Vorinostat
FDA Drug Information • Also known as: Zolinza
- Brand Names
- Zolinza
- Dosage Form
- CAPSULE
- Product Type
- DRUG FOR FURTHER PROCESSING
Description
11 DESCRIPTION ZOLINZA contains vorinostat, which is described chemically as N- hydroxy- N'- phenyloctanediamide. The empirical formula is C 14 H 20 N 2 O 3 . The molecular weight is 264.32 and the structural formula is: Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride. It has no chiral centers and is non-hygroscopic. The differential scanning calorimetry ranged from 161.7 (endotherm) to 163.9°C. The pH of saturated water solutions of vorinostat drug substance was 6.6. The pKa of vorinostat was determined to be 9.2. Each 100 mg ZOLINZA capsule for oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium dioxide, gelatin and sodium lauryl sulfate. Chemical Structure
What Is Vorinostat Used For?
1 INDICATIONS AND USAGE ZOLINZA ® is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION 400 mg orally once daily with food. ( 2.1 ) If patient is intolerant to therapy, reduce the dose to 300 mg orally once daily with food. If necessary, reduce the dose further to 300 mg once daily with food for 5 consecutive days each week. ( 2.2 , 5 ) Reduce dose in patients with mild or moderate hepatic impairment. ( 2.2 ) 2.1 Dosing Information The recommended dose is 400 mg orally once daily with food. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. ZOLINZA capsules should not be opened or crushed [see How Supplied/Storage and Handling (16) ] . 2.2 Dose Modifications For Toxicity If a patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. The dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week, as necessary. Hepatic Impairment Reduce the starting dose to 300 mg orally once daily with food in patients with mild to moderate hepatic impairment (bilirubin 1 to 3 × ULN or AST greater than ULN). There is insufficient evidence to recommend a starting dose for patients with severe hepatic impairment (bilirubin greater than 3 × ULN) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions have been associated with ZOLINZA in clinical trials and are discussed in greater detail in other sections of the label: Thromboembolism [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.3) ] Hyperglycemia [see Warnings and Precautions (5.4) ] Clinical Chemistry Abnormalities [see Warnings and Precautions (5.5) ] Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors [see Warnings and Precautions (5.6) ] The most common adverse reactions (incidence ≥20%) are diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZOLINZA was evaluated in 107 CTCL patients in two single arm clinical studies in which 86 patients received 400 mg once daily. The data described below reflect exposure to ZOLINZA 400 mg once daily in the 86 patients for a median number of 97.5 days on therapy (range 2 to 480+ days). Seventeen (19.8%) patients were exposed beyond 24 weeks and 8 (9.3%) patients were exposed beyond 1 year. The population of CTCL patients studied was 37 to 83 years of age, 47.7% female, 52.3% male, and 81.4% white, 16.3% black, and 1.2% Asian or multi-racial. Common Adverse Reactions The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were pulmonary embolism and anemia. Table 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0). Table 1: Clinical or Laboratory Adverse Reactions Occurring in CTCL Patients (Incidence ≥10% of patients) ZOLINZA 400 mg once daily (N=86) Adverse Reactions All Grades Grades 3-4 n % n % Fatigue 45 52.3 3 3.5 Diarrhea 45 52.3 0 0.0 Nausea 35 40.7 3 3.5 Dysgeusia 24 27.9 0 0.0 Thrombocytopenia 22 25.6 5 5.8 Anorexia 21 24.4 2 2.3 Weight Decreased 18 20.9 1 1.2 Muscle Spasms 17 19.8 2 2.3 Alopecia 16 18.6 0 0.0 Dry Mouth 14 16.3 0 0.0 Blood Creatinine Increased 14 16.3 0 0.0 Chills 14 16.3 1 1.2 Vomiting 13 15.1 1 1.2 Constipation 13 15.1 0 0.0 Dizziness 13 15.1 1 1.2 Anemia 12 14.0 2 2.3 Decreased Appetite 12 14.0 1 1.2 Peripheral Edema 11 12.8 0 0.0 Headache 10 11.6 0 0.0 Pruritus 10 11.6 1 1.2 Cough 9 10.5 0 0.0 Upper Respiratory Infection 9 10.5 0 0.0 Pyrexia 9 10.5 1 1.2 The frequencies of more severe thrombocytopenia, anemia [see Warnings and Precautions (5.2) ] and fatigue were increased at doses higher than 400 mg once daily of ZOLINZA. Serious Adverse Reactions The most common serious adverse reactions in the 86 CTCL patients in two clinical trials were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell carcinoma reported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86) of patients. There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction....
Drug Interactions
7 DRUG INTERACTIONS Coumarin-derivative anticoagulants: Prolongation of prothrombin time and International Normalized Ratio (INR) have been observed with concomitant use. Monitor INR frequently. ( 7.1 ) 7.1 Coumarin-Derivative Anticoagulants Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered ZOLINZA and coumarin derivatives. 7.2 Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months [see Warnings and Precautions (5.6) ].
Contraindications
4 CONTRAINDICATIONS None. None ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies, ZOLINZA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are insufficient data on ZOLINZA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of vorinostat to pregnant rats and rabbits during the period of organogenesis caused adverse developmental outcomes at maternal exposures approximately 0.5 times the human exposure based on AUC 0-24 hours (see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal plasma at levels up to 50% of maternal concentrations. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC 0-24 hours ). Treatment-related developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) were seen in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day (<0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the...
Overdosage
10 OVERDOSAGE No specific information is available on the treatment of overdosage of ZOLINZA. In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING ZOLINZA capsules, 100 mg, are white, opaque hard gelatin capsules with "568" over "100 mg" printed within the radial bar in black ink on the capsule body. They are supplied as follows: NDC 0006-0568-40. Each bottle contains 120 capsules. Storage and Handling Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. ZOLINZA (vorinostat) capsules should not be opened or crushed. Direct contact of the powder in ZOLINZA capsules with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed and/or broken capsules [see Nonclinical Toxicology (13.1) ].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.