Forty-Eighth Annual Teaching Conference Pediatrics for the Practitioner -UT Health Science Center San Antonio School of Medicine June 10-12, 2011

Transcription

1 SAFE USE OF ANTIDEPRESSANTS IN THE BLACK BOX ERA Adelaide Robb, MD Associate Professor, Psychiatry and Pediatrics Source DISCLOSURE Advisory Board Speaker s Bureau Bristol Myers Squibb Epocrates Research Contract Royalties Stock Janssen Forest Glaxo Smith Kline McNeil Merck/Scherring Lilly Lundbeck Pfizer Otsuka Shinogi Supernus NICHD CHADD OVERVIEW The SSRIs and approvals FDA rules and changes Definitions of black box and medication guide Data leading up to the antidepressant black box FDA published articles on suicide rates adults and kids The antidepressant black box The information from GPRD/ Jick article and Bridges What to do with your patients

2 Selective Serotonin Reuptake Inhibitors Common Side Pharmocologic Special Drug name Initial dose Increment Maximum Half Life Effects Considerations Considerations nausea, vomiting, inhibits CYP2D6, little Fluoxetine anxiety,sexual long time to discontinuation Prozac 10-20mg 10-20mg 80mg 4-6days dysfunction therapeutic syndrome nausea,sexual Sertaline dysfunction, mild inhibition clinical effect 3-6 Zoloft 25-50mg mg 200mg 26hrs insomnia CYP2D6 weeks sedating, Incr. nausea,dry weight, Paroxetine mouth,sex more anticholinergic syndrome discontinuation Paxil 10-20mg 10mg 60mg hrs dysfunction higher Incr. GI poss discontinuation Fluvoxamine less sexual potent inhibition risk, drug Luvox 25-50mg 25-50mg 300mg hrs dysfunction p4502d6 interactions nausea, dry mouth, somnolence, concern of slight Citalopram insomnia,sexual less p4502d6 increase Celexa 10-20mg 10mg 60mg 35 hr dysfunction inhibition overdose risk nausea,delayed ejaculation, insomnia, somnolence, single isomer of Escitalopram diarrhea, citalopram, no Lexapro 5-10mg 5mg 20mg 27-32hr sweating clear advantage no generic FDA HISTORY Division of Chemistry Investigated adulteration of questionable food additives and drugs of the time Bureau of Chemistry the Food and Drugs Act Prohibited interstate transport of drugs Drugs must meet USP and NF standards misbranded Food or drug label could not be false or misleading 1937-Sulfanilamide experience diethylene glycol for pediatrics, died of antifreeze poisoning FDA HISTORY II 1938-Food Drug and Cosmetic Act FD&C Act need a prescription, must demonstrate SAFETY 1951 Durham Humphrey Amendment OTC v RX labeling FDA authority to classify 1957 Thalidomide Europe, 1960 NDA in US; 1962 Dr. Kelsey says not enough info NDA withdrawn 1962 Kefauver-Harris Amendments, drugs need to be safe and EFFECTIVE; need to have efficacy of all drugs FDA approved since 1938; trials need informed consent

3 FDA HISTORY III 1965-Drug Abuse Control amendments passed 1968-Drug Abuse Control amendments and other laws were compiled to form DEA 1997 FDAMA-FDA modernization act, prescription drug users fee act (PDUFA); pay registration fee have priority drugs 1997 Pediatric Rule all drugs must be tested in kids as part of package-later struck down by courts 2002 Best Pharmaceutical Act for Children mo extra patent if do FDA required studies FDA HISTORY IV-CHILDREN 2007 BPCA and PREA reauthorized 2003 Pediatric Research Equity Act PREA Established the Pediatric Advisory Committee The FDA Stick Mandates pediatric studies of drugs by drug companies Failure to comply may render drugs misbranded Retroactive to drugs approved since April 1, 1999 Studies must show safety, efficacy and appropriate dosing BPAC and PREA sunset 2012 unless reenacted by Congress DEFINITIONS Black box-the highest level of warning before a drug is removed from the market Stronger than bolded warning Medication guide-a specialized handout required by the manufacturer to be dispensed with every prescription for the drug, usually but not always given out as part of a black box program Not all black boxed drugs have med guides and vice versa

4 FDA ADVISORY COMMITTEE Give independent advice to the FDA Committee decisions are NOT binding Committee members are NOT full time FDA employees Membership by law must be fairly balanced and composed of: Recognized clinical experts in field of study Researchers Academic professors Lay consumer Industry representative (non voting) General public, can address any advisory committee during a 60 minute open forum discussion prior to committee deliberations. SUICIDE RATES BY AGE/100,000 Age Range Rate 5-9 years years years years SUICIDE BY AGE, RACE & GENDER Population years years EA males AA males EA females AA females

5 FDA DATA KIDS I Hammad et al Arch Gen Psychiatry Mar;63(3):332-9 Investigate the relationship between antidepressant drugs and suicidality in pediatric patients participating in randomized, placebo-controlled trials 23 trials conducted in 9 drug companysupported programs evaluating the effectiveness of antidepressants in pediatric patients and 1 multi-center trial (TADS) that evaluated fluoxetine hydrochloride FDA DATA KIDS II All placebo-controlled trials submitted to the FDA 4582 patients in 24 trials 16 MDD, 4 OCD, 2 GAD,1 ADHD, & 1 SAD Only 20 trials were included in the risk ratio analysis of suicidality because 4 trials had no events in the drug or placebo groups Meta-analysis was conducted to obtain overall suicidality risk estimates for each drug individually, for SSRI's in depression trials as a group, and for all 20 trials combined FDA DATA KIDS III No completed suicides in any of these trials TADS was the only individual trial to show a statistically significant risk ratio (4.62; 95% confidence interval [CI], Overall risk ratio for SSRI s in MDD trials was 1.66 (95% CI, ) and for all drugs across all indications was 1.95 (95% CI, ). The overall risk difference for all drugs across all indications was 0.02 (95% CI, )

6 FDA DATA KIDS IV Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality over placebo Highest was 1.95 risk ratio This data led to the black box warning saying 2% suicidality on placebo and 4% on medication Still way below suicide attempt rates for MDD in same age group and 29% ideation rate at entry into TADS ANTIDEPRESSANT FDA HEARINGS Child and Adult psychiatry decidedly absent at first and second hearings Many plaintiff s lawyers, scientologists, and others came to complain Very few child psychiatrists and even fewer adult psychiatrists came No pediatric support One patient who benefited came We lost by numbers alone FDA BLACK BOX WARNING Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents and young adults in short term studies of depression and other psychiatric disorders Short term studies did not show and increase in suicidality with antidepressants compared to placebo in adults beyond age 24 Depression and other psychiatric disorders are themselves associated with increases in the risk of suicide All patients starting antidepressants should be monitored appropriately and observed closely Families and caregivers should discuss with the HCP right away any observations of worsening depression symptoms, suicidal thinking and behavior, or unusual changes in behavior

7 FDA BB RECOMMENDATIONS If left untreated, depression can worsen and make life difficult for your adolescent and the entire family. Depression in adolescents is associated with:* High risk of completed and attempted suicide Significant morbidity Other psychiatric disorders Adult depression Disruptive behavior Substance abuse Eating disorders Withdrawal from peers School absenteeism and decreased performance Disruption of social functioning (work, school, relationships) Emotional distress Early pregnancy Physical illness *The effect of Lexapro on these outcomes has not been studied. How can treatment help? The appropriate treatment plan for your adolescent is important because it may help your adolescent: Feel better Improve social and family relationships Improve performance at school Enjoy activities and hobbies more Get greater enjoyment out of life CONTROVERSY OVER SUICIDE Paxil withdrawn due to increased suicidal ideation in active treatment arm compared with placebo arm in pediatric MDD trials 3.2% v 1.5% FDA warning do not use in pediatric MDD Effexor in GAD and MDD increased anger and increase suicidal ideation of 2% v 0% in placebo arm Company warning do not use pediatric MDD FDA hearings 2004 ANTIDEPRESSANTS AND RISK OF SUICIDAL BEHAVIORS Jick et al JAMA 21 July 04, used GPRD data base of GP s in England from and looked at year olds who had first start of antidepressants Paroxetine, Fluoxetine, Amitriptylene and Dothiepin 159,810 users, must use only 1 and within 90 days of index date Non-fatal suicidal behavior 555 cases and 2062 age, sex matched controls Relative risk to Doth of non-fatal suicidal behavior 0.83 Ami, 1.16 Flu, 1.29 Par

8 JICK II RR of non-fatal suicidal behavior days 1to 9 c/w >90 d 4.07, 10-29d 2.88, 30-89d 1.53 RR of non-fatal suicidal behavior who stopped antidepressants 0.71 c/w >90d on meds and 0.91 c/w d on meds i.e. no increase in RR with cessation of treatment No difference in RR by age including in yo, but more attempters female 65% and 12.3% 10-19yo c/w 31.9% 20-29yo and 24.1% 30-39yo JICK III COMPLETED SUICIDE 17 completed suicides who received 1 study drug in 90d with no prior documented suicidal behavior (prior suicide attempt known to confer 18 fold RR of repeat attempt or suicide) or history of multiple AD drugs (2.8 fold RR of SA or S) 76% male NONE 10-19yo; 53% 20-39yo, 47% 40-69yo, 3 Ami, 7 Dot, 4 Flu, 3 Par Days 1to 9 38 fold RR c/w 90d, d 5.1RR, RR Same time period yo suicides in GPRD data base none had received an antidepressant drug SUICIDE TRENDS AFTER BLACK BOX Letter by JA Bridge et al JAMA (9) Steady decline 10 years in youth <20 In increased by 18% largest single change in 15 years national fatal injury data Risk of suicide per 100,000 person years Used trend line from to estimate 2004 and 2005 data Did observed number of deaths minus expected deaths to determine excess death Overall suicide decreased 5.3% from 2004 to 2005 Actual rate still above expected by gender and age excess suicides, excess suicides

9 META-ANALYSIS AD AND SI/SA Bridge JAMA April pubmed, FDA, MHRA clinical trials <19yo % v 2% risk 27 trials 15 MDD, 6 OCD, 6 nonocd Efficacy responder status drug>pbo NNT MDD 10, 6 OCD, non-ocd 3 NNH 143 for AD MDD, OCD, non-ocd Outcomes change from baseline in scale Risk outcome SI/SA using Columbia scheme CGI/CDRS-R, CYBOCS, non-ocd CGI and PARS

10 META-ANALYSIS AD AND SI/SA MDD 13 trials 2910 participants rates of response 61% ad v 50% pbo, pooled risk difference 11% NNT 10 Pooled suicide rates AD 3% Pbo 2% Pooled risk difference 1% NNH 112 OCD 6 trials 705 participants rates of response 52% ad v 32% pbo, pooled risk difference 20% NNT 6 Pooled suicide rates AD 1% Pbo 0.3% Pooled risk difference 0.5% NNH 200 META-ANALYSIS AD AND SI/SA Non-OCD 6 trials 1136 participants rates of response 69% ad v 39% pbo, pooled risk difference 37% NNT 3 Pooled suicide rates AD 1% Pbo 0.3% Pooled risk difference 0.7% NNH MDD age split adolescents > children Flu pooled risk response kids 21% teens 2% FLU ES higher with more severe.69 v.39 MDD ES inversely proportional to duration OCD teen child pooled risk no effect of PBO run in 3 non-ocd pooled risk 46% teens v 29% No evidence of publication bias CHANGES SINCE BLACK BOX In Netherlands from 2003 to 2005 the rate of antidepressant prescriptions to patients under 18 fell 22% From 2003 to 2005 suicides in patients under 18 rose 50% from 34 suicides to 51 suicides-presented at ACNP CDC adolescent suicide rates rose in 2004-first time in a decade when antidepressant rates dropped Autopsy study of adolescent suicides-few had antidepressants in their system

11 CHANGES SINCE BLACK BOX II Study of suicide attempts by county in US notes those with highest antidepressant use have lowest suicide rates AJP 2006 FDA meta-analysis of adult rates shows 2 fold increase in ideation/attempt of those <25 years old on drug compared with placebo WHAT WE LEARNED If we don t fight others decide for us No one else will stand up for treatment for our patients Stigma is bad enough If patients worry meds cause death, people will not get help Enlist the pediatricians, their numbers are bigger, and they will lobby if they think it helps their patients WHAT TO DO WITH PEDIATRIC PATIENTS If a new pediatric patient needs an antidepressant, you must explain risks and benefits including suicidal ideation and attempts Offer therapy first if that is family s preference Document suicide assessment in the chart In psychiatry only 2 drugs have ever been shown to lower suicide risk, lithium in bipolar and clozapine for schizophrenia

12 WHAT TO DO WITH PEDIATRIC PATIENTS Our goal for treatment with medications is to return to baseline functioning, not to lower suicide risk Remember based on Jick article period of highest risk is during first 2 weeks You may need to advocate for extra visits with insurance company so your pediatric patients have better care and coverage Ongoing assessment and education is necessary QUESTIONS?