Journal of Clinical Oncology Publishes Data on Zolinza (vorinostat), Merck's Treatment for Advanced Cutaneous T-cell Lymphoma

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Jul 20, 2007 - Results from a clinical study conducted with patients who were diagnosed with advanced, refractory cutaneous T-cell lymphoma (CTCL) showed nearly a third of patients responded to treatment with ZOLINZA(TM) (vorinostat), as measured by objective response rate, according to data published in this week's Journal of Clinical Oncology. ZOLINZA, Merck's most recent anticancer treatment, is approved for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent or recurrent disease on or following two systemic therapies. CTCL is a cancer of the T-cells, a type of white blood cell, which affects the skin and is a form of non-Hodgkin's lymphoma.

In the open-label, single-arm study, 30 percent of all patients (22 of 74, 95% CI (19.7 to 41.5%)) with CTCL achieved an objective response to daily oral treatment with ZOLINZA as did 30 percent of patients with Stage IIB or higher disease (18 of 61, 95% CI (18.5 to 42.6%)). Objective response rate, the primary endpoint of the study, was defined as at least four weeks of either a complete response (defined as no evidence of disease) or a partial response (defined as greater than or equal to 50 percent decrease in a skin assessment score compared to baseline). One patient with Stage IIB CTCL achieved a complete clinical response with ZOLINZA.

"The findings from this clinical study are quite encouraging, particularly given that the effect of ZOLINZA was evaluated based on stringent criteria to determine objective response," said Elise Olsen, M.D., director, Cutaneous Lymphoma Treatment and Research Center at Duke University Medical Center, and lead author of the study. "Furthermore, the effect of ZOLINZA was consistent in the overall patient population and among patients in later stage (IIB or higher) disease."

Study assessed other efficacy measures

Other findings from the study showed the median time to objective response was less than two months (55 days) in all patients, however, in rare cases, it took up to six months for patients to achieve an objective response to ZOLINZA. The median duration of response was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed six months in all patients; and the median time to progression approached five months (148 days) in all patients treated with ZOLINZA.

The most common side effects observed in the study were diarrhea (49 percent), fatigue (46 percent), nausea (43 percent), anorexia (26 percent), dysgeusia (24 percent) and thrombocytopenia (22 percent).

About the study

The clinical study was an open-label, non-randomized trial that included 74 patients with CTCL who had previously failed at least two prior systemic therapies. Patients were given ZOLINZA 400 mg once daily until disease progression or intolerable toxicity, with modifications to the dose, as needed.

The median age of patients in the study was 60 years. Fifty-one percent of the patients were male and 49 percent were female. Eighteen percent of patients had Stage IB or IIA CTCL and 82 percent had Stage IIB and higher CTCL. The median number of prior systemic therapies was three. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool.

Important safety information about ZOLINZA

As pulmonary embolism and deep vein thrombosis have been reported as adverse reactions, physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events. Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. If platelet counts and/or hemoglobin are reduced during treatment with ZOLINZA, the dose should be modified or therapy discontinued. Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.

Based on reports of dehydration as a serious drug-related adverse event in clinical trials, patients should be instructed to drink at least two L/Day of fluids for adequate hydration. Hyperglycemia has been observed in patients receiving ZOLINZA. Serum glucose should be monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or therapy for increased glucose may be necessary. QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment. Hypokalemia or hypomagnesemia should be corrected prior to administration of ZOLINZA.

The most common serious adverse events, regardless of causality, in the 86 CTCL patients in two clinical studies were pulmonary embolism reported in 4.7 percent (4/86) of patients, squamous cell carcinoma reported in 3.5 percent (3/86) of patients and anemia reported in 2.3 percent (2/86) of patients. The most common adverse events observed in clinical trials with ZOLINZA for CTCL, regardless of causality, were fatigue (52 percent), diarrhea (52 percent), nausea (41 percent), dysgeusia (28 percent), thrombocytopenia (26 percent), anorexia (24 percent), decreased weight (21 percent) and muscle spasm (20 percent).

Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. 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 two weeks for the first two months.

ZOLINZA was not evaluated in patients with hepatic impairment. As ZOLINZA is predominately eliminated through metabolism, patients with hepatic impairment should be treated with caution.

Dosing and administration for ZOLINZA

The recommended dose of ZOLINZA is 400 mg orally once daily with food. If the 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 five consecutive days each week. Treatment with ZOLINZA may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. ZOLINZA capsules should not be opened or crushed.

About ZOLINZA

ZOLINZA was approved in October 2006 by the U.S. Food and Drug Administration for the treatment of the cutaneous manifestations in patients with CTCL who have progressive, persistent or recurrent disease on or following two systemic therapies. ZOLINZA is accessible to patients through Merck's Accessing Coverage Today (ACT) program. ACT is a three-part program specifically designed to assist patients in obtaining ZOLINZA, help with insurance reimbursement issues, and provide support for those qualified individuals lacking insurance coverage for ZOLINZA. Patients without insurance coverage may be eligible for Merck's Patient Assistant Program, which allows them to receive ZOLINZA free of charge. Merck also is contributing to co-pay assistance foundations that provide co-pay assistance to qualified individuals. To enroll in the ACT program, patients need to call 1-866-363-6379 once they receive a prescription for ZOLINZA.

CTCL - a type of lymphoma cancer

CTCL, a type of non-Hodgkin's lymphoma, is a form of cancer in T-cells, a type of white blood cell. Normal T-cells function by regulating the body's immune system in its job of fighting infections and other foreign antigens. In CTCL, the malignant T-cells are drawn to the skin, where some are deposited. Patients usually develop CTCL after age 50, but it may present at any age. CTCL affects up to 20,000 patients in the United States, with another 1,500 new cases reported each year.

About Merck Oncology

Merck Oncology focuses on all aspects of cancer care - prevention, treatment, and supportive care. Through strong internal research capabilities, selective alliances and acquisitions, and enabling technologies such as the Molecular Profiling platform of Rosetta, Merck Oncology is looking to lead in the discovery, development and delivery of targeted anticancer therapies customized for patient subpopulations. Merck Oncology conducts research at sites in Boston, Seattle, West Point, Japan and Italy.

About Merck

Merck & Co., Inc., is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Prescribing information and patient product information for ZOLINZA(TM) are attached. -0-

                                                              9762600

    HIGHLIGHTS OF PRESCRIBING INFORMATION


    These highlights do not include all the information needed to use

ZOLINZA safely and effectively. See full prescribing information for

ZOLINZA.


    ZOLINZA(TM) (vorinostat) Capsules


    Initial U.S. Approval: 2006


    INDICATIONS AND USAGE


    ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for:


    --  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


    --  400 mg orally once daily with food. (2.1)


    --  If patient is intolerant to therapy, the dose may be reduced

        to 300 mg orally once daily with food. If necessary, the dose

        may be further reduced to 300 mg once daily with food for

        5 consecutive days each week. (2.2, 5)


    DOSAGE FORMS AND STRENGTHS


    --  Capsules: 100 mg (3)


    CONTRAINDICATIONS


    --  None (4)


    WARNINGS AND PRECAUTIONS


    --  Pulmonary embolism and deep vein thrombosis have been

        reported. Monitor patient for pertinent signs and symptoms.

        (5.1)


    --  Dose-related thrombocytopenia and anemia have occurred and may

        require dose modification or discontinuation. (2.2, 5.2, 6)


    --  Gastrointestinal disturbances (e.g., nausea, vomiting and

        diarrhea) have been reported. Patients may require

        antiemetics, antidiarrheals and fluid and electrolyte

        replacement (to prevent dehydration). (5.3, 6, 17.1)


    --  Hyperglycemia has been observed. Adjustment of diet and/or

        therapy for increased glucose may be necessary. (5.4, 5.6)


    --  QTc prolongation has been observed. Monitor electrolytes and

        ECGs at baseline and periodically during treatment. (5.5, 5.6)


    --  Monitor blood cell counts and chemistry tests, including

        electrolytes, glucose and serum creatinine, every 2 weeks

        during the first 2 months of therapy and monthly thereafter.

        (5.6)


    --  Severe thrombocytopenia and gastrointestinal bleeding have

        been reported with concomitant use of ZOLINZA and other HDAC

        inhibitors (e.g., valproic acid). Monitor platelet count.

        (5.7, 7.2)


    --  Fetal harm can occur when administered to a pregnant woman.

        Women should be apprised of the potential harm to the fetus.

        (5.8)


    ADVERSE REACTIONS


    --  The most common adverse reactions (incidence =greater than

        20%) are diarrhea, fatigue, nausea, thrombocytopenia, anorexia

        and dysgeusia. (6)


    To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc.

at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


    DRUG INTERACTIONS


    --  Coumarin-derivative anticoagulants: Prolongation of

        prothrombin time and International Normalized Ratio have been

        observed with concomitant use. Monitor carefully. (7.1)


    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient

labeling.


    Revised: 10/2006


    FULL PRESCRIBING INFORMATION: CONTENTS*


    1 INDICATIONS AND USAGE


    2 DOSAGE AND ADMINISTRATION


    2.1 Dosing Information


    2.2 Dose Modifications


    2.3 Dosing in Special Populations


    3 DOSAGE FORMS AND STRENGTHS


    4 CONTRAINDICATIONS


    5 WARNINGS AND PRECAUTIONS


    5.1 Thromboembolism


    5.2 Hematologic


    5.3 Gastrointestinal


    5.4 Hyperglycemia


    5.5 QTc Prolongation


    5.6 Monitoring: Laboratory Tests


    5.7 Other Histone Deacetylase (HDAC) Inhibitors


    5.8 Pregnancy


    6 ADVERSE REACTIONS


    6.1 Clinical Trials Experience


    7 DRUG INTERACTIONS


    7.1 Coumarin-Derivative Anticoagulants


    7.2 Other HDAC Inhibitors


    8 USE IN SPECIFIC POPULATIONS


    8.1 Pregnancy


    8.3 Nursing Mothers


    8.4 Pediatric Use


    8.5 Geriatric Use


    8.6 Use in Patients with Hepatic Impairment


    8.7 Use in Patients with Renal Impairment


    10 OVERDOSAGE


    11 DESCRIPTION


    12 CLINICAL PHARMACOLOGY


    12.1 Mechanism of Action


    12.3 Pharmacokinetics


    13 NONCLINICAL TOXICOLOGY


    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


    14 CLINICAL STUDIES


    15 REFERENCES


    16 HOW SUPPLIED/STORAGE AND HANDLING


    17 PATIENT COUNSELING INFORMATION


    17.1 Instructions


    17.2 FDA-Approved Patient Labeling


    *Sections or subsections omitted from the full prescribing

information are not listed.



    FULL PRESCRIBING INFORMATION


    1 INDICATIONS AND USAGE


    ZOLINZA(1) 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.


    2 DOSAGE AND ADMINISTRATION


    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


    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.


    2.3 Dosing in Special Populations


    No information is available in patients with renal or hepatic

impairment (see Pharmacokinetics (12.3)).


    3 DOSAGE FORMS AND STRENGTHS


    100 mg white, opaque, hard gelatin capsules with "568" over

"100 mg" printed within radial bar in black ink on the capsule body.


    4 CONTRAINDICATIONS


    None


    5 WARNINGS AND PRECAUTIONS


    5.1 Thromboembolism


    As pulmonary embolism and deep vein thrombosis have been reported

as adverse reactions, physicians should be alert to the signs and

symptoms of these events, particularly in patients with a prior

history of thromboembolic events (see Adverse Reactions (6)).


    5.2 Hematologic


    Treatment with ZOLINZA can cause dose-related thrombocytopenia and

anemia. If platelet counts and/or hemoglobin are reduced during

treatment with ZOLINZA, the dose should be modified or therapy

discontinued. (See Dosage and Administration (2.2), Warnings and

Precautions (5.6) and Adverse Reactions (6).)


    5.3 Gastrointestinal


    Gastrointestinal disturbances, including nausea, vomiting and

diarrhea, have been reported (see Adverse Reactions (6)) and may

require the use of antiemetic and antidiarrheal medications. Fluid and

electrolytes should be replaced to prevent dehydration (see Adverse

Reactions (6.1)). Pre-existing nausea, vomiting, and diarrhea should

be adequately controlled before beginning therapy with ZOLINZA.


    5.4 Hyperglycemia


    Hyperglycemia has been observed in patients receiving ZOLINZA (see

Adverse Reactions (6.1)). Serum glucose should be monitored,

especially in diabetic or potentially diabetic patients. Adjustment of

diet and/or therapy for increased glucose may be necessary.


    5.5 QTc Prolongation


    A definitive study of the effect of vorinostat on QTc has not been

conducted. Three of 86 CTCL patients exposed to 400 mg once daily had

Grade 1 (greater than 450-470 msec) or 2 (greater than 470-500 msec or

increase of greater than 60 msec above baseline) clinical adverse

events of QTc prolongation. In a retrospective analysis of three Phase

1 and two Phase 2 studies, 116 patients had a baseline and at least

one follow-up ECG. Four patients had Grade 2 (greater than 470-500

msec or increase of greater than 60 msec above baseline) and 1 patient

had Grade 3 (greater than 500 msec) QTc prolongation. In 49 non-CTCL

patients from 3 clinical trials who had complete evaluation of QT

interval, 2 had QTc measurements of greater than 500 msec and 1 had a

QTc prolongation of greater than 60 msec.


    5.6 Monitoring: Laboratory Tests


    Careful monitoring of blood cell counts and chemistry tests,

including electrolytes, glucose and serum creatinine, should be

performed every 2 weeks during the first 2 months of therapy and

monthly thereafter. Electrolyte monitoring should include potassium,

magnesium and calcium. Baseline and periodic ECGs should be performed

during treatment. ZOLINZA should be administered with particular

caution in patients with congenital long QT syndrome, and patients

taking anti-arrhythmic medicines or other medicinal products that lead

to QT prolongation. Hypokalemia or hypomagnesemia should be corrected

prior to administration of ZOLINZA, and consideration should be given

to monitoring potassium and magnesium in symptomatic patients (e.g.,

patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac

symptoms). (See Warnings and Precautions (5.5).)


    5.7 Other Histone Deacetylase (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 during the

first 2 months. (See Drug Interactions (7.2)).


    5.8 Pregnancy


    Pregnancy Category D


    ZOLINZA can cause fetal harm when administered to a pregnant

woman. There are no adequate and well-controlled studies of ZOLINZA in

pregnant women. 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 (about 0.5 times the human

exposure based on AUC0-24 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) 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 (less than 0.1 times the human

exposure based on AUC) in rats and rabbits, respectively. A

dose-related increase in the incidence of malformations of the gall

bladder was noted in all drug treatment groups in rabbits versus the

concurrent control. If this drug is used during pregnancy, or if the

patient becomes pregnant while taking this drug, the patient should be

apprised of the potential hazard to the fetus.


    6 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.


    6.1 Clinical Trials Experience


    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.


    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.


    Common Adverse Reactions


    Table 1 summarizes the frequency of CTCL patients with specific

adverse events, regardless of causality, using the National Cancer

Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE,

version 3.0).


                                Table 1


   Clinical or Laboratory Adverse Events Occurring in CTCL Patients


         (Incidence greater than or equal to 10% of patients)


                                                       ZOLINZA 400 mg

                                                          once daily

                                                            (N=86)

----------------------------------------------------------------------

  Adverse Events                                          All   Grades

                                                         Grades  3-5*

----------------------------------------------------------------------

                                                        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

----------------------------------------------------------------------



    * No Grade 5 events were reported.


    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 events, regardless of causality,

in the 86 CTCL patients in two clinical studies 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, pelvi-ureteric

obstruction, sepsis, spinal cord injury, streptococcal bacteremia,

syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction.


    Discontinuations


    Of the CTCL patients who received the 400-mg once daily dose, 9.3%

(8/86) of patients discontinued ZOLINZA due to adverse events. These

adverse events, 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.


    Dose Modifications


    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 events. These adverse events included increased serum

creatinine, decreased appetite, hypokalemia, leukopenia, nausea,

neutropenia, thrombocytopenia and vomiting. The median time to the

first adverse event resulting in dose reduction was 42 days (range 17

to 263 days).


    Laboratory Abnormalities


    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 event in 8.1% (7/86) of CTCL

patients who received the 400-mg once daily dose. (See Warnings and

Precautions (5.4).)


    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.


    Dehydration


    Based on reports of dehydration as a serious drug-related adverse

event in clinical trials, patients were instructed to drink at least

2 L/day of fluids for adequate hydration. (See Warnings and

Precautions (5.3, 5.6).)


    Adverse Reactions in Non-CTCL Patients


    The frequencies of individual adverse events were substantially

higher in the non-CTCL population. Drug-related serious adverse events

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-Barre syndrome, renal

failure, urinary retention, cough, hemoptysis, hypertension, and

vasculitis.


    7 DRUG INTERACTIONS


    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 carefully

monitor PT and INR 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 (5.7).)


    8 USE IN SPECIFIC POPULATIONS


    8.1 Pregnancy


    Pregnancy Category D (See Warnings and Precautions (5.8))


    8.3 Nursing Mothers


    It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the

potential for serious adverse reactions in nursing infants from

ZOLINZA, a decision should be made whether to discontinue nursing or

discontinue the drug, taking into account the importance of the drug

to the mother.


    8.4 Pediatric Use


    The safety and effectiveness of ZOLINZA in pediatric patients have

not been established.


    8.5 Geriatric Use


    Of the total number of patients with CTCL in trials (N=107), 46

percent were 65 years of age and over, while 15 percent were 75 years

of age and over. No overall differences in safety or effectiveness

were observed between these subjects and younger subjects, and other

reported clinical experience has not identified differences in

responses between the elderly and younger patients, but greater

sensitivity of some older individuals cannot be ruled out.


    8.6 Use in Patients with Hepatic Impairment


    Vorinostat was not evaluated in patients with hepatic impairment.

As vorinostat is predominantly eliminated through metabolism, patients

with hepatic impairment should be treated with caution. (See Clinical

Pharmacology (12.3).)


    8.7 Use in Patients with Renal Impairment


    Vorinostat was not evaluated in patients with renal impairment.

However, renal excretion does not play a role in the elimination of

vorinostat. Patients with pre-existing renal impairment should be

treated with caution. (See Clinical Pharmacology (12.3).)


    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.


    11 DESCRIPTION


    ZOLINZA contains vorinostat, which is described chemically as

N-hydroxy-N'-phenyloctanediamide.


    The empirical formula is C14H20N2O3. The molecular weight is

264.32 and the structural formula is:


    (OBJECT OMITTED)


    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(degree)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.


    12 CLINICAL PHARMACOLOGY


    12.1 Mechanism of Action


    Vorinostat inhibits the enzymatic activity of histone deacetylases

HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar

concentrations (IC50 less than 86 nM). These enzymes catalyze the

removal of acetyl groups from the lysine residues of proteins,

including histones and transcription factors. In some cancer cells,

there is an overexpression of HDACs, or an aberrant recruitment of

HDACs to oncogenic transcription factors causing hypoacetylation of

core nucleosomal histones. Hypoacetylation of histones is associated

with a condensed chromatin structure and repression of gene

transcription. Inhibition of HDAC activity allows for the accumulation

of acetyl groups on the histone lysine residues resulting in an open

chromatin structure and transcriptional activation. In vitro,

vorinostat causes the accumulation of acetylated histones and induces

cell cycle arrest and/or apoptosis of some transformed cells. The

mechanism of the antineoplastic effect of vorinostat has not been

fully characterized.


    12.3 Pharmacokinetics


    Absorption


    The pharmacokinetics of vorinostat were evaluated in 23 patients

with relapsed or refractory advanced cancer. After oral administration

of a single 400-mg dose of vorinostat with a high-fat meal, the mean

+/- standard deviation area under the curve (AUC) and peak serum

concentration (Cmax) and the median (range) time to maximum

concentration (Tmax) were 5.5+/-1.8 uM-hr, 1.2+/-0.62 microM and

4 (2-10) hours, respectively.


    In the fasted state, oral administration of a single 400-mg dose

of vorinostat resulted in a mean AUC and Cmax and median Tmax of

4.2+/-1.9 microM-hr and 1.2+/-0.35 microM and 1.5 (0.5-10) hours,

respectively. Therefore, oral administration of vorinostat with a

high-fat meal resulted in an increase (33%) in the extent of

absorption and a modest decrease in the rate of absorption (Tmax

delayed 2.5 hours) compared to the fasted state. However, these small

effects are not expected to be clinically meaningful. In clinical

trials of patients with CTCL, vorinostat was taken with food.


    At steady state in the fed-state, oral administration of multiple

400-mg doses of vorinostat resulted in a mean AUC and Cmax and a

median Tmax of 6.0+/-2.0 microM-hr, 1.2+/-0.53 microM and 4

(0.5-14) hours, respectively.


    Distribution


    Vorinostat is approximately 71% bound to human plasma proteins

over the range of concentrations of 0.5 to 50 microg/mL.


    Metabolism


    The major pathways of vorinostat metabolism involve

glucuronidation and hydrolysis followed by (beta)-oxidation. Human

serum levels of two metabolites, O-glucuronide of vorinostat and

4-anilino-4-oxobutanoic acid were measured. Both metabolites are

pharmacologically inactive. Compared to vorinostat, the mean steady

state serum exposures in humans of the O-glucuronide of vorinostat and

4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher,

respectively.


    In vitro studies using human liver microsomes indicate negligible

biotransformation by cytochromes P450 (CYP).


    Excretion


    Vorinostat is eliminated predominantly through metabolism with

less than 1% of the dose recovered as unchanged drug in urine,

indicating that renal excretion does not play a role in the

elimination of vorinostat. The mean urinary recovery of two

pharmacologically inactive metabolites at steady state was 16+/-5.8%

of vorinostat dose as the O-glucuronide of vorinostat, and 36+/-8.6%

of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary

recovery of vorinostat and these two metabolites averaged 52+/-13.3%

of vorinostat dose. The mean terminal half-life (t 1/2) was about 2.0

hours for both vorinostat and the O-glucuronide metabolite, while that

of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.


    Special Populations


    Based upon an exploratory analysis of limited data, gender, race

and age do not appear to have meaningful effects on the

pharmacokinetics of vorinostat.


    Pediatric


    Vorinostat was not evaluated in patients less than 18 years of 

age.


    Hepatic Insufficiency


    Vorinostat was not evaluated in patients with hepatic impairment.

(See Use In Specific Populations (8.6).)


    Renal Insufficiency


    Vorinostat was not evaluated in patients with renal impairment.

However, renal excretion does not play a role in the elimination of

vorinostat. (See Use In Specific Populations (8.7).)


    Pharmacokinetic effects of vorinostat with other agents


    Vorinostat is not an inhibitor of CYP drug metabolizing enzymes in

human liver microsomes at steady state Cmax of the 400 mg dose (Cmax

of 1.2 microM vs IC50 of greater than 75 microM). Gene expression

studies in human hepatocytes detected some potential for suppression

of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher

(= greater than 10 microM) than pharmacologically relevant. Thus,

vorinostat is not expected to affect the pharmacokinetics of other

agents. As vorinostat is not eliminated via the CYP pathways, it is

anticipated that vorinostat will not be subject to drug-drug

interactions when co-administered with drugs that are known CYP

inhibitors or inducers. However, no formal clinical studies have been

conducted to evaluate drug interactions with vorinostat.


    13 NONCLINICAL TOXICOLOGY


    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


    Carcinogenicity studies have not been performed with vorinostat.


    Vorinostat was mutagenic in vitro in the bacterial reverse

mutation assays (Ames test), caused chromosomal aberrations in vitro

in Chinese hamster ovary (CHO) cells and increased the incidence of

micro-nucleated erythrocytes when administered to mice (Mouse

Micronucleus Assay).


    Effects on the female reproductive system were identified in the

oral fertility study when females were dosed for 14 days prior to

mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to

rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times

the expected clinical exposure based on AUC. Dose dependent increases

in corpora lutea were noted at = greater than 15 mg/kg/day, which

resulted in increased peri-implantation losses were noted at (greater

than =)50 mg/kg/day. At 150 mg/kg/day, there were increases in the

incidences of dead fetuses and in resorptions.


    No effects on reproductive performance were observed in male rats

dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and

0.70 times the expected clinical exposure based on AUC), for 70 days

prior to mating with untreated females. (See Warnings and Precautions

(5.8))


    14 CLINICAL STUDIES


    Cutaneous T-cell Lymphoma


    In two open-label clinical studies, patients with refractory CTCL

have been evaluated to determine their response rate to oral ZOLINZA.

One study was a single-arm clinical study and the other assessed

several dosing regimens. In both studies, patients were treated until

disease progression or intolerable toxicity.


    Study 1


    In an open-label, single-arm, multicenter non-randomized study, 74

patients with advanced CTCL were treated with ZOLINZA at a dose of

400 mg once daily. The primary endpoint was response rate to oral

ZOLINZA in the treatment of skin disease in patients with advanced

CTCL (Stage IIB and higher) who had progressive, persistent, or

recurrent disease on or following two systemic therapies. Enrolled

patients should have received, been intolerant to or not a candidate

for bexarotene. Extent of skin disease was quantitatively assessed by

investigators using a modified Severity Weighted Assessment Tool

(SWAT). The investigator measured the percentage total body surface

area (%TBSA) involvement separately for patches, plaques, and tumors

within 12 body regions using the patient's palm as a "ruler". The

total %TBSA for each lesion type was multiplied by a severity

weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive

the SWAT score. Efficacy was measured as either a Complete Clinical

Response (CCR) defined as no evidence of disease, or Partial Response

(PR) defined as a = greater than 50% decrease in SWAT skin assessment

score compared to baseline. Both CCR and PR had to be maintained for

at least 4 weeks.


    Secondary efficacy endpoints included response duration, time to

progression, and time to objective response.


    The population had been exposed to a median of three prior

therapies (range 1 to 12).


    Table 2 summarizes the demographic and disease characteristics of

the Study 1 population.


                                Table 2


                   Baseline Patient Characteristics


                       (All Patients As Treated)



                                                            Vorinostat

  Characteristics                                             (N=74)

----------------------------------------------------------------------

  Age (year)

----------------------------------------------------------------------

  Mean (SD)                                                61.2 (11.3)

  Median (Range)                                     60.0 (39.0, 83.0)

----------------------------------------------------------------------

  Gender, n (%)

----------------------------------------------------------------------

  Male                                                      38 (51.4%)

  Female                                                    36 (48.6%)

----------------------------------------------------------------------

  CTCL stage, n (%)

----------------------------------------------------------------------

  IB                                                        11 (14.9%)

  IIA                                                         2 (2.7%)

  IIB                                                       19 (25.7%)

  III                                                       22 (29.7%)

  IVA                                                       16 (21.6%)

  IVB                                                         4 (5.4%)

----------------------------------------------------------------------

  Racial Origin, n (%)

----------------------------------------------------------------------

  Asian                                                       1 (1.4%)

  Black                                                     11 (14.9%)

  Other                                                       1 (1.4%)

  White                                                     61 (82.4%)

----------------------------------------------------------------------

  Time from Initial CTCL Diagnosis (year)

----------------------------------------------------------------------

  Median (Range)                                       2.6 (0.0, 27.3)

----------------------------------------------------------------------

  Clinical Characteristics

----------------------------------------------------------------------

  Number of prior systemic treatments, median (range)  3.0 (1.0, 12.0)

----------------------------------------------------------------------



    The overall objective response rate was 29.7% (22/74, 95% Cl (19.7

to 41.5%)) in all patients treated with ZOLINZA. In patients with

Stage IIB and higher CTCL, the overall objective response rate was

29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median

times to response were 55 and 56 days (range 28 to 171 days),

respectively in the overall population and in patients with Stage IIB

and higher CTCL. However, in rare cases it took up to 6 months for

patients to achieve an objective response to ZOLINZA.


    The median response duration was not reached since the majority of

responses continued at the time of analysis, but was estimated to

exceed 6 months for both the overall population and in patients with

Stage IIB and higher CTCL. When end of response was defined as a 50%

increase in SWAT score from the nadir, the estimated median response

duration was 168 days and the median time to tumor progression was 202

days.


    Using a 25% increase in SWAT score from the nadir as criterion for

tumor progression, the estimated median time-to-progression was 148

days for the overall population and 169 days in the 61 patients with

Stage IIB and higher CTCL.


    Response to any previous systemic therapy does not appear to be

predictive of response to ZOLINZA.


    Study 2


    In an open-label, non-randomized study, ZOLINZA was evaluated to

determine the response rate for patients with CTCL who were refractory

or intolerant to at least one treatment. In this study, 33 patients

were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort

2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for

14 days followed by a 7-day rest (induction). In Cohort 3, if at least

a partial response was not observed then patients were dosed with a

maintenance regimen of 200 mg twice daily. The primary efficacy

endpoint, objective response, was measured by the 7-point Physician's

Global Assessment (PGA) scale. The investigator assessed improvement

or worsening in overall disease compared to baseline based on overall

clinical impression. Index and non-index cutaneous lesions as well as

cutaneous tumors, lymph nodes and all other disease manifestations

were also assessed and included in the overall clinical impression.

CCR required 100% clearing of all findings, and PR required at least

50% improvement in disease findings.


    The median age was 67.0 years (range 26.0 to 82.0). Fifty-five

percent of patients were male, and 45% of patients were female.

Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of

patients had Stage IIB, III, IVA, or IVB CTCL. The median number of

prior systemic therapies was 4 (range 0.0 to 11.0).


    In all patients treated, the objective response was 24.2% (8/33)

in the overall population, 25% (7/28) in patients with Stage IIB or

higher disease and 36.4% (4/11) in patients with Sezary syndrome. The

overall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort

2 and Cohort 3, respectively. The 300 mg twice daily regimen had

higher toxicity with no additional clinical benefit over the 400 mg

once daily regimen. No CCR was observed.


    Among the 8 patients who responded to study treatment, the median

time to response was 83.5 days (range 25 to 153 days). The median

response duration was 106 days (range 66 to 136 days). Median time to

progression was 211.5 days (range 94 to 255 days).


    15 REFERENCES


    1.NIOSH Alert: Preventing occupational exposures to antineoplastic

and other hazardous drugs in healthcare settings. 2004. U.S.

Department of Health and Human Services, Public Health Service,

Centers for Disease Control and Prevention, National Institute for

Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.


    2.OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2.

Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.

http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html


    3.NIH (2002). 1999 recommendations for the safe handling of

cytotoxic drugs. U.S. Department of Health and Human Services, Public

Health Service, National Institutes of Health, NIH Publication No.

92-2621.


    4.American Society of Health-System Pharmacists. (2006) ASHP

Guidelines on Handling Hazardous Drugs.


    5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005.

Chemotherapy and biotherapy guidelines and recommendations for

practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.


    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(degree)C (68-77(degree)F), excursions permitted

between 15-30(degree)C (59-86(degree)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.1-5 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)).


    17 PATIENT COUNSELING INFORMATION


    (See FDA-Approved Patient Labeling (17.2))


    17.1 Instructions


    Patients should be instructed to drink at least 2 L/day of fluid

to prevent dehydration and should promptly report excessive vomiting

or diarrhea to their physician. Patients should be instructed about

the signs of deep vein thrombosis and should consult their physician

should any evidence of deep vein thrombosis develop. Patients

receiving ZOLINZA should seek immediate medical attention if unusual

bleeding occurs. ZOLINZA capsules should not be opened or crushed.


    Patients should be instructed to read the patient insert

carefully.


    Manufactured for:


    MERCK & CO., INC., Whitehouse Station, NJ 08889, USA


    Manufactured by:


    Patheon, Inc.


    Mississauga, Ontario, Canada L5N 7K9


    Printed in USA


    9762600


    U.S. Patent Nos. RE 38,506 E, 6,087,367


    17.2 FDA-Approved Patient Labeling


    (1)Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey

08889 USA


    COPYRIGHT (C) 2006 MERCK & CO., Inc.


    All rights reserved



                                                 Patient Information

                                                             9762600

                       ZOLINZA(TM) (zo LINZ ah)

                             (vorinostat)

                               Capsules


    Read the patient information that comes with ZOLINZA(1) before you

start taking it and each time you get a refill. There may be new

information. This leaflet is a summary of the information for

patients. Your doctor or pharmacist can give you additional

information. This leaflet does not take the place of talking with your

doctor about your medical condition or your treatment.


    What is ZOLINZA?


    ZOLINZA is a prescription medicine used to treat a type of cancer

called cutaneous T-cell lymphoma (CTCL) in patients when the CTCL gets

worse, does not go away, or comes back after treatment with other

medicines.


    ZOLINZA has not been studied in children under the age of 18.


    What should I tell my doctor before taking ZOLINZA?


    Tell your doctor about all of your medical conditions, including

if you:


    --  Have any allergies


    --  Have had a blood clot in your lung (pulmonary embolus)


    --  Have had a blood clot in a vein (a blood vessel) anywhere in

        your body (deep vein thrombosis)


    --  Have nausea, vomiting, or diarrhea


    --  Have high blood sugar or diabetes


    --  Have heart problems


    --  Are pregnant or plan to become pregnant. ZOLINZA may harm your

        unborn baby. ZOLINZA has not been studied in pregnant women.

        If you use ZOLINZA during pregnancy, tell your doctor

        immediately.


    --  Are breast-feeding or plan to breast-feed. It is not known if

        ZOLINZA will pass into your breast milk. Talk to your doctor

        about the best way to feed your baby while you are taking

        ZOLINZA.


    Tell your doctor about all of the medicines you take, including

prescription and non-prescription medicines, vitamins and herbal

supplements. Some medicines may affect how ZOLINZA works, or ZOLINZA

may affect how your other medicines work. Especially tell your doctor

if you take:


    --  Valproic acid: a medicine used to treat seizures. Your doctor

        will decide if you should continue to take valproic acid and

        may want to test your blood more frequently.


    --  COUMADIN(R): (warfarin) or any other blood thinner. Ask your

        doctor if you are not sure if you are taking a blood thinner.

        Your doctor may want to test your blood more frequently.


    Know the medicines you take. Keep a list of your medicines and

show it to your doctor and pharmacist when you get a new medicine.


    How should I take ZOLINZA?


    --  Take ZOLINZA exactly as your doctor tells you to.


    --  Your doctor will tell you how many ZOLINZA capsules to take

        and when to take them.


    --  Swallow each capsule whole. Do not chew or break open the

        capsule. If you can't swallow ZOLINZA capsules whole, tell

        your doctor. You may need a different medicine.


    --  Take ZOLINZA with food.


    --  If ZOLINZA capsules are accidentally opened or crushed, do not

        touch the capsules or the powder contents of the capsules. If

        the powder from an open or crushed capsule gets on your skin

        or in your eyes, wash the contacted area well with plenty of

        plain water. Call your doctor.


    --  Drink at least eight 8-ounce glasses of liquids every day

        while taking ZOLINZA. Drinking enough fluids may help to

        decrease the chances of losing too much fluid from your body

        (dehydration) especially if you are having symptoms such as

        nausea, vomiting or diarrhea while taking ZOLINZA.


    --  If you miss a dose, take it as soon as you remember. If you do

        not remember until it is almost time for your next dose, just

        skip the missed dose. Just take the next dose at your regular

        time. Do not take two doses of ZOLINZA at the same time.


    --  If you take too much ZOLINZA, call your doctor, local

        emergency room, or poison control center right away.


    --  Your doctor will check your blood cell counts, blood sugar,

        and other chemistries every two weeks for the first two months

        of your treatment with ZOLINZA and then monthly. Your doctor

        may decide to do other tests to check your health as needed.


    --  If you have high blood sugar (hyperglycemia) or diabetes,

        continue to monitor your blood sugar as your doctor tells you

        to. Your doctor may need to change your diet or medicine to

        help control your blood sugar while you take ZOLINZA. Be sure

        to tell your doctor if you are unable to eat or drink normally

        due to nausea, vomiting or diarrhea.


    What are the possible side effects of ZOLINZA?


    ZOLINZA may cause serious side effects. Tell your doctor right

away if you have any of the following symptoms:


    --  Blood clots in the legs (deep vein thrombosis)


        --  sudden swelling in a leg


        --  pain or tenderness in the leg. The pain may only be felt

            when standing or walking.


        --  increased warmth in the area where the swelling is.


        --  skin redness or change in skin color


    --  Blood clots that travel to the lungs (pulmonary embolus)


        -- sudden sharp chest pain               -- rapid pulse

        -- shortness of breath                   -- fainting

        -- cough with bloody secretions          -- feeling anxious

        -- sweating


    --  Dehydration (loss of too much fluid from the body). This can

        happen if you are having nausea, vomiting or diarrhea and can

        not drink fluids well.


    --  Low blood cell counts: Your doctor will periodically do blood

        tests to check your blood counts.


        --  Low red blood cells. Low red blood cells may make you feel

            tired and get tired easily. You may look pale, and feel

            short of breath.


        --  Low platelets. Low platelets can cause unusual bleeding or

            bruising under the skin. Talk to your doctor right away if

            this happens.


    --  High blood sugar (blood glucose). If you have high blood sugar

        or diabetes, monitor your blood sugar frequently as directed

        by your doctor. Tell your doctor right away if your blood

        sugar is higher than normal.


    --  Electrocardiogram abnormality. An electrocardiogram, or EKG,

        is a test that records the electrical activity of your heart.

        Your doctor will check your blood electrolytes and

        electrocardiogram periodically.


    In addition, the most common side effects with ZOLINZA include:


    --  Stomach and intestinal problems, including diarrhea, nausea,

        vomiting, loss of appetite, constipation and weight loss


    --  Tiredness


    --  Dizziness


    --  Headache


    --  Changes in the way things taste and dry mouth


    --  Muscle aches


    --  Hair loss


    --  Chills


    --  Fever


    --  Upper respiratory infection


    --  Cough


    --  Increase in blood creatinine


    --  Swelling in the foot, ankle and leg


    --  Itching


    Tell your doctor if you have any side effect that bothers you or

that does not go away.


    These are not all the possible side effects of ZOLINZA. For more

information, ask your doctor or pharmacist.


    General information about ZOLINZA


    Medicines are sometimes prescribed for conditions that are not

mentioned in patient information leaflets. Do not use ZOLINZA for a

condition for which it was not prescribed. Do not give ZOLINZA to

other people, even if they have the same symptoms you have. It may

harm them.


    Keep ZOLINZA and all medicines out of the reach of children.


    This leaflet summarizes the most important information about

ZOLINZA. If you would like to know more information, talk to your

doctor. You can ask your doctor or pharmacist for information about

ZOLINZA that is written for health professionals.


    What are the ingredients in ZOLINZA?


    Active ingredient: vorinostat


    Inactive ingredients: microcrystalline cellulose, sodium

croscarmellose and magnesium stearate. The inactive ingredients in the

capsule shell are titanium dioxide, gelatin, and sodium lauryl

sulfate.


    How should I store ZOLINZA?


    Store ZOLINZA at room temperature, 68(degrees)F to 77(degrees) F

(20(degrees)C to 25(degrees)C).


    Issued: October 2006


    MERCK & CO., INC.


    Whitehouse Station, NJ 08889, USA


    9762600


    (1) Trademark of Merck & Co., Inc., Whitehouse Station, New

Jersey, 08889 USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights

reserved

Contact

Merck & Co., Inc.
Media:
Ron Rogers, 908-423-6449
or
Pam Eisele, 267-305-7896
or
Investors:
Graeme Bell, 908-423-5185

Posted: July 2007

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