The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1510 Volume 56 December 19, 2016 IN THIS ISSUE Celecoxib Safety Revisited p 159 Drugs for Psychotic Disorders p 160 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 58 December 19, 2016 Take CME Exams ISSUE ISSUE No 1433 1510 ALSO IN THIS ISSUE Drugs for Psychotic Disorders p 160 Volume 56 ▶ Celecoxib Safety Revisited The results of a clinical trial (PRECISION)1 comparing the cardiovascular safety of the COX-2 selective NSAID celecoxib (Celebrex, and generics) with that of ibuprofen and naproxen, which are nonselective, have been described in the lay press in terms that may overestimate the safety of celecoxib NSAID PHARMACOLOGY — NSAIDs inhibit the enzyme cyclooxygenase (COX), which is required for synthesis of prostaglandins and thromboxane COX-1 inhibition blocks the protective effect of prostaglandins on the gastric mucosa, which can cause gastrointestinal toxicity, and has an antiplatelet effect that can cause bleeding COX-2 inhibition produces therapeutic antiinflammatory and analgesic effects, but it has effects on vascular endothelium that can be prothrombotic Ibuprofen and naproxen inhibit COX-1 more than COX-2 The COX-2 selective NSAID rofecoxib (Vioxx), which inhibits COX-2 80 times more than COX-1, was removed from the market because of cardiovascular toxicity Celecoxib, which inhibits COX-2 times more than COX-1, also has been associated with an increased risk of cardiovascular toxicity.2,3 All NSAIDs inhibit renal prostaglandins, decrease renal blood flow, cause fluid retention, and may cause hypertension and renal failure, especially in the elderly.4 THE PRECISION TRIAL — A total of 24,081 patients with osteoarthritis (90%) or rheumatoid arthritis (10%) and established cardiovascular disease or increased risk of developing cardiovascular disease were randomized to receive celecoxib 100 mg twice daily, ibuprofen 600 mg three times daily, or naproxen 375 mg twice daily; the mean treatment duration was 20.3 months and the mean follow-up period was 34.1 months About 50% of the patients were taking lowdose aspirin at baseline A primary outcome event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 188 patients taking celecoxib (2.3%), 201 taking naproxen (2.5%), and 218 taking ibuprofen (2.7%); celecoxib was determined to be noninferior to both ibuprofen and naproxen with regard to cardiovascular safety.1 SOME LIMITATIONS — By the end of the PRECISION trial, 68.8% of patients had stopped taking their assigned drug The dosage of celecoxib was limited to 200 mg per day for patients with osteoarthritis; as a result, the average daily dose of celecoxib was lower than the doses previously associated with cardiovascular toxicity Increases in the dosage of ibuprofen and naproxen were permitted Ibuprofen and naproxen, but not celecoxib, inhibit aspirin binding to platelet COX-1; thus, the cardioprotective effects of aspirin may have been blunted in patients who were taking ibuprofen or naproxen.5 CONCLUSION — The average dosage of the COX-2 selective NSAID celecoxib (Celebrex, and generics) used in the PRECISION trial was too low to support the determination that celecoxib is noninferior to ibuprofen and naproxen with regard to cardiovascular safety COX-2 selective NSAIDs cause less gastrointestinal toxicity and bleeding than nonselective NSAIDs, but they may have a prothrombotic effect, and all NSAIDs are nephrotoxic Elderly patients, who are most at risk, should exercise caution in taking any NSAID, including celecoxib ■ SE Nissen et al Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis N Engl J Med 2016 Nov 13 (epub) JM Wright The double-edged sword of COX-2 selective NSAIDs CMAJ 2002; 167:1131 SD Solomon et al Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention N Engl J Med 2005; 352:1071 MA Perazella COX-2 selective inhibitors: analysis of the renal effects Expert Opin Drug Saf 2002; 1:53 GA FitzGerald ImPRECISION: Limitations to interpretation of a large randomized clinical trial Circulation 2016 Nov 13 (epub) 159 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ▶ ® Drugs for Psychotic Disorders Oral antipsychotic drugs used for treatment of schizophrenia, schizoaffective disorder, delusional disorder, and other manifestations of psychosis or mania are listed in Table on page 161 Parenteral antipsychotic drugs used for treatment of these disorders are listed in Table on page 162 EFFECTIVENESS — Antipsychotic drugs are more effective in treating the positive symptoms of schizophrenia (agitation, hallucinations, delusions) than the negative symptoms (apathy, social withdrawal, blunted affect).1,2 Oral – Second-generation antipsychotics are used more commonly than less expensive first-generation drugs, even though controlled trials generally have failed to demonstrate a clear advantage in efficacy, except with clozapine and possibly olanzapine.3 Clozapine is generally considered the most effective antipsychotic drug for treatment of schizophrenia.4 It has been effective for treatment of psychotic symptoms that have not responded to other drugs and has been more effective than other antipsychotics in decreasing the risk of suicide.5 Olanzapine has been more effective than aripiprazole, quetiapine, risperidone, or ziprasidone in reducing psychotic symptoms.6 Risperidone has been more effective than quetiapine or ziprasidone.7 The more recently approved antipsychotic drugs paliperidone,8 asenapine,9 iloperidone,10 lurasidone,11 brexpiprazole,12 and cariprazine13 may be effective for some patients, but their efficacy and safety relative to older drugs remain to be established Parenteral – Short-acting parenteral antipsychotics can be helpful for acute treatment of agitation associated with schizophrenia or bipolar mania Long-acting parenteral antipsychotics generally have been used in patients with a history of relapse due to poor adherence to oral maintenance therapy Longacting injectable formulations can improve adherence, hospitalization and relapse rates, and long-term outcomes for patients with schizophrenia, even though a benefit has not been consistently demonstrated in trials comparing long-acting injectable formulations with oral formulations.14,15 In one head-to-head trial, once-monthly paliperidone palmitate was no more effective than haloperidol decanoate, which costs much less.16 Data on newer long-acting parenteral 160 Vol 58 (1510) December 19, 2016 Choice of an Antipsychotic Drug ▶ Clozapine is generally the most effective antipsychotic drug ▶ ▶ ▶ for treatment of schizophrenia, but it is usually reserved for refractory disease because of its adverse effects Olanzapine may be slightly more effective than other antipsychotic drugs (except clozapine), but its adverse metabolic effects may make it unacceptable for long-term use Other second-generation antipsychotics are not clearly more effective than less expensive first-generation drugs, but they are less likely to cause tardive dyskinesia Long-acting injectable antipsychotics may be useful when adherence is a problem formulations such as paliperidone palmitate 3-month, olanzapine, and aripiprazole are limited.17,18 Inhaled – The first-generation antipsychotic loxapine is available as an inhalation powder (Adasuve) for acute treatment of agitation associated with schizophrenia or bipolar disorder in patients who are able to use an inhaler and who are not at risk for bronchospasm.19 ADVERSE EFFECTS — Movement disorders, metabolic effects, and other adverse effects can interfere with patient adherence to antipsychotic drugs The FDA requires labels of both first- and secondgeneration antipsychotics to include a boxed warning about an increased risk of death in elderly patients with dementia-related psychosis.20 First-Generation – All first-generation antipsychotics have been variably associated with sexual dysfunction, hyperprolactinemia, neuroleptic malignant syndrome, extrapyramidal symptoms, akathisia, and tardive dyskinesia The risk of extrapyramidal symptoms and tardive dyskinesia may be minimized if dosing is targeted to the lowest dose at which mild extrapyramidal motor effects first appear.21 Chlorpromazine commonly causes sedation, postural hypotension, and weight gain, as well as anticholinergic and occasional extrapyramidal adverse effects Haloperidol and fluphenazine are less likely to cause sedation, postural hypotension, anticholinergic effects, or weight gain, but are more likely to cause extrapyramidal symptoms Perphenazine, loxapine, and molindone are generally less sedating than chlorpromazine and somewhat less likely than haloperidol and fluphenazine to cause extrapyramidal symptoms Second-Generation – Second-generation antipsychotics have a relatively lower risk of causing extrapyramidal symptoms and are less likely than firstgeneration antipsychotics to cause tardive dyskinesia and neuroleptic malignant syndrome, but akathisia is a persistent problem.22,23 Second-generation The Medical Letter ® Vol 58 (1510) December 19, 2016 Table Some Oral Antipsychotics Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1 Cost2 10-50 mg bid 2.5-10 mg divided tid or qid 200 mg bid 10 mg once/d $367.80 130.60 mg once/d or divided mg bid 57.50 Loxapine4 – generic 10, 25, 50, 100, 200 mg tabs 1, 2.5, 5, 10 mg tabs; 2.5 mg/5 mL elixir; mg/mL conc 0.5, 1, 2, 5, 10, 20 mg tabs; mg/mL conc 5, 10, 25, 50 mg caps 10 mg bid 86.40 Molindone – generic Perphenazine – generic 5, 10, 25 mg tabs 2, 4, 8, 16 mg tabs 50-75 mg/d mg tid Thioridazine5 – generic Thiothixene – generic Trifluoperazine – generic 10, 25, 50, 100 mg tabs 1, 2, 5, 10 mg caps 1, 2, 5, 10 mg tabs 50-100 mg tid mg tid 2-5 mg bid 60-100 mg in 2-4 divided doses 5-25 mg tid or qid 24 mg in divided doses 100-200 mg bid 10 mg bid 10 mg bid 2, 5, 10, 15, 20, 30 mg tabs 10-15 mg once/d 10-30 mg once/d 10, 15 mg ODT 2.5, 5, 10 mg sublingual tabs 0.25, 0.5, 1, 2, 3, mg tabs 10-15 mg once/d mg bid6 1-4 mg once/d7 10-15 mg once/d 5-10 mg bid6 2-4 mg once/d 1.5, 3, 4.5, mg caps 25, 50, 100, 200 mg tabs 25, 100 mg tabs 50 mg/mL susp 12.5, 25, 100, 150, 200 mg ODT 1.5 mg/d8 12.5 mg once/d or bid 1.5-6 mg once/d 300-900 mg divided bid or tid 1, 2, 4, 6, 8, 10, 12 mg tabs mg bid10 6-12 mg bid 20, 40, 60, 80, 120 mg tabs 40 mg once/d 40-160 mg once/d 2.5, 5, 7.5, 10, 15, 20 mg tabs 5-10 mg once/d 10-20 mg once/d 1.5, 3, 6, mg ER tabs mg once/d 6-12 mg once/d 17 mg tabs 34 mg once/d 34 mg once/d 25, 50, 100, 200, 300, 400 mg tabs 25 mg bid 150-750 mg in or divided doses 41.40 615.60 50, 150, 200, 300, 400 mg ER tabs 0.25, 0.5, 1, 2, 3, mg tabs; mg/mL soln 0.25, 0.5, 1, 2, 3, mg ODT 0.5, 1, 2, 3, mg ODT 20, 40, 60, 80 mg caps 300 mg once/d mg once/d or divided bid 400-800 mg once/d 4-6 mg once/d or divided bid 20-40 mg bid 20-80 mg bid 750.00 11.20 714.30 373.20 857.10 80.00 880.40 Drug First-Generation Chlorpromazine3 – generic Fluphenazine3 – generic Haloperidol3 – generic Second-Generation Aripiprazole3 – generic Abilify (Otsuka) orally disintegrating – generic Asenapine – Saphris (Allergan) Brexpiprazole – Rexulti (Otsuka/Lundbeck) Cariprazine – Vraylar (Allergan) Clozapine9 – generic Clozaril (Novartis) Versacloz (Jazz) orally disintegrating – generic FazaClo (Jazz) Iloperidone – generic Fanapt (Vanda) Lurasidone – Latuda11 (Sunovion) Olanzapine3 – generic Zyprexa (Lilly) orally disintegrating – generic Zyprexa Zydis Paliperidone3 – generic Invega (Janssen) Pimavanserin – Nuplazid 12 (Acadia) Quetiapine – generic Seroquel (AstraZeneca) extended release – Seroquel XR13 Risperidone3 – generic Risperdal (Janssen) orally disintegrating – generic Risperdal M-TAB Ziprasidone – generic11 Geodon3 (Pfizer) 5, 10, 15, 20 mg ODT 114.30 174.20 47.00 187.40 116.40 302.50 892.00 919.00 1006.10 934.70 1006.10 200.70 1145.10 1387.40 588.60 1440.00 N.A 1139.20 1013.10 16.20 553.20 78.70 582.60 N.A 934.00 1950.00 conc = concentrate; ER = extended release; N.A = cost not available; ODT = orally disintegrating tablet; susp = suspension Initial and usual maintenance dosage for schizophrenia Dosage adjustment may be needed for renal or hepatic impairment Approximate WAC for 30 days’ treatment with the lowest usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Also available parenterally Also available as a powder for oral inhalation (Adasuve) for acute treatment of agitation associated with schizophrenia or bipolar disorder in adults Thioridazine is associated with dose-related prolongation of the QTc interval and should be reserved for schizophrenic patients who fail to respond to other drugs Tablet should be placed under the tongue and allowed to dissolve completely Avoid eating or drinking for 10 minutes after administration The recommended starting dosage is mg once daily on days 1-4 The dose should be increased to mg/day on days 5-7 and then to mg/day on day 8 Dosage can be increased to mg/day on day Clozapine can cause seizures and severe neutropenia and should be reserved for patients with schizophrenia who fail to respond to other drugs 10 Dose should be doubled each day to reach a target of 12-24 mg/day 11 Must be taken with food (≥350 calories with lurasidone and 500 calories with ziprasidone [K Gandelman et al J Clin Psychiatry 2009; 70:58] to maximize absorption) 12 Only approved for treatment of hallucinations and delusions associated with Parkinson's disease (Med Lett Drugs Ther 2016; 58:74) 13 A 400-mg ER generic formulation has recently been approved, but the cost is not yet available 161 The Medical Letter Vol 58 (1510) ® December 19, 2016 Table Some Parenteral Antipsychotics Drug Cost3 Some Available Formulations Usual Adult Dosage1,2 25 mg/mL ampules 2.5 mg/mL vials, ampules 2.5 mg/mL vials mg/mL vials mg/mL ampules 25 mg IM 2.5-5 mg IM 1.25 mg IM 2-5 mg IM $22.10 2.10 18.30 1.50 10.30 10 mg vials 5-10 mg IM 20 mg single-use vials 10-20 mg IM N.A 39.10 19.00 Fluphenazine decanoate – generic Haloperidol decanoate – generic Haldol (Janssen) Long-Acting Second-Generation 25 mg/mL vials 50, 100 mg/mL vials, ampules 50, 100 mg/mL ampules 12.5-25 mg IM or SC q2-3 wks 10-15 times previous daily oral dose IM once/month Aripiprazole – Abilify Maintena (Otsuka/Lundbeck) Aripiprazole lauroxil – Aristada (Alkermes) 300, 400 mg prefilled syringes, vials 441, 662, 882 mg prefilled syringes 400 mg IM once/month 441-882 mg IM once/month or 882 mg IM q6 wks Olanzapine pamoate – Zyprexa Relprevv (Lilly) 210, 300, 405 mg single-use vials Paliperidone palmitate – Invega Sustenna (Janssen) 39, 78, 117, 156, 234 mg prefilled syringes 273, 410, 546, 819 mg prefilled syringes 12.5, 25, 37.5, 50 mg vials 150-300 mg IM q2 wks or 300-405 mg IM once/month 117-234 mg IM once/month 1095.10 410-819 mg IM q3 months 3285.306 Short-Acting First-Generation Chlorpromazine – generic Droperidol – generic Fluphenazine hydrochloride – generic Haloperidol lactate – generic Haldol (Janssen) Short-Acting Second-Generation Olanzapine – generic Zyprexa (Lilly) Ziprasidone – Geodon (Pfizer) Long-Acting First-Generation Invega Trinza Risperidone – Risperdal Consta (Janssen) 25-50 mg IM q2 wks 137.804 6.005 166.00 1796.00 1087.00 842.40 794.00 N.A = cost not available Dosage adjustment may be needed for renal or hepatic impairment Short-acting formulations: single dose for acute agitation; repeat doses may be needed Long-acting formuations: dosage for schizophrenia, based on patient’s stable oral maintenance dosage Approximate WAC for weeks’ or month’s treatment with the lowest usual adult dosage for long-acting, or cost of a single injection of the lowest usual dosage for short-acting WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Cost of one 5-mL vial Cost of a 100-mg dose Cost of one 410-mg syringe antipsychotics have a higher risk than first-generation drugs of causing metabolic syndrome, including weight gain, hyperglycemia, and hyperlipidemia Table (see page 163) lists some adverse effects of secondgeneration antipsychotics and the relative likelihood of their occurrence Clozapine causes granulocytopenia in about 1% of patients; weekly monitoring of blood counts is required It can also cause orthostatic hypotension, bradycardia, and syncope Seizures occur in 1-4% of patients and are dose-related Increased salivation and enuresis can occur.24 Gastrointestinal hypomotility, which can be severe and result in toxic megacolon, is common in patients taking clozapine and can result in life-threatening complications; prophylactic laxatives are recommended.25 Weight gain and hyperlipidemia are also common Myocarditis, which often occurs within the first few weeks of treatment and is fatal in up to 50% of cases, has been reported in as many as 0.5-3% of patients.26 162 Despite its structural similarity to clozapine, olanzapine is unlikely to cause severe neutropenia or seizures It does cause weight gain and other metabolic adverse effects, including diabetes mellitus Postural hypotension, somnolence, constipation, hyperlipidemia, dizziness, and akathisia can also occur Increases in serum hepatic transaminases have been reported DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has been reported rarely with olanzapine.27,28 Adverse effects of risperidone have included parkinsonism, akathisia, dystonia, insomnia, constipation, dizziness, salivary hypersecretion, weight gain, and prolactin elevation (much more than other second-generation antipsychotics except for paliperidone, which is the active metabolite of risperidone) At doses >6 mg/day, the risk of extrapyramidal symptoms increases with only a modest increase in efficacy In addition to prolactin elevation, adverse effects of paliperidone include The Medical Letter Vol 58 (1510) ® December 19, 2016 Table Some Relative Adverse Effects of Second-Generation Antipsychotics Drug Diabetes Aripiprazole Asenapine Brexpiprazole* Cariprazine* Clozapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone +/– + + +/– ++++ ++ +/– ++++ ++ ++ ++ +/– Weight Gain Extrapyramidal Symptoms + ++ ++ + ++++ ++ +/– ++++ +++ +++ +++ +/– ++ ++ + +++ +/– +/– ++ + +++ +/– +++ +/– QTc Interval Prolongation Elevated Prolactin +/– + – – + ++ +/– + + + + ++ – ++ +/– – +/– +/– +/– + +++ +/– +++ + * Limited experience extrapyramidal symptoms, nausea, somnolence, dizziness, tachycardia, and QT interval prolongation Quetiapine commonly causes somnolence, dizziness, constipation, postural hypotension, hyperglycemia, and weight gain Although its package insert recommends twice-yearly ophthalmologic monitoring, clinical use of quetiapine probably does not cause cataract formation.29 Ziprasidone seldom causes significant weight gain, hyperlipidemia, or hyperglycemia Its adverse effects have included mild to moderate somnolence, extrapyramidal symptoms and, occasionally, paradoxical excitement Prolongation of the QT interval has been reported, but a postmarketing trial in >18,000 patients did not find an increase in cardiac deaths with ziprasidone compared to olanzapine.30 DRESS syndrome has been reported rarely with ziprasidone.31 Aripiprazole can cause anxiety, headache, nausea, constipation, lightheadedness, agitation, and akathisia It is less likely than most secondgeneration antipsychotics to cause hyperlipidemia, hyperglycemia, weight gain, and hyperprolactinemia.32 Impulse-control problems, such as compulsive eating, shopping, and sexual activity, have been reported rarely.33 Asenapine can cause insomnia, somnolence, nausea, vomiting, and weight gain.34 In published studies to date, brexpiprazole has been associated with fewer clinically relevant adverse effects than other antipsychotics; insomnia, weight gain, headache, and agitation have been reported.12,35 Cariprazine can cause akathisia, extrapyramidal symptoms, tremor, and small changes in metabolic parameters.36 Table Some Drug Interactions with Second-Generation Antipsychotics1 Drug Metabolism/Transport Comments Aripiprazole Asenapine Brexpiprazole 3A4, 2D6 1A2 3A4, 2D6 Cariprazine 3A4, 2D6 Clozapine 1A2, 3A4, 2D6, 2C19 Iloperidone Lurasidone 3A4, 2D6 3A4 Olanzapine 1A2, 2D6, P-gp Paliperidone Quetiapine Risperidone Ziprasidone 3A4, 2D6, P-gp 3A4 3A4, 2D6, P-gp 3A4 Dose adjustments required with strong 3A4 or 2D6 inhibitors and with strong 3A4 inducers Low potential for interactions Dose adjustments required with strong or moderate 3A4 or 2D6 inhibitors and with strong 3A4 inducers Dose adjustments required with strong 3A4 inhibitors; concurrent use with 3A4 inducers is not recommended Many interactions, primarily with 1A2 inhibitors and inducers; concurrent use with strong 3A4 inducers is not recommended Dose adjustments required with strong 3A4 or 2D6 inhibitors Contraindicated with strong 3A4 inducers and inhibitors; dose adjustments required with moderate 3A4 inhibitors Low potential for interactions; serum concentrations altered by strong 1A2 inhibitors or inducers Dose adjustments may be necessary with strong 3A4/P-gp inducers Dose adjustments required with strong 3A4 inducers and inhibitors Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducers Serum concentrations modestly affected by 3A4 inhibitors and inducers Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016 Aug (epub) Available at secure.medicalletter.org/downloads/ CYP_PGP_Tables.pdf Accessed December 8, 2016 163 The Medical Letter ® Iloperidone can cause orthostatic hypotension, QT interval prolongation, dizziness, somnolence, dry mouth, and weight gain, but is relatively free of extrapyramidal effects, including akathisia.37 Lurasidone can cause akathisia, nausea, extrapyramidal symptoms, and somnolence, but is among the least likely to be associated with weight gain.38 PREGNANCY — Data on use of antipsychotic drugs during pregnancy are limited39; none have been proven to be teratogenic Chlorpromazine was once used to treat morning sickness, apparently without teratogenesis Neonates exposed to antipsychotic drugs in the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms following delivery The risks of hyperglycemia and weight gain are greater with second-generation antipsychotics, which have been associated with high birth weight and babies that are large for gestational age.40 ■ P Fusar-Poli et al Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials Schizophr Bull 2015; 41:892 HJ Möller and P Czobor Pharmacological treatment of negative symptoms in schizophrenia Eur Arch Psychiatry Clin Neurosci 2015; 265:567 S Leucht et al Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis Lancet 2009; 373:31 TS Stroup et al Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia Am J Psychiatry 2016; 173:166 HY Meltzer et al Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) Arch Gen Psychiatry 2003; 60:82 K Komossa et al Olanzapine versus other atypical antipsychotics for schizophrenia Cochrane Database Syst Rev 2010; 3:CD006654 TS Stroup et al Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic Am J Psychiatry 2006; 163:611 Paliperidone (Invega) for schizophrenia Med Lett Drugs Ther 2007; 49:21 C Orr et al Asenapine for the treatment of psychotic disorders: a systematic review and meta-analysis Can J Psychiatry 2016 Aug (epub) 10 Iloperidone (Fanapt) - another second-generation antipsychotic Med Lett Drugs Ther 2010; 52:13 11 Lurasidone (Latuda) for schizophrenia Med Lett Drugs Ther 2011; 53:13 12 Brexpiprazole (Rexulti) for schizophrenia and depression Med Lett Drugs Ther 2015; 57:116 13 Cariprazine (Vraylar) for schizophrenia and bipolar I disorder Med Lett Drugs Ther 2016; 58:51 14 RA Rosenheck et al Long-acting risperidone and oral antipsychotics in unstable schizophrenia N Engl J Med 2011; 364:842 15 PF Buckley et al Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study Schizophr Bull 2015; 41:449 16 JP McEvoy et al Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial JAMA 2014; 311:1978 17 Two long-acting injectable antipsychotics for schizophrenia 164 Vol 58 (1510) December 19, 2016 Med Lett Drugs Ther 2015; 57:152 18 R Emsley et al Long-acting injectable antipsychotics in early psychosis: a literature review Early Interv Psychiatry 2013; 7:247 19 Inhaled loxapine (Adasuve) for acute agitation Med Lett Drugs Ther 2014; 56:31 20 R Liperoti et al All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia: a retrospective cohort study J Clin Psychiatry 2009; 70:1340 21 O Freudenreich and JP McEvoy Optimizing outcome with antipsychotic treatment in first-episode schizophrenia: balancing efficacy and side effects Clin Schizophr Relat Psychoses 2012; 6:115 22 S Ryu et al Tardive dyskinesia and tardive dystonia with secondgeneration antipsychotics in non-elderly schizophrenic patients unexposed to first-generation antipsychotics: a cross-sectional and retrospective study J Clin Psychopharmacol 2015; 35:13 23 A O’Brien Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis Int J Geriatr Psychiatry 2016; 31:683 24 J Fitzsimons et al A review of clozapine safety Expert Opin Drug Saf 2005; 4:731 25 S Every-Palmer et al Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross-sectional study EBioMedicine 2016; 5:125 26 SC Cook et al Clozapine-induced myocarditis: prevention and considerations in rechallenge Psychosomatics 2015; 56:685 27 FDA Drug Safety Communication: FDA warns about rare but serious skin reactions with mental health drug olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax) Available at: www.fda.gov/Drugs/DrugSafety/ucm499441 Accessed December 8, 2016 28 TJ Bommersbach et al Management of psychotropic druginduced DRESS syndrome: a systematic review Mayo Clin Proc 2016; 91:787 29 AM Laties et al Cataractogenic potential of quetiapine versus risperidone in the long-term treatment of patients with schizophrenia or schizoaffective disorder: a randomized, open-label, ophthalmologist-masked, flexible-dose, non-inferiority trial J Psychopharmacol 2015; 29:69 30 BL Strom et al Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) Am J Psychiatry 2011; 168:193 31 VC Chan et al US Food and Drug Administration warning about the risk of drug reaction with eosinophilia and systemic symptoms with ziprasidone J Clin Psychiatry 2015; 76:e1138 32 CU Pae A review of the safety and tolerability of aripiprazole Expert Opin Drug Saf 2009; 8:373 33 FDA Drug Safety Communication: FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada) Available at: www.fda.gov/Drugs/DrugSafety/ucm498662.htm Accessed December 8, 2016 34 J Weber and PL McCormack Asenapine CNS Drugs 2009; 23:781 35 JM Kane et al Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia Schizophr Res 2016; 174:93 36 JM Kane et al Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, Phase III clinical trial J Clin Psychopharmacol 2015; 35:367 37 JM Kane et al Long-term efficacy and safety of iloperidone: results from clinical trials for the treatment of schizophrenia J Clin Psychopharmacol 2008; 28(2 Suppl 1):S29 38 R Musil et al Weight gain and antipsychotics: a drug safety review Expert Opin Drug Saf 2015; 14:73 39 KF Huybrechts et al Antipsychotic use in pregnancy and the risk for congential malformations JAMA Psychiatry 2016; 73:938 40 S Gentile Antipsychotic therapy during early and late pregnancy A systematic review Schizophr Bull 2010; 36:518 The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme-program Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 130 question exam enables you to earn 26 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive exams are offered every January and July enabling you to earn up to 52 credits per year $49/exam ▶ Free Individual Exams – Free to active subscribers of The Medical Letter Answer 10 questions per issue and submit answers online Earn credits/exam A score of 70% or greater is required to pass the exam ▶ Paid Individual Exams – Available to non-subscribers Answer 10 questions per issue and submit answers online Earn credits/exam $12/exam A score of 70% or greater is required to pass the exam ACCREDITATION INFORMATION: ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians The Medical Letter designates this enduring material for a maximum of AMA PRA Category Credits™ Physicians should claim only the credit commensurate with the extent of their participation in the activity This CME activity was planned and produced in accordance with the ACCME Essentials and Policies ABIM MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit Your participation information will be shared with ABIM through PARS AAFP : This enduring material activity, The Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 52 Prescribed credits by the American Academy of Family Physicians Term of approval begins January 1, 2016 Term of approval is for one year from this date Each issue is approved for Prescribed credits Credit may be claimed for one year from the date of each issue Physicians should claim only the credit commensurate with the extent of their participation in the activity ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education This exam is acceptable for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU) This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA) The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA PRA Category Credit™ from organizations accredited by ACCME NCCPA also accepts AAFP Prescribed credits for recertification The Medical Letter is accredited by both ACCME and AAFP The American Nurses Credentialing Center (ANCC) and the American Academy of Nurse Practitioners (AANP) accept AMA PRA Category Credit™ from organizations accredited by the ACCME Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits) as per our reciprocal agreement with the American Academy of Family Physicians MISSION: The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development of healthcare providers including physicians, nurse practitioners, pharmacists, and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and administration, adverse effects, and drug interactions The Medical Letter delivers educational content in the form of self-study material The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter does not sell advertising or receive any commercial support GOAL: Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make independent and informed therapeutic choices in their practice LEARNING OBJECTIVES: Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice Upon completion of this program, the participant will be able to: Discuss the results and limitations of the PRECISON trial evaluating the cardiovascular safety of the COX-2 selective NSAID celecoxib (Celebrex, and generics) Discuss the pharmacologic options available for treatment of psychotic disorders and compare them based on their efficacy, dosage and administration, potential adverse effects, and drug interactions Determine the most appropriate therapy given the clinical presentation of an individual patient with schizophrenia Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows 7/8/10, Mac OS X+; current versions of Microsoft IE/Edge, Mozilla Firefox, Google Chrome, Safari, or any other compatible Web browser Highspeed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1510 Questions (Correspond to questions #121-130 in Comprehensive Exam #75, available January 2017) Celecoxib Safety Revisited Nonselective NSAIDs such as naproxen can cause: a gastrointestinal toxicity b bleeding c fluid retention d all of the above The PRECISION trial found that celecoxib was noninferior to ibuprofen and naproxen with regard to cardiovascular safety, but: a it was a retrospective trial with confounding factors b the average daily dose of celecoxib was lower than the doses previously associated with cardiovascular toxicity c none of the drugs were superior in efficacy to placebo d all of the above Drugs for Psychotic Disorders In comparing first- and second-generation antipsychotic drugs, which of the following is true? a first-generation drugs are less likely to cause tardive dyskinesia b controlled trials generally have found second-generation drugs more effective c second-generation drugs are more expensive d all of the above Which antipsychotic drug is generally considered the most effective for treatment of schizophrenia? a clozapine b olanzapine c risperidone d haloperidol Second-generation antipsychotics are more likely than firstgeneration drugs to cause: a anticholinergic effects b metabolic syndrome c extrapyramidal symptoms d all of the above A 37-year-old man with schizophrenia and bronchial asthma was well-controlled for many years on oral haloperidol It has recently become more difficult for his caretaker to persuade him to take the drug Which of the following would be a reasonable choice of therapy for this patient? a clozapine b a benzodiazepine c haloperidol decanoate d loxapine inhalation powder The labels of both first- and second-generation antipsychotics include a boxed warning about the risk of: a tardive dyskinesia in young patients b DRESS syndrome c neuroleptic malignant syndrome d death in elderly patients with dementia-related psychosis Clozapine can cause: a granulocytopenia b.gastrointestinal hypomotility c myocarditis d all of the above A 26-year-old woman with schizophrenia has been taking risperidone for the past years She has responded to treatment, but has gained about 40 pounds since starting the drug You are considering switching her to lurasidone Which of the following statements about the use of risperidone and lurasidone is true? a risperidone is an older drug with a longer record of safety b lurasidone is less likely to cause diabetes than risperidone c among all the drugs in this class, lurasidone is among those least likely to cause weight gain d all of the above 10 The second-generation antipsychotics most likely to cause weight gain and diabetes are: a quetiapine and risperidone b risperidone and paliperidone c clozapine and olanzapine d iloperidone and quetiapine ACPE UPN: Per Issue Exam: 0379-0000-16-510-H01-P; Release: December 19, Expire: December 19, 2017 Comprehensive Exam 75: 0379-0000-17-075-H01-P; Release: January 2017, Expire: January 2018 PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm, Pharm.D.; ASSOCIATE EDITORS: Susan M Daron, Pharm.D., Amy Faucard, MLS, Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski; EXECUTIVE DIRECTOR OF MARKETING AND COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc does not sell advertising or receive any commercial support No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Get Connected: Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2016 ISSN 1523-2859 Subscriptions (US): year - $129; years - $232; years - $345 $65 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: info@medicalletter.org Call: 800-211-2769 ext 315 Special rates available for bulk subscriptions The Medical Letter ... information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical. .. further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 58 December 19, 2016 Take CME Exams ISSUE ISSUE No 1433 1510 ALSO IN THIS ISSUE Drugs for Psychotic... with the extent of their participation in the activity ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education