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Home , Aripiprazole, Aripiprazole lauroxil, Chlorpromazine, Clozapine, Haloperidol decanoate, Olanzapine

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When should you consider combining 2 long-acting injectable ?

Lauren A. Diefenderfer, PharmD, BCPP

s. S, age 39, with a 15-year his- treatment-resistant ,1-4 it is not tory of schizophrenia and severe an option for patients who cannot adhere to M paranoid , is admitted required laboratory monitoring. Treatment after physically assaulting a staff member guidelines state that there is limited evi- at a group home. She is receiving paliperi- dence for combining 2 antipsychotics (aside done palmitate, 234 mg every 4 weeks. This from augmentation of treatment) has reduced the severity of her symptoms, and that such use should be closely moni- Vicki L. Ellingrod, but she continues to have persistent delu- tored and documented.2-4 Use of a single PharmD, FCCP sions that affect her ability to accept redirec- LAIA is recommended when the patient Department Editor tion from staff. Ms. S frequently accuses staff prefers the formulation or to avoid treat- and peers of sexual assault, says that she is ment nonadherence; however, treatment pregnant, and does not adhere to treatment guidelines do not address the simultaneous recommendations for laboratory monitor- use of 2 LAIAs.2,4-6 A few case reports have ing because the “staff uses her blood for described successful use of dual LAIAs experiments.” (Table 1,7-11 page 43). Five of these are sum- Ms. S frequently requires administration marized here (Yazdi et al10 was published in of oral and IM , as needed, when German and is only included in Table 1,7-11 she becomes aggressive with the staff. She page 43). has poor insight into her mental illness and does not believe that she needs . Ladds et al.7 A 49-year-old woman with Ms. S has a long history of stopping her oral schizophrenia who was hospitalized for after a few days, reporting that aggressive and bizarre behavior and had it is “harming her baby.” Monotherapy has been institutionalized for 20 years stopped been tried with various long-acting inject- taking her medication regimen.7 She started able antipsychotics (LAIAs), but she still taking 8-hour showers with bleach, talking exhibits persistent delusions. The treatment team decides to add a second LAIA, haloperi- Practice Points dol decanoate, 200 mg every 4 weeks, to her • Although treatment guidelines do regimen. not address the use of 2 long-acting Savvy Psychopharmacology injectable antipsychotics (LAIAs), is produced in partnership they recognize the need for 2 oral with the College Treatment-resistant schizophrenia pro- of Psychiatric antipsychotics in cases of treatment and Neurologic vides a challenge for practicing clinicians. resistance; however, evidence is limited. Pharmacists Although clozapine is preferred for cpnp.org • Carefully consider LAIA properties when mhc.cpnp.org (journal) Dr. Diefenderfer is Clinical Pharmacist, Center for Behavioral Medicine, choosing a regimen for dual treatment. Kansas City, Missouri. Disclosure • Use the lowest effective dose of each The author reports no financial relationships with any company LAIA to limit adverse effects and improve Current whose products are mentioned in this article or with manufacturers of patient tolerability of the regimen. 42 October 2017 competing products. Savvy Psychopharmacology

Table 1 Published case reports of dual LAIA treatment Case report Patient Diagnosis Dual LAIA regimen Ladds et al7 Female, age 49 Schizophrenia microspheresa decanoatea Wartelsteiner Male Schizophrenia, Risperidone microspheres, 100 mg every 2 and Hofer8 paranoid type weeks pamoate, 300 mg every 2 weeks Scangos Vietnamese male, Schizophrenia Olanzapine pamoate, 405 mg once a month 9 et al age 26 Haloperidol decanoatea Yazdi et al10,b 44 years old Schizoaffective Risperidone microspheres, 50 mg every 2 disorder weeks decanoate, 500 mg every 2 Clinical Point weeks A few case reports Ross and African American Schizophrenia, palmitate, 156 mg once a month 11 Fabian male, age 44 paranoid type , 400 mg every 2 have reported weeks successful use of aDose not reported bCase report published in German dual LAIAs LAIA: long-acting injectable antipsychotic

incoherently, and believing that someone done. Both were switched to was poisoning her. She had poor response LAIA formulations to address medication to oral risperidone monotherapy; how- nonadherence. His symptoms remained ever, 2 months after adding oral fluphen- stable with risperidone microspheres, azine and benztropine to her regimen, her 100 mg, and olanzapine pamoate, 300 mg, symptoms substantially improved (doses each administered every 2 weeks. He did not reported). Because she had impaired not experience any adverse effects with this insight into the need for daily medication, combination therapy. she was started on depot fluphenazine decanoate and risperidone microspheres Scangos et al.9 A 26-year-old Vietnamese (doses not reported) before discharge. No man with schizophrenia and an exten- substantial adverse effects were noted with sive history of unprovoked, psychotically this regimen. driven assaults was given multiple anti- psychotics (including clozapine) during Wartelsteiner and Hofer.8 A man who hospitalizations, and his medication regi- had been diagnosed with paranoid schizo- men consistently included 2 antipsychotics. phrenia at age 20 presented with thought After contracting viral gastroenteritis, he blocking, incoherence, persecutory delu- refused oral medications and required sions, and uncontrolled self-damaging short-acting IM administration of both hal- behavior.8 He had been admitted 27 times operidol, 5 mg, twice a day, and olanzap- over 7 years; during this time he received ine, 10 mg, twice a day. Because of concerns many antipsychotic monotherapies and about continuing this regimen, he was combination regimens. A total of 8 oral switched to haloperidol decanoate (dose antipsychotics (including clozapine) and not reported) and olanzapine pamoate, 5 LAIAs had been administered during 405 mg, administered once per month. The these trials. He significantly improved with injections were scheduled to alternate so Current Psychiatry the combination of olanzapine and risperi- that the patient would receive 1 Vol. 16, No. 10 43 Savvy Psychopharmacology

Table 2 Summary of long-acting antipsychotic properties

a Drug Dose range (mg) Frequency Injection site(s) T1/2 (days) Adverse effects Monitoring First-generation antipsychotics Fluphenazine 12.5 to 100 Every 2 to 4 weeks Gluteal or deltoid Approximately 14 , , tardive decanoate12 , drowsiness dyskinesia Haloperidol 10 to 15 times Every 4 weeks Gluteal or deltoid Approximately 21 , hypotension, Hypotension, tardive decanoate13 oral dose hypertension, extrapyramidal dyskinesia symptoms Second-generation antipsychotics 160 to 400 Monthly Gluteal or deltoid Approximately 46.5 , , Metabolic monitoring, monohydrate14 injection site pain, Clinical Point Aripiprazole 441 to 882 Monthly, or every 6 Gluteal, deltoid 29.2 to 34.9 Akathisia Metabolic monitoring, lauroxil15 weeks (882 mg only) (441 mg only) tardive dyskinesia Prior to initiating Olanzapine 150 to 405 Every 2 or 4 weeks Gluteal 30 , sedation, weight 3-hour post-injection treatment with pamoate16 gain, cough, diarrhea, back observation at pain, , , registered health care 2 LAIAs, previous dry mouth, nasopharyngitis, facility, metabolic tolerability of each increased appetite, monitoring, tardive dyskinesia medication must be Paliperidone 39 to 234 Every 4 weeks Gluteal or deltoid 25 to 49 Injection site reactions, Metabolic monitoring, confirmed palmitate (1 month)17 somnolence/sedation, tardive dyskinesia , akathisia, extrapyramidal disorder Paliperidone 273 to 819 Every 3 months Gluteal or deltoid 84 to 95 (deltoid) or Injection site reaction, weight Metabolic monitoring, palmitate (3 month)18 118 to 139 (gluteal) gain, headache, upper tardive dyskinesia respiratory tract infection, akathisia, Risperidone 12.5 to 50 Every 2 weeks Gluteal or deltoid 3 to 6 Headache, parkinsonism, Metabolic monitoring, microspheres19 dizziness, akathisia, , tardive dyskinesia , dyspepsia, sedation, weight gain, pain in extremity, dry mouth aFor second-generation agents in clinical trials of patients with schizophrenia at rates >5%

every 2 weeks. The patient’s assaultive What to consider before initiating behavior was significantly reduced, and no dual LAIA treatment adverse effects were reported. Evaluate the frequency of administration, flexibility of dosing, administration site, Ross and Fabian.11 An African American adverse effects, and monitoring require- man, age 44, was receiving haloperidol ments of each LAIA (Table 212-19) to ensure decanoate, 400 mg every 2 weeks, and oral the patient’s optimal tolerability of the regi- haloperidol, 20 mg/d.11 Because of residual men. Previous tolerability of each medica- Discuss this article at symptoms, a history of nonadherence, and tion must be confirmed by evaluating the www.facebook.com/ concerns about increasing the haloperidol patient’s medication history or oral or IM CurrentPsychiatry decanoate dose or frequency, oral haloperi- administration of each agent prior to initiat- dol was discontinued and paliperidone pal- ing the LAIA. mitate, 156 mg every 4 weeks, was started. When choosing 2 agents that are each The patient was able to transition into a administered once every 4 weeks, consider step-down unit, and no adverse effects administering the medications together Current Psychiatry 44 October 2017 were reported. every 4 weeks or alternating administration Savvy Psychopharmacology

Table 2 Related Resource Summary of long-acting antipsychotic properties • Correll CU, Citrome L, Haddad PM, et al. The use of long-acting Drug Dose range (mg) Frequency Injection site(s) T (days) Adverse effectsa Monitoring injectable antipsychotics in schizophrenia: evaluating the 1/2 evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24. First-generation antipsychotics Drug Brand Names Fluphenazine 12.5 to 100 Every 2 to 4 weeks Gluteal or deltoid Approximately 14 Extrapyramidal symptoms, Hypotension, tardive Aripiprazole monohydrate • Olanzapine pamoate • decanoate12 hypertension, drowsiness dyskinesia Abilify Maintena Zyprexa Relprevv Haloperidol 10 to 15 times Every 4 weeks Gluteal or deltoid Approximately 21 Tachycardia, hypotension, Hypotension, tardive • Paliperidone palmitate decanoate13 oral dose hypertension, extrapyramidal dyskinesia Aristada (1 month) • Invega symptoms Fluphenazine decanoate • Sustenna Prolixin D Paliperidone palmitate Second-generation antipsychotics Haloperidol decanoate • (3 month) • Invega Trinza Aripiprazole 160 to 400 Monthly Gluteal or deltoid Approximately 46.5 Weight gain, akathisia, Metabolic monitoring, Haldol D Risperidone microspheres • monohydrate14 injection site pain, sedation tardive dyskinesia Risperdal Consta Aripiprazole 441 to 882 Monthly, or every 6 Gluteal, deltoid 29.2 to 34.9 Akathisia Metabolic monitoring, lauroxil15 weeks (882 mg only) (441 mg only) tardive dyskinesia Clinical Point Olanzapine 150 to 405 Every 2 or 4 weeks Gluteal 30 Headache, sedation, weight 3-hour post-injection Consider whether pamoate16 gain, cough, diarrhea, back observation at Cost may influence the decision to use the patient needs pain, nausea, somnolence, registered health care 2 LAIAs. The majority of LAIAs in the dry mouth, nasopharyngitis, facility, metabolic close follow-up or increased appetite, vomiting monitoring, tardive United States are available only as branded dyskinesia formulations. Insurance companies may is more resistant to Paliperidone 39 to 234 Every 4 weeks Gluteal or deltoid 25 to 49 Injection site reactions, Metabolic monitoring, require prior authorization for the use of receiving injections palmitate (1 month)17 somnolence/sedation, tardive dyskinesia 2 LAIAs. when scheduling dizziness, akathisia, Although there are no treatment guide- extrapyramidal disorder lines for combining 2 LAIAs, this practice administrations Paliperidone 273 to 819 Every 3 months Gluteal or deltoid 84 to 95 (deltoid) or Injection site reaction, weight Metabolic monitoring, palmitate (3 month)18 118 to 139 (gluteal) gain, headache, upper tardive dyskinesia has been used. A few case reports have respiratory tract infection, described successful use of dual LAIA akathisia, parkinsonism treatment, but one should consider the Risperidone 12.5 to 50 Every 2 weeks Gluteal or deltoid 3 to 6 Headache, parkinsonism, Metabolic monitoring, risk of the publication’s bias. Overall, 19 microspheres dizziness, akathisia, fatigue, tardive dyskinesia the decision to use 2 LAIAs is difficult constipation, dyspepsia, sedation, weight gain, pain in because there is lack of a large evidence extremity, dry mouth base supporting the practice or direction aFor second-generation agents in clinical trials of patients with schizophrenia at rates >5% from treatment guidelines. Because of this, dual LAIA treatment should not be used for most patients. In cases of treatment- resistant schizophrenia where clozapine is so that the patient receives an injection every not an option and adherence is a concern, 2 weeks. Receiving an injection once every it is reasonable to consider this strategy on 2 weeks might be beneficial for patients a case-by-case basis. who need close follow-up or are more sen- sitive to injection site reactions, whereas References 1. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment- a regimen of once every 4 weeks might be resistant schizophrenic. A double-blind comparison with beneficial for patients who are more resistant . Arch Gen Psychiatry. 1988;45(9):789-796. 2. Lehman A, Lieberman JA, Dixon LB, et al; American to receiving the injections, so there is poten- Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with tially less time spent agitated or anxious schizophrenia, second edition. Am J Psychiatry. 2004;161(suppl leading up to the date of the injection. 2):1-56. 3. Hasan A, Falkai P, Wobrock T, et al; the WFSBP Task Force on Use the lowest effective dose of each Treatment Guidelines for Schizophrenia. World Federation LAIA to limit adverse effects and improve of Societies of (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 tolerability of the regimen. Monitor patients on the acute treatment of schizophrenia and management of closely for adverse reactions and discon- treatment resistance. World J Biol Psychiatry. 2012;13(5):318-78. 4. Barnes TR; Schizophrenia Consensus Group of British tinue the regimen as soon as possible if a Association for Psychopharmacology. Evidence-based Current Psychiatry severe adverse reaction occurs. guidelines for the pharmacological treatment of schizophrenia: Vol. 16, No. 10 45 Savvy Psychopharmacology

recommendations from the British Association for 10. Yazdi K, Rosenleitner J, Pischinger B. Combination of two Psychopharmacology. J Psychopharmacol. 2011;25(5):567-620. depot antipsychotic drugs [in German]. Nervenarzt. 2014;85(7): 5. Hasan A, Falkai P, Wobrock T, et al; WFSBP Task Force on 870-871. Treatment Guidelines for Schizophrenia. World Federation 11. Ross C, Fabian T. High dose haloperidol decanoate of Societies of Biological Psychiatry (WFSBP) guidelines for augmentation with paliperidone palmitate. Presented biological treatment of schizophrenia, part 2: update 2012 on at: College of Psychiatric and Neurologic Pharmacists the long-term treatment of schizophrenia and management 16th Annual Meeting; April 21-24, 2013; Colorado Springs, of antipsychotic-induced side effects. World J Biol Psychiatry. CO. 2013;14(1):2-44. 12. Fluphenazine decanoate [package insert]. Schaumburg, IL: 6. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al; APP Pharmaceuticals, LLC; 2010. Schizophrenia Patient Outcomes Research Team (PORT). 13. Haloperidol decanoate [package insert]. Rockford, IL: Mylan; The Schizophrenia Patient Outcomes Research Team 2014. (PORT): updated treatment recommendations 2009. 14. Abilify Maintena [package insert]. Rockville, MD: Otsuka Schizophr Bull. 2010;36(1):94-103. America Pharmaceutical, Inc.; 2016. 7. Ladds B, Cosme R, Rivera F. Concurrent use of two depot 15. Aristada [package insert]. Waltham, MA: ; 2016. antipsychotic medications in schizophrenia. The Internet Journal of Psychiatry. 2009;1(1):1-3. 16. Zyprexa Relprevv [package insert]. Indianapolis, IN: Lilly USA, LLC; 2016. 8. Wartelsteiner F, Hofer A. Treating schizophrenia with 2 long- 17. Invega Sustenna [package insert]. Titusville, NJ: Janssen Clinical Point acting injectable antipsychotic drugs: a case report. J Clin Pharmaceuticals, Inc.; 2009. Psychopharmacol. 2015;35(4):474-475. 18. Invega Trinza [package insert]. Titusville, NJ: Janssen In patients with 9. Scangos KW, Caton M, Newman WJ. Multiple long- Pharmaceuticals, Inc.; 2015. acting injectable antipsychotics for treatment-resistant treatment-resistant schizophrenia: case report. J Clin Psychopharmacol. 19. Risperdal Consta [package insert]. Titusville, NJ: Janssen 2016;36(3):283-285. Pharmaceuticals, Inc.; 2007. schizophrenia, where clozapine is not an option, consider dual LAIAs on a case-by- case basis

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