ATERIA M EDICA

Volume 1, Issue 8 January 2013

sive episodes. About 90% of patients who have one manic episode will have another within 5 years. Ninety Bipolar Disorder: Medication percent of these individuals will have at least one psy- Management in Primary Care chiatric hospitalization, with two-thirds having two or more hospitalizations in their lifetime.6 Depressive Benjamin Chun, PharmD Candidate symptoms in BD I patients are more frequent than manic symptoms, occurring three times more frequent- ly than mania and 37 times more frequently than hypo- ipolar disorder (BD) affects about 5.7 million mania.6 Although BD II is less well understood, func- American adults in a given year, making it one tional impairment has been linked to severity of de- B of the most common psychiatric disorders.1,2 pressive episodes and addictive disorders.6 Moreover, Due to barriers accessing specialty mental health ser- the course of BD is highly influenced by and vices and the stigma associated with the disease, pa- substance abuse. Two-thirds of patients with BD will tients with BD are increasingly being managed exclu- meet the diagnostic criteria for addictive disorder over sively in the primary care setting; about 10 to 38% of their life time. patients with BD are treated in primary care.3,4 Moreo- Patients with BD have a myriad of presentations. ver, BD is one of the most expensive behavioral health They can present with a major depressive episode, care diagnoses, with an estimated total annual cost of manic episode, hypomanic episode, or a combination $45.2 billion in the US.5 The onset of bipolar disorder of manic and depressive symptoms (mixed episode). ranges from 15-24 years of age, with 90% of cases ap- Several diagnostic tools maybe used as adjuncts to clin- parent by age 30. BD can affect both sexes equally, but ical diagnosis of BD in adults. Table 1 summarizes females are at a greater risk of “rapid cycling” or hav- sensitivity and specificity of diagnostic scales to assess ing four or more mood episodes in one year. Men tend manic symptomatology of BD. to undergo more manic episodes whereas women are Of the five scales listed above, the three best vali- prone to more depressive episodes.6 dated for diagnosing bipolar patients are the PSQ, BD is divided into three subtypes: BD I, BD II, MDQ, and BPRS.7 While there are many tools availa- and BD otherwise not specified (NOS). BD I is char- ble to assist in diagnosing and assessing BD, the MDQ acterized by having a history of at least one episode of is especially useful for the outpatient psychiatric popu- mania and BD II by a history of at least one hypoman- lation. The MDQ is commonly used in the primary ic episode plus at least one major depressive episode. care setting due to its accuracy and ease of use.8 NOS is defined as having bipolar features that do not meet either BD I or II criteria. Table 1 | Diagnostic scales to assess BD.7 The course of BD I is marked by relapses and re- Scale Sensitivity Specificity mission which often alternates with manic and depres- Clinician Administered Rat- 85% 87% ing Scale for Mania Mini International Neuropsy- INSIDE THIS ISSUE: 89% 97% BIPOLAR DISORDER: MEDICATION MANAGEMENT chiatric Inventory (MINI) Psychosis Screening Ques- IN PRIMARY CARE 96%% 95% tionnaire (PSQ) Mood Disorder Question- ACLIDINIUM BROMIDE (TUDORZA PRESSAIR®): 72% 90% naire (MDQ) A NOVEL LONG-ACTING ANTIMUSCARINIC Brief Psychiatric Rating FOR COPD 67% 72% Scale (BPRS) 1 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 ACUTE MANAGEMENT OF BD sodes, second generation antipsychotic monotherapy may be considered. Although depression is typically the initial presen- tation of acute BD in primary care, patients may also MAINTENANCE TREATMENT OF BD present with other symptoms.9 Acute BD is marked by episodes of mania and hypomania, as well as mixed General Guidelines episodes of concurrent major depression and mania or Following remission of acute bipolar episodes and hypomania.10 Despite differences in acute presentation for all new diagnoses of BD, maintenance therapy is of manic, hypomania, and mixed episodes, acute treat- required to delay or prevent another episode. Relapses, ment is similar in these patients. Patients presenting which occur in most patients, are associated with many with severe BD symptoms likely require psychiatry as- negative outcomes, such as greater number of suicide sessment and hospitalization. However, initiation of attempts, poor social and occupational functioning, acute treatment for patients with mild-to-moderate and cognitive impairment.8 In the Systematic Treat- symptoms may be appropriate in the primary care set- ment Enhancement Program for Bipolar Disorder ting. There are no established criteria to distinguish (STEP-BD), nearly 50% of 858 patients had a recur- severity, and assessment of patients’ psychiatric history, rent episode within two years.12 Because of recurrence physical exam, and comorbid conditions are useful for rates, most practice guidelines recommend that mainte- referral.11 nance treatment be started for every patient.13-16 To Monotherapy is the most common first line ap- minimize pill burden, side effects, and promote greater proach to treating acute BD symptoms, while combi- adherence, most patients are started on monotherapy nation pharmacotherapy is typically reserved for se- rather than combination therapy. Monotherapy studies verely ill patients with imminent risk of suicide or with lithium, lamotrigine, valproate, and a few second threat. Based on randomized clinical trials and guide- generation antipsychotics (aripiprazole, , and lines, medication classes commonly used to treat acute ) have revealed these agents to be more ef- mania, mixed episodes, or hypomania include lithium, fective than placebo. Although several monotherapy anticonvulsants, antipsychotics, and benzodiazepines. studies have demonstrated greater efficacy than place- For patients with hypomania or mild-to-moderate bo in preventing mania, depression, or both, a meta- symptoms of mania or mixed episodes, monotherapy analysis of eight studies (n=1,124 patients) found sig- with second generation antipsychotics may be consid- nificant reductions in mania scores with adjunctive ered. First line medication combinations for patients haloperidol, olanzapine, risperidone, and quetiapine with severe symptoms of acute mania or mixed epi- compared with lithium or divalproex monotherapy.17 sodes include lithium or valproate plus an antipsychot- Despite maintenance therapy, recurrence rates remain ic. In mixed episodes, valproate may be preferred over high, resulting in many patients requiring combination lithium, as it has demonstrated greater efficacy.10 Sys- therapy to control their symptoms.12 Typical mainte- tematic reviews found that improvements in manic or nance combination therapy includes lithium or mixed episodes were significantly greater in patients valproate plus a second generation antipsychotic.13-16 who received adjunctive antipsychotics.11 However, no head-to-head trials have compared the efficacy of dif- Lithium ferent adjunctive antipsychotics; thus, the choice of an Lithium is considered the gold standard of mainte- antipsychotic is based upon other factors such as past nance therapy in BD, based on the wealth of evidence response, comorbidities, side effect profile, drug-drug supporting its efficacy. The initial dose is 300 mg two interactions, patient preference, and cost. Commonly to three times per day, then titrated to achieve a target used antipsychotics include many second generation 12-hour serum trough level of 0.6 to 1.2 mEq/L (or antipsychotics such as olanzapine, quetiapine, aripipra- lower if necessary due to tolerability). Immediate- zole, risperadone, and ziprasidone. First generation release lithium preparations should be given in two or antipsychotics such as haloperidol and three divided daily doses, whereas extended release may also help with symptoms of mania and mixed epi- products can be given once or twice daily. Lithium has sodes, but are associated with high rates of extrapy- unique because it is a monovalent ramidal symptoms (EPS).7 For patients who cannot cation that is rapidly absorbed, widely distributed, not tolerate oral medications, intramuscular antipsychotics metabolized, and is excreted in the urine and in other may be considered. For patients with hypomania or body fluids.18 Lithium levels are considered to be at mild-to-moderate symptoms of mania or mixed epi- steady state at approximately day 5 and serum samples 2 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 should be drawn 8 to 12 hours post-dose. Once a de- found that recurrence was reduced for patients who sired serum concentration has been achieved, levels received lithium monotherapy (HR 0.71, 95% CI 0.51- should be rechecked in 2 weeks and every 3 to 6 1.00) or the combination lithium plus valproate (HR months once stable or clinically indicated.14 Of note, 0.59, 95% CI 0.42-0.83) compared with valproate extended-release preparations such as Lithobid may monotherapy. There was no significant difference be- have a higher 12 hour post-dose serum concentration. tween lithium monotherapy compared with combina- The dose should be adjusted based on the steady-state tion therapy.27 serum concentration drawn 8 to 12 hours (+/- 30 minutes) after the last dose. Lamotrigine Approximately 35 to 93% of patients treated with Lamotrigine was the second medication to receive lithium will experience adverse effects.18 Lithium’s side FDA approval for the maintenance of BD. Lamotrigi- effect profile and long term health effects have been ne is typically started at a dose of 25 mg per day for well characterized, with the most common side effects two weeks and then increased to 50 mg per day in di- being polyuria, polydipsia, tremor, weight gain, and vided doses. The dose can then be titrated up by 25 to cognitive dullness.19 Initial side effects are often dose- 50 mg per day at weekly intervals to a target dose of 50 related and are worse at peak serum concentrations (1- to 200 mg per day, with a usual dose range of 50 to 2 hours post-dose). Approaches to minimize adverse 300 mg per day. Doses of 200 mg per day were more effects include lowering the dose, taking it with food, effective than lower doses, and there were no ad- and using the extended release formulation.14 Chronic vantages to using 400 mg per day.28,29 In contrast to lithium use may also cause renal and thyroid dysfunc- lithium, lamotrigine does not require serum concentra- tion. Lithium reduces the kidney’s ability to concen- tion monitoring; however, lamotrigine does require trate urine and can cause nephrogenic diabetes insipi- slow titration to reduce the risk of serious and life- dus which can be treated with loop diuretics, thiazide threatening skin rashes, including Stevens-Johnson diuretic, or triamterene. Moreover, long-term lithium syndrome. Other common side effects include nausea, therapy has a 10 to 20% risk of developing morpho- dyspepsia, pain, insomnia, and non-serious skin rash- logical renal changes that are associated with increased es.14,30 The pregnancy category of lamotrigine is C. serum creatinine concentrations.14,18,21,22 Thyroid ef- A meta-analysis of three randomized maintenance fects or subclinical hypothyroidism from lithium are trials found that lamotrigine reduced the risk of relapse due to lithium’s capacity to interfere with iodine trap- (any mood episode) by 16% compared to placebo (risk ping in the thyroid and the release of thyroid hor- ratio 0.84, 95% CI 0.71-0.99).20 Moreover, lamotrigine mone.21 Lithium-induced hypothyroidism is not dose- significantly reduced depressive relapses (HR 0.65, related and is observed 10-times more frequently in 95% CI 0.46-0.91), but failed to demonstrate a signifi- women, usually occurring after 6 to 18 months of ther- cant risk reduction in relapse due to manic episodes apy.14,18,23 Regular monitoring of thyroid function via (risk ratio 0.91, 95% CI 0.64-1.30). In an open-label serum TSH measurements should be performed dur- study that compared lithium to lamotrigine, there was ing lithium treatment. Other monitoring parameters no difference in effectiveness (hazard rate ratio 0.92, include serum electrolytes, CBC with differential, uri- 95% CI 0.60-1.40).31 Effectiveness was determined by nalysis, and ECG exams if medically warranted. Alt- a composite primary endpoint which included psycho- hough lithium is generally regarded as teratogenic with tropic treatment in addition to study drugs and benzo- a FDA pregnancy category of D, the absolute risk is diazepines still required at month 6, hospitalization still considered to be small.24,25 required at month 6, psychotropic treatment during at A meta-analysis of five randomized trials, with 753 least one week required after month 6, and hospitaliza- patients, found that patients who received lithium tion during at least one week required after month 6. compared to placebo had significantly fewer relapses Overall, lamotrigine was better tolerated than lithium, (HR 0.68, 95% CI 0.53-0.86) and significantly reduced with most common adverse effects being headache manic relapses compared to placebo (HR 0.53, 95% CI (14%) and dizziness (15%).31 0.35-0.79).20 Moreover, a subsequent two-year random- ized maintenance trial found that time-to-recurrence of Valproate mania (HR 0.37, 95% CI 0.27-0.53) and depression Although valproate is not approved by the FDA (HR 0.59, 95% CI 0.42-0.84) were significantly longer for maintenance treatment of BD, there is good evi- in patients treated with lithium than placebo.26 Lastly, a dence to support the use of valproate for maintenance two year open-label randomized maintenance trial also therapy. Valproate is initially prescribed at 20 mg/kg/ 3 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 day in 2 divided daily doses and adjusted by 250 to 500 nancy.41 Moreover, aripiprazole, quetiapine, and mg every 1 to 3 days based on clinical response and olanzapine all have a FDA pregnancy category rating tolerability. Although therapeutic serum concentrations of C. Thus, benefit must outweigh the risk when using of valproate have not been established in BD, most second generation antipsychotics in pregnancy. clinicians use the therapeutic serum range of 50 to 125 mcg/mL taken 12 hours after the last dose.14,32 How- Aripiprazole ever, routine monitoring of valproate concentrations in Aripiprazole is initially started at a dose of 10 or 15 the general bipolar disorder population is not warrant- mg per day and can be increased to 15 to 30 mg per ed.36 Common side effects from valproate include day. Common side effects include tremor, akathisia, somnolence, weight gain, gastrointestinal distress, anxiety, nausea, dry mouth, and weight gain. Extra py- tremors, decreased platelet counts, and alopecia. ramidal symptoms most commonly present as akathis- Moreover, compared to the side effect profile of lithi- ia, which typically occurs early in treatment and dimin- um, valproate was associated with more weight gain ishes over time. Starting with a lower dose of 2 or 5 mg and is also thought to be the most teratogenic of all per day may help prevent these adverse effects. maintenance treatments with a FDA pregnancy catego- Aripiprazole has demonstrated efficacy compared ry of D.33,34 to placebo as both monotherapy and in combination In a one-year randomized trial that assigned 279 with valproate.37,38 Compared to placebo, aripiprazole patients to valproate or placebo, there were significant- was shown to be effective in preventing manic epi- ly fewer recurrences of any mood episode in patients sodes (HR 0.35, 95% CI 0.16-0.75) but not depressive who received valproate (24 vs. 38%, respectively), but episodes (HR 0.81, 95% CI 0.36-1.81).37 Moreover, in time to recurrence did not differ significantly between combination with either lithium or valproate, aripipra- valproate or placebo groups.35 Valproate also appeared zole was associated with a relapse rate of 17% to be more effective in delaying or preventing depres- (lithium/valproate plus aripirazole) versus 29% in pla- sion than mania.20,35 In the more recent BALANCE cebo (lithium/valproate plus placebo) (p=0.014).38 study, which compared lithium, valproate, or both Significantly fewer manic relapses (15% vs 5%, p = agents in combination, it was found that the combina- 0.013), but not depressive episodes (10% vs. 13%, p = tion was associated with longer time to a new episode 0.384) also occurred in aripiprazole-treated compared compared to valproate alone (HR 0.59, 95% CI 0.42- with placebo-treated patients.38 0.83) but not compared to lithium alone.27 Lithium was also more effective than valproate in preventing de- Quetiapine pressive episodes (HR 0.63, 95% CI 0.41-0.96) com- The initial titration of quetiapine to an effective pared to valproate. However, studies suggest that the maintenance dose is slightly different for patients with combination of valproate plus second generation anti- depressive episodes compared to patients with manic psychotic is more effective than monotherapy of either symptoms. For management of depressive episodes, agent and is as effective as lithium plus a second gener- quetiapine is started at 50 mg at bedtime on day 1 of ation antipsychotic.25,38-40 therapy. The dosage should then be increased to 100 mg once daily on the second day of therapy, 200 mg Atypical Antipsychotics once daily on the third day, and 300 mg on the fourth Limited data support the use of atypical antipsy- day. Patients can further be titrated up to 400 to 600 chotics for maintenance treatment of BD.13-16 Howev- mg from day 5 to 8. For management of acute mania, er, more studies are being conducted and both double- the initial dosage is 100 mg on day one in 2 divided blind and open-label studies suggest that these agents doses. The dosage of quetiapine should be further in- are useful in the long-term management of BD, either creased in increments of 100 mg daily in 2 divided dos- alone or in combination with mood stabilizers, such as es to 400 mg on the fourth day of therapy. Subsequent lithium or valproate. However, no head-to-head trials dose adjustments up to 800 mg by the sixth day should have compared the effectiveness of atypical antipsy- be made in increments not exceeding 200 mg daily. chotics. In addition, the short and long term adverse Maintenance dosing ranges from 400 to 800 mg per effects of the second generation antipsychotics can day.42 limit their use for maintenance treatment. Although Common adverse effects of quetiapine include second generation antipsychotics usually do not appear weight gain, sedation, hyperglycemia, hyperlipidemia, to be associated with fetal deaths or teratogenic effects, and dizziness. As a maintenance treatment, quetiapine there are limited data to support their use during preg- causes less weight gain and sedation compared to 4 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 olanzapine, but not aripiprazole. Quetiapine is also as- ered as first line treatment for patients with depression sociated with an increased risk of diabetes and worsen- dominant or severe depression. Second line treatment ing lipid profile.43 However, queitapine is the least like- for BD maintenance includes adjunctive therapy with a ly of the second-generation antipsychotics to be associ- second generation antipsychotic. The choice of specific ated with classic EPS.42 second generation antipsychotic depends on patient Quetiapine has demonstrated efficacy when com- specific factors, medication efficacy, side effect profile, bined with lithium or valproate in two randomized and cost. double-blind placebo studies.39,40 Moreover, a two- year randomized maintenance trial found that time-to-  recurrence of any mood event was significantly longer for quetiapine versus placebo (HR 0.29, 95% CI 0.23- REFERENCES 0.38).44 Quetiapine also increased time to recurrence of both manic events (HR 0.29, 95% CI 0.21-0.40) and 1. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, depressive events (HR 0.30, 95% CI 0.20-0.44) com- severity, and comorbidity of twelve-month DSM-IV disor- ders in the National Comorbidity Survey Replication (NCS- pared to placebo. R). Arch Gen Psychiatry 2005;62(6):617-27. 2. U.S. Census Bureau Population Estimates by Demographic Olanzapine Characteristics. Table 2: Annual Estimates of the Population The usual initial oral dosage of olanzapine is 10 or by Selected Age Groups and Sex for the United States: April 15 mg daily, given as a single dose. Dosage adjustments 1, 2000 to July 1, 2004 (NC-EST2004-02) Source: Population Division, U.S. Census Bureau Release Date: June 9, 2005. can be made at 5 mg intervals per day, with a dose Available at: http://www.census.gov/popest/national/asrh/. range of 5 to 20 mg daily. Olanzapine can also be ad- 3. Kilbourne AM, Goodrich DE, O’Donnell AN, Miller CJ. ministered intramuscularly (IM). An IM administration Integrating Bipolar Disorder Management in Primary Care. of a 5 mg dose results in a maximum olanzapine plas- Curr Psychiatry Rep 2012;14(6):687-95. ma concentration that is about five-fold higher than 4. Peele PB, Xu Y, Kupfer DJ. Insurance expenditures on bipo- lar disorder: Clinical and parity concerns. Am J Psychia- that of a 5 mg oral dose and is reserved for patients try 2003;160:1286-90. with acute agitation for prompt control of bipolar ma- 5. Kleinman L, Lowin A, Flood E, et al. Costs of bipolar disor- nia.42 Common side effects include sedation, hypercho- der. Pharmacoeconomics 2003;21(9):601-22. lesterolemia, hypertriglyceridemia, hyperglycemia, 6. Stovall, J. Bipolar disorder in adults: Epidemiology and diag- weight gain, and akathisia (at higher doses).45,47 Meta- nosis. In: UpToDate, Rose, BD (Ed), Wellesley, MA, 2004. 7. Scottish Intercollegiate Guidelines Network (SIGN). Bipolar bolic adverse effects tend to be rapid and can be seen affective disorder; national clinical guideline. Available at: early in treatment.47 http://www.sign.ac.uk/pdf/sign82.pdf. In a randomized placebo-controlled trial of 8. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development olanzapine, time to symptomatic relapse into any and validation of a screening instrument for bipolar spectrum mood episode was significantly longer among patients disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000;157(11):1873-5. receiving olanzapine (median=174 days) compared 9. Hirschfeld RM. Why care about bipolar disorder? A primary with placebo (median=22 days; HR 2.67, 95% CI 2.03- care physician’s guide to screening and referral. Adv Stud 3.50).48 However, in a systematic review and meta- Med 2003;3:223-7. analysis of olanzapine, olanzapine was only more effec- 10. American Psychiatric Association. Diagnostic and Statistical tive than placebo at preventing manic relapses (RR Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, Washington, DC, 2000. 0.59, 95% CI 0.39-0.88), but not relapse into any mood 11. Smith LA, Cornelius V, Warnock A, et al. Acute bipolar ma- episode (RR 1.12, 95% CI 0.46-2.70).46 nia: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatr Scand 2007;115:12-20. CONCLUSIONS 12. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recur- rence in bipolar disorder: primary outcomes from the Sys- tematic Treatment Enhancement Program for Bipolar Disor- Maintenance therapy for bipolar patients is im- der (STEP-BD). Am J Psychiatry 2006;163:217-24. portant, given the recurrent nature of the disease. 13. Hirschfeld RMA: Guideline Watch: Practice Guideline for the Treat- While lithium and lamotrigine currently have the most ment of Patients With Bipolar Disorder. Arlington, VA: American robust evidence supporting their efficacy, valproate Psychiatric Association. Available online at http:// and second generation antipsychotics have also been www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. 14. American Psychiatric Association. Practice guideline for the proven effective. 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Major mal- for Psychopharmacology. Evidence based guidelines for formations with valproic acid. Can Fam Physician treating bipolar disorder: revised second edition – recommen- 2006;52:441-7. dations from the British Association for Psychopharmacolo- 34. Dreifuss FE, Langer DH. Side effects of valproate. Am J gy. J Psychopharmcol 2009;23:346-88. Med 1988;84:34-41. 17. Smith LA, Cornelius V, Warnock A, et al. Acute bipolar ma- 35. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, nia: a systematic review and meta-analysis of co-therapy vs. placebo-controlled 12 month trial of divalproex and lithium monotherapy. Acta Psychiatr Scand 2007;115:12-20. in treatment of outpatients with bipolar I disorder. Arch Gen 18. McEvoy GK, Miller J, Snow EK, et al. Lithium salts. AHFS Psychiatry 2000;57(5):481-9. Drug Information 2007. Bethesda, MD: American Society of 36. Haymond J, Ensom MH. Does valproic acid warrant thera- Health-System Pharmacists 2007:2566–75. peutic drug monitoring in bipolar affective disorder? Ther 19. Nolen WA, Luckenbaugh DA, Altshuler LL, et al. Correlates Drug Monit 2010;32(1):19-29. of 1-year prospective outcome in bipolar disorder: results 37. Keck PE Jr, Calabrese JR, McIntyre RS, et al. Aripiprazolem- from the Stanley Foundation bipolar network. Am J Psychia- onotherapy for maintenance therapy in bipolar I disorder: A try 2004;161:1447-54. 100-week, double-blind study versus placebo. J Clin Psychia- 20. Smith LA, Cornelius V, Warnock A, et al. Effectiveness of try 2007;68:1480-91. mood stabilizers and antipsychotics in the maintenance phase 38. Marcus R, Khan A, Rollin L. Efficacy of aripiprazole adjunc- of bipolar disorder: a systematic review of randomized con- tive to lithium or valproate in the long-term treatment of trolled trials. Bipolar Disord 2007;9(4):394-412. patients with bipolar I disorder with an inadequate response 21. Gitlin MJ, Cochran SD, Jamison KR. Maintenance lithium to lithium or valproate monotherapy: a multicenter, double- treatment. Side effects and compliance. J Clin Psychiatry blind, randomized study. Bipolar Disord 2011;13:133-44. 1989;50:127-31. 39. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of 22. Gitlin M. Lithium and the kidney: an updated review. Drug quetiapine in combination with lithium or divalproex for Safety 1999;20:231-43. maintenance of patients with bipolar I disorder (international 23. Kleiner J, Altshuler L, Hendrick V, et al. Lithium-induced trial 126). J Affect Disord 2008;109:251-63. subclinical hypothyroidism: review of the literature and 40. Suppes T, Vieta E, Liu S, Bet al. Maintenance treatment for guidelines for treatment. J Clin Psychiatry 1999;60:249-55. patients with bipolar I disorder: results from a north Ameri- 24. Yonkers KA, Wisner KL, Stowe Z, et al. Management of can study of quetiapine in combination with lithium or di- Bipolar disorder during pregnancy and the postpartum peri- valproex. Am J Psychiatry 2009;166:476-88. od. Am J Psychiatry 2004;161(4):608-20. 41. Einarsons A, Boskovic R. Use and safety of antipsychotic 25. Cohen LS, Wang B, Nonacs R, et al. Treatment of mood drugs during pregnancy. J Psychiatr Pract 2009;15(3):183-92. disorders during pregnancy and postpartum. Psychiatr Clin 42. Product Information: SEROQUEL(R) oral tablets, quetiap- North Am 2010;33(2):273-93. ine fumarate oral tablets. AstraZeneca, Wilmington, United 26. Weisler RH, Nolen WA, Neijber A, et al; Trial 144 Study Kingdom, 2009. Investigators. Continuation of quetiapine versus switching to 43. American Diabetes Association, American Psychiatric Asso- placebo or lithium for maintenance treatment of bipolar I ciation, American Association of Clinical Endocrinologist, disorder (Trial 144: a randomized controlled study). J Clin North American Association for the Study of Obesity. Con- Psychiatry 2011;72(11):1452-64. sensus development conference on antipsychotic drugs and 27. BALANCE investigators and collaborators. Lithium plus obesity and diabetes. Diabetes Care 2004;27(2):596-601. valproate combination therapy versus monotherapy for re- 44. Weisler RH, Nolen WA, Neijber A, et al. Continuation of lapse prevention in bipolar I disorder (BALANCE): A ran- quetiapine versus switching to placebo or lithium for mainte- domized open-label trial. Lancet 2010;375:385-95. nance treatment of bipolar I disorder (Trial 144: a random- 28. Bowden CL, Calabrese JR, Sachs G, et al. A placebo con- ized controlled study). J Clin Psychiatry 2011;72(11):1452-64. trolled 18 month trial of lamotrigine and lithium maintenance 45. Product Information: ZYPREXA(R) oral tablets, IM injec- treatment in recently manic or hypomanic patients with bipo- tion, ZYPREXA(R) ZYDIS(R) orally disintegrating tablets, lar I disorder. Arch Gen Psychiatry 2003;60:392-400. olanzapine oral tablets, IM injection, orally disintegrating 29. Bowden CL, Calabrese JR, Sachs G, et al. A placebo con- tablets. Eli Lilly and Company, Indianapolis, IN, 2006. trolled 180month trial of lamotrigine and lithium mainte- 46. Cipriani A, Rendell J, Geddes JR. Olanzapine in the long- nance treatment in recently depressed patients with bipolar I term treatment of bipolar disorder: a systematic review and disorder. J Clin Psychiatry 2003;64:1013-24. meta-analysis. J Psychopharmacol 2010;24(12):1729-38. 30. Bowden CL, Asnis GM, Ginsberg LD, et al. Safety and toler- 47. Fernandez-Egea E, Miller B, Garcia-Rizo C, et al. Metabolic ability of lamotrigine for bipolar disorder. Drug Saf effects of olanzapine in patients with newly diagnosed psy- (3):173-84. chosis. J Clin Psychopharmacol 2011;31(2):154-9. 31. Licht RW, Nielsen JN, Gram LF, et al. Lamotrigine versus 48. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, place- lithium as maintenance treatment in bipolar I disorder: an bo-controlled trial of olanzapine as maintenance therapy in open, randomized effectiveness study mimicking clinical patients with bipolar I disorder responding to acute treatment practice. The 6th trial of the Danish University Antidepressant with olanzapine. Am J Psychiatry 2006;163(2):247-56.

6 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 Though formal drug interaction studies were not con- Aclidinium Bromide (Tudorza ducted, in vitro studies using human liver microsomes Pressair®): A Novel Long-Acting indicated that aclidinium bromide and its major metab- olites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, Antimuscarinic for COPD 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentra-

tions up to 1,000-fold higher than the maximum plas- Amit Kapadia, PharmD Candidate ma concentration that would be expected to be achieved at the therapeutic dose.6 Hepatic impairment hronic obstructive pulmonary disease should not have significant effects on the drug’s phar- (COPD) is a chronic inflammatory disease of macokinetics based on the relatively rapid the lung and the fourth leading cause of into inactive metabolites and lack of interaction with C 1 chronic morbidity and mortality in the United States. CYP enzymes, although this has not been specifically In 2008, COPD resulted in over 15 million hospital studied to date. The AUC and Cmax of aclidinium and visits and 137,000 deaths in the United States alone.2 its metabolites were similar when comparing healthy The annual cost per patient can range from $1,600 to volunteers and those with renal impairment.6 This over $10,000 depending on the stage of the disease would suggest that no dosing adjustments need be without incorporating the additional costs of possible made to account for renal impairment. exacerbations.3 The GOLD guidelines recommend the use of long CLINICAL TRIALS acting or long acting β2-agonists for patients with moderate-to-severe disease or as an alter- The safety and efficacy of aclidinium bromide was nate to short-acting agents in patients with mild disease established via two phase II clinical trials and two (Table 1).1 phase III clinical trials (ACCORD COPD I and AT- Until recently, has been the TAIN) which are summarized in Table 2. A minimum only long acting anticholinergic drug available in the clinically important FEV1 difference of 100-140 mL US for the treatment of COPD. However, in July from baseline is required for a COPD treatment to be 2012, the FDA approved aclidinium bromide (Tudorza considered effective.10,11 Thus for the following trials, Pressair®), a long-acting antimuscarinic agent (anti- we will focus on the 400 mcg twice daily dose which ), for the treatment of moderate-to-severe was the only dose shown to consistently meet this min- COPD. The purpose of this article is to review the imum clinically important effect on FEV1 in the AT- pharmacology, safety and efficacy of aclidinium bro- mide based on clinical studies. Editor’s Summary: Aclidinium Bromide (Tudorza Pressair®) HARMACOLOGY HARMACOKINETICS P & P Description & Indication Aclidinium bromide is a long-acting antimuscarinic  Long-acting antimuscarinic that reversibly binds M3 agent or anticholinergic with similar binding affinity to receptors in airway smooth muscle, resulting in bron- chodilation 6 M1-M5 receptors. Competitive and reversible binding  Approved for treatment of moderate-to-severe COPD to M3 receptors in airway smooth muscle results in bronchodilation. Similar to tiotropium bromide, in vivo Dosing and in vitro studies show that the bronchodilatory ef-  400 mcg dose administered twice daily via dry powder fects of aclidinium bromide are dose-dependent and inhaler (DPI) last longer than 24 hours.6 Efficacy Aclidinium bromide has an oral of  The 400 mcg twice daily dose improves trough FEV1 by 6% in healthy subjects and reaches peak steady state approximately 120 mL relative to placebo and peak plasma levels within 10 minutes of administration. 6 FEV1 by approximately 200-220 mL relative to placebo The volume of distribution is approximately 300 L fol-  Appears to have similar efficacy to tiotropium and for- lowing intravenous administration of 400 mcg given moterol in clinical trials IV.6 Onset of lung improvement (demonstrated by Safety increase in FEV1) occurs within 30 minutes of admin-  Generally well-tolerated with adverse effects in trials istration.6 Aclidinium bromide is rapidly hydrolyzed occurring at a rate similar to placebo into two pharmacologically inactive metabolites.  Systemic anticholinergic effects should be uncommon

7 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 Table 1 | Initial Pharmacologic Management of COPD.1 Patient Group Recommended 1st Choice Alternate Choice A SAC prn or SABA prn LAC or LABA or (SAC + SABA) B LAC or LABA LAC + LABA C (ICS + LABA) or LAC LAC + LABA (ICS + LAC) or (ICS + LABA + LAC) or (ICS + LABA + D (ICS + LABA) or LAC PDE4 inhibitor) or (LAC + LABA) or (LAC + PDE4 inhibitor)

LAC = long-acting anticholingergic; LABA = long-acting β2 agonist; SAC = short-acting anticholinergic; SABA = short-acting β2 agonist; ICS = in- haled corticosteroid; PDE = phosphodiesterase inhibitor.

TAIN and ACCORD COPD I trials. In the following 12/12h (area under the curve where the numbers repre- discussion regarding change in FEV1 in response to sent the time period for which data were collected di- therapy, improvements will be described relative to vided by the number of hours over which the data are placebo effect, otherwise known as “placebo- averaged). Both aclidinium and tiotropium showed sig- subtracted changes” (i.e., effect of active treatment mi- nificant improvement over placebo (221 mL increase nus effect of placebo treatment) to demonstrate the in FEV•1 AUC, P<0.0001; and 244 mL increase in FE- effectiveness of active treatment. V1 AUC, P<0.0001, respectively) for the primary end- The phase II study conducted by Fuhr was a ran- point at 15 days. No significant differences were ob- domized double-blind, double-dummy, crossover trial.8 served between active treatment arms in the primary Patients were randomly assigned to 400 mcg of endpoint at 15 days; however, aclidinium did cause sig- aclidinium bromide twice daily, 18 mcg of tiotropium nificantly greater improvement in FEV1 compared bromide daily, or placebo for 15 days with a 9-15 day with tiotropium on day 1 (Figure 1). washout period between treatments. The primary end- This study was limited by a small study populations point was mean change from baseline FEV1 AUC0- (n=27) and duration (15 days of medication per treat-

Table 2 | Summary of clinical trials of aclidinium bromide. a Study Design Treatment Improvement in FEV1

Fuhr study  n= 27  Aclidinium 400 mcg BID Aclidinium: 221 mL (p<0.0001 vs. 8  Phase II, Double blind, placebo  Tiotropium 18 mcg BID pbo) and active controlled crossover  Placebo BID study Tiotropium: 244 mL (no statistical  Duration: 15 days (9-15 day wash- comparison available vs aclidinium) out period between crossover) Singh  n=79  Aclidinium 100 mcg BID Aclidinium 9 study  Phase II, double blind, double  Aclidinium 200 mcg BID  100 mcg: 154 mL(p<0.0001 vs. pbo) dummy, placebo and active com-  Aclidinium 400 mcg BID  200 mcg: 176 mL(p<0.0001 vs pbo) parator controlled crossover study  12 mcg QD  400 mcg: 208 mL(p<0.0001 vs pbo)  Duration: 7 days (5-9 day washout  Placebo BID period between crossover) Formoterol: 210 mL (p<0.05 vs 400 mcg aclidinium)

ACCORD  n=467  Aclidinium 200 mcg BID Aclidinium (trough) 10 COPD I  Randomized, double-blind, place-  Aclidinium 400 mcg BID  200 mcg: 86 mL (p<0.0001 vs pbo) bo controlled parallel group study  Placebo BID  400 mcg: 124 mL(p<0.0001 vs pbo)  Duration: 2-week run-in, 12 week treatment period and 2 week follow up 11 ATTAIN  n=737  Aclidinium 200 mcg BID Aclidinium (trough)  Randomized, double-blind, place-  Aclidinium 400 mcg BID  200 mcg: 99 mL (p<0.0001 vs pbo) bo controlled parallel group study  Placebo BID  400 mcg: 128 mL(p<0.0001 vs pbo)  Duration: 2 week run in period and Aclidinium (peak) then 24 weeks of treatment  200 mcg: 185 mL(p<0.0001 vs pbo)  400 mcg: 209 mL(p<0.0001 vs pbo) PBO = placebo; BID = twice daily; QD = once daily. a Data in this column are presented as placebo-subtracted improvement in FEV1 (i.e., improvement in FEV1 in aclidinium group minus improvement in FEV1 in placebo group). 8 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 8 Figure 1 | Mean change from baseline FEV1 between aclidinium, tiotropium, and placebo. ment arm). Strengths include a strong treatment com- average of 2 predose FEV1 values. The secondary effi- parator and an appropriate outcome measurement. cacy endpoint was change from baseline to week 12 in The study demonstrated that aclidinium 400 mcg in- peak FEV1. At 12 weeks, 400 mcg twice daily im- haled twice daily provides similar bronchodilation proved trough FEV1 by 124 mL (p<0.0001) (Figure 2; compared to tiotropium and significantly greater bron- panel A) and peak FEV1 by 192 mL (p<0.0001) over chodilation compared to placebo.8 placebo (Figure 2; panel B). The Singh study was a phase II double-blind, dou- Significant improvement in FEV1 (125 mL for 400 ble-dummy, placebo and active-comparator controlled mcg) occurred 30 minutes after the first administra- crossover study.9 Patients were randomly assigned to tion. Additionally, maximum bronchodilation provided twice daily aclidinium 100 mcg, 200 mcg, or 400 mcg, by aclidinium was achieved on the first day of treat- or 12 mcg formoterol or placebo for 7 days with a 5-9 ment and was maintained throughout the 12 weeks. day washout period.12 The primary endpoint was mean This study had a much larger sample size (n=590) than change from baseline in FEV1 normalized AUC0-12 on previous studies and directly compared aclidinium with day 7. At all three doses, aclidinium showed improve- placebo. Based on the results of this trial, aclidinium ment over placebo with 400 mcg twice daily increasing appears to have greater efficacy when compared with FEV1 by 208 mL as compared to formoterol which placebo. increased FEV1 by 210 mL. This study was similarly The ATTAIN study was a phase III double-blind, limited by small study population and duration. Its randomized, placebo-controlled, parallel-group study. major strengths include a comparator which is stand- Patients were randomly assigned to 200 mcg or 400 ard of care (formoterol) and the use of an appropriate mcg of aclidinium twice daily or placebo for a 2 week marker of COPD, FEV1, as the primary outcome. run in period and then 24 weeks of treatment. The Thus this study demonstrated that aclidinium bromide primary efficacy endpoint was change in trough FEV1 had the greatest efficacy at a dose of 400 mcg twice at week 24. At week 24, 400 mcg twice daily showed a daily, and that this efficacy was superior to placebo and 128 mL (p<0.0001 ) improvement in FEV1 compared similar to formoterol in increasing FEV1. to placebo (Figure 3). This study compared aclidinium ACCORD COPD I was a phase III randomized, to placebo over 24 weeks and maintained “n” over the double-blind, placebo-controlled parallel-group study. number required per treatment arm for a power=90% It was conducted over a 2-week run-in, 12 week treat- by enrolling a sufficient number of patients to account ment period and 2 week follow-up, comparing twice for the number of dropouts. In addition, this trial daily aclidinium 200 mcg, 400 mcg and placebo. The showed improved FEV1 over 24 weeks compared to primary efficacy endpoint was change from baseline to placebo that was sustained over the entire treatment week 12 in morning predose (trough) FEV1 and the period. 9 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 11 Figure 3 | Change in trough FEV1 in ATTAIN trial.

400 mcg given twice a day provided significant bron- chodilation compared to placebo. Patient should de- press the green button to release the medication which will turn the red control window green, indicating the device is ready for inhalation (Figure 4).6 Patients should then inhale until they hear a click indicating the medication has been inhaled from the device. The pa- tient should then hold their breath for as long they can and then exhale slowly from their nose. The control window should once again be red indicating the medi- cation has been successfully inhaled. The inhaler con- tains 60 doses to be used over 30 days and the number remaining will be indicated on the device counter.

SAFETY & ADVERSE EVENTS

Aclidinium was generally well tolerated with similar side effect profiles to its treatment comparators and placebo. The most documented side effect was COPD exacerbation which occurred less frequently with 400 mcg of aclidinium twice daily compared to placebo in 10 the ACCORD COPD I (Table 3) and ATTAIN Figure 2 | Change in trough (A) and peak (B) FEV1. (Table 4) trials. Rates for discontinuation due to ad- DOSING & ADMINISTRATION verse effects were similar between aclidinium 400 mcg

Aclidinium bromide is administered via Genuair, a proprietary, breath-actuated multidose dry powder in- haler (DPI). Genuair contains 1 month of therapy, does not require cleaning, and is disposable.7 In addi- tion, it has a trigger threshold function to prevent dou- ble dosing, a lock out mechanism to prevent further use after last dose has been administered and a dose indicator to keep track of how many doses are left.7 Aclidinium bromide is administered as one 400 mcg inhalation twice a day. Though it was initially de- termined that a 200 mcg dose improved FEV1 over placebo, this improvement was below the minimum clinically important difference of 100-140 mL.10,11 Figure 4 | Genuair inhaler used for aclidinium bro- Thus via ACCORD COPD I, it was determined that mide. 10 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 Table 3 | Most frequently reported adverse events from the ACCORD COPD I trial.10 Placebo, n (%) Aclidinium 200 mcg, n (%) Aclidinium 400 mcg, n (%) Side Effect n=186 n=184 n=190 COPD exacerbation 23 (12.4) 17 (9.2) 14 (7.4) Dyspnea 6 (3.2) 4 (2.2) 5 (2.6) Arthralgia 1 (0.5) 4 (2.2) 5 (2.6) Cough 5 (2.7) 4 (2.2) 4 (2.1) Diarrhea 3 (1.6) 3 (1.6) 4 (2.1) Oropharyngeal pain 3 (1.6) 2 (1.1) 4 (2.1) Fatigue 4 (2.2) 0 (0) 4 (2.1) Headache 4 (2.2) 6 (3.3) 3 (1.6) Nasopharyngitis 2 (1.1) 6 (3.3) 3 (1.6) Insomnia 6 (3.2) 3 (1.6) 3 (1.6) Urinary tract infection 4 (2.2) 2 (1.1) 3 (1.6) Back pain 1 (0.5) 5 (2.7) 3 (1.6) Upper respiratory tract infection 7 (3.8) 2 (1.1) 2 (1.1) Nausea 4 (2.2) 2 (1.1) 2 (1.1) Dizziness 1 (0.5) 4 (2.2) 2 (1.1) Bronchitis 4 (2.2) 2 (1.1) 0 (0) and placebo in both ACCORD COPD I (3.8% vs CONCLUSIONS 3.7% for placebo and aclidinium, respectively) and AT- TAIN (4.0% vs. 3.0% in placebo vs. aclidinium groups, Aclidinium bromide, a novel long acting antimus- respectively). carinic antagonist for the treatment of moderate-to- Monitoring for efficacy should begin with baseline severe COPD, has shown both efficacy and safety in pulmonary function tests, specifically FEV1. The pa- comparison with placebo and a similar efficacy and tient should notice some relief as early as 30 min after safety profile compared with current standards of care the first administration. The GOLD guidelines recom- (tiotropium and formoterol). In addition, the new pro- mend that FEV1 be measured yearly thereafter to de- prietary delivery system may ease administration and termine disease progression. If symptoms do not im- provide additional safety mechanisms over current in- prove or worsen, or side effects associated with treat- halation devices. Based on the currently available litera- ment become intolerable it is suggested to terminate ture, aclidinium may be another valid option for the use of aclidinium and refer to prescriber for other treatment of COPD, particularly for patients intolerant treatment options. to or unable to use tiotropium bromide.

Table 4 | Most frequently reported adverse events in the ATTAIN trial.11 Aclidinium 200 mcg BID Aclidinium 400 mcg BID Side effect Placebo (n=273) (n=277) (n=269) COPD exacerbation 56 (20.5) 44 (15.9) 38 (14.1) Headache 22 (8.1) 30 (10.8) 33 (12.3) Nasopharyngitis 23 (8.4) 32 (11.6) 30 (11.2) Rhinitis 7 (2.6) 4 (1.4) 9 (3.3) Diarrhea 3 (1.1) 5 (1.8) 8 (3.0) Bronchitis 6 (2.2) 1 (0.4) 7 (2.6) Hypertension 9 (3.3) 5 (1.8) 7 (2.6) Cough 5 (1.8) 7 (2.5) 7 (2.6) Toothache 1 (0.4) 3 (1.1) 6 (2.2) Back Pain 10 (3.7) 12 (4.3) 5 (1.9) Influenza 6 (2.2) 3 (1.1) 5 (1.9) Arthralgia 6 (2.2) 5 (1.8) 3 (1.1) Urinary tract infection 2 (0.7) 6 (2.2) 2 (0.7) Dyspepsia 6 (2.2) 5 (1.8) 1 (0.4) 11 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013 REFERENCES

1. Rabe KF, Hurd S, Anzueto A. Global Initiative for Chronic , et al: Global strate- gy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD execu- tive summary. Am J Respir Crit Care Med 2007;176 (6):532-55. 2. National Heart, Lung, and Blood Institute. 2004 NHLBI morbidity and mortality chartbook on cardio- vascular, lung and blood diseases [Internet]. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. Available from: http://www.nhlbi.nih.gov/resources/ docs/cht-book.htm. Accessed November 2, 2012. 3. Chapman KR, Mannino DM, Soriano JB, et al. Epide- miology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006;27(1):188-207. 4. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3(11):e442. 5. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370 (9589):765-73. 6. Tudorza PressairÒ [package insert]. St. Louis, MO: For- est Pharmaceuticals, Inc; 2012. 7. Magnussen H, Watz H, Zimmermann I, Macht S, Greg- uletz R, Falques M, et al. Peak inspiratory flow through the Genuair inhaler in patients with moderate or severe COPD. Respir Med 2009;103(12):1832-7. 8. Fuhr R, Magnussen H, Sarem K, Llovera AR, Kirsten A, Falques M, et al. Efficacy of aclidinium bromide 400ug twice daily compared with placebo and tiotropi- um in patients with moderate to severe COPD. Chest 2012;141(3):745-52. 9. Singh D, Magnussen H, Kirsten A, Mindt S, Caracta C, Seoane B, et al. A randomized, placebo- and active- controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Phar- MATERIA MEDICA macol Ther 2012;25(3):248-53. 10. Kerwin EM, D’Urzo AD, Gelb AE, Lakkis H, Gil EG, A publication of the Department of Clinical Caracta CE. Efficacy and safety of a 12-week treatment Pharmacy, Skaggs School of Pharmacy and with twice-daily aclidinium bromide in COPD patients Pharmaceutical Sciences (ACCORD COPD I). COPD 2012;9(2):90-101. 11. Jones PW, Singh D, Bateman ED, Agusti A, Lamarca University of Colorado R, de Miquel G, et al. Efficacy and safety of twice daily aclidinium bromide in COPD patients: the ATTAIN Editor study. Eur Respir J 2012;40:830-836. Steven M. Smith, PharmD, MPH 12. Jones B, Kenward G. Design and analysis of crossover trials. 2nd ed. London: Chapman and Hall; 2003. Associate Editor Katy E. Trinkley, PharmD

The material contained in this newsletter has been prepared by the Skaggs School of Pharmacy for informational purposes only. The  articles are the work product of the individual authors to whom each article is attributed. The articles contained herein should not be used without proper permission or citation. Should you have questions about any of the content in this newsletter please contact the Editor. 12 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 1, Issue 8 January 2013