APPLYING ANTIPSYCHOTIC PHARMACOKINETICS TO BEST DOSING PRACTICES: DEPOT MEDICATIONS

APPLYING ANTIPSYCHOTIC PHARMACOKINETICS TO BEST DOSING PRACTICES: DEPOT MEDICATIONS

Objectives Review the kinetic parameters of depot antipsychotics Review loading strategies for those depot medications which can be loaded Describe how knowledge of plasma antipsychotic data can inform appropriate use of depot medications

The Value of Antipsychotic Plasma Levels

Concepts a. Plasma levels and not dose are the best predictors of antipsychotic response P450 genetics of patients are usually unknown Some patients are nonadherent Many patients receive concurrent medications that are P450 or PGP inhibitors or inducers b. Clinical studies provide one source of plasma level/response relationships c. For newer antipsychotics, PET scans provide data on plasma level thresholds to achieve 80% D 2 blockade

D 2 Antagonist: Receptor Occupancy Sweet Spot: 60%-80% Kapur S and Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? - A New Hypothesis. Am J Psych 2001;158(3):360-369.

D 2 Partial Antagonist: Receptor Occupancy Sweet Spot: 85%-100% Mamo D, et al. Differential Effects of Aripiprazole on D2, 5-HT2, and 5-HT1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study. Am J Psych 2007;164(9): 1411-1417.

Response and Tolerability Threshold Levels Data From Clinical Studies Data From Imaging Studies Response Threshold (ng/ml) Tolerability threshold (ng/ml) Level associated with 60% D 2 occupancy Level associated with 80% D 2 occupancy Haloperidol 3-5 18 20 1.2 2.0 Fluphenazine 0.8 1.0 2.7 2.8???? Risperidone + 9-OH Risperidone???? ~ 17 ng/ml 45-47 Olanzapine 23.2 176 ~ 20 ng/ml 70-78 Clozapine 350? 800-1000???? Meyer JM. A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes. CNS Spectrums 2014;19(5):432-38.

Levels and Adherence Clinicians grossly underestimate medication nonadherence. Using 70% as the threshold for medication adherence, 57% of chronic schizophrenia patients are nonadherent using MEMS cap technology, patient self-report is 5%, and physician estimate 7%. 1 Many patients characterized as treatment resistant have subtherapeutic plasma levels. 2 "The purpose of the present study was to determine the extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. Antipsychotic plasma levels were measured in 36 patients identified as having treatmentresistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range." 1. Byerly M, et al. Psychiatric Services 2007;58:844-847. 2. McCutcheon R., et al. Journal of Psychopharmacology 2015;29(8) 892-897.

Oral Dose-Plasma Level Relationships Meyer JM, et al. Psychopharmacology of Persistent Violence and Aggression. Psych Clin N Am 2016;39(4):541-556. Aripiprazole Clozapine Haloperidol Concentration (ng/ml) = 12 x oral dose (mg/d) Aripiprazole/Dehydroaripiprazole Ratio: 4.4 (range 3.6-5.0) Aripiprazole Dehydroaripiprazole 10 mg/d -> 126 ± 78 ng/ml 35 ± 4 ng/ml 20 mg/d -> 230 ± 193 ng/ml 46 ± 37 ng/ml 30 mg/d -> 400 ± 236 ng/ml 83 ± 18 ng/ml 40 year old male, 80 kg, clozapine/norclozapine ratio of 1.32 Concentration (ng/ml) = 1.08 x oral dose (mg/d) Concentration (ng/ml) = 0.67 x oral dose (mg/d) 325 mg -> 350 ng/ml (nonsmokers) 525 mg -> 350 ng/ml (smokers) (nonsmokers) (smokers) 40 year old female, 70 kg, clozapine/norclozapine ratio of 1.32 Concentration (ng/ml) = 1.32 x oral dose (mg/d) Concentration (ng/ml) = 0.80 x oral dose (mg/d) 265 mg -> 350 ng/ml (nonsmokers) 435 mg -> 350 ng/ml (smokers) Concentration (ng/ml) = 0.78 x oral dose (mg/d) 2 mg/d -> 1.57 ± 1.42 ng/ml 10 mg/d -> 7.79 ± 4.79 ng/ml (nonsmokers) (smokers)

Oral Dose-Plasma Level Relationships Fluphenazine Concentration (ng/ml) = 0.08 x oral dose (mg/d) Concentration (ng/ml) = 0.04 x oral dose (mg/d) (nonsmokers) (smokers) 22.9 mg -> 1.83 ± 0.94 ng/ml (nonsmokers) 20.4 mg -> 0.89 ± 0.43 ng/ml (smokers) Olanzapine Concentration (ng/ml) = 2.00 x oral dose (mg/d) Concentration (ng/ml) = 1.43 x oral dose (mg/d) 10 mg -> 20 ng/ml (nonsmokers) 14 mg -> 20 ng/ml (smokers) (nonsmokers) (smokers) Meyer JM, et al. Psychopharmacology of Persistent Violence and Aggression. Psych Clin N Am 2016;39(4):541-556. Risperidone + 9-OH Risperidone (active moiety) Active Moiety Concentration (ng/ml) = 7.00 x oral dose (mg/d) Risp/9-OH Risp Ratio: 0.2 (range 0.1-0.3) 2 mg/d -> C/D Ratio = 7.05 6 mg/d -> C/D Ratio = 7.15 10 mg/d -> C/D Ratio = 7.28 16 mg/d -> C/D Ratio = 6.95

Preparation Diluent Loaded Fluphenazine Decanoate Haloperidol Decanoate Aripiprazole Monohydrate Aripiprazole Lauroxil Preparations and Basic Kinetics Oral Supplementation Dosage T max (days) Steady State T 1/2 (days) Sesame Oil Yes -- 12.5-100 mg/2 weeks 0.3-1.5 14 Sesame Oil Yes -- 25-400 mg/4 weeks 3-9 21 Water No 14 days 300-400 mg/4 weeks 6.5-7.1 29.9 46.5 Water No 21 days 441-882 mg/4 weeks 882 mg/6 weeks 1064 mg/2 months 41 53.9 57.2 Olanzapine Pamoate Water Yes -- 150-300 mg/2 weeks OR 300-405 mg/4 weeks 7 30 Paliperidone Palmitate Paliperidone Palmitate 3-month Risperidone Microspheres Water Yes -- 39-234 mg/4 weeks 13 25-49 Water No -- 273-819 mg/12 weeks 30-33 84-95 (deltoid) 118-139 (gluteal) Water No 21 days 12.5-50 mg/2 weeks 21 3-6

Haloperidol and Fluphenazine Decanoate

US FDA Approval: 01/14/1986 Haloperidol Decanoate

Oral Haloperidol Concentration/Dose Relationships Mean Plasma Level (ng/ml) SD 2 mg 1 1.57 1.42 5 mg 2 2.2 0.9 10 mg 2 7.7 3.2 10 mg 3 7.79 4.79 20 mg 2 12.8 4.0 1. Kapur S, et al. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology 1997;131:148-52. 2. Van Putten T, et al. Neuroleptic Plasma Levels. Schiz Bulletin 1991;17(2):197-216. 3. Wei FC, et al. A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy. The Journal of Clinical Psychiatry. 1996;57:298-302.

D 2 Occupancy vs. Plasma Haloperidol Level D 2 Receptor Occupancy nmol/l 0 1.88 3.76 5.64 7.52 9.40 ng/ml Regenthal R, et al. Haloperidol serum concentrations and D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Int Clin Psychopharmacol 1997;12(5):255-261.

Global Improvement at the End of a Fixed Dose Haloperidol Study (n = 68) Plasma Level Range Mean Plasma Level (ng/ml) ± SD Very much improved or much improved on the CGI scale % Improved < 2 ng/ml 1.3 ± 0.5 1 out of 11 9% 2-5 ng/ml 3.2 ± 0.7 6 out of 14 43% 5-12 ng/ml 8.2 ± 1.6 22 out of 30 73% > 12 ng/ml 15.2 ± 2.7 5 out of 13 39% Midha KK, et al. Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia. J Psychiatr Neurosci 1994;19(4):254-264.

Probability of Adverse Effects by Plasma Haloperidol Level Midha KK, et al. Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia. J Psychiatr Neurosci 1994;19(4):254-264.

Typical Depots Basic Kinetics Drug Vehicle Dosage T max (days) T 1/2 (days) Single Dose T 1/2 (days) Multiple Dose Fluphenazine decanoate Sesame Oil 12.5-100 mg/ 2-6 weeks 0.3-1.5 6-9 14 Haloperidol decanoate Sesame Oil 25-400 mg/ 4 weeks 3-9? 21 Davis JM, et al. Depot antipsychotic drugs: place in therapy. Drugs 1994;47(5):741-773.

Haloperidol Dec 100 mg: Single Dose Kinetics Chang W-H, et al. Disposition of haloperidol and reduced haloperidol plasma levels after single dose haloperidol decanoate administration. Human Psychopharmacol 1995;10(1):47-51.

Haloperidol Decanoate: Conversion from Oral Studies using 10, 20, or 30 times the oral daily dose have been performed 20 times the oral daily dose FOR MONTHLY MAINTENANCE provided optimum plasma concentrations DURING THE EARLY PHASE OF TREATMENT Oral haloperidol bioavailability is 65% (range 60-70%) Example: pt on 10 mg/day x 30 days x 65% = 195 mg/month ~ 20 x oral daily dose Over time, may be able to decrease the maintenance dose once steady state is reached based on plasma level monitoring Jann et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinetics 1985;10:315-333.

100 mg Loading Study: 100 mg weekly x 4, 100 mg at weeks 6, 8, then 100 mg every 4 weeks starting wk 12 Weekly 100 mg IM x 4 Dose decreased to 100 mg IM monthly Oral Stopped, 1 st Weekly 100 mg Injection Given Jann MW, Wei FC, Lin HN, et al. Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20:73-86.

Haloperidol Dec Loading Study: Implications 1. 100 mg loaded weekly for 4 wks provides coverage equal to 10 mg/d; however, need oral coverage of 5 mg during the first 1-2 weeks to maintain levels comparable to 10 mg/d before the first injection Depending on patient acuity, one could opt to skip supplemental medication during the first week, or, if agitated/violent, give 5 mg/d PO or IM for 7 days after the first depot injection 2. If the patient requires 10 mg oral/d, the maintenance dose of 200 mg/4 wks should start 2 weeks after the 3rd weekly loading injection of 100 mg to achieve comparable plasma levels Jann MW, Wei FC, Lin HN, et al. Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20:73-86.

Haloperidol Dec Loading Study: Example A pt with schizophrenia refuses oral medications and is violent. He is loaded with haloperidol decanoate 200 mg IM weekly over 3 weeks with excellent response and no adverse effects. Question 1: What is the maintenance dose for this patient? Answer: Based on the long-term data from the Jann 1996 study, the maintenance dose is 2x the weekly loading dose. For this pt, it will be 400 mg. Since injections of > 3 cc (300 mg) are not tolerated, the monthly dose will be given as 200 mg IM every 2 weeks. Question 2: When is the maintenance dose started? Answer: Based on the kinetic data from the Jann 1996 study, the maintenance dose should start 2 weeks after the last loading injection. Jann MW, Wei FC, Lin HN, et al. Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20:73-86.

US FDA Approval: 06/20/1972 Fluphenazine Decanoate

Typical Depots Basic Kinetics Drug Vehicle Dosage T max (days) T 1/2 (days) Single Dose T 1/2 (days) Multiple Dose Fluphenazine decanoate Sesame Oil 12.5-100 mg/ 2-6 weeks 0.3-1.5 6-9 14 Haloperidol decanoate Sesame Oil 25-400 mg/ 4 weeks 3-9? 21 Davis JM, et al. Depot antipsychotic drugs: place in therapy. Drugs 1994;47(5):741-773.

Fluphenazine Levels and D 2 Occupancy Plasma Fluphenazine Level Striatal Occupancy 2.23 ng/ml 1 89% 4.4 ng/ml 2 92% R, 100% L 5.2 ng/ml 2 100% R, 97% L 6.13 ng/ml 1 91% 7.88 ng/ml 1 92% 11.38 ng/ml 1 96% 16.19 ng/ml 1 97% 1. Nyberg S et al. D(2) and 5-HT(2) receptor occupancy in high-dose neuroleptic-treated patients. IJNP 1998;1:95-101. 2. Coppens HJ et al. High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients. Biol Psychiatry 1991;29:629-634.

Probability Curves of Response and Disabling Side Effects by Plasma Fluphenazine Level Improvement Disabling side effects Response Threshold Van Putten T. Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia. J Psychiatr Neurosci 1994;19(4):254-264.

Fluphenazine Decanoate: Single-Dose Pharmacokinetics Ereshefsky L, Saklad SR, Jann MW. Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches. J Clin Psychiatry 1984;45 (suppl):50-58.

Loading Fluphenazine Decanoate: Levels on 50 mg/week Jann et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinetics 1985;10:315-333.

Fluphenazine Decanoate: Chronic Dosing (25 mg/2 wks) Marder SR. Plasma levels of fluphenazine in patients receiving fluphenazine decanoate. Relationship to clinical response. Br J Psych 1991;158:658-665.

Risperidone Microspheres and Paliperidone Palmitate

General Comments on Consta, Sustenna, Trinza Similar pharmacology for risperidone and 9-OH risperidone but very different kinetics between Consta and Sustenna Recommend that patient have a test dose of risperidone (for either Consta or Sustenna) or paliperidone (for Sustenna) if never received at any time previously Trinza (3-month injection of paliperidone palmitate) is only for those on Sustenna for at least 4 months

Active Moiety Plasma Levels After Single 25 mg LAI Risperidone Dose Long T Max > 3-4 weeks of oral coverage Risperidone + 9-OH Risperidone (ng/ml) 0 1 2 3 4 5 6 7 8 9 10 11 12 25-mg dose, N = 14. Data on file, Janssen Pharmaceutica Products, L.P. Time (wk)

Paliperidone Palmitate Aqueous-based suspension of nanomolecular size crystals O O N Paliperidone palmitate N N O N O Due to its extremely low water solubility, paliperidone palmitate slowly dissolves at the injection site and is enzymatically hydrolyzed to paliperidone Kinetics determined by particle size: Smaller Particles (monthly) Half-life: 25-49 days F T Max 13 days Larger Particles (3-month) Half-life: 84 95 days (deltoid) T Max 30-33 days 118 139 days (gluteal) INVEGA SUSTENNA and TRINZA [Prescribing Information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Paliperidone Concentrations: Sustenna Loading 40 Median Paliperidone Plasma Conc (ng/ml) 30 20 10 0 234 mg Deltoid injections* 156 mg 1 8 15 22 29 36 117 mg Estimated exposure window for 6-12 mg paliperidone ER Day *Initiation doses must be administered in the deltoid muscle for those coming from oral or who are on no active medication. Deltoid absorption is 28% greater than for gluteal injection. INVEGA SUSTENNA [PI]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Initial Sustenna Dosing Initiation dosing: from oral Maintenance doses q 4 wks Day 1 1 week later 1 month later 1 month later 234 mg Deltoid 156 mg Deltoid 37-234 mg Delt or Glut 37-234 mg Delt or Glut ± 2 days Flexible dosing window ± 1 week Flexible dosing window ± 1 week Flexible dosing window Initiation dosing from depot: When switching patients from long-acting injectable antipsychotics, give Sustenna in place of the next scheduled depot injection and then at monthly intervals. Dose is based on prior drug requirements. The one-week initiation dosing regimen is not required. Injection volumes are dose proportional: 234-1.5 ml, 156-1 ml, 117 mg - 0.75 ml, 78 mg - 0.5 ml, 39 mg - 0.25 ml INVEGA SUSTENNA [Prescribing Information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Trinza Dose Equivalence Stable Monthly Sustenna Dose Trinza Dose 78 mg 273 mg 117 mg 410 mg 156 mg 546 mg 234 mg 819 mg Injection of Trinza is given in lieu of next routine Sustenna dose Routine 3-month doses can be given ± 2 weeks from 3-month time INVEGA TRINZA [Prescribing Information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.

D 2 Occupancy vs. Plasma Moiety Level (Risperidone + 9-OH Risperidone) 50 mg Consta Remington G, et al. A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry 2006;163:396-401.

Active Moiety Plasma Levels From High Dose Consta (Risperidone + 9-OH Risperidone) Dose 12 Wk Study 1 52 Wk Study 2 26 Wk Study 3 25 mg 18.7 ± 9.23 18.1 ± 16.1 -- 50 mg 35.5 ± 18.7 32.2 ± 18.0 29.6 ± 15.8 75 mg 44.7 ± 20.6 47.4 ± 27.6 -- 100 mg -- -- 62.4 ± 38.0 1. Kane JM, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003;160:1125-32. 2. Fleischhacker WW, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry 2003;64:1250-7. 3. Meltzer HY, et al. A six month randomized controlled trial of long acting injectable risperidone 50 and 100mg in treatment resistant schizophrenia. Schizophr Res 2014;154:14-22. doi: 10.1016/j.schres.2014.02.015.

D 2 Occupancy vs. Plasma 9-OH Risperidone Level 234 mg Sustenna Arakawa R, Ito H, Takano A, et al. Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia. Psychopharmacology 2008;197:229-235. Epub 2007 Dec 6.

Active Moiety Plasma Levels From Sustenna (9-OH Risperidone) Dose Days (N) Mean ± SD Median 25 th Percentile 75 th Percentile 39 mg 92 (n=78) 10.2 ± 8.5 8.9 5.7 11.1 156 mg 92 (n=84) 21.0 ± 13.0 18.6 10.8 25.5 234 mg 92 (n=88) 28.4 ± 14.9 27.0 16.1 35.1 Pandina GJ, Lindenmayer JP, Lull J, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 2010;30:235-244. doi: 10.1097/JCP.0b013e3181dd03.

Aripiprazole Monohydrate (Maintena)

Aripiprazole Monohydrate Approved in February 2013 Lyophilized powder of aripiprazole monohydrate crystals with mean particle size of 1 10 μm (primarily 2 4 μm) The particles are poorly soluble, resulting in slow and prolonged dissolution and absorption. Administered in aqueous suspension Oral coverage required for 14 days Dosage adjustments for 2D6 and 3A4 inhibitors Cannot be used with potent 3A4 inducers Meyer JM. CNS Spectrums 2013.

Aripiprazole Oral Dose and Plasma Levels Mean Plasma Level By Dose (ng/ml) Aripip Dehydro 10 mg 126 ± 78 35 ± 4 20 mg 230 ± 193 46 ± 37 30 mg 400 ± 236 83 ± 18 Sparshatt A, et al. J Clin Psych 2010; 71(11):1447-1456.

Aripiprazole Monohydrate Kinetics 400 mg dose achieves steady state levels equivalent to 20 mg oral Meyer JM. CNS Spectrums 2013.

Aripiprazole Monohydrate: Missed Doses If the second or third doses are missed: If more than 4 weeks and less than 5 weeks have elapsed since the last injection, administer the injection as soon as possible. If more than 5 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 14 days with the next administered injection. If the fourth or subsequent doses are missed: If more than 4 weeks and less than 6 weeks have elapsed since the last injection, administer the injection as soon as possible. If more than 6 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 14 days with the next administered injection. Maintena (Aripiprazole Monohydrate) Package Insert. Otsuka 2015

Maintena Dose Adjustments Patients Taking 400 mg of ABILIFY MAINTENA CYP2D6 Poor metabolizers CYP2D6 Poor metabolizers taking concomitant CYP3A4 inhibitors Patients Taking 400 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors CYP2D6 and CYP3A4 inhibitors CYP3A4 inducers Patients Taking 300 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors CYP2D6 and CYP3A4 inhibitors CYP3A4 inducers Adjusted Dose 300 mg 200 mg 300 mg 200 mg Avoid Use 200 mg 160 mg Avoid Use Maintena [Prescribing Information]. Otsuka USA

Aripiprazole Lauroxil (Aristada)

Aripiprazole Lauroxil Approved in October 2015 Lyophilized powder of aripiprazole lauroxil crystals The particles are poorly soluble, resulting in slow and prolonged dissolution and absorption. Administered as aqueous suspension. Due to long half-life, 4 week, 6 week and 8 week dosing available Oral coverage required for 21 days Different missed dose and CYP adjustment rules than Maintena Aristada (Aripiprazole Lauroxil) Package Insert. Alkermes 2017

Aripiprazole Lauroxil: Dosing Equivalence Oral Aripiprazole Dose ARISTADA Dose Intramuscular Site 10 mg per day 441 mg per month Deltoid or Gluteal 15 mg per day 662 mg per month 882 mg every 6 weeks 1064 mg every 2 months Gluteal 20 mg or higher per day 882 mg per month Gluteal Aristada (Aripiprazole Lauroxil) Package Insert. Alkermes 2017

Simulated Average Aripiprazole Concentrations The box represents the 75th and 25th percentiles, the line within each box marks the median, the whiskers indicate the 10th and 90th percentiles, and the dots represent the 5th and 95th percentiles. Hard ML, et al. Poster presented at the 16th International Congress on Schizophrenia Research, San Diego, California, March 24 28, 2017.

Simulated Mean Aripiprazole Concentration Time Profiles FDA Center For Drug Evaluation and Research Application Number 207533orig1s000 Clinical Pharmacology and Biopharmaceutics Reviews for NDA #: 207533; Proposed Brand Name: ARISTADA; Generic Name: Aripiprazole Lauroxil

Aripiprazole Lauroxil: Plasma Levels After Last Dose Hard ML, et al. Poster presented at the 16th International Congress on Schizophrenia Research, San Diego, California, March 24 28, 2017.

Aripiprazole Lauroxil: Missed Dose Guidelines Dose of Patient s Last Injection No Oral Supplementation Required Length of Time Since Last Injection Supplement with 7 Days Oral Aripiprazole Supplement with 21 Days Oral Aripiprazole Monthly 441 mg 6 weeks > 6 and 7 weeks > 7 weeks Monthly 662 mg 8 weeks > 8 and 12 weeks > 12 weeks Monthly 882 mg 8 weeks > 8 and 12 weeks > 12 weeks 882 mg every 6 weeks 8 weeks > 8 and 12 weeks > 12 weeks 1064 mg every 2 months 10 weeks > 8 and 12 weeks > 12 weeks Aristada (Aripiprazole Lauroxil) Package Insert. Alkermes 2017

Aristada Dose Adjustments Concomitant Medicine Dose Change * Strong CYP3A4 Inhibitor Strong 2D6 Inhibitor Both Strong CYP3A4 and Strong 2D6 Inhibitor CYP3A4 Inducers Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: No dose adjustment required. Avoid use for patients at 662 mg, 882 mg, or 1064 mg dose. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. No dose adjustment for 662 mg, 882 mg, or 1064 mg dose; increase the 441 mg dose to 662 mg. * For the 882 mg dose administered every 6 weeks and the 1064 mg administered every 2 months, the next lower strength should be 441 mg administered monthly. Aristada (Aripiprazole Lauroxil) Package Insert. Alkermes 2017

Summary 1. Depot medications offer most schizophrenia patients their best chance at stability 2. Plasma antipsychotic levels are the best guide to the extent of patient medication exposure. Many treatment resistant patients are nonadherent or simply underdosed. Oral meds: trough levels are obtained before the morning dose, approximately 12 hours after the QHS dose Depot meds: trough levels are obtained the last few days of the injection cycle 3. Kinetics determine which agents can be loaded and the appropriate loading strategies to achieve levels comparable to the desired oral equivalents