receiving Zolinza^® at a dose of 400 mg once daily, 10.5% discontinued treatment due to treatment-related adverse reactions, in particular, anemia, angioedema, asthenia, chest pain, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, skin lesions, and death.

Dose modification

In the subgroup of patients with cutaneous T-cell lymphoma receiving Zolinza^® at a dose of 400 mg once daily, 10.5% of patients required a dose reduction of Zolinza^® due to adverse reactions, in particular, increased plasma creatinine concentration, decreased appetite, hypokalemia, leukopenia, neutropenia, thrombocytopenia, and vomiting. The average time to the first adverse event leading to a dose reduction was 42 days (from 17 to 263 days).

Laboratory and instrumental data

Deviations in laboratory parameters were observed in 86 patients taking the drug at a daily dose of 400 mg and in 1 patient taking 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 (grade 3) observed only in 5 patients. The association of hyperglycemia with the treatment was established in 4.7% of patients with cutaneous T-cell lymphoma taking the drug at a daily dose of 400 mg.

Transient mild increase in plasma creatinine concentration was observed in 47.1% of patients with cutaneous T-cell lymphoma.

Proteinuria was observed in 51.4% (38 out of 74) of examined patients. The clinical significance of proteinuria has not been established.

Dehydration

Based on cases of dehydration observed in clinical studies, considered as a serious treatment-related adverse reaction, patients were advised to maintain a drinking regimen – at least 2 liters of fluid per day to ensure adequate hydration. After following this recommendation, the frequency of dehydration episodes decreased.

Adverse effects in patients with other oncological (non-cutaneous T-cell lymphoma) diseases

Clinical studies included patients with solid tumors or other oncohematological diseases (non-cutaneous T-cell lymphoma) who took Zolinza^® as monotherapy or in combination with other antineoplastic 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. Adverse reactions observed only in the group of patients with solid tumors and other oncohematological diseases included isolated episodes: blurred vision and hearing, dysphagia, asthenia, abdominal pain, diverticulitis, hyponatremia, non-small cell lung cancer, tumor bleeding, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, episodes of increased blood pressure and vasculitis.

In some patients during the recovery period after intestinal surgery, impaired healing of the anastomosis was observed. In this regard, caution should be exercised when using Zolinza^® in the postoperative period if the patient requires intestinal surgery.

Contraindications

• Hypersensitivity to the components of the drug;
• Severe hepatic impairment;
• Age under 18 years;
• Pregnancy;
• Lactation period (breastfeeding).

With caution moderate hepatic impairment; history of thromboembolism; baseline nausea, vomiting and diarrhea (should be eliminated before starting treatment); diabetes mellitus and risk of developing diabetes mellitus.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies of the use of Zolinza^® during pregnancy have not been conducted.

Women of childbearing potential should avoid pregnancy during treatment with Zolinza^®. If the need for treatment with Zolinza^® arises during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential harm of treatment to the fetus.

There are no data on the excretion of the drug in breast milk. Considering that most drugs are secreted into breast milk and that Zolinza^® may cause adverse effects in the infant, breastfeeding during treatment with the drug is not recommended.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

The drug should be prescribed with caution in moderate hepatic impairment.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

Contact of the capsule contents with the skin and mucous membranes should be avoided. In case of contact, rinse the powder thoroughly with water.

Digestive system disorders

If gastrointestinal disorders develop during therapy, including nausea, vomiting, and diarrhea (see section “Adverse Reactions”), the appointment of antiemetic and antidiarrheal agents may be required. To prevent dehydration and maintain electrolyte balance, rehydration and electrolyte replenishment are recommended. If the patient has nausea, vomiting, and diarrhea before starting treatment, they must be eliminated before using Zolinza^®.

Changes in Hematological Parameters

Treatment with Zolinza^® may be accompanied by the development of dose-dependent thrombocytopenia and anemia. If a significant decrease in platelet count and/or hemoglobin level occurs during treatment with Zolinza^®, the dose of the drug should be reduced or treatment should be temporarily discontinued.

Vascular Disorders

During treatment, complications such as pulmonary embolism and deep vein thrombosis may develop (see the “Adverse Reactions” section). Close monitoring of patients, especially those with a relevant medical history, is necessary for the timely detection of symptoms of pulmonary embolism and deep vein thrombosis.

Liver Function Impairment

A study of the use of Zolinza^® in 42 patients with other oncological diseases (not cutaneous T-cell lymphoma) and hepatic impairment showed that the drug should be used with caution in patients with mild and moderate hepatic impairment (see the “Pharmacokinetics” and “Contraindications” sections).

Hyperglycemia

Plasma glucose concentration should be monitored, especially in patients with pre-existing diabetes or at risk of developing diabetes. Diet and/or hypoglycemic therapy may be required.

Changes in Laboratory Parameters

Close monitoring of clinical and biochemical blood test parameters, including plasma electrolyte concentrations (potassium, magnesium, calcium), glucose, and creatinine, should be performed at least once every 2 weeks during the first 2 months of treatment, and subsequently monthly. Hypokalemia and hypomagnesemia must be corrected prior to the initiation of Zolinza^® treatment. Potassium and magnesium levels should also be monitored in patients with nausea, vomiting, diarrhea, dehydration, and cardiovascular disorders.

Elderly Patients

According to clinical studies, the efficacy and safety of Zolinza^® in elderly patients (over 65 years of age) were comparable to those in younger patients (under 65 years of age). Dose adjustment based on age is not required.

Use in Pediatrics

The safety and efficacy of the drug in children have not been studied.

Effect on Ability to Drive and Use Machines

There are no data to suggest any potential negative effect of Zolinza^® on the ability to drive vehicles or operate complex machinery.

Overdose

There is no specific information on the treatment of overdose with Zolinza^®. The following maximum daily doses of the drug were studied in clinical trials: 600 mg (once daily), 800 mg (400 mg twice daily), and 900 mg (300 mg three times daily). In patients who received the drug at a dose higher than the recommended study dose (but not exceeding the maximum studied dose), no adverse effects were observed.

The pharmacological effects of the drug may persist after the drug is eliminated from the blood (i.e., be observed at zero plasma concentrations of active vorinostat).

Treatment in case of overdose should consist of standard supportive measures: removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, and administration of supportive therapy if necessary.

Drug Interactions

Coumarin-derived Anticoagulants

When Zolinza^® and coumarin anticoagulants were taken concomitantly, prolongation of prothrombin time and an increase in INR (International Normalized Ratio) were rarely observed in patients. If concomitant treatment with Zolinza^® and coumarin derivatives is necessary, careful monitoring of coagulation parameters is recommended.

Other Histone Deacetylase Inhibitors

Zolinza^® should not be administered concomitantly with other histone deacetylase inhibitors (in particular, valproic acid) due to the potential for additive side effects characteristic of this class of drugs. Concomitant treatment with Zolinza^® and valproic acid resulted in the development of severe (grade 4) thrombocytopenia with gastrointestinal bleeding and anemia.

Interactions with Other Medicinal Products

Vorinostat inhibits microsomal isoenzymes of the cytochrome P450 system involved in the metabolism of other medicinal products only at high concentrations (IC₅₀>75 μmol/L). Gene expression studies in human hepatocytes revealed the potential for vorinostat to suppress the activity of CYP2C9 and CYP3A4 isoenzymes at concentrations ≥10 μmol/L, which exceed pharmacological levels. Therefore, the effect of vorinostat on the pharmacokinetics of other drugs is not expected in clinical practice. Since cytochrome P450 isoenzymes are not involved in the metabolic transformations of the drug, no drug interactions are expected with the concomitant administration of vorinostat and drugs that inhibit or induce cytochrome P450 isoenzymes. However, specific drug interaction studies with vorinostat have not been conducted.

In vitro studies have shown that Vorinostat is not a substrate for human P-glycoprotein (P-gp). Furthermore, Vorinostat does not have an inhibitory effect on the P-gp-mediated transport of vinblastine (a marker P-gp substrate) at concentrations up to 100 μM. Thus, Vorinostat is unlikely to inhibit P-gp at the pharmacologically active concentration of 2 μM (C_max) in humans.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.