Long-acting injectable antipsychotics: What to do about missed doses Use a stepwise approach based on the unique properties of the specific medication Jasmine Carpenter, PharmD, BCPS, BCPP ntipsychotic agents are the mainstay of treatment for patients PACT/Mental Health Clinical Pharmacy Specialist 1-3 Department of Pharmacy and Mental Health with schizophrenia, and when taken regularly, they can Veterans Affairs Medical Center greatly improve patient outcomes. Unfortunately, many stud- Washington, DC A ies have documented poor adherence to antipsychotic regimens in Kong Kit Wong, PharmD patients with schizophrenia, which often leads to an exacerbation of Transitional Care Clinical Pharmacist symptoms and preventable hospitalizations.4-8 In order to improve Department of Clinical Pharmacy Services Kaiser Permanente of the Mid-Atlantic States adherence, many clinicians prescribe long-acting injectable antipsy- Arlington, VA chotics (LAIAs). LAIAs help improve adherence, but these benefits are seen only in Disclosures patients who receive their injections within a specific time frame.9-11 The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers LAIAs administered outside of this time frame (missed doses) can lead of competing products. to reoccurrence or exacerbation of symptoms. This article explains how to adequately manage missed LAIA doses. First-generation long-acting injectable antipsychotics Two first-generation antipsychotics are available as a long-acting inject- able formulation: haloperidol decanoate and fluphenazine decanoate. Due to the increased risk of extrapyramidal symptoms, use of these agents have decreased, and they are often less preferred than second- generation LAIAs. Furthermore, unlike many of the newer second- generation LAIAs, first-generation LAIAs lack literature on how to manage missed doses. Therefore, clinicians should analyze the pharma- cokinetic properties of these agents (Table 1,12-28 page 12), as well as the patient’s medical history and clinical presentation, in order to determine how best to address missed doses. continued Current Psychiatry ROY SCOTT. ALL RIGHTS RESERVED. ROY SCOTT. Vol. 17, No. 7 11 Table 1 Pharmacokinetic properties of haloperidol and fluphenazine decanoate Haloperidol decanoate Fluphenazine decanoate Dosing interval Every 4 weeks Every 2 to 4 weeks Plasma peak after administration 6 days 24 hours Time to reach steady state 3 to 4 months 4 to 6 weeks Long-acting Half-life 3 weeks 8 to 14 days antipsychotics Therapeutic window 3 to 15 ng/mL 0.2 to 2 ng/mL Source: References 12-28 Figure 1 Recommendations for addressing missed doses of haloperidol decanoate long-acting injection Clinical Point At steady state and ≤6 weeks Steady state not reached It has been ≥13 weeks since since the last injection or it has been >6 to the last injection 12 weeks since last dose When addressing • The patient should receive • Plasma levels may fall lower • The patient should be stabilized missed doses of the next injection as soon as than the therapeutic window on an oral antipsychotic possible • Give the next injection as soon • Haloperidol decanoate should risperidone long- as possible be reinitiated • Provide oral antipsychotic acting injection, supplementation if symptoms reoccur check to see if the • Around Day 6 after injection (time to peak), monitor closely medication has for adverse effects reached steady state Haloperidol decanoate plasma concentra- following fluphenazine decanoate dis- tions peak approximately 6 days after the continuation.27,28 Based on these findings, injection.12 The medication has a half-life Figure 2 (page 14) summarizes our recom- of 3 weeks. One study found that haloperi- mendations for addressing missed fluphen- dol plasma concentrations were detectable azine decanoate doses. 13 weeks after the discontinuation of halo- peridol decanoate.17 This same study also found that the change in plasma levels from Second-generation LAIAs 3 to 6 weeks after the last dose was minimal.17 Six second-generation LAIAs are available Based on these findings, Figure 1 summa- in the United States. Compared with the rizes our recommendations for addressing first-generation LAIAs, second-generation missed haloperidol decanoate doses. LAIAs have more extensive guidance on how to address missed doses. Fluphenazine decanoate levels peak 24 hours after the injection.18 An estimated Risperidone long-acting injection. When therapeutic range for fluphenazine is addressing missed doses of risperidone 0.2 to 2 ng/mL.21-25 One study that evalu- long-acting injection, first determine Discuss this article at ated fluphenazine decanoate levels follow- whether the medication has reached steady www.facebook.com/ ing discontinuation after reaching steady state. Steady state occurs approximately MDedgePsychiatry state found there was no significant dif- after the fourth consecutive injection ference in plasma levels 6 weeks after the (approximately 2 months).29 last dose of fluphenazine, but a significant If a patient missed a dose but has not decrease in levels 8 to 12 weeks after the last reached steady state, he or she should dose.26 Other studies found that fluphen- receive the next dose as well as oral anti- Current Psychiatry 12 July 2018 azine levels were detectable 21 to 24 weeks psychotic supplementation for 3 weeks.30 If continued on page 14 continued from page 12 Figure 2 Recommendations for addressing missed doses of fluphenazine decanoate long-acting injection At steady state and ≤6 weeks Steady state not reached or It has been >24 weeks since since the last injection it has been >6 to 24 weeks the last injection since last dose Long-acting • The patient should receive • Plasma levels may fall lower • The patient should be stabilized antipsychotics the next injection as soon as than the therapeutic window on an oral antipsychotic possible • Give the next injection as soon • Fluphenazine decanoate should as possible be reinitiated • Provide oral antipsychotic supplementation if there is symptom reoccurrance • Within the first 24 hours after injection (time to peak), monitor closely for adverse effects Clinical Point Figure 3 To address a missed Recommendations for addressing missed doses of risperidone paliperidone long-acting injection monthly injection, determine if the Steady state not reached and At steady state and ≤6 weeks At steady state and >6 weeks patient is receiving >2 weeks since last dose since the last injection since the last injection initiation or • Give next injection as • Give next injection as soon • Give next injection as soon as possible plus oral as possible soon as possible plus oral maintenance dosing supplementation for 3 weeks supplementation for 3 weeks the patient has reached steady state and if maintenance dose of PP1M (in the deltoid it has been ≤6 weeks since the last injection, or gluteal muscle). The second initiation give the next injection as soon as possible. injection may be given 4 days before or after However, if steady state has been reached the scheduled administration date. The ini- and it has been >6 weeks since the last injec- tiation doses should be adjusted in patients tion, give the next injection, along with 3 with mild renal function (creatinine clear- weeks of oral antipsychotic supplementa- ance 50 to 80 mL/min).31 Figure 4 (page 15) tion (Figure 3). summarizes the guidance for addressing a missed or delayed second injection during Paliperidone palmitate monthly long- the initiation phase. acting injection. Once the initiation Maintenance phase. During the mainte- dosing phase of paliperidone palmitate nance phase, PP1M can be administered monthly long-acting injection (PP1M) is 7 days before or after the monthly due date. completed, the maintenance dose is admin- If the patient has missed a maintenance istered every 4 weeks. When addressing injection and it has been <6 weeks since missed doses of PP1M, first determine the last dose, the maintenance injection whether the patient is in the initiation or can be given as soon as possible (Figure 5, maintenance dosing phase.31 page 15).31 If it has been 6 weeks to 6 months Initiation phase. Patients are in the initia- since the last injection, the patient should tion dosing phase during the first 2 injec- receive their prescribed maintenance dose tions of PP1M. During the initiation phase, as soon as possible and the same dose 1 the patient first receives 234 mg and then week later, with both injections in the del- 156 mg 1 week later, both in the deltoid mus- toid muscle. Following the second dose, the Current Psychiatry 14 July 2018 cle. One month later, the patient receives a patient can resume their regular monthly Figure 4 Recommendations for addressing missed doses of paliperidone palmitate monthly long-acting injection during the initiation phase MDedge.com/psychiatry <4 weeks since the Between 4 to 7 weeks since >7 weeks since the first injection the first injection first injection • Give the second injection • Give 2 doses of 156 mg in the • Restart the initiation phase as soon as possible (in the deltoid muscle 1 week apart deltoid muscle) • Give the maintenance injection • Administer the maintenance 1 month later (in either the injection 5 weeks after the first deltoid or gluteal muscle) injection Figure 5 Recommendations for addressing missed doses of paliperidone palmitate monthly long-action injection during the maintenance phase Clinical Point Paliperidone <6 weeks since the Between 6 weeks to 6 months >6 months since the last injection since the last injection last injection 3-month long-acting • Give the next maintenance • Give the maintenance injection • The patient should undergo injection can be injection as soon as possible in the deltoid muscle as soon as reinitiation possible and then again 1 week given 2 weeks before later (in the deltoid muscle)a • Resume the maintenance dose or after the date of 1 month later (in either the deltoid or gluteal muscle) the scheduled dose aExcept for a maintenance dose of 234 mg.