New deltoid administration for risperidone

Long-acting injectable risperidone is now available for deltoid intramuscular injection.1

The use of long-acting injectable antipsychotics is one of the many strategies to improve medication compliance among schizophrenic patients. Depot preparations have many advantages, including:

• Improved adherence and the prevention or delay of relapse;^2,3
• Early identification of non-adherence;⁴  
• Clear attribution of cause of relapse or non-response;⁴  
• Regular interactions between patient and healthcare provider;⁴  and
• Improved global functioning.⁴

Depot medication also avoids first-pass metabolism, thereby producing predictable and stable plasma levels, as well as avoiding abrupt discontinuation of treatment if injection is missed. Studies have shown this route of administration to be preferred by many patients,⁵ with patients less likely to discontinue medication for any reason.^6,7

Risperdal Consta (risperidone intramuscular injection) is the first second-generation antipsychotic to become available in a depot preparation. Results from the Switch to Risperidone Microspheres (StoRMi)⁸ study demonstrated long term use (18 months) significantly improves the symptoms of schizophrenia. Symptom improvement was measured by the Positive and Negative Syndrome Scale (PANSS), with 47% of patients demonstrating a 20% or more reduction in PANSS total scores.⁸

Several studies have shown that Risperdal Consta is associated with much reduced discontinuation rates compared to oral risperidone.^7,9-11 Adherence categorised as ‘always’ was as high as 85.6% in Australian patients over a 12 month follow-up period.¹² The low discontinuation rates and high adherence seen with Risperdal Consta may be the result of improving insight,¹³ reducing side effects¹⁴ and simple treatment regimes using bi-weekly injections.

The low discontinuation rates seen with Risperdal Consta translate to reduced rates of relapse. In an open label, multicentre, two-year trial comparing the long term efficacy of Risperdal Consta to oral quetiapine (Seroquel), significantly fewer patients in the Risperdal Consta group discontinued the study compared to patients in the quetiapine group. Furthermore, when compared to quetiapine, Risperdal Consta was associated with a significantly lower risk of relapse.¹⁵

Long term symptomatic remission with Risperdal Consta were analysed in the StoRMi study. Of the 529 patients receiving 50 mg Risperdal Consta bi-weekly, 53.6% of patients at endpoint (18 months) met severity criteria for remission, compared to only 22.3% at baseline. Of those who had met remission criteria at six months, 93.7% achieved sustained remission at endpoint. Remission was defined as achieving a score of ≤ 3 on all 8 items of the PANSS scale for more than 6 months.⁸

Originally licensed for gluteal intramuscular administration, Risperdal Consta is now available for deltoid administration. The recommended dose for adults is 25 mg administered intramuscularly bi-weekly. Higher doses (37.5 mg) may benefit some patients; however, the maximum dose should not exceed 50 mg every 2 weeks. The preparation and mixing of Risperdal Consta is identical for both gluteal and deltoid administration.¹

The current available data from two multicentre, open label studies involving stable chronic schizophrenia patients show that deltoid administration of Risperdal Consta is bioequivalent to gluteal muscle administration, with similar safety data and tolerability.^16,17,20

One study investigated the pharmacokinetics and bioavailabilty of Risperdal Consta administered into the deltoid muscle by way of two treatment panels. Panel 1 comprised randomised single injections of Risperdal Consta into the gluteal muscle (25 mg; treatment A) and deltoid muscle (37.5 mg; treatment B) separated by an 85 day observation period. Panel two comprised randomised administration of Risperdal Consta 50 mg as a single injection into the gluteal muscle (treatment C) and deltoid muscle (treatment D), also separated by an 85 day observation period.^16,17,20

All four treatment arms had similar plasma concentration-time profiles of the active Risperdal Consta fraction. The median time to reach maximal concentration was approximately 30 days, regardless of injection site or dose administered. The median half-life of the active antipsychotic fraction averaged 2-4 days for all treatments. Deltoid administration was bioequivalent, with respect to peak and total exposure, to gluteal administration.^16,17,20

Safety data and tolerability of the long-acting injectable risperidone was evaluated in both studies. The second study included 53 patients with schizophrenia previously treated with 25 mg or 37.5 mg Risperdal Consta administered into the gluteal muscle and who clinically required a higher dose (37.5 or 50 mg respectively). Subjects received either 37.5 mg or 50 mg respectively administered into the deltoid muscle. Over the study duration (eight weeks), those initially receiving 37.5 mg could have their dose increased to 50 mg and those initiated on 50 mg could have their dose reduced to 37.5 mg, dependant on clinical evaluation.^17,20

In both studies, Risperdal Consta was safe and well tolerated irrespective of administration site, dose and whether administered as single or multiple sequential injections. The incidence of treatment emergent adverse events were low, with headache and nasopharyngitis the most frequent.^16,20 The majority of subjects did not experience injection site reactions. Where these did occur, most were mild in nature and did not result in any withdrawals from the study.^16,17,20 Serious adverse events occurred in 10 (6%) subjects in study one^16,20 and two subjects (4%) in study two,¹⁷ which were considered to be unrelated to the study drug by the investigators. Both studies showed high completion rates which were comparable between the two.²⁰

The deltoid muscle is a preferential site for intramuscular injection for many female patients¹⁸ and, in a survey of 891 physicians and nurses,¹⁹ 67% agreed deltoid administration would reduce social embarrassment compared to gluteal administration. Deltoid administration also alleviates the need for a screened off area and allows face-to-face contact.¹⁹ Hence deltoid administration of Risperdal Consta offers all the advantages of a long-acting injectable antipsychotic while providing increased acceptance and convenience compared to gluteal administration.^18,19

References

1. Product information: Risperdal Consta. North Ryde, NSW: Janssen-Cilag Pty Ltd; 5 March 2009.
2. Davis JM, Matalon L, Watanabe MD, Blake L. Depot antipsychotic drugs: Place in therapy. Drugs. 1994; 47(5): 741-73.
3. Mentschel CC, Leucht SM, Kane JM. Depot-drugs may reduce relapses in schizophrenic outpatients: A meta-analysis [Abstr. NR191]. 156th Annual Meeting of the American Psychiatric Association (APA) Abstract Book. San Francisco, USA: 17-22 May 2003; p.71.
4. Adams C, Fenton MKP, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry. 2001; 179: 290-9.
5. Walburn J, Gray R, Gournay K, Quraishi S, David AS. Systematic review of patient and nurse attitudes to depot antipsychotic medications. Br J Psychiatry. 2001; 179: 300-7.
6. Moller HJ, Llorca PM, Sacchetti E, Martin SD, Medori R, Parellada E. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Int Clin Psychopharmacol. 2005; 20(3): 121-30.
7. Kissling W, Heres S, Lloyd K, Sacchetti E, Bouhours P, Medori R, et al. Direct transition to long-acting risperidone – analysis of long term efficacy. J Psychopharmacol. 2005;19(5 Suppl):15-21.
8. Llorca PM, Sacchetti E, Lloyd K, Kissling W, Medori R. Long-term remission in schizophrenia and related psychoses with long-acting risperidone: Results obtained in an open-label study with an observation period of 18 months. Int J Clin Pharmacol Ther. 2008; 46(1): 14-22.
9. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353(12): 1209-23..
10. Emsley R, Medori R, Koen L, Oosthuizen PP, Niehaus DJ, Rabinowitz J. Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: A preliminary study. J Clin Psychopharmacol.  2008; 28(2): 210-3.
11. Fleischhacker WW, Eerdekens M, Karcher K, Remington G, Llorca PM, Chrzanowski W, 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(10): 1250-7.
12. Hustig H, Lambert T, Emmerson B, Povey M, Jacobs A, Methven C, et al.  Improvements in illness severity and functioning in Australian schizophrenia patients treated with risperidone long-acting injection (RLAI) for 12 months. Poster presented at: 15th European Congress of Psychiatry (AEP); Madrid, Spain: 17-21 March 2007.
13. Gharabawi GM, Lasser RA, Bossie CA, Zhu Y, Amador X. Insight and its relationship to clinical outcomes in patients with schizophrenia or schizoaffective disorder receiving long-acting risperidone. Int Clin Psychopharmacol. 2006; 21(4): 233-40.
14. Saleem P, Firmino H, Psiquiatria S, et al. Young patients (18-30 years) with schizophrenia and schizoaffective disorder: Results of direct switching to long-acting injectable risperidone (StoRMi trial) [Poster 352]. Poster presented at: 12th Biennial Winter Workshop on Schizophrenia (WWS); Davos, Switzerland: 7-13 February 2004.
15. Medori R, Wapenaar R, de Arce R, Rouillon F, Gaebel W, Cordes J, Eriksson L, et al. Relapse prevention and effectiveness in schizophrenia with risperidone long-acting injectable (RLAI) versus quetiapine [Poster NR4094]. Poster presented at: 161st Annual Meeting of the American Psychiatric Association (APA); Washington DC, USA: 3-8 May 2008.
16. Thyssen A, Ning X, Herben V, Rusch S, Kushner S, Kusumaker V, et al. Pharmacokinetics of long-acting injectable risperidone injected in deltoid muscle compared to gluteal muscle injection in subjects with schizophrenia [Poster NR4003]. Poster presented at: 161st Annual Meeting of the American Psychiatric Association (APA); Washington DC, USA: 3-8 May 2008.
17. Ning X, Thyssen A, Quiroz J, Kushner S, Rusch S, Herben V, et al. Tolerability and safety of long-acting injectable risperidone in chronic schizophrenia subjects using deltoid muscle as an alternative injection site [Poster NR4004]. Poster presented at: 161st Annual Meeting of the American Psychiatric Association (APA); Washington DC, USA: 3-8 May 2008.
18. Cocoman A, Murray J. Intramuscular injections: A review of best practice for mental health nurses. J Psychiatr Ment Health Nurs. 2008; 15(5): 424-34.
19. Geerts P, Bloem S, Van Bulck A. Deltoid administration of long-acting antipsychotics: Physician and nurse attitudes [Poster WCP3864]. Poster presented at: 14th World Congress of Psychiatry (WPA); Prague, Czech Republic: 20-25 September 2008.
20. Thyssen A, Rusch S, Kushner S, Quiroz J, Kusumakar V, Herben V, et al. Long-acting injectable risperidone in the deltoid compared with the gluteal muscle [Poster WCP3887]. Poster presented at: 14th World Congress of Psychiatry (WPA); Prague, Czech Republic: 20-25 September 2008.