Intramuscular Preparations of Antipsychotics Uses and Relevance in Clinical Practice
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Drugs 2003; 63 (5): 493-512 REVIEW ARTICLE 0012-6667/03/0005-0493/$33.00/0 © Adis International Limited. All rights reserved. Intramuscular Preparations of Antipsychotics Uses and Relevance in Clinical Practice A. Cario Altamura, Francesca Sassella, Annalisa Santini, Clauno Montresor, Sara Fumagalli and Emanuela Mundo Department of Psychiatry, Department of Clinical Sciences ‘Luigi Sacco’, University of Milan, Milan, Italy Contents Abstract . 493 1. Different Antipsychotic Formulations: Mechanisms of Action and General Pharmacokinetic Considerations . 494 2. Long and Short Acting Intramuscular Preparations . 495 2.1 Types of Preparations and Therapeutic Indications . 495 2.2 Adverse Effect Profiles . 497 2.3 Switching Patients from Oral to Depot Antipsychotic Therapy . 498 3. Intramuscular Preparations of Typical Antipsychotics . 499 3.1 Haloperidol Decanoate . 499 3.2 Fluphenazine Enanthate and Decanoate . 500 3.3 Clopenthixol Decanoate . 500 3.4 Zuclopenthixol Decanoate . 501 3.5 Flupenthixol Decanoate . 501 3.6 Perphenazine Enanthate and Decanoate . 502 3.7 Pipotiazine Palmitate and Undecylate . 502 3.8 Fluspirilene . 503 4. Intramuscular Preparations of Atypical Antipsychotics . 503 4.1 Olanzapine . 503 4.2 Risperidone . 505 4.3 Ziprasidone . 506 5. Conclusions . 507 Abstract Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called ‘depot’, are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classi- 494 Altamura et al. cal compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine en- anthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, espe- cially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formu- lations of atypical antipsychotics are not yet widely available. 1. Different Antipsychotic Formulations: risperidone, olanzapine, quetiapine and zipra- Mechanisms of Action and General sidone) with high affinity for 5-HT2A receptors, but [1] Pharmacokinetic Considerations also for D1 and D2 receptors. These pharmaco- dynamic properties are likely to be responsible for Antipsychotic drug treatment was introduced their higher efficacy particularly on the negative/ into clinical psychiatry in the 1950s with chlor- anergic/depressive dimension of schizophrenia.[2,3] promazine. Since then, molecules of different On the other hand, it should be noted that a meta- chemical structures, ranging from tricyclic pheno- analysis completed on 52 randomised trials com- thiazines to thioxanthenes, butyrophenones, diben- paring atypical with conventional antipsychotics zoxazepines, substituted benzamides, and ben- suggested that when the dose was less than 13 zisoxazole derivatives have been used in the mg/day of haloperidol (or equivalent), atypical an- treatment of psychotic disorders. In addition, the new ‘atypical’ antipsychotics, developed after the tipsychotics had no benefits in terms of efficacy or [4] successful re-introduction of clozapine, have been overall tolerability compared with typical com- developed and employed widely for the treatment pounds. of major psychoses. Antipsychotics have been always available in These drugs were developed to overcome limi- both oral and parenteral formulations. In the 1960s tations mainly due to extrapyramidal side-effects long-acting or ‘depot’ formulations of typical an- (EPS) of typical antipsychotics which are dopa- tipsychotic drugs were added for clinical use by mine D2 antagonists. They are a heterogeneous parenteral route. Depot antipsychotics are effec- group of compounds (amisulpride, clozapine, tive and can be safely used, and they may confer a Adis International Limited. All rights reserved. Drugs 2003; 63 (5) Intramuscular Preparations of Antipsychotics 495 small benefit over oral compounds on the global preparations is preferred over oral medication outcome of the patient.[5] Most of them are synthe- when patients are not co-operative and require sised by esterification of the active drug to a long medication with a faster onset of action and good chain fatty acid and are subsequently dissolved in bioavailability.[15] a vegetable oil.[6] Depot treatment of psychotic In this article we review the uses and advan- outpatients offered some advantages when com- tages of short- and long-acting intramuscular pared with conventional formulations of the same preparations of antipsychotics, taking into account compounds, that is better compliance and bioavail- recent advances in this field, such as the develop- ability,[7,8] and they may be used in the mainte- ment intramuscular preparations for the atypical nance treatment of psychotic patients, usually after antipsychotics risperidone, olanzapine and zipra- clinical stabilisation with oral treatment.[9] sidone. The attitudes of long-term psychiatric patients It should be noted that in the more recent liter- towards depot antipsychotic medication is gener- ature there is paucity of data on depot formulations ally positive, although future randomised, control- of typical antipsychotics. This is probably because led trials should include satisfaction as an outcome of the growing interest in novel compounds seen measure.[10,11] The pharmacokinetic profiles show as a more effective treatment in the long-term man- prolonged times to reach peak plasma concentra- agement of psychotic disorders, with a favourable tions, as well as extended elimination half-lives tolerability profile.[17] especially after multiple injections.[12] However, even when the active molecule is the same, there 2. Long and Short Acting can still be differences in reaching the peak con- Intramuscular Preparations centration depending on the vehicle of esterifica- tion used, as in the case of fluphenazine enanthate 2.1 Types of Preparations and [13-15] and decanoate. Therapeutic Indications Short-acting intramuscular preparations of an- tipsychotics are particularly suitable for the man- Intramuscular formulations of antipsychotics agement of acute psychotic symptoms, agitation can be subdivided into two groups on the basis of and aggressive behaviour or delirium.[16] This in- their pharmacokinetic features: dication is supported by the fact that intramuscular • short-acting preparations (time to peak plasma formulations bypass the gastrointestinal tract and concentration 30 minutes); the first-pass metabolism, being immediately ac- • long-acting or depot preparations (half-life tive. Rapid tranquillisation with intramuscular ranging from 3.5 to 21 days) [see table I]. Table I. Summary of the pharmacokinetic properties of depot intramuscular antipsychotics Drug Doses (mg) Administration interval t1⁄2 tmax Clopenthixol decanoate 50–600 2-4 weeks 19 days 4–7 days Perphenazine enanthate 25–200 2 weeks 4–6 days 2–3 days Pipothiazine palmitate 25–400 4 weeks 15–16 days 12–24 hours Haloperidol decanoate 20–400 4 weeks 21 days 3–9 days Flupentixol decanoate 10–50 4 weeks 8 days 3–7 days Fluspirilene 2–6 1 week 7 days 24–72 hours Fluphenazine decanoate 12.5–100 6 weeks 14.3 days 8–10 hours Fluphenazine enanthate 12.5–100 6 weeks 3.5–4 days 2–3 days Zuclopenthixol decanoate 50–800 2-4 weeks 19 days 1 week Risperidone 25–75 2 weeks t1⁄2 = elimination half-life; tmax = time to peak-plasma concentration. Adis International Limited. All rights reserved. Drugs 2003; 63 (5) 496 Altamura et al. Short-acting intramuscular formulations are the administration of lower doses of the same used to manage a variety of acute psychotic states drug.[29] On the basis of what has been reported in and symptoms. Short-acting