Long-Acting Antipsychotic Injections

Depot Antipsychotic injections Active Ingredient Brand name Peak levels Duration of action Steady state Flupentixol dec. Depixol® 7-10 days 3-4 weeks 10-12 weeks Fluphenazine dec. Modecate® 6-48 hours 1-3 weeks 6-12 weeks Haloperidol dec. Haldol® 3-9 days 6 weeks Pipothiazine palmit. Piportil® 9-10 days 4-6 weeks 8-12 weeks Zuclopenthixol dec. Clopixol® 4-9 days 2-4 weeks Clopixol and depixol are formulated with thin vegetable oil (fractionated coconut oil) Modecate, haldol and piportil are formulated with sesame oil

Test Doses Depot antipsychotic injections are long acting injections so side-effects are likely to be long lived Test with low initial dose to assess likely side-effects and tolerability to the oil used to formulate the injection. Write test dose in the right place of chart…. Depot injections are rarely associated with anaphylaxis, but it is recommended that the first and second doses are given in a clinic where adrenaline is available.

Maintenance Doses Start with low doses Use lowest effective dose Use longest possible recommended interval to reduce the number of potentially painful injections As it takes longer for depot injections to reach steady state blood levels, allow sufficient time to elapse before changing doses

How Is Risperdal Consta ® Different to Other Depots? Encapsulated micro-spheres. The drug is not stable in the solution. Dose can not be assured if part vials are administered. Administer only full vials. Long Teflon® coated needle to ensure IM administration. It requires refrigeration. If out of fridge for 20 min shelf life is reduced to 7 days. Allow to warm to room temperature 20 min prior to injection. Can be administered into the deltoid site

Paliperidone – potential benefits & convenience No cold chain Reduced wastage Prefilled syringe No reconstitution Monthly injection Frees up valuable nursing resource Patient preference? No need for oral supplementation More acceptable for patients? No post-injection monitoring

Paliperidone – dosing & indication Broad dose range 50, 75, 100, 150 mg (~ 25, 37.5, 50, 75 mg Risperidone LAI) Small volume of injection 0.5, 0.75, 1.0, 1.5 mL Deltoid and gluteal administration Deltoid quicker steady state (see later) Greater patient choice “Normalisation” of injection process

Paliperidone – efficacy, safety & tolerability Tmax 13 days gradual increase in plasma levels Half-life 25-49 days (dose dependant) No sudden drop-off in plasma levels Aqueous injection Less risk of hypersensitivity, nodules, pain? Early onset of action Efficacy seen from Day 8 Limited hepatic metabolism Low risk of CYP450 drug-drug interactions

Paliperidone – Deltoid vs Gluteal profile Background: The aim of this study was to compare the PK profile of paliperidone palmitate 100 mg eq. administered into the deltoid (n=24) or gluteal muscle (n=25). Methods: In this multiple-dose, open-label, parallel-group study, patients with schizophrenia were randomized to receive four consecutive injections (Days 1, 8, 36 and 64). Results: A total of 49 patients with schizophrenia were enrolled and 42 (86%) patients completed the study. The median plasma concentration–time profile of paliperidone after IM administration of paliperidone palmitate 100 mg eq. in the deltoid muscle was consistently higher compared with IM injection in the gluteal muscle. The relative exposure of paliperidone after the fourth IM injection was approximately 30% (90% CI=100.56; 168.93) and 20% (90% CI=93.09; 154.69) higher for Cmax and AUCτ, respectively, in the deltoid muscle compared with the gluteal muscle After four injections, median AUC∞ was similar for both injection sites Conclusion: Paliperidone palmitate 100 mg eq., had an increased AUCτ, and higher Cmax when injected into the deltoid versus gluteal muscle, although similar tmax and AUC∞ were noted for both injection sites. Deltoid administration – higher Cmax and AUCτ, but similar tmax and AUC∞ 1. Xeplion® EU SmPC; 2. Cleton et al. Poster no. PI-75 presented at ASCPT: Orlando, April 2–5, 2008 9

MAINTENANCE REGIMEN (1 month after 2nd initiation dose) INITIATION REGIMEN 1 month later +/- 7 days 1 month later +/- 7 days Day 1 Day 8 +/- 2 days 75 mg eq. (recommended*) Deltoid/gluteal† 75 mg eq. (recommended*) Deltoid/gluteal† 150 mg eq. Deltoid 100 mg eq. Deltoid This slide summarizes the recommended dosing strategy for Xeplion® Several different dosing strategies were used in the early clinical trials of Xeplion® Based on a 5000 patient simulation (and the results from the clinical trials) the most effective, or optimized, dosing strategy was established1 The dosing of Xeplion® is straightforward The summary of product characteristics (SmPC) recommended administration is an injection of Xeplion® 150 mg eq. into the deltoid muscle on Day 1, followed by a deltoid injection of 100 mg eq. on Day 82 Subsequent doses can be administered into either the deltoid or gluteal muscle, with a recommended monthly maintenance dose of 75 mg eq.; some patients may benefit from lower or higher doses within the recommended range of 25−150 mg eq. based on individual patient tolerability and/or efficacy2 The 25 mg eq. dose will not be available in the UK A flexible dosing window exists for the second initiation dose (Day 8) of ±2 days and scheduled monthly maintenance doses ±1 week2 No oral supplementation is necessary2 This initiation regimen uses doses that are suitable for all patients, including those who are stable, and should not be limited to those who are experiencing an acute exacerbation of symptoms1 References Gopal et al. Curr Med Res Opin 2010;26:377–387 Xeplion® EU SmPC Dose range** 25–150 mg eq. Deltoid/gluteal† Dose range** 25–150 mg eq. Deltoid/gluteal† *Recommended monthly dose **Some patients may benefit from lower or higher doses based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper range †A switch from gluteal to deltoid (and vice versa) should be considered in the event of injection site pain (if discomfort is not well tolerated).It is also recommended to alternate between left and right sides Xeplion® EU SmPC; Gopal et al. Curr Med Res Opin 2010;26:377–387 10

Xeplion®: Product summary Risperdal Consta Xeplion® 2 weekly injection Monthly injection Requires cold storage No cold chain 3 weeks delay Fast Onset Oral Supplementation No oral Supplementation 3 available doses 4 available doses 19 Steps to Inject Inject and go