ࡱ> mojkl bjbjVV 8<<d]]]]]qqq8Uq ["/"(W"W"W"#X#$yZ{Z{Z{Z{Z{Z{Z]_F{Z]$##$${Z]]W"W"4ZHo%o%o%$R]W"]W"yZo%$yZo%o%STZW" bqe$R'WNeZZH [uW_$_ZZ&_])Z<$$o%$$$$${Z{Zo%$$$ [$$$$_$$$$$$$$$ #: Vilazodone (Viibryd) National Drug Monograph February 2012 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: Vilazodone is a serotonin reuptake inhibitor and partial agonist at 5HT1a receptors. FDA labeled indications: Major depressive disorder (MDD). Pharmacokinetics: Primarily metabolized via CYP3A4. Dose: Oral: Start at 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then increased to 40 mg once daily. Vilazodone should be taken with food, as administration without food may decrease drug concentrations by approximately 50%. It is recommended that the dose of vilazodone be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. Consider decreasing the vilazodone dose to 20 mg if co-administered with a moderate inhibitor of CYP3A4 and side effects are intolerable. Efficacy: Vilazodone has demonstrated efficacy superior to placebo in patients with major depressive disorder. However, it has not been studied in randomized controlled trials beyond 8 weeks of use. Major depressive disorder generally requires antidepressant continuation for 6 to 9 months beyond symptom remission to prevent relapse. Adverse drug events: The most frequent adverse effects reported during clinical trials were nausea, diarrhea, and headache. However, other adverse effects like those caused by other serotonergic antidepressants may occur. Discontinuation withdrawal symptoms have been reported with serotonergic antidepressants and a dose taper may be needed to minimize these symptoms. Warnings: Vilazodone has many of the same warnings and precautions as other antidepressants regarding increased suicidal thinking and behavior in children, adolescents, and young adults < 24 years; serotonin syndrome; and concurrent use with monoamine oxidase inhibitors. Drug interactions: Interactions involving the cytochrome P450 system, in particular CYP3A4 may increase vilazodone concentrations. Also vilazodone is highly bound to protein plasma and may increase the free concentrations of other highly protein bound drugs. Based on the available data, vilazodone does not offer advantages over the other currently available antidepressants. Vilazodone is available in 10 mg, 20 mg, and 40 mg tablets at a cost of $2.92 per tablet (day). Introduction Vilazodone, a new oral antidepressant, received FDA-approval on January 21, 2011 with a labeled indication for the treatment of major depressive disorder (MDD) in adults. The purpose of this monograph is to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating vilazodone for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics1-5 The mechanism of action of vilazodone is inhibition of reuptake of serotonin and partial agonism at 5HT1a receptors. The antidepressant effect is thought to be due to vilazodones SSRI quality. It is unknown if the partial agonism of 5HT1a receptors by vilazodone produces any beneficial effect. It has been hypothesized that vilazodone has a faster onset, compared to SSRIs alone, as the additional partial agonism of the 5HT1a receptor results in a more rapid and specific desensitization of the somatodendritic 5HT1a autoreceptors. Chronic administration of a SSRI results in desensitization of presynaptic 5HT1a autoreceptors. The median time to maximum plasma concentration is 4 to 5 hours. At steady state and under fed conditions, the mean plasma concentration was observed to be 156 ng/mL, and the mean area under the curve (AUC) was 1645 ng(h/mL. Vilazodones bioavailability is 72% when taken with food. Vilazodone demonstrates dose-proportional pharmacokinetics. Steady state is reached after 3 days of dosing. Vilazodone primarily undergoes hepatic metabolism and the terminal half-life is approximately 25 hours. Table 1 Pharmacokinetics ParameterVilazodoneSertralineCitalopramMetabolismHepatic via CYP3A4 (Primary), CYP2C19 and CYP2D6 (Minor); also possibly by carboxylesterase Hepatic via N-demethylation (Primary)Hepatic via CYP3A4 and CYP2C19; N-demethylation (Primary)EliminationUrine (1%), feces (2%) unchangedUrine (40-45%) and feces (40-45%) with12-14% unchangedUrine (20%) with 12-13% unchangedHalf-life~25 hours~24 hours~35 hoursProtein Binding96-99%99%80%Bioavailability72% with food100%80% FDA Approved Indication(s)1 FDA labeled indications: Treatment of major depressive disorder in adults. Potential off-label uses: Other antidepressants have label indications for or are used off-label to treat anxiety disorders, bipolar depression, PTSD, chronic pain, and vasomotor symptoms. Results of a search of PubMed and clinical trials.gov found vilazodone has been studied only as a treatment for MDD. Current VA National Formulary Alternatives Other antidepressants on the VANF include SSRIs (citalopram, fluoxetine, sertraline, paroxetine); tricyclic antidepressants (TCAs); venlafaxine; bupropion; mirtazapine; trazodone; and monoamine oxidase inhibitors (MAOIs). Only MAOIs are restricted to mental health providers with criteria for use. Dosage and Administration1 Initiation of treatment The recommended dose for vilazodone is 40 mg once daily. When starting vilazodone, the drug must be titrated. Start at 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then increased to 40 mg once daily. The maximum daily dose is 40 mg/day. Dose adjustment in patients with impaired kidney function No dosage adjustment is recommended in mild, moderate, or severe renal impairment. Dose adjustment in hepatic impairment Mild-to-moderate impairment: No dosage adjustment is recommended. Severe hepatic impairment: Vilazodone has not been studied in severe hepatic impairment. Dose adjustment in the elderly No dose adjustment is recommended on the basis of age. Administration Vilazodone should be taken with food. Administration without food may decrease drug concentrations by approximately 50% and may diminish effectiveness. There are no specific recommendations regarding timing of administration as long as the drug is taken with food. The dose of vilazodone should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. Consider decreasing vilazodone dose to 20 mg if co-administered with a moderate inhibitor of CYP3A4 and side effects are intolerable. Discontinuation of treatment Withdrawal symptoms have been reported with discontinuation of sertonergic drugs like vilazodone. Gradual dose reduction is recommended to prevent withdrawal symptoms. Efficacy6-8,10,11,13 Efficacy Measures Major Depressive Disorder: Montgomery-Asberg Depression Rating Scale (MADRS): A clinician rated 10-item scale that assesses mood, anxiety, appetite, sleep, functional status, ability to think and general psychiatric distress. Hamilton Depression Rating Scale (HAM-D-17): A clinician-rated 17-item checklist, ranked on a 04 or 02 scale that assesses the severity of depressive symptoms in patients with primary depressive illness and monitoring changes with treatment. Clinical Global Impression (CGI) Scale: Clinician-rated scale globally assessing response to medication treatment. Scales measure improvement (CGI-I) and severity of illness (CGI-S). Summary of efficacy findings Major Depressive Disorder: Rickels and colleagues completed a randomized, double-blind, placebo-controlled trial that was 8 weeks in durationcomparing vilazodone (10 mg once daily for 7 days, 20 mg daily for the next 7 days, then 40 mg daily for the duration of the study) to placebo. Table 2 lists the inclusion and exclusion criteria. The primary efficacy endpoint was mean change from baseline to week 8 on the MADRS total score. Secondary efficacy endpoints were response, defined as > 50% decrease in total score from baseline to week 8 on the MADRS and HAM-D-17 total scores, or a score of 1 or 2 on the Clinical Global Impressions-Severity of Illness and Improvement (CGI-I) at week 8. Remission was not an outcome measure. For efficacy comparisons, the intention-to-treat (ITT) population (which included all randomly assigned patients who took study medication and had a post baseline efficacy measurement within 7 days of the last dose of study medication) with last-observation-carried-forward (LOCF) method was used. The modified ITT population included all patients in the ITT population who completed the MADRS at week 8. For safety analyses (population consisted of all randomly assigned patients who took a dose of study medication), descriptive statistics and categorical methods were used to summarize safety data by treatment groups. A total of 561 patients were screened and 410 patients were randomly assigned to treatment groups (205 patients randomly assigned to each group). Of the 152 patients in the vilazodone group who completed the 8 week study, 139 (91.4%) completed the dosage titration at 2 weeks and were maintained on vilazodone 40 mg/day. Statistically significant improvements in the MADRS and HAM-D-17 scores were observed for vilazodone compared to placebo at week 1 (p<.05) (Table 3). Mean change from baseline to week 8 on the MADRS, HAM-D-17, CGI-S, and Hamilton Anxiety Rating Scale (HAM-A) scores were significantly greater in the vilazodone group than in the placebo group (0.001, 0.022, 0.001, and 0.045 respectively; Table 4). The mean CGI-I score was significantly improved (lower score) in the vilazodone group compared with the placebo group. Response rates for vilazodone on the MADRS, HAM-D-17, and CGI-I were all significantly better than with placebo (Table 5). Table 2 Criteria for the MDD Clinical Trials Evaluating Efficacy Inclusion CriteriaExclusion Criteria18 to 65 years of age with a diagnosis of MDD per DSM-IV-TR criteria, single or recurrent episode, and the duration of their current major depressive episode was at least 4 weeks and no more than 2 years >22 score on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) > 2 score on the HAM-D-17 item 1 (depressed mood) Current Axis I disorder other than MDD or had one within 6 months of the screening (with the exception of generalized anxiety disorder and social phobia or simple phobia, which were allowed) A history of schizophrenia, schizoaffective disorder, or bipolar I or II disorder Substance abuse within 3 months of or substance dependence within 6 months of the screening visit MDD with psychotic features, postpartum onset, or seasonal pattern Current psychotherapy or had received psychotherapy within 12 weeks of the screening visit Patients who posed a serious suicidal or homicidal risk or who had made a suicide attempt Patients with an inadequate response to at least 2 consecutive antidepressants from different classes given at adequate doses for an adequate duration for the current episode Patients who received electroconvulsive therapy Patients who were taking psychotropic drugs and/or migraine medications with a serotonergic mechanism of action Patients with known hypersensitivity to SSRIs or 5-HT1a agonists Patients with a history of clinically significant cardiac, renal, neurologic, cerebrovascular, hepatic, hematologic, metabolic, or pulmonary disease Patients with Sicca syndrome Patients who had taken an investigational drug or participated in an investigational drug trial within the past 30 days Table 3 Mean Change from Baseline to Visit Week (1-8) in the MADRS Score Between Vilazodone and Placeboa Khan, et al. 7 Rickels, et al. 6 Visit WeekDifferenceP ValueDifferenceP Value1-0.4.35-1.7.00012-1.0.09-1.7.00634-1.6.05-2.9.00056-2.3.02-4.1<.00018-2.9.006-3.6.0007a Based on mixed-effects model for repeated-measures analyses. Table 4 Primary Analysis: Least-Squares Mean (LSM) Change From Baseline in Rating Scores BaselineLeast-Squares Mean Change at Week 8VilazodonePlaceboVilazodonePlaceboP ValueScaleN = 198N = 199N = 198N = 199MADRS30.8 +/- 3.930.7 +/- 3.9-12.9 +/- 0.8-9.6 +/- 0.8.001HAM-D-1724.8 +/- 2.424.9 +/- 2.4-10.4 +/- 0.6-8.6 +/- 0.6.022CGI-I2.6 0 +/- 0.13.0 +/- 0.1.001CGI-S4.50 +/- 0.54.40 +/- 0.5-1.40 +/- 0.1-1.0 +/- 0.1.001HAM-A18.3 +/- 5.118.5 +/- 5.3-6.60 +/- 0.6-5.1 +/- 0.5.045 Table 5 Secondary Analysis: Response at Week 8 for Intention-to-Treat Population, Last-Observation-Carried-Forward Analysis Vilazodone, N=198Placebo, N= 199ParameterN (%)95% CI, %N (%)95% CI, %p ValueaMADRS responseb80 (40.4)33.6 to 47.256 (28.1)21.9 to 34.4.007HAM-D-17 responseb88 (44.4)37.5 to 51.465 (32.7)26.1 to 39.2.011CGI-I responsec95 (48.0)41.0 to 54.965 (32.7)26.1 to 39.2.001aCochran-Mantel-Haenszel test. bScore decrease > 50%. cScore of 1 or 2. Another study, completed by Khan and associates, evaluated the efficacy of vilazodone and had a very similar design as the study by Rickels et al. The primary efficacy endpoint was mean change in MADRS total score from baseline to end of treatment (8 weeks). Secondary efficacy endpoints were mean change from baseline to end of treatment in the HAM-D-17 and HAM-D-21, HAM-A, CGI-S, and CGI-I scales; MADRS response (defined as > 50% decrease from baseline); and HAM-D-17 remission (defined as HAM-D-17 score < 7). The primary efficacy analysis was conducted in the ITT population (which included all randomly assigned patients receiving study drug with a post baseline efficacy assessment) using the LOCF method. Safety outcomes (population consisted of all patients receiving study drug with a post baseline safety assessment) were summarized by treatment group and study visit using descriptive statistics. A total of 659 patients were screened, and 481 patients were randomly assigned to treatment groups (n = 240 for vilazodone [10 mg/day for 7 days, followed by 20 mg/day for the next 7 days, then 40 mg/day] and n = 241 for placebo). Improvements on the MADRS scores were observed for both the vilazodone and placebo group at week 1, however, the difference between groups was not significant (Table 3). Mean change from baseline to week 8 on the MADRS, HAM-D-17, HAM-D-21, HAM-A, CGI-S, and CGI-I scores were significantly greater in the vilazodone group than in the placebo group (Table 6). The mean CGI-I score was significantly improved (lower score) in the vilazodone group compared with the placebo group. At the end of treatment, MADRS and HAM-D-17 response and remission rates were higher in the vilazodone group than in the placebo group. Response rates for vilazodone on the MADRS and HAM-D-17 were significantly better than with placebo (0.002 and 0.013, respectively). There were no significant differences in remission rates for vilazodone based on the MADRS and HAM-D-17. Table 6 Primary Analysis: Least-Squares Mean (LSM) Change From Baseline in Rating Scores Least-Squares Mean (SE) Change From Baseline To End of TreatmentBaselineLSM Change at Week 8PVilazodone (n = 231)Placebo (n = 232)Vilazodone (n = 231)Placebo (n = 232)MADRS31.9 (3.5)32.0 (3.6)-13.3 (0.9)-10.8 (0.9).009HAM-D-1725.0 (2.4)25.3 (2.6)-10.7 (0.7)-9.10 (0.7).026HAM-D-2126.8 (3.0)27.2 (3.0)-11.6 (0.7)-9.90 (0.7).029HAM-A18.0 (5.3)18.1 (5.8)-7.00 (0.6)-5.70 (0.6).037CGI-S4.50 (0.5)4.50 (0.5)-1.40 (0.1)-1.10 (0.1).004CGI-I2.50 (0.1)2.80 (0.1).004Response and Remission Rates at End of Treatment, n (%)Vilazodone (n = 231)Placebo (n = 232)PMADRS response101 (43.7)70 (30.3).002MADRS remission63.0 (27.3)47 (20.3).066HAM-D-17 response102 (44.2)76 (32.9).013HAM-D-17 remission56.0 (24.2)41 (17.7).088 Phase II Efficacy Studies Major Depressive Disorder: The efficacy of vilazodone (5 mg/day to 100 mg/day) was evaluated in 5 phase II studies, and 3 of which had active controls. Change from baseline to the end visit on the HAM-D-17 total score was the primary efficacy outcome. The 3 studies with active controls were considered failed and the other two studies were negative for the primary outcome. For the secondary outcome, improvement in MADRS, two of the fixed-dose trials showed a dose response difference between vilazodone and placebo (Table 7). Table 7. Secondary Analysis: Least Squares Mean (LSM) Change from Baseline using a Last Observation Carried Forward Approach for Two Fixed-Dose Phase 2 Trials Difference in MADRS Score (vilazodoneplacebo)P valueTrial #24610 mg/d-2.3.1220 mg/d-2.8.06Trial #2485 mg/d-0.4.7310 mg/d-1.9.1620 mg/d-2.5.06 Long-Term Efficacy Studies Major Depressive Disorder: Robinson and colleagues completed a 1-year, open label study assessing the safety and tolerability of vilazodone in patients with MDD and the long-term effectiveness. See Table 8 for study inclusion and exclusion criteria. The study consisted of 3 periods: washout, screening, and 1-year open label treatment with vilazodone. The washout period was 12 weeks for depot neuroleptics, 4 weeks for MAOIs and fluoxetine, and 2 weeks for other antidepressants. Patients were titrated to a recommended vilazodone therapeutic dose of 40 mg daily (10 mg once daily for 7 days, 20 mg daily for the next 7 days, then 40 mg daily for the duration of the study). Safety was assessed by adverse events, physical and laboratory evaluations, electrocardiograms (ECGs), and concomitant drug use. The Changes in Sexual Functioning Questionnaire (CSFQ) was used to evaluate sexual function and effectiveness was assessed by the MADRS, CGI-S, and CGI-I scales. Patients were evaluated weekly for the first month, every 2 weeks for the second month, and every 4 weeks thereafter. The safety population consisted of those patients receiving study drug with a post baseline safety assessment. No formal hypothesis testing was done for safety or effectiveness measures. A total of 616 patients were enrolled and of these, 314 (51%) completed at least 6 months and 254 (41.2%) completed the entire study. The majority of patients (>90%; n=542) were able to follow the fixed-titration schedule with no dose adjustments. Mean MADRS, CGI-S, and CGI-I scores declined (improved) from baseline to 1 year (Table 9). The long-term efficacy of vilazodone is limited as the only evidence published is this 1-year open label trial that lacks a control group. Table 8 Criteria for the MDD Clinical Trials Evaluating Long-Term Efficacy Inclusion Criteria Exclusion CriteriaAge 18-70 years of age with a diagnosis of MDD according to the DSM-IV-TR and confirmed by the Mini International Neuropsychiatric Interview > 18 score on the 17-item Hamilton Rating Score for Depression at screening and baselinePatients with schizophrenia, schizoaffective disorder, or bipolar type I or II disorder; substance abuse or dependence (within a year); suicide attempt (within 6 months); or serious suicidal or homicidal risk Patients on psychotropic drugs, varenicline, and St. Johns wort Patients with a medical condition that might interfere with study participation Table 9 Mean (SD) Change From Baseline in Rating Scores Rating ScoresBaselineWeek 8Week 241 yearMADRS29.9 (4.5)11.4 (7.6)8.2 (7.1)7.1 (7.4)CGI-S4.3 (0.5)2.5 (1.1)1.7 (1.1)CGI-I3.5 (0.7)1.9 (0.9)1.4 (0.8)*SD = standard deviation Adverse Events (Safety Data) 1, 6,7,9,12 Safety Measures Sexual Dysfunction: Changes in Sexual Functioning Questionnaire (CSFQ): A questionnaire (36 items for men and 35 items for women) that measures disease- and medication-related changes in sexual functioning by evaluating current and lifetime sexual functioning. Arizona Sexual Experience Scale (ASEX): A 5-item scale (range 5 to 30) used to assess sexual dysfunction. Deaths and Other Serious Adverse Events Khan and colleagues reported 5 serious adverse events (angina pectoris, carotid arteriosclerosis, chest pain, cholecystitis, and pneumonia). Rickels and associates reported 6 adverse events occurring in 5 patients (one occurrence of the following: lymphadenopathy, concussion, prostate cancer, suicide attempt; two occurrences of depression). Robinson and colleagues reported 33 serious adverse events occurring in 23 patients (3.8%), most of which were judged as not related to vilazodone; 8 patients had adverse events of either suicidal ideation or behavior. No deaths occurred in these studies. Common Adverse Events Rickels, et al. reported that 19 (9.3%) patients in the vilazodone group and 10 (4.9%) patients in the placebo group discontinued treatment due to adverse events. Adverse events occurred in 164 (80%) patients in the vilazodone group and 130 (63.7%) patients in the placebo group. Sexual dysfunction was evaluated using the ASEX scale. The mean ASEX scores at baseline among men were 15.8 and 16.5 in the placebo and vilazodone groups, respectively, and, among women, the mean baseline ASEX score was 21.2 in both treatment groups. The change from baseline to week 8 was -0.4 to -1.3 for both sexes in both treatment groups indicating slight improvement. Kahn et al. reported that 12 patients on vilazodone (5.1%) versus 4 (1.7%) on placebo discontinued treatment due to adverse events. See table 10 for types of adverse events. Sexual dysfunction was evaluated using the CSFQ questionnaire. The mean CSFQ scores at baseline among men were 46.5 and 46.6 in the vilazodone and placebo groups, respectively, and, among women, the mean baseline CSFQ scores were 39.4 and 40.2 in the vilazodone and placebo groups, respectively. Improvement in CSFQ score was observed for both sexes and for both treatment groups (vilazodone versus placebo, CSFQ improved by 0.6 and 1.8 points for men, respectively, and 1.9 and 2.3 points for women, respectively). However, sexual dysfunction adverse events as a whole were more frequent in the vilazodone group, occurring in 21 patients compared to only 1 patient in the placebo group. Decreased libido was the most frequent type of sexual dysfunction reported occurring in 11 vilazodone patients (4.7%) and in no placebo patients. Table 10 Most Frequently Reported Adverse Events in Placebo-Controlled Trials Adverse eventRickels, et al.6Kahn, et al.7VilazodonePlaceboVilazodonePlaceboDiarrhea23.9%7.30%P < .0530.6%10.7%Nausea18.5%4.40%P < .0526%5.6%Headache13.2%14.2%12.8%10.3% Adverse events from a one-year, open-label trial by Robinson et al are reported in Table 11. At least 1 adverse event occurred in 93.8% of patients and, of which, the most frequent being diarrhea, nausea, and headache. A total of 124 patients (20.7%) discontinued treatment due to adverse events. Nausea (n = 8, 1.3%) and diarrhea (n = 7, 1.2%) were the most common adverse events that led to discontinuation. There were no clinically important changes in physical examination, ECG, or laboratory values. At baseline, mean CSFQ scores for both sexes were indicative of sexual dysfunction (46.9 for men and 38.7 for women) and improved throughout treatment. Table 11 Adverse Events Occurring in > 5% of Patients in the Long-Term Efficacy Trial9 Adverse EventVilazodone (N = 599), n (%)Diarrhea214 (35.7)Nausea189 (31.6)Headache120 (20.0)Upper respiratory tract infection82 (13.7)Insomnia78 (13.0)Dry mouth66 (11.0)Dizziness64 (10.7)Somnolence64 (10.7)Abnormal dreams62 (10.4)Weight increased57 (9.5)Increased appetite54 (9.0)Fatigue46 (7.7)Nasopharyngitis45 (7.5)Vomiting44 (7.3)Anxiety36 (6.0)Urinary tract infection35 (5.8)Back pain33 (5.5) Table 12 Common Adverse Reactions Occurring > 2% of Vilazodone-Treated Patients and Greater Than Placebo-Treated Patients1 System Organ Class Vilazodone 40 mg/day N = 436Placebo N = 433Gastrointestinal disordersDiarrhea289Nausea235Dry mouth85Vomiting51Dyspepsia32Flatulence32Gastoenteritis 3< 1Nervous system disordersDizziness95Somnolence32Paresthesia31Tremor20Psychiatric disordersInsomnia62Abnormal dreams41Libido decreased4< 1Restlessness*3< 1Orgasm abnormal **30General disordersFatigue43Feeling jittery2< 1Cardiac disordersPalpitations2< 1Musculoskeletal and connective tissue disordersArthralgia32Reproductive system and breast disorderDelayed ejaculation***20Erectile dysfunction***21Metabolism and nutrition disordersIncreased appetite21*Includes restlessness, akathisia, and restless legs syndrome **Includes orgasm abnormal and anorgasmia ***Male patients only (Placebo n = 182; Vilazodone n = 170) Tolerability In the Khan and colleagues study, a similar number of patients in each group, 19.6% in the vilazodone group and 19.1% in the placebo group, discontinued treatment prematurely (Table 13). Of those who completed the study, 12 vilazodone patients (5.1%) versus 4 placebo patients (1.7%) discontinued treatment due to adverse events; gastrointestinal events led to treatment discontinuation in 4 vilazodone patients (2 nausea, 1 vomiting, and 1 dyspepsia) and none in the placebo group. In the Rickels and associates study, a similar number of patients in each group, 25.9% in the vilazodone group and 24.9% in the placebo group, discontinued treatment prematurely (Table 13). Of those who completed the study, 19 vilazodone patients (9.3%) versus 10 placebo patients (4.9%) discontinued treatment due to adverse effects. Table 13 Reasons for Premature Discontinuation in Placebo Controlled Trials Reason for Premature DiscontinuationKhan et al. Rickels et al.Vilazodone N = 47 (19.6%)Placebo N = 46 (19.1%)Vilazodone N = 53 (25.9%)Placebo N = 51 (24.9%)Lost to Follow-Up171720 18 Adverse Events124 19 10Withdrew Consent1111 512Lack of Efficacy37 49Noncompliance35 42Other12 10 In the 1-year open label trial by Robinson and associates, 124 patients (20.7%) discontinued treatment due to adverse events and the most frequent being nausea (n = 8, 1.3%) and diarrhea (n = 7, 1.2%). Contraindications1 Do not use vilazodone concomitantly with a MAOI or within 14 days of stopping or starting a MAOI. Warnings and Precautions1 Boxed Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults (18 24 years) taking antidepressants for MDD and/or other psychiatric disorders. Worsening of depression, emergence of suicidal thoughts and/or behavior. Development of serotonin syndrome during treatment with vilazodone alone or in combination with other serotonergic drugs such as other antidepressants and triptans. Abnormal bleeding. Concurrent use with other drugs that affect clotting or increase the risk of bleeding, e.g., NSAIDS, should be used with caution and patients informed of the increased risk and how to respond. Activation of mania or hypomania. Discontinuation symptoms after stopping serotonergic antidepressants either abruptly or during dose reduction have been reported. Hyponatremia has been reported as a result of treatment with SSRIs and SNRIs. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) appears to be the cause. Use in Pregnancy Pregnancy Category C. Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. Third trimester exposure of SSRIs have resulted in prolonged hospitalization, respiratory support, and tube feeding for the neonate. There are no adequate and well-controlled studies of vilazodone in pregnant women so careful consideration should be made when determining if the potential benefits outweigh the potential risks of treatment in pregnant women. Use in Breast Feeding Vilazodone is excreted into the milk of lactating rats. It is unknown as to whether vilazodone is excreted into human breast milk. Sentinel Events No data available. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name vilazodone: trazodone, nefazodone. lurasidone LA/SA for trade name Viibryd: Vivarin Drug Interactions1 Drug-Drug Interactions As with all antidepressants concomitant use with MAOIs is to be avoided. Concurrent use with NSAIDs may increase the risk of gastrointestinal bleeding or bleeding in general. Prolonged bleeding times may occur when used with anticoagulants such as warfarin. Concomitant use with potent CYP3A4 inhibitors may increase vilazodones concentrations. Administration of a strong CYP3A4 inhibitor may increase vilazodones plasma concentrations by approximately 50%. Drugs that induce CYP3A4 may reduce vilazodone systemic exposure, however, the effect on plasma concentrations has not been evaluated. Drugs which inhibit other CYP isozymes are not expected to significantly alter vilazodones pharmacokinetics. Vilazodone is highly bound to protein plasma and may increase the free concentrations of other highly protein bound drugs. Drug-Lab Interactions No drug-lab interactions have been identified. Acquisition Costs Table 14 Acquisition Costs of Vilazodone, Sertraline, and Citalopram DrugDoseCost/Day/Patient ($)Cost/Year/Patient ($)Vilazodone 10 mg once daily2.921065.80Vilazodone20 mg once daily2.921065.80Vilazodone40 mg once daily2.921065.80Sertraline200 mg once daily (2x100mg tabs)0.18467.16Citalopram40 mg once daily0.03813.87Prices as of January 17, 2012. Prices may not reflect all discounts. Prices are not updated after the monograph is posted. Pharmacoeconomic Analysis No pharmacoeconomic data are available. Conclusions Vilazodone is the first dual serotonin reuptake inhibitor and 5HT1a receptor partial agonist. Vilazodone has demonstrated superior efficacy when compared to placebo for major depressive disorder. The most frequent adverse effects reported during clinical trials were nausea, diarrhea, and headache. Based on the available data, vilazodone does not offer advantages over the other currently available antidepressants. It has been hypothesized that, compared to SSRIs, vilazodone has a faster onset due to its partial agonism at 5HT1a receptors and that it has less sexual dysfunction, however, there is no evidence (i.e, active control trials) to support either of these claims. No human studies have compared vilazodone to other antidepressants or for other indications besides MDD. Disadvantages of vilazodone include initial dose titration, the need to be taken with food to ensure adequate plasma concentrations, tapering upon discontinuation to prevent withdrawal side effects, and it has not been studied in randomized control trials beyond 8 weeks. References: Viibryd (vilazodone) package insert. Forest Laboratories. January 2011. Khan A. Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression. Expert Opin. Investig. Drugs (2009)18(11):1753-64. Dawson L and Watson J. Vilazodone: A 5HT1a receptor agonist/serotonin transporter inhibitor for the treatment of affective disorders. CNS Neuroscience & Therapeutics. 15(2009)107-17. Product Information: ZOLOFT(R) oral tablet, oral solution, sertraline hydrochloride oral tablet, oral solution. Pfizer Roerig, New York, NY, 2005. Product Information: CELEXA (R) oral tablet, solution, citalopram hydrobromide oral tablet, solution. Forest Pharmaceuticals Inc, St. Louis, MO, 2005. Rickels K, Athanasiou M, Robinson D, et al. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70(3):326-33. Khan A, Cutler A, Kajdasz K, et al. A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. J Clin Psychiatry 2011;72(4):441-7. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:5662. Robinson D, Kajdasz D, Gallipoli S, et al. A 1-Year, Open-Label Study Assessing the Safety and Tolerability of Vilazodone in Patients With Major Depressive Disorder. J Clin Psychopharmacol. 2011;31:643-6. Guy W, Bonato RR (eds): Manual for the ECDEU Assessment Battery, revised 2nd ed. Chevy Chase, Md, National Institute of Mental Health, 1970, pp 12.112.6 FDA/CEDR resources page. Food and Drug Administration Web site.  HYPERLINK "http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022567Orig1s000TOC.cfm" http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022567Orig1s000TOC.cfm Accessed January 11, 2012. Clayton A, McGarvey E, Clavet G. The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacology Bulletin [serial online]. 1997;33(4):731-745. Laughren T, Gobburu J, Temple R, et al. Vilazodone: Clinical Basis for the US Food and Drug Administrations Approval of a New Antidepressant. J Clin Psychiatry. 2011;72(9):1166-73. Prepared February 2012 by Colleen Hall, PharmD & Matthew Fuller, PharmD, BCPS, BCPP Contact person: Todd Semla, MS, PharmD, BCPS     Vilazodone Updated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov PAGE 1 -5:; ; = { R V FGvw;𷬠umbhoyhoyOJQJhoyOJQJhJh;"OJQJhJhT>*OJQJhJhT6OJQJhTOJQJhJhTH*OJQJhJhTOJQJ hJhTh5^hTCJOJQJaJ"h5^hT6CJOJQJ]aJh5^hTCJhTh;" h5^hTh5^hTCJ$-; I J gdT & FgdTgdT(($d&d-DM NP(($d&d-DM NP"(($d&d-DM NPgdT v0189 &0;FQ$IfZ^ZgdT$a$gdTgdTgdT & Fgdoy & FgdTgdT01Q  z#KOR[e  8?n| "&  &0۞h5^hT5\h5^hT^J jhTOJQJhUhTH*OJQJh5^hTH*OJQJ hT>*H*h5^hT>*H* h5^hTh5^hTB*phhTOJQJh5^hTOJQJ70;EFPQRH /1:<߿߿߿ߩ!hi hTB*OJQJ^Jphhi hTOJQJ^JhTOJQJh5^hT>*H*h5^hTOJQJ\h5^hTOJQJ!h5^hTB*CJOJQJphhT h5^hTh5^hT5OJQJ hT5h5^hT5,QR]71111$Ifkd$$Ifl\T,"~   (04 lap('He___V $IfgdT$Ifkd3$$Ifl\T,"~  04 lae____$Ifkd $$Ifl\T,"~  04 lae____$Ifkd$$Ifl\T,"~  04 la gaaaa$Ifkd$$Ifl\T,"~  04 la1~ ge`XXS``SgdT$a$gdTgdTkd]$$Ifl\T,"~  04 la @Y` #$%=0VWX !!}!!!"K"L""" # # #)####᫞{{{lh5^hTB*OJQJphhvhTOJQJh5^hT>*OJQJaJhTOJQJaJh5^hTOJQJaJh5^hT6OJQJaJh5^hT>*H*hTOJQJhpwhTOJQJh5^hTOJQJ h5^hTh;"%hi hTB*CJOJQJ^Jph)  %=WX P !!!" # #)####$a$gdT & 0` P@1$7$8$H$gdTgdTgdT####$H$$$ % %%%%&!&B&&&L'M'i'j'''((`))))´o\\TLh7OJQJh+OJQJ%hF7,hTB*OJQJ^JaJph333(hF7,hT>*B*OJQJ^JaJph333hTB*OJQJ^JaJph333%hhTB*OJQJ^JaJph333hhTOJQJ^JhhT>*OJQJ^JhTOJQJh5^hTOJQJh5^hT>*OJQJhXhTOJQJ^JhT h5^hT hT>*H*##$$%&&&''))++///0$0 $$Ifa$gdT $^a$gdTgdT) *!*r*++,,,,0-1-9-/////00$0%0]0^000:1;1\5Ĵĕwh\hLhLhh5^hT>*CJOJQJaJhTCJOJQJaJh5^hTCJOJQJaJh5^hT5>*OJQJh5^hT5CJOJQJaJ"h5^hT5CJOJQJ\aJhT5CJOJQJ\h5^hT5CJOJQJ\h5^hT5CJOJQJhTOJQJh5^hTOJQJh5^h+OJQJh7OJQJh+OJQJ$0%00:1m1,2~2jPPP66 & F $If^`gdT & F E$If^`EgdTkd!$$If00:`' &  t00*644 lap~22#3~3344'5h55666jzkd$$If 00:`' & t00*644 la & F $If^`gdT \5^5666666 7 777 7#797:7L7M7T7U7k7l7777777777 8ɻttg[hTCJOJQJaJhTCJH*OJQJaJhmhT6OJQJhmhTOJQJhTH*OJQJhy=hTOJQJhmhT5OJQJhLohT5CJH*OJQJhLohT5CJOJQJhT5OJQJh5^hT5>*OJQJh5^hTCJOJQJaJhPhTCJH*OJQJaJ666667"7$$Ifa$gdToI$If"7#7.797A7L7T7NH7777$$Ifa$gdToI$Ifkd$$IflF${  t06    44 lapT7U7W7\7`7e7k7NH7777$$Ifa$gdToI$Ifkdx$$Iflr${{{{| t0644 lak7l7n7s7w7|77NH7777$$Ifa$gdToI$Ifkd$$Iflr${{{{| t0644 la7777777NH7777$$Ifa$gdToI$Ifkd$$Iflr${{{{| t0644 la7777777NH7777$$Ifa$gdToI$Ifkdg $$Iflr${{{{| t0644 la7777777NH7777$$Ifa$gdToI$Ifkd $$Iflr${{{{| t0644 la77 8 8e8f8o8NLLG;; $$Ifa$gdTgdTkd $$Iflr${{{{| t0644 la 8 8 8888>8?8E8F8J8K8V8W8]8^8c8e8888,9-9p9q99999:::%:&:::::;;H;·ϊ}rfrfrhG hTH*OJQJhG hTOJQJhEXhTCJOJQJhEXhT5CJOJQJhTOJQJhUhT>*OJQJhUhTOJQJh5^hTOJQJh=MhTCJOJQJhT5CJOJQJh=MhT5CJOJQJhT5OJQJh AGhTCJOJQJaJ(o88888888BkdV $$IflFX," L  t%%%06    44 lap%%% $$Ifa$gdT888888/kdD $$IflֈX h," t0644 la $$Ifa$gdT888888/kd $$IflֈX h," t0644 la $$Ifa$gdT88 99'9,9 $$Ifa$gdT,9-969C9P9^9;//// $$Ifa$gdTkd $$IflֈX h," t0644 la^9k9p9q9w9y9/kd!$$IflֈX h," t0644 la $$Ifa$gdTy9{99999/kd$$IflֈX h," t0644 la $$Ifa$gdT9999999 $$Ifa$gdT99999 :;//// $$Ifa$gdTkd_$$IflֈX h," t0644 la ::::::/--kd$$IflֈX h," t0644 la $$Ifa$gdT::::::::Dkd$$IflFV,"6    t%%%0    44 lap%%% $$Ifa$gdT:::::;0kd$$Iflֈ VB,"6 J t044 la $$Ifa$gdT; ;;$;1;6; $$Ifa$gdT6;7;J;T;a;k;<0000 $$Ifa$gdTkdj$$Iflֈ VB,"6 J t044 laH;J;;;;;;;;;;; < <<<g=j=l=m=t=x===========>>??@@@@@.A/ACCCɹɱ~shT5CJOJQJhT5OJQJh5^h7OJQJh7OJQJh5^hT>*OJQJh5^hTOJQJhTOJQJhEXhT>*CJOJQJaJhEXhTCJOJQJaJhEXhTCJH*OJQJaJhG hTOJQJhG hTH*OJQJ-k;x;};~;;;0kdL$$Iflֈ VB,"6 J t044 la $$Ifa$gdT;;;;;;0kd.$$Iflֈ VB,"6 J t044 la $$Ifa$gdT;;; < <>>??CC5DvDwDvukd$$Ifl6$$  t %044 lap % $$Ifa$gdTgdT CDDDDDD'D(D.D/D4D5DDDDDEE EEEE'E+E3E9E>EDEJEPEVE\EdEgEpEvE{EEEEEEEEEEEEEEEEEEEEEFF F"F(F-F3FFFFFFFFFF͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹͹hTOJQJh5^hT6OJQJh5^hTOJQJh5^hT5CJOJQJhT5CJOJQJh=MhT5CJOJQJIwDxDDDDDDDDDTkd$$Ifl\pV6$  8 t044 la $$Ifa$gdT DDDDDD $$Ifa$gdTDDDDE:1%% $$Ifa$gdT $IfgdTkdc$$IflֈpV6$F8 t044 laEE E%E&E.kdJ$$IflֈpV6$F8 t044 la $$Ifa$gdT&E/E:EEEQE]EbE $$Ifa$gdT $IfgdTbEcElEwEE:1%% $$Ifa$gdT $IfgdTkd1$$IflֈpV6$F8 t044 laEEEEE.kd$$IflֈpV6$F8 t044 la $$Ifa$gdTEEEEEEE $$Ifa$gdT $IfgdTEEEEE:1%% $$Ifa$gdT $IfgdTkd$$IflֈpV6$F8 t044 laEFFFF.kd$$IflֈpV6$F8 t044 la $$Ifa$gdTFFFF)F4F9F $$Ifa$gdT $IfgdT9F:FrF:. $$Ifa$gdTkd$$IflֈpV6$F8 t044 larFsFtFFFF}}}} $$Ifa$gdTukd$$Ifl6$$  t %044 lap %FFFFFF`WKKK $$Ifa$gdT $IfgdTkdZ$$Ifl\pV6$  8 t044 laFFFFFF`WKKK $$Ifa$gdT $IfgdTkd$$Ifl\pV6$  8 t044 laFFFF GGGG"G%G8G?GBGIGQGRGlG~IIII"JRJSJJJJJJK"M%M&MBMCMhMiMM.O⿱|shhXhTOJQJhT5OJQJhFhT5OJQJhmhT6OJQJaJhmhTOJQJaJhLohT5CJOJQJhh+h;"5OJQJaJh;"5OJQJaJhTOJQJaJhahT5OJQJaJhT5OJQJaJh5^hTOJQJhTOJQJ&FFGGG G`WKKK $$Ifa$gdT $IfgdTkd$$Ifl\pV6$  8 t044 la G!G4G@GJGOG^UIII $$Ifa$gdT $IfgdTkd$$IflF\pV6$  8 t044 laOGPGQGRGlGG~IIIII`[[[[[[[[[gdTkdJ $$Ifl\pV6$  8 t044 la II"J#JRJZJ$$Ifa$gdTo. $IfgdTgdTZJ[JfJgJhJNE44$$Ifa$gdTo. $IfgdTkd!$$IflFp$x  t06    44 laphJiJqJvJzJo^^^$$Ifa$gdTo.kd!$$IflFp$x t06    44 lag+zJ{JJJJo^^^$$Ifa$gdTo.kd"$$IflFp$x t06    44 lag+JJJJJofUU$$Ifa$gdTo. $IfgdTkdM#$$IflFp$x t06    44 lag+JJJJJo^^^$$Ifa$gdTo.kd#$$IflFp$x t06    44 lag+JJJJJo^^^$$Ifa$gdTo.kd$$$IflFp$x t06    44 lag+JJJJJo^^^$$Ifa$gdTo.kdT%$$IflFp$x t06    44 lag+JJJJJKMM.O/OOOQojjjjjjjjjjjgdTkd&$$IflFp$x t06    44 lag+ .OOrPsPQQQQRR@RARTTTTTTT,U.U8U9URU\U]UgUhUiUjUsUuUvU̼📄vvkkkkkkk\h5^hTCJOJQJaJhuwhTOJQJh^ hT5CJOJQJhJhTCJOJQJaJh#hTH*OJQJhJhT5CJOJQJaJhT5CJOJQJ\h5^hT5CJOJQJ\h5^hT5CJOJQJhT5CJOJQJh5^hTOJQJhTOJQJhy@OJQJ QQR-R@RARRE8 & F!$IfgdTkd&$$Ifl0,"LL  t0644 lap $IfgdT  $IfgdT $^a$gdTgdTR'SS9TTTTTTTTTzuul``` $$Ifa$gdT $IfgdTgdTxkdp'$$Ifl0,"LL t0644 la & F!$IfgdT TT $$Ifa$gdTTTkd'$$IflrbH,"LLL t2%%%%%0644 lap2%%%%%TTU UU!U"U9kd')$$IflrbH,"LLL t0644 la $$Ifa$gdT $IfgdT"U(U4U?UAUKULU9kd)$$IflrbH,"LLL t0644 la $$Ifa$gdT $IfgdTLURU]UhUjUtUuU9kd*$$IflrbH,"LLL t0644 la $$Ifa$gdT $IfgdTuUUUUUUV7W8WaWYYYY`\a\R`S````` $$Ifa$gdT $IfgdT gdTo ggdTvUUUUUUUUUUVVV7W8WaWXZXXXXXXYYYYYYYvc\QQQQQQQh5^hTOJQJ hPhT%hvhTB*OJQJ^JaJph333"hT>*B*OJQJ^JaJph333hTB*OJQJ^JaJph333(hPhT>*B*OJQJ^JaJph333hPhTOJQJhTOJQJhPhT5OJQJhT5OJQJ hTH*hn+hTH* h5^hThT5OJQJaJhTCJOJQJaJYYYYZ~\\\]Q`S`Y`[`a`b`l`m`u`v`}`~```````````jaddd%d&dUdVdWd䵩䵩웋~nhn+hT5CJH*OJQJhT5CJH*OJQJh^ hT5>*CJOJQJh^ hT5CJOJQJhn+hTH*OJQJhTH*OJQJh=MhTCJOJQJh=MhT5CJOJQJh5^hTOJQJhTOJQJhT5CJOJQJh5^hTH*'```````JA5555 $$Ifa$gdT $IfgdTkd@+$$Ifl4Ff,"`<  t%%%06    44 lap%%%```aa aaa!a $IfgdTFf- $$Ifa$gdT!a"a)a/a8/# $$Ifa$gdT $IfgdTkd/$$Iflֈf} ,"Kq t0644 la/a5a=aAaFa $$Ifa$gdTFaGaPaVa8/# $$Ifa$gdT $IfgdTkd0$$Iflֈf} ,"Kq t0644 laVa\a]acaia $$Ifa$gdTiajakaccWd83333gdTkd1$$Iflֈf} ,"Kq t0644 laWdedddddWkd2$$Ifl0,"  t%%0644 lap%% $$Ifa$gdT $IfgdTdddd~r $$Ifa$gdT $IfgdTxkdV3$$Ifl0," t0644 ladddd~r $$Ifa$gdT $IfgdTxkd3$$Ifl0," t0644 ladddd~r $$Ifa$gdT $IfgdTxkdp4$$Ifl0," t0644 ladddd~r $$Ifa$gdT $IfgdTxkd4$$Ifl0," t0644 lade ee~r $$Ifa$gdT $IfgdTxkd5$$Ifl0," t0644 laeee)e~r $$Ifa$gdT $IfgdTxkd6$$Ifl0," t0644 la)e*e5e?e~r $$Ifa$gdT $IfgdTxkd6$$Ifl0," t0644 la?e@ePeZe~r $$Ifa$gdT $IfgdTxkd17$$Ifl0," t0644 laZe[eleue~r $$Ifa$gdT $IfgdTxkd7$$Ifl0," t0644 laueveee~r $$Ifa$gdT $IfgdTxkdK8$$Ifl0," t0644 laeeee~r $$Ifa$gdT $IfgdTxkd8$$Ifl0," t0644 laeeee~r $$Ifa$gdT $IfgdTxkde9$$Ifl0," t0644 laeeee~r $$Ifa$gdT $IfgdTxkd9$$Ifl0," t0644 laeeee~r $$Ifa$gdT $IfgdTxkd:$$Ifl0," t0644 laeeef~r $$Ifa$gdT $IfgdTxkd ;$$Ifl0," t0644 laffff~r $$Ifa$gdT $IfgdTxkd;$$Ifl0," t0644 laffffffffffff}{{rffffff $$Ifa$gdT $IfgdTgdT}kd&<$$Ifl0," t0644 laga Wdfff"f$f,f-f4f5f>f?fHfIfPfQf[f\fcfdfpfqfxfyf}f~ffffffffflggggIh[hhhԷ~i~~~(h5^hT5B*CJOJQJaJph%h5^hTB*CJOJQJaJph+h5^hT5B*CJOJQJ\aJphhn+hT5CJH*OJQJhT5CJH*OJQJh=MhT5>*CJOJQJh=MhT5CJOJQJhT5CJOJQJhTOJQJhuwhTOJQJ)fffff}qq $$Ifa$gdT $IfgdTykd<$$Ifl F0B!l e  t96    44 lapffg g gqh\\ $$Ifa$gdT $IfgdTkd=$$IflZF0B!l e   t96    44 lap g gggg}qq $$Ifa$gdT $IfgdTykd>$$IflF0B!l e  t96    44 lapgg#g%g'g}qq $$Ifa$gdT $IfgdTykdp?$$IflF0B!l e  t96    44 lap'g(g1g3g5g}qq $$Ifa$gdT $IfgdTykdM@$$IflF0B!l e  t96    44 lap5g6g@gBgDg}qq $$Ifa$gdT $IfgdTykd*A$$IflZF0B!l e  t96    44 lapDgEgPgRgTg}qq $$Ifa$gdT $IfgdTykdB$$IflF0B!l e  t96    44 lapTgUgegggkg}qq $$Ifa$gdT $IfgdTykdB$$IflF0B!l e  t96    44 lapkglgggg}qq $$Ifa$gdT $IfgdTykdC$$IflF0B!l e  t96    44 lapgggggqh\\ $$Ifa$gdT $IfgdTkdD$$IflF0B!l e   t96    44 lapggggg}qq $$Ifa$gdT $IfgdTykdE$$IflF0B!l e  t96    44 lapggggg}qq $$Ifa$gdT $IfgdTykdtF$$IflF0B!l e  t96    44 lapggggg}qq $$Ifa$gdT $IfgdTykdQG$$IflF0B!l e  t96    44 lapggggg}qq $$Ifa$gdT $IfgdTykd.H$$IflF0B!l e  t96    44 lapgggggqh\\ $$Ifa$gdT $IfgdTkd I$$IflZF0B!l e   t96    44 lapggghh}qq $$Ifa$gdT $IfgdTykdJ$$IflF0B!l e  t96    44 laphhhhh}qq $$Ifa$gdT $IfgdTykdJ$$IflF0B!l e  t96    44 laphh*h,h0h}qq $$Ifa$gdT $IfgdTykdK$$IflF0B!l e  t96    44 lap0h1hDhFhHh}qq $$Ifa$gdT $IfgdTykdL$$IflF0B!l e  t96    44 lapHhIh[h]h_h}qq $$Ifa$gdT $IfgdTykdM$$IflF0B!l e  t96    44 lap_h`hhhjhlhqh\\ $$Ifa$gdT $IfgdTkdcN$$IflZF0B!l e   t96    44 laplhmh}hhh}qq $$Ifa$gdT $IfgdTykdjO$$IflF0B!l e  t96    44 laphhhhh}qq $$Ifa$gdT $IfgdTykdGP$$IflF0B!l e  t96    44 laphhhhhqh\\ $$Ifa$gdT $IfgdTkd$Q$$IflF0B!l e   t96    44 laphhhhh}qq $$Ifa$gdT $IfgdTykd+R$$IflF0B!l e  t96    44 laphhhhibiiiiMjZj:kokvkk@lel mmmmm"oooopp쮟|peWMh5^hT>*H*h5^hT>*OJQJ\hohTOJQJhKhT5OJQJhT5OJQJh5^hTOJQJhTOJQJ h5^hTh5^hTCJOJQJaJ%h5^hTB*CJOJQJaJph(h5^hT5B*CJOJQJaJph+h5^hT5B*CJOJQJ\aJph%h5^hTB*CJOJQJaJphhhhhhhhqh\\\\ $$Ifa$gdT $IfgdTkdS$$IflF0B!l e   t96    44 laphhii i!i"i`WKKKK $$Ifa$gdT $IfgdTkdT$$Iflr0B!5,6l e   t9644 lap"i#i:ii@iBiKB6666 $$Ifa$gdT $IfgdTkd U$$Iflr0B!5,6l e    t9644 lapBiCi[i]i_i`iai`WKKKK $$Ifa$gdT $IfgdTkd/V$$Iflr0B!5,6l e   t9644 lapaibiiiiii`WKKKK $$Ifa$gdT $IfgdTkd*W$$Iflr0B!5,6l e   t9644 lapiiiiiiiKB6666 $$Ifa$gdT $IfgdTkd%X$$Iflr0B!5,6l e    t9644 lapiiii`TT $$Ifa$gdTkdJY$$Iflr0B!5,6l e   t9644 lapiiijMjZj?l@lmmmWFEƀ֚gdTgdTgdTUkdEZ$$Ifl00L  t96w$44 la mnnnn n+n7kdZ$$Ifl4F~ $` \ "  t06    44 lagp$$Ifa$gdTo+n:nBnQn\nknsnn$$Ifa$gdTonn kd[$$Ifl4r~ ,$  |  t20644 lagp2nnnnnnn8kd\$$Iflr~ ,$ | t0644 lag$$Ifa$gdTonnnnnnn8kd]$$Iflr~ ,$ | t0644 lag$$Ifa$gdTonnnnnnn8kd^$$Iflr~ ,$ | t0644 lag$$Ifa$gdTonnnnnn$$Ifa$gdTo$$Ifa$gdTonno o oI88'$$Ifa$gdTo$$Ifa$gdTokdP_$$Iflr~ ,$ | t0644 lag ooooooo8kd`$$Iflr~ ,$ | t0644 lag$$Ifa$gdTooo!o"o#o$o833gdTkd`$$Iflr~ ,$ | t0644 lag$$Ifa$gdTo$ooopkplppDqq3rs*ssUtWtttOvPvvvvww & FgdT & 0` P@1$7$8$H$gdTgdTgdTpkplpppppr1rrrvvwJwxxxxxxxxxxy y!yRyWyHzSzzzZ|`|c|y|||||||||豨訍ysysys hTCJh5^hTCJhvhTOJQJh3hT6OJQJh@UhT56OJQJ]hT6OJQJhsxhT6OJQJh@UhT56OJQJhThTOJQJh5^hT>*H* h5^hTh5^hTOJQJh5^hTOJQJaJ-wJwxxxx y!yjyy%zzy{{c|y||||} }}4} $$IfgdT$$IfgdTgdT & FgdTgdT||||}}(})}4}5}G}Q}R}V}Y}[}\}^}_}`}q}{}|}}}}}}}}}}}}}}}}}}}}}}}}}}~~~~;~~~~ h5^hTh5^hTB*phh5^hTB*CJphhTB*CJphh5^hTCJOJQJh5^hT5CJOJQJ\hT5CJ\h5^hT5CJ\ hTCJh5^hTCJ74}5}A}R}W}7,,$$$If $$IfgdTkda$$Ifl\H#]W p$ (%%%%04 lap(%%%%W}_}`}k}|}}}ZRRRR$$Ifkdb$$Ifl\H#]W p$ 04 la $$IfgdT}}}}}}g____$$Ifkdc$$Ifl\H#]W p$ 04 la}}}}}}g____$$IfkdPd$$Ifl\H#]W p$ 04 la}}} ~~~g____$$Ifkde$$Ifl\H#]W p$ 04 la~~~~~~~gb`^Y^WWWWgdTgdTkde$$Ifl\H#]W p$ 04 la ~~~!# À(+123.wՂ׃uq҇VźŲͲͦͲͲͲͲhn+hT5^Jhn+hT5H*hn+hT56hn+hT5h%1hTH*OJQJhTOJQJhJhTOJQJhoyOJQJh%1hTOJQJh5^hTH*OJQJh5^hTOJQJ h5^hTh5^hT5>*-X:хV]Ջ׋؋ًڋۋ܋݋ދߋgdT^gdT & F"7$8$H$gdT & F"gdTV@A\]ԋՋ׋~ogcQ@ h5^hT5B*OJQJph#h5^hT5>*B*OJQJphhThF7,hT5hPhTCJOJQJ^JhT6CJOJQJ^Jh hTCJOJQJ^J#hTB*CJOJQJ^JaJph333)hPhTB*CJOJQJ^JaJph333hTCJOJQJ^J hn+hT0JCJOJQJ^J%jhn+hTCJOJQJU^Jhn+hTCJOJQJ^J7dfgijlmop{|}~ $$Ifa$$If$a$gdoy$a$gdoy$d&dNPgdT$d&dNPgdT567GcdeghjkmnpzČŌӌԌú}h;"0JmHnHu h70Jjh70JUhdh70J6]jh76U] h76]h7hoyhoyCJhe.jhe.UhT h5^hT5B*OJQJphhT5B*OJQJphh;"5B*OJQJph!{rlc $$Ifa$$If $IfgdTkdf$$IflF$S t06    4 la{ywwa$d&dNPgdTkd;g$$IflF$S t06    4 la6&P1+:pT/ =!"#$% 1$$If!vh55~ 55 #v#v~ #v#v :V l (0,55~ 55 / 4p($$If!vh55~ 55 #v#v~ #v#v :V l0,55~ 55 / 4$$If!vh55~ 55 #v#v~ #v#v :V l0,55~ 55 4$$If!vh55~ 55 #v#v~ #v#v :V l0,55~ 55 4$$If!vh55~ 55 #v#v~ #v#v :V l0,55~ 55 4$$If!vh55~ 55 #v#v~ #v#v :V l0,55~ 55 4$$If0!vh5 5&#v #v&:V   t00*6,5 5&ap$$If0!vh5 5&#v #v&:V   t00*65 5&a$$If!vh5{55#v{#v#v:V l  t065{55p$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh5{5{5{5{5|#v{#v|:V l t065{5|$$If!vh55 5L#v#v #vL:V l  t%%%0655 5Lp%%%$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh555555#v:V l t065$$If!vh56 5 5#v6 #v #v:V l  t%%%056 5 5p%%%$$If!vh56 55555J#v6 #v#v#v#v#vJ:V l t056 55555J$$If!vh56 55555J#v6 #v#v#v#v#vJ:V l t056 55555J$$If!vh56 55555J#v6 #v#v#v#v#vJ:V l t056 55555J$$If!vh56 55555J#v6 #v#v#v#v#vJ:V l t056 55555J$$If!vh5$#v$:V l  t %05$p %$$If!vh55 5 58#v#v #v #v8:V l t055 5 58$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558$$If!vh555F5558#v#v#vF#v#v#v8:V l t0555F5558/ $$If!vh5$#v$:V l  t %05$p %$$If!vh55 5 58#v#v #v #v8:V l t055 5 58$$If!vh55 5 58#v#v #v #v8:V l t055 5 58$$If!vh55 5 58#v#v #v #v8:V l t055 5 58$$If!vh55 5 58#v#v #v #v8:V lF t055 5 58$$If!vh55 5 58#v#v #v #v8:V l t055 5 58$$If!vh555x #v#v#vx :V l  t06555x p$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh555x #v#v#vx :V l t06555x g+$$If!vh5L5L#vL:V l  t065L/ p$$If!vh5L5L#vL:V l t065L/ ($$If!vh555L5L5L#v#v#vL:V l t2%%%%%06555Lp2%%%%%$$If!vh555L5L5L#v#v#vL:V l t06555L$$If!vh555L5L5L#v#v#vL:V l t06555L$$If!vh555L5L5L#v#v#vL:V l t06555L$$If!vh55<5 #v#v<#v :V l4  t%%%06+55<5 p%%%}$$If!vh555K555q#v#v#vK#v#v#vq:V l4 t<%%%%%%06+555K555qp<%%%%%%kd;,$$Ifl4ֈf} ," Kq t<%%%%%%0644 lap<%%%%%%$$If!vh555K555q#v#v#vK#v#v#vq:V l t06555K555q$$If!vh555K555q#v#v#vK#v#v#vq:V l t06555K555q$$If!vh555K555q#v#v#vK#v#v#vq:V l t06555K555q$$If!vh55#v#v:V l  t%%0655p%%$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655$$If!vh55#v#v:V l t0655ga$$If!vh5l5 5e #vl#v #ve :V l  t96,5l5 5e / /  / ap$$If!vh5l5 5e #vl#v #ve :V lZ  t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V lZ t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l  t96,5l5 5e / /  / ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V lZ  t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V lZ  t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l  t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l t96,5l5 5e / / / /  ap$$If!vh5l5 5e #vl#v #ve :V l  t96,5l5 5e / / / /  ap$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l t96,5l5 5e 5 / / / /  ap#$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l  t96,5l5 5e 5 / / / /  ap$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l t96,5l5 5e 5 / / / /  ap$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l t96,5l5 5e 5 / / / /  ap#$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l  t96,5l5 5e 5 / / / /  ap$$If!vh5l5 5e 5 5 #vl#v #ve #v :V l t96,5l5 5e 5 / / / /  ap^$$If!vh5 5 #v :V l t96w$,5 a$$If!vh5 5\ 5"#v #v\ #v":V l4  t06+5 5\ 5"gpH$$If!vh5 5555|#v #v#v#v|:V l4  t206+5 555|gp2$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5 5555|#v #v#v#v|:V l t065 555|g$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l (%%%%05]5W 5p5$ 4p(%%%%$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l05]5W 5p5$ 4$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l05]5W 5p5$ 4$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l05]5W 5p5$ 4$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l05]5W 5p5$ 4$$If!vh5]5W 5p5$ #v]#vW #vp#v$ :V l05]5W 5p5$ 4$$If!vh5Y5#5#vY#v##v:V l t065S554$$If!vh5Y5#5#vY#v##v:V l t065S554^* (_HmH nH sH tH <`< xNormalCJ_HmH sH tH J@J 'U Q Heading 1$xx@&5>*OJQJL@L  Heading 2$x@&5CJOJQJ88  Heading 3$@&5@@  Heading 4$@& 6B*ph|| &M Heading 6A$$$d&d-D @&M NPa$5CJ\aJLRL  Heading 7$<@&5CJOJQJ88  Heading 8$@&5DA`D Default Paragraph FontVi@V  Table Normal :V 44 la (k (No List @>@@ )Title$a$5B*OJQJphJJ@J Subtitle$a$5B*CJOJQJph:B@: Body Text CJOJQJ:@":  Footnote TextCJ0U@10 Hyperlink>*B*4@B4 Header  !8OR8 Table B*CJphr6@br d)< List Bullet 2> & F & 0` P@1$7$8$H$@ @r@ Footer  ! CJOJQJ.)@. Page NumberHH % Balloon TextCJOJQJ^JaJ6Q6 TableFootnoteD"@D Caption $x5CJOJQJ\^O^ `Style Heading 1 + Black xx B*\phFVF NFollowedHyperlink >*B* phT^@T &{ Normal (Web)dd[$\$B* CJaJphBB 4 Table CharB*CJOJQJphjj 5D Table Grid7:V 0 B'B [6Comment ReferenceCJaJ8"8 #[6 Comment Text"CJ:1: "[6Comment Text Char@j!"@ %[6Comment Subject$5\F2QF $[6Comment Subject Char5\TaT MHeading 6 Char5CJ\aJfH q FqF MHeading 1 Char5>*CJOJQJbb M Light Grid - Accent 3 (^m$OJPJQJaJDD M Title Char5B*CJOJQJphPK![Content_Types].xmlj0Eжr(΢Iw},-j4 wP-t#bΙ{UTU^hd}㨫)*1P' ^W0)T9<l#$yi};~@(Hu* Dנz/0ǰ $ X3aZ,D0j~3߶b~i>3\`?/[G\!-Rk.sԻ..a濭?PK!֧6 _rels/.relsj0 }Q%v/C/}(h"O = C?hv=Ʌ%[xp{۵_Pѣ<1H0ORBdJE4b$q_6LR7`0̞O,En7Lib/SeеPK!kytheme/theme/themeManager.xml M @}w7c(EbˮCAǠҟ7՛K Y, e.|,H,lxɴIsQ}#Ր ֵ+!,^$j=GW)E+& 8PK!Ptheme/theme/theme1.xmlYOo6w toc'vuر-MniP@I}úama[إ4:lЯGRX^6؊>$ !)O^rC$y@/yH*񄴽)޵߻UDb`}"qۋJחX^)I`nEp)liV[]1M<OP6r=zgbIguSebORD۫qu gZo~ٺlAplxpT0+[}`jzAV2Fi@qv֬5\|ʜ̭NleXdsjcs7f W+Ն7`g ȘJj|h(KD- dXiJ؇(x$( :;˹! I_TS 1?E??ZBΪmU/?~xY'y5g&΋/ɋ>GMGeD3Vq%'#q$8K)fw9:ĵ x}rxwr:\TZaG*y8IjbRc|XŻǿI u3KGnD1NIBs RuK>V.EL+M2#'fi ~V vl{u8zH *:(W☕ ~JTe\O*tHGHY}KNP*ݾ˦TѼ9/#A7qZ$*c?qUnwN%Oi4 =3ڗP 1Pm \\9Mؓ2aD];Yt\[x]}Wr|]g- eW )6-rCSj id DЇAΜIqbJ#x꺃 6k#ASh&ʌt(Q%p%m&]caSl=X\P1Mh9MVdDAaVB[݈fJíP|8 քAV^f Hn- "d>znNJ ة>b&2vKyϼD:,AGm\nziÙ.uχYC6OMf3or$5NHT[XF64T,ќM0E)`#5XY`פ;%1U٥m;R>QD DcpU'&LE/pm%]8firS4d 7y\`JnίI R3U~7+׸#m qBiDi*L69mY&iHE=(K&N!V.KeLDĕ{D vEꦚdeNƟe(MN9ߜR6&3(a/DUz<{ˊYȳV)9Z[4^n5!J?Q3eBoCM m<.vpIYfZY_p[=al-Y}Nc͙ŋ4vfavl'SA8|*u{-ߟ0%M07%<ҍPK! ѐ'theme/theme/_rels/themeManager.xml.relsM 0wooӺ&݈Э5 6?$Q ,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{P8g/]QAsم(#L[PK-![Content_Types].xmlPK-!֧6 +_rels/.relsPK-!kytheme/theme/themeManager.xmlPK-!Ptheme/theme/theme1.xmlPK-! ѐ' theme/theme/_rels/themeManager.xml.relsPK]  0#)\5 8H;CF.OvUYWdhp|~VGJKRTVYbqu Q #$0~26"7T7k77777o8888,9^9y999 :::;6;k;;;wDDDE&EbEEEEEF9FrFFFF GOGIZJhJzJJJJJJQRTTT"ULUuU``!a/aFaVaiaWdddddde)e?eZeueeeeeeffff gg'g5gDgTgkgggggggghh0hHh_hlhhhhhh"iBiaiiiim+nnnnnnn oo$ow4}W}}}}~HILMNOPQSUWXZ[\]^_`acdefghijklmnoprstvwxyz{|}~@X<`oX!@  @ 0(  B S  ?H0(   _Ref80503453 _Hlt314209004 _Hlt314209005@@dfgijlmopԄdfgijlmopԄ-5AAMMctctttvv{{dpz~~Ԅ$QR1r\{BZZ@7SG  ,4 n;`2AR5z0ao|"Dж|1%nc!)RZ|*ZZ@Ww- b2nr-4|nx4^d\7h*(\Ks8":r\&:䚱2l<@n'@X>xJHRLHPzJ!NJnhhNnpwRX&kU^d"V^d dYZZ@ZR]AaS"gR0eiZZ@"Kt`m ^`OJQJo(- hh^h`OJQJo(h ^`OJQJo("  ^`OJQJo("  pp^p`OJQJo("  @ @ ^@ `OJQJo("  ^`OJQJo("  ^`OJQJo("  ^`OJQJo("  ^`OJQJo("  PP^P`OJQJo(" hh^h`56B*CJOJQJo(hh^h`o(.^`B*OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHhh^h`56B*CJOJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHh^`o(.h ^`hH.h pL^p`LhH.h @ ^@ `hH.h ^`hH.h L^`LhH.h ^`hH.h ^`hH.h PL^P`LhH.^`B*OJQJo(hh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(hh^h`o(.h ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH ^`OJQJo(h ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHh ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(^`B*OJQJo(h^`o(. ^`hH. pL^p`LhH. @ ^@ `hH. ^`hH. L^`LhH. ^`hH. ^`hH. PL^P`LhH.hh^h`56B*CJOJQJo(h^`o(.h ^`hH.h pL^p`LhH.h @ ^@ `hH.h ^`hH.h L^`LhH.h ^`hH.h ^`hH.h PL^P`LhH.hh^h`OJQJo(hHh8^8`OJQJo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJo(hHoh^`OJQJo(hH^`B*OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH ^`OJQJo( ^`OJQJo(hh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(h-^`5B*CJOJQJ^JaJo(phhH.^`.pp^p`.@ @ ^@ `.^`.^`.^`.^`.PP^P`.hh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(h ^`hH.h ^`hH.h pL^p`LhH.h @ ^@ `hH.h ^`hH.h L^`LhH.h ^`hH.h ^`hH.h PL^P`LhH.$AX&kUS"g"VxJHx4Z|1%,4 hNZ|*0ei2l<@{Bc!)Ww-7SG dY\7\&:b2ao\Ks85z-4pwR1;`"Kt'@J!NDLHo]Aa$$1.ŞVbzdFc7x1nH(Xh)D>                                    YB                 :a                 YB                                   žؙt       h8h                 eE&`Ew ;"e.y@oyTpx=7+df@p@Unknown vhaclehallc Colleen HallG* Times New Roman5Symbol3. * Arial5. *aTahoma7.{ @Calibri;Wingdings?= * Courier NewA BCambria Math"h7 7 qCp Cp C!nr4d!!r 2qHX ?%2!xxFG VHAPBHSemlaT$                           ! " # Oh+'0  4 @ L Xdlt|FG Normal.dotmVHAPBHSemlaT2Microsoft Office Word@@Ӑ>@:vF@:vF p՜.+,D՜.+,4 hp   VHA PBM SHGC!  Title(X` _PID_HLINKS_NewReviewCycleA8 3[Nhttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022567Orig1s000TOC.cfml.http://www.pbm.va.gov/  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'(*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXY[\]^_`acdefghinqsrtuvwxyzRoot Entry F1p@Data g1Table)`WordDocument8SummaryInformation(ZDocumentSummaryInformation8bCompObjyMsoDataStore11  !"#$%&'()*+,-./012345678:;<>?@BCD  F'Microsoft Office Word 97-2003 Document MSWordDocWord.Document.89q This value indicates the number of saves or revisions. The application is responsible for updating this value after each revision. DocumentLibraryFormDocumentLibraryFormDocumentLibraryForm