Vorinostat

Vorinostat comes as a capsule to take by mouth. It is usually taken once a day with food. Your doctor will tell you whether to take vorinostat every day or only on some days of the week. Take vorinostat at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take vorinostat exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole; do not open, chew, or crush them. If you are not able to swallow the capsules whole, call your doctor. If vorinostat capsules are accidentally opened or crushed, do not touch the capsules or the powder. If the powder from an open or crushed capsule gets on your skin or in your eyes or nose, wash the area well with plenty of water and call your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Make sure to drink at least eight 8-ounce (240-milliliter) cups of water or other liquids every day while taking vorinostat so you do not become dehydrated.

Unless your doctor tells you otherwise, continue your normal diet.

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.

Vorinostat is used to treat skin problems caused by cutaneous T-cell lymphoma.

Vorinostat is usually given after other treatments have been tried without successful treatment.

Vorinostat may also be used for purposes not listed in this medication guide.

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 [see WARNINGS AND PRECAUTIONS].

Thromboembolism [see WARNINGS AND PRECAUTIONS]

Myelosuppression [see WARNINGS AND PRECAUTIONS]

Gastrointestinal Toxicity [see WARNINGS AND PRECAUTIONS]

Hyperglycemia [see WARNINGS AND PRECAUTIONS]

Clinical Chemistry Abnormalities [see WARNINGS AND PRECAUTIONS]

Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors [see WARNINGS AND PRECAUTIONS]

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.

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.

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)

The frequencies of more severe thrombocytopenia, anemia [see WARNINGS AND PRECAUTIONS] and fatigue were increased at doses higher than 400 mg once daily of ZOLINZA.

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.

Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued ZOLINZA due to adverse reactions. These adverse reactions, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury.

Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of ZOLINZA due to adverse reactions. These adverse reactions included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse reactions resulting in dose reduction was 42 days (range 17 to 263 days).

Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose.

Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse reaction in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose. [See WARNINGS AND PRECAUTIONS]

Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3.

Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown.

Based on reports of dehydration as a serious drug-related adverse reaction in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. [See WARNINGS AND PRECAUTIONS]

The frequencies of individual adverse reactions were substantially higher in the non-CTCL population. Drug-related serious adverse reactions reported in the non-CTCL population which were not observed in the CTCL population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barr� syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis.

In patients recovering from bowel surgery and treated perioperatively with ZOLINZA, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred.

Read the entire FDA prescribing information for Zolinza (Vorinostat)

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. It has been shown that use of vorinostat in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

• Keep this medication in the container it came in, tightly closed, and out of reach of children.
• Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Vorinostat is used to treat skin problems caused by cutaneous T-cell lymphoma.

Vorinostat is usually given after other treatments have been tried without successful treatment.

Vorinostat may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Not metabolized by CYP isoenzymes.1 Pharmacokinetic interactions unlikely with drugs that are CYP enzyme inducers or inhibitors.1

Does not inhibit CYP isoenzymes in vitro at therapeutic serum concentrations.1 Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.1

Specific Drugs

• Histone deacetylase inhibitor; antineoplastic agent.1 2 3

• Inhibits enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations;1 3 HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1 3

• Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones observed in some cancer cells.1 3

• Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.1 3

• Inhibition of HDAC activity allows for accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation.1 3

• In vitro, causes accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.1 3

• It is used to treat a type of lymphoma that affects the skin.

Use vorinostat as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine with food.
• Swallow whole. Do not chew, open, or crush.
• If you have trouble swallowing, talk with your doctor.
• If the capsule is opened or broken, do not touch the contents. If the contents are touched or they get in the eyes, wash hands or eyes right away.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Feeling tired or weak.
• Chills.
• Cough.
• Muscle spasm.
• Not hungry.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Weight loss.
• Hard stools (constipation).
• Change in taste.
• Hair loss.
• Signs of a common cold.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Zolinza: 100 mg

• Antineoplastic Agent, Histone Deacetylase (HDAC) Inhibitor

In a pharmacokinetic study in cancers other than cutaneous T-cell lymphoma, the AUC was increased 50% in patients with mild and moderate impairment, and increased 66% in patients with severe impairment, compared to patients with normal hepatic function.

Although not recommended by the manufacturer, a 50 mg/mL oral suspension may be prepared with capsules. Add 20 mL Ora-Plus® into a glass bottle (≥4 oz). Add the contents of twenty 100 mg capsules and shake thoroughly to disperse (may take up to 3 minutes). Add 20 mL Ora-Sweet® and shake to disperse. Label “shake well”. Stable for 14 days at room temperature.

Administer with food. Do not open, crush, break, or chew capsules. Avoid direct skin or mucous membrane contact with crushed or broken capsules and/or capsule contents. Maintain adequate hydration (≥2 L/day fluids) during treatment.

400 mg orally once daily with food

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Vorinostat capsules should not be opened or crushed.