FDA Approves ZOLINZA(TM) (Vorinostat) for the Treatment of Cutaneous Manifestations in Patients with Cutaneous T-Cell Lymphoma Who Have Tried and Failed Other Therapies.

ZOLINZA is Merck's First Anticancer Treatment in Decades to Be Approved by the FDA

WHITEHOUSE STATION, N.J. -- Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved oral ZOLINZA[TM] (vorinostat) 400 mg once daily for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin's lymphoma, 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.

ZOLINZA is a histone deacetylase (HDAC) inhibitor. Based on in vitro studies, ZOLINZA inhibits the enzymatic activity of HDAC1, HDAC2, HDAC3 (Class I) and HDAC 6 (class II) at nanomolar concentrations (IC50<86 nM). In some cancer cells, excess amounts of the enzyme HDAC prevent the activation of genes that control normal cell activity. ZOLINZA is believed to decrease the activity of HDAC. Decreasing the activity of HDAC allows for the activation of genes that may help to slow or stop the growth of cancer cells. The exact mechanism of the anticancer effect of ZOLINZA has not been fully characterized.

"With today's FDA approval of ZOLINZA, there is now an effective new option in the fight against cutaneous manifestations of cutaneous T-cell lymphoma, specifically in patients who have tried and failed other cancer treatment options," said Elise Olsen, M.D., director, CTCL Clinic & Research Center at Duke University Medical Center and lead investigator of one of the studies that led to the approval.

The approval is based on two open-label clinical studies in which CTCL patients with refractory CTCL were evaluated to determine their response rate to oral ZOLINZA. One study was a Phase IIb, single-arm pivotal clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity.

In the open-label, single-arm, pivotal study, the median age of patients 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 of patients 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 (SWAT).

The overall objective response rate in this study was 29.7 percent (22 of 74, 95% CI [19.7 to 41.5%]) in all patients treated with ZOLINZA. Objective response was defined as at least four weeks of either a complete response, defined as no evidence of disease, or partial response, defined as greater than or equal to 50 percent decrease in a skin assessment score compared to baseline.

Secondary endpoints in this study included: time to objective response, time-to-progression, and duration of objective response. In the study, the median time to 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. The median time to progression approached five months (148 days) in all patients, based on a criterion for tumor progression of a 25 percent increase in SWAT score from the nadir.

The safety of ZOLINZA was evaluated in 107 cutaneous T-cell lymphoma patients in two single-arm clinical studies in which 86 patients received ZOLINZA 400 mg once daily. The most common side effects, regardless of causality, included fatigue (52 percent), diarrhea (52 percent), nausea (41 percent), change in taste (28 percent), low platelet count (26 percent), anorexia (24 percent), weight decrease (21 percent), and muscle spasms (20 percent).

"It is very gratifying to have ZOLINZA approved by the FDA for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who have tried and failed other therapies. I am confident it will be an important new addition to treat patients with CTCL," said Paul Marks, M.D., president emeritus and member of the Sloan-Kettering Institute. "ZOLINZA was developed in an academic collaboration between the chemistry group of Ronald Breslow at Columbia University and my cancer biology group at Memorial Sloan-Kettering. It is exciting to have Merck as a partner in the clinical development and FDA approval of ZOLINZA."

Dosing and administration

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.

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 as least two L/Day of fluids for adequate hydration. Hyperclycemia 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 was reported in 3.5 percent (3/86) of patients and anemia was reported in 2.3 percent (2/86) of patients.

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 metabolisym, patients with hepatic impairment should be treated with caution.

Availability and access

ZOLINZA will be made 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 Assistance Program, which allows them to receive ZOLINZA free of charge. Merck is also 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.

About CTCL

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. 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 cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, 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 are attached.

ZOLINZA[TM] is a registered trademark of Merck & Co., Inc.

                                                              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 =>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 than450-470 msec) or 2 (greater than470-500 msec or
increase of greater than60 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 than470-500 msec
or increase of greater than60 msec above baseline) and 1 patient had
Grade 3 (greater than500 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 than500 msec and 1 had a
QTc prolongation of greater than60 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 (about0.5 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 than0.1 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 (IC50less than86 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 about2.0
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 than18 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 than75 microM). Gene expression
studies in human hepatocytes detected some potential for suppression
of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher
(=>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 =>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 =>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