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

Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved oral ZOLINZA™ (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™ is a registered trademark of Merck & Co., Inc. 9762600 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to useZOLINZA safely and effectively. See full prescribing information forZOLINZA. 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 withcutaneous T-cell lymphoma (CTCL) who have progressive, persistent orrecurrent 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 patientlabeling. 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 prescribinginformation are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ZOLINZA(1) is indicated for the treatment of cutaneousmanifestations in patients with cutaneous T-cell lymphoma who haveprogressive, persistent or recurrent disease on or following twosystemic 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 ofprogressive disease or unacceptable toxicity. ZOLINZA capsules should not be opened or crushed (see HowSupplied/Storage and Handling (16)). 2.2 Dose Modifications If a patient is intolerant to therapy, the dose may be reduced to300 mg orally once daily with food. The dose may be further reduced to300 mg once daily with food for 5 consecutive days each week, asnecessary. 2.3 Dosing in Special Populations No information is available in patients with renal or hepaticimpairment (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 reportedas adverse reactions, physicians should be alert to the signs andsymptoms of these events, particularly in patients with a priorhistory of thromboembolic events (see Adverse Reactions (6)). 5.2 Hematologic Treatment with ZOLINZA can cause dose-related thrombocytopenia andanemia. If platelet counts and/or hemoglobin are reduced duringtreatment with ZOLINZA, the dose should be modified or therapydiscontinued. (See Dosage and Administration (2.2), Warnings andPrecautions (5.6) and Adverse Reactions (6).) 5.3 Gastrointestinal Gastrointestinal disturbances, including nausea, vomiting anddiarrhea, have been reported (see Adverse Reactions (6)) and mayrequire the use of antiemetic and antidiarrheal medications. Fluid andelectrolytes should be replaced to prevent dehydration (see AdverseReactions (6.1)). Pre-existing nausea, vomiting, and diarrhea shouldbe adequately controlled before beginning therapy with ZOLINZA. 5.4 Hyperglycemia Hyperglycemia has been observed in patients receiving ZOLINZA (seeAdverse Reactions (6.1)). Serum glucose should be monitored,especially in diabetic or potentially diabetic patients. Adjustment ofdiet 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 beenconducted. Three of 86 CTCL patients exposed to 400 mg once daily hadGrade 1 (greater than450-470 msec) or 2 (greater than470-500 msec orincrease of greater than60 msec above baseline) clinical adverseevents of QTc prolongation. In a retrospective analysis of three Phase1 and two Phase 2 studies, 116 patients had a baseline and at leastone follow-up ECG. Four patients had Grade 2 (greater than470-500 msecor increase of greater than60 msec above baseline) and 1 patient hadGrade 3 (greater than500 msec) QTc prolongation. In 49 non-CTCLpatients from 3 clinical trials who had complete evaluation of QTinterval, 2 had QTc measurements of greater than500 msec and 1 had aQTc 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 beperformed every 2 weeks during the first 2 months of therapy andmonthly thereafter. Electrolyte monitoring should include potassium,magnesium and calcium. Baseline and periodic ECGs should be performedduring treatment. ZOLINZA should be administered with particularcaution in patients with congenital long QT syndrome, and patientstaking anti-arrhythmic medicines or other medicinal products that leadto QT prolongation. Hypokalemia or hypomagnesemia should be correctedprior to administration of ZOLINZA, and consideration should be givento monitoring potassium and magnesium in symptomatic patients (e.g.,patients with nausea, vomiting, diarrhea, fluid imbalance or cardiacsymptoms). (See Warnings and Precautions (5.5).) 5.7 Other Histone Deacetylase (HDAC) Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have beenreported with concomitant use of ZOLINZA and other HDAC inhibitors(e.g., valproic acid). Monitor platelet count every 2 weeks during thefirst 2 months. (See Drug Interactions (7.2)). 5.8 Pregnancy Pregnancy Category D ZOLINZA can cause fetal harm when administered to a pregnantwoman. There are no adequate and well-controlled studies of ZOLINZA inpregnant women. Results of animal studies indicate that vorinostatcrosses 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 weretested in rats and rabbits, respectively (about0.5 times the humanexposure based on AUC0-24 hours). Treatment-related developmentaleffects including decreased mean live fetal weights, incompleteossifications of the skull, thoracic vertebra, sternebra, and skeletalvariations (cervical ribs, supernumerary ribs, vertebral count andsacral arch variations) in rats at the highest dose of vorinostattested. Reductions in mean live fetal weight and an elevated incidenceof incomplete ossification of the metacarpals were seen in rabbitsdosed at 150 mg/kg/day. The no observed effect levels (NOELs) forthese findings were 15 and 50 mg/kg/day (less than0.1 times the humanexposure based on AUC) in rats and rabbits, respectively. Adose-related increase in the incidence of malformations of the gallbladder was noted in all drug treatment groups in rabbits versus theconcurrent control. If this drug is used during pregnancy, or if thepatient becomes pregnant while taking this drug, the patient should beapprised of the potential hazard to the fetus. 6 ADVERSE REACTIONS The most common drug-related adverse reactions can be classifiedinto 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea,anorexia, weight decrease, vomiting, constipation), constitutionalsymptoms (fatigue, chills), hematologic abnormalities(thrombocytopenia, anemia), and taste disorders (dysgeusia, drymouth). The most common serious drug-related adverse reactions werepulmonary embolism and anemia. 6.1 Clinical Trials Experience The safety of ZOLINZA was evaluated in 107 CTCL patients in twosingle arm clinical studies in which 86 patients received 400 mg oncedaily. The data described below reflect exposure to ZOLINZA 400 mg oncedaily 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 beyond24 weeks and 8 (9.3%) patients were exposed beyond 1 year. Thepopulation 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 ormulti-racial. Because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trials ofa drug cannot be directly compared to rates in the clinical trials ofanother drug and may not reflect the rates observed in practice. Common Adverse Reactions Table 1 summarizes the frequency of CTCL patients with specificadverse events, regardless of causality, using the National CancerInstitute-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 (seeWarnings and Precautions (5.2)) and fatigue were increased at doseshigher 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 pulmonaryembolism reported in 4.7% (4/86) of patients, squamous cell carcinomareported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86)of patients. There were single events of cholecystitis, death (ofunknown cause), deep vein thrombosis, enterococcal infection,exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobarpneumonia, myocardial infarction, ischemic stroke, pelvi-uretericobstruction, 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. Theseadverse events, regardless of causality, included anemia,angioneurotic edema, asthenia, chest pain, exfoliative dermatitis,death, deep vein thrombosis, ischemic stroke, lethargy, pulmonaryembolism, 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 dueto adverse events. These adverse events included increased serumcreatinine, decreased appetite, hypokalemia, leukopenia, nausea,neutropenia, thrombocytopenia and vomiting. The median time to thefirst adverse event resulting in dose reduction was 42 days (range 17to 263 days). Laboratory Abnormalities Laboratory abnormalities were reported in all of the 86 CTCLpatients who received the 400-mg once-daily dose. Increased serum glucose was reported as a laboratory abnormalityin 69% (59/86) of CTCL patients who received the 400-mg once dailydose; only 4 of these abnormalities were severe (Grade 3). Increasedserum glucose was reported as an adverse event in 8.1% (7/86) of CTCLpatients who received the 400-mg once daily dose. (See Warnings andPrecautions (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. Ofthese laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 wereGrade 2, and 1 was Grade 3. Proteinuria was detected as a laboratory abnormality (51.4%) in 38of 74 patients tested. The clinical significance of this finding isunknown. Dehydration Based on reports of dehydration as a serious drug-related adverseevent in clinical trials, patients were instructed to drink at least2 L/day of fluids for adequate hydration. (See Warnings andPrecautions (5.3, 5.6).) Adverse Reactions in Non-CTCL Patients The frequencies of individual adverse events were substantiallyhigher in the non-CTCL population. Drug-related serious adverse eventsreported in the non-CTCL population which were not observed in theCTCL population included single events of blurred vision, asthenia,hyponatremia, tumor hemorrhage, Guillain-Barre syndrome, renalfailure, urinary retention, cough, hemoptysis, hypertension, andvasculitis. 7 DRUG INTERACTIONS 7.1 Coumarin-Derivative Anticoagulants Prolongation of prothrombin time (PT) and International NormalizedRatio (INR) were observed in patients receiving ZOLINZA concomitantlywith coumarin-derivative anticoagulants. Physicians should carefullymonitor PT and INR in patients concurrently administered ZOLINZA andcoumarin derivatives. 7.2 Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have beenreported with concomitant use of ZOLINZA and other HDAC inhibitors(e.g., valproic acid). Monitor platelet count every 2 weeks for thefirst 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 thepotential for serious adverse reactions in nursing infants fromZOLINZA, a decision should be made whether to discontinue nursing ordiscontinue the drug, taking into account the importance of the drugto the mother. 8.4 Pediatric Use The safety and effectiveness of ZOLINZA in pediatric patients havenot been established. 8.5 Geriatric Use Of the total number of patients with CTCL in trials (N=107), 46percent were 65 years of age and over, while 15 percent were 75 yearsof age and over. No overall differences in safety or effectivenesswere observed between these subjects and younger subjects, and otherreported clinical experience has not identified differences inresponses between the elderly and younger patients, but greatersensitivity 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, patientswith hepatic impairment should be treated with caution. (See ClinicalPharmacology (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 ofvorinostat. Patients with pre-existing renal impairment should betreated with caution. (See Clinical Pharmacology (12.3).) 10 OVERDOSAGE No specific information is available on the treatment ofoverdosage of ZOLINZA. In the event of overdose, it is reasonable to employ the usualsupportive measures, e.g., remove unabsorbed material from thegastrointestinal tract, employ clinical monitoring, and institutesupportive therapy, if required. It is not known if vorinostat isdialyzable. 11 DESCRIPTION ZOLINZA contains vorinostat, which is described chemically asN-hydroxy-N'-phenyloctanediamide. The empirical formula is C14H20N2O3. The molecular weight is264.32 and the structural formula is: (OBJECT OMITTED) Vorinostat is a white to light orange powder. It is very slightlysoluble in water, slightly soluble in ethanol, isopropanol andacetone, freely soluble in dimethyl sulfoxide and insoluble inmethylene chloride. It has no chiral centers and is non-hygroscopic.The differential scanning calorimetry ranged from 161.7 (endotherm) to163.9(degree)C. The pH of saturated water solutions of vorinostat drugsubstance was 6.6. The pKa of vorinostat was determined to be 9.2. Each 100 mg ZOLINZA capsule for oral administration contains100 mg vorinostat and the following inactive ingredients:microcrystalline cellulose, sodium croscarmellose and magnesiumstearate. The capsule shell excipients are titanium dioxide, gelatinand sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vorinostat inhibits the enzymatic activity of histone deacetylasesHDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolarconcentrations (IC50less than86 nM). These enzymes catalyze theremoval 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 ofHDACs to oncogenic transcription factors causing hypoacetylation ofcore nucleosomal histones. Hypoacetylation of histones is associatedwith a condensed chromatin structure and repression of genetranscription. Inhibition of HDAC activity allows for the accumulationof acetyl groups on the histone lysine residues resulting in an openchromatin structure and transcriptional activation. In vitro,vorinostat causes the accumulation of acetylated histones and inducescell cycle arrest and/or apoptosis of some transformed cells. Themechanism of the antineoplastic effect of vorinostat has not beenfully characterized. 12.3 Pharmacokinetics Absorption The pharmacokinetics of vorinostat were evaluated in 23 patientswith relapsed or refractory advanced cancer. After oral administrationof a single 400-mg dose of vorinostat with a high-fat meal, the mean+/- standard deviation area under the curve (AUC) and peak serumconcentration (Cmax) and the median (range) time to maximumconcentration (Tmax) were 5.5+/-1.8 uM-hr, 1.2+/-0.62 microM and4 (2-10) hours, respectively. In the fasted state, oral administration of a single 400-mg doseof vorinostat resulted in a mean AUC and Cmax and median Tmax of4.2+/-1.9 microM-hr and 1.2+/-0.35 microM and 1.5 (0.5-10) hours,respectively. Therefore, oral administration of vorinostat with ahigh-fat meal resulted in an increase (33%) in the extent ofabsorption and a modest decrease in the rate of absorption (Tmaxdelayed 2.5 hours) compared to the fasted state. However, these smalleffects are not expected to be clinically meaningful. In clinicaltrials of patients with CTCL, vorinostat was taken with food. At steady state in the fed-state, oral administration of multiple400-mg doses of vorinostat resulted in a mean AUC and Cmax and amedian 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 proteinsover the range of concentrations of 0.5 to 50 microg/mL. Metabolism The major pathways of vorinostat metabolism involveglucuronidation and hydrolysis followed by (beta)-oxidation. Humanserum levels of two metabolites, O-glucuronide of vorinostat and4-anilino-4-oxobutanoic acid were measured. Both metabolites arepharmacologically inactive. Compared to vorinostat, the mean steadystate serum exposures in humans of the O-glucuronide of vorinostat and4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher,respectively. In vitro studies using human liver microsomes indicate negligiblebiotransformation by cytochromes P450 (CYP). Excretion Vorinostat is eliminated predominantly through metabolism withless than 1% of the dose recovered as unchanged drug in urine,indicating that renal excretion does not play a role in theelimination of vorinostat. The mean urinary recovery of twopharmacologically 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 urinaryrecovery of vorinostat and these two metabolites averaged 52+/-13.3%of vorinostat dose. The mean terminal half-life (t 1/2) was about2.0hours for both vorinostat and the O-glucuronide metabolite, while thatof the 4-anilino-4-oxobutanoic acid metabolite was 11 hours. Special Populations Based upon an exploratory analysis of limited data, gender, raceand age do not appear to have meaningful effects on thepharmacokinetics 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 ofvorinostat. (See Use In Specific Populations (8.7).) Pharmacokinetic effects of vorinostat with other agents Vorinostat is not an inhibitor of CYP drug metabolizing enzymes inhuman liver microsomes at steady state Cmax of the 400 mg dose (Cmaxof 1.2 microM vs IC50 of greater than75 microM). Gene expressionstudies in human hepatocytes detected some potential for suppressionof CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher(=>10 microM) than pharmacologically relevant. Thus, vorinostat is notexpected to affect the pharmacokinetics of other agents. As vorinostatis not eliminated via the CYP pathways, it is anticipated thatvorinostat will not be subject to drug-drug interactions whenco-administered with drugs that are known CYP inhibitors or inducers.However, no formal clinical studies have been conducted to evaluatedrug 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 reversemutation assays (Ames test), caused chromosomal aberrations in vitroin Chinese hamster ovary (CHO) cells and increased the incidence ofmicro-nucleated erythrocytes when administered to mice (MouseMicronucleus Assay). Effects on the female reproductive system were identified in theoral fertility study when females were dosed for 14 days prior tomating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day torats resulted in approximate exposures of 0.15, 0.36 and 0.70 timesthe expected clinical exposure based on AUC. Dose dependent increasesin corpora lutea were noted at =>15 mg/kg/day, which resulted inincreased peri-implantation losses were noted at (greater than=)50mg/kg/day. At 150 mg/kg/day, there were increases in the incidences ofdead fetuses and in resorptions. No effects on reproductive performance were observed in male ratsdosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and0.70 times the expected clinical exposure based on AUC), for 70 daysprior 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 CTCLhave been evaluated to determine their response rate to oral ZOLINZA.One study was a single-arm clinical study and the other assessedseveral dosing regimens. In both studies, patients were treated untildisease progression or intolerable toxicity. Study 1 In an open-label, single-arm, multicenter non-randomized study, 74patients with advanced CTCL were treated with ZOLINZA at a dose of400 mg once daily. The primary endpoint was response rate to oralZOLINZA in the treatment of skin disease in patients with advancedCTCL (Stage IIB and higher) who had progressive, persistent, orrecurrent disease on or following two systemic therapies. Enrolledpatients should have received, been intolerant to or not a candidatefor bexarotene. Extent of skin disease was quantitatively assessed byinvestigators using a modified Severity Weighted Assessment Tool(SWAT). The investigator measured the percentage total body surfacearea (%TBSA) involvement separately for patches, plaques, and tumorswithin 12 body regions using the patient's palm as a "ruler". Thetotal %TBSA for each lesion type was multiplied by a severityweighting factor (1=patch, 2=plaque and 4=tumor) and summed to derivethe SWAT score. Efficacy was measured as either a Complete ClinicalResponse (CCR) defined as no evidence of disease, or Partial Response(PR) defined as a =>50% decrease in SWAT skin assessment scorecompared to baseline. Both CCR and PR had to be maintained for atleast 4 weeks. Secondary efficacy endpoints included response duration, time toprogression, and time to objective response. The population had been exposed to a median of three priortherapies (range 1 to 12). Table 2 summarizes the demographic and disease characteristics ofthe 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 (19.7to 41.5%)) in all patients treated with ZOLINZA. In patients withStage IIB and higher CTCL, the overall objective response rate was29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Mediantimes to response were 55 and 56 days (range 28 to 171 days),respectively in the overall population and in patients with Stage IIBand higher CTCL. However, in rare cases it took up to 6 months forpatients to achieve an objective response to ZOLINZA. The median response duration was not reached since the majority ofresponses continued at the time of analysis, but was estimated toexceed 6 months for both the overall population and in patients withStage IIB and higher CTCL. When end of response was defined as a 50%increase in SWAT score from the nadir, the estimated median responseduration was 168 days and the median time to tumor progression was 202days. Using a 25% increase in SWAT score from the nadir as criterion fortumor progression, the estimated median time-to-progression was 148days for the overall population and 169 days in the 61 patients withStage IIB and higher CTCL. Response to any previous systemic therapy does not appear to bepredictive of response to ZOLINZA. Study 2 In an open-label, non-randomized study, ZOLINZA was evaluated todetermine the response rate for patients with CTCL who were refractoryor intolerant to at least one treatment. In this study, 33 patientswere assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for14 days followed by a 7-day rest (induction). In Cohort 3, if at leasta partial response was not observed then patients were dosed with amaintenance regimen of 200 mg twice daily. The primary efficacyendpoint, objective response, was measured by the 7-point Physician'sGlobal Assessment (PGA) scale. The investigator assessed improvementor worsening in overall disease compared to baseline based on overallclinical impression. Index and non-index cutaneous lesions as well ascutaneous tumors, lymph nodes and all other disease manifestationswere also assessed and included in the overall clinical impression.CCR required 100% clearing of all findings, and PR required at least50% improvement in disease findings. The median age was 67.0 years (range 26.0 to 82.0). Fifty-fivepercent of patients were male, and 45% of patients were female.Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% ofpatients had Stage IIB, III, IVA, or IVB CTCL. The median number ofprior 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 orhigher disease and 36.4% (4/11) in patients with Sezary syndrome. Theoverall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort2 and Cohort 3, respectively. The 300 mg twice daily regimen hadhigher toxicity with no additional clinical benefit over the 400 mgonce daily regimen. No CCR was observed. Among the 8 patients who responded to study treatment, the mediantime to response was 83.5 days (range 25 to 153 days). The medianresponse duration was 106 days (range 66 to 136 days). Median time toprogression was 211.5 days (range 94 to 255 days). 15 REFERENCES 1.NIOSH Alert: Preventing occupational exposures to antineoplasticand 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 forOccupational 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 ofcytotoxic drugs. U.S. Department of Health and Human Services, PublicHealth Service, National Institutes of Health, NIH Publication No.92-2621. 4.American Society of Health-System Pharmacists. (2006) ASHPGuidelines on Handling Hazardous Drugs. 5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005.Chemotherapy and biotherapy guidelines and recommendations forpractice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. 16 HOW SUPPLIED/STORAGE AND HANDLING ZOLINZA capsules, 100 mg, are white, opaque hard gelatin capsuleswith "568" over "100 mg" printed within the radial bar in black ink onthe 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 permittedbetween 15-30(degree)C (59-86(degree)F). (See USP Controlled RoomTemperature.) Procedures for proper handling and disposal of anticancer drugsshould be considered. Several guidelines on this subject have beenpublished.1-5 There is no general agreement that all of the proceduresrecommended 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 ormucous membranes should be avoided. If such contact occurs, washthoroughly as outlined in the references. Personnel should avoidexposure 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 fluidto prevent dehydration and should promptly report excessive vomitingor diarrhea to their physician. Patients should be instructed aboutthe signs of deep vein thrombosis and should consult their physicianshould any evidence of deep vein thrombosis develop. Patientsreceiving ZOLINZA should seek immediate medical attention if unusualbleeding occurs. ZOLINZA capsules should not be opened or crushed. Patients should be instructed to read the patient insertcarefully. 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 Jersey08889 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 youstart taking it and each time you get a refill. There may be newinformation. This leaflet is a summary of the information forpatients. Your doctor or pharmacist can give you additionalinformation. This leaflet does not take the place of talking with yourdoctor about your medical condition or your treatment. What is ZOLINZA? ZOLINZA is a prescription medicine used to treat a type of cancercalled cutaneous T-cell lymphoma (CTCL) in patients when the CTCL getsworse, does not go away, or comes back after treatment with othermedicines. 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, includingif 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, includingprescription and non-prescription medicines, vitamins and herbalsupplements. Some medicines may affect how ZOLINZA works, or ZOLINZAmay affect how your other medicines work. Especially tell your doctorif 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 andshow 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 rightaway 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 orthat does not go away. These are not all the possible side effects of ZOLINZA. For moreinformation, ask your doctor or pharmacist. General information about ZOLINZA Medicines are sometimes prescribed for conditions that are notmentioned in patient information leaflets. Do not use ZOLINZA for acondition for which it was not prescribed. Do not give ZOLINZA toother people, even if they have the same symptoms you have. It mayharm them. Keep ZOLINZA and all medicines out of the reach of children. This leaflet summarizes the most important information aboutZOLINZA. If you would like to know more information, talk to yourdoctor. You can ask your doctor or pharmacist for information aboutZOLINZA that is written for health professionals. What are the ingredients in ZOLINZA? Active ingredient: vorinostat Inactive ingredients: microcrystalline cellulose, sodiumcroscarmellose and magnesium stearate. The inactive ingredients in thecapsule shell are titanium dioxide, gelatin, and sodium laurylsulfate. 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, NewJersey, 08889 USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rightsreserved