Application for the Inclusion of New Medications for the WHO Formulary

Transcription

1 17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009 Application for the Inclusion of New Medications for the WHO Formulary 1. Summary Statement of the Proposal for Inclusion The WHO formulary for psychiatric drugs is very sparse. It includes only one drug for depression Amitriptyline. This is an older drug and is not often used in developed countries today. The list for antipsychotic drugs is little better. It includes chlorpromazine, fluphenazine and haloperidol. These are all older drugs and while effective in treating psychotic disorders they have such unpleasant side effects that many patients refuse to take them We propose inclusion of new drugs with fewer side effects. 2. Name of the Focal Point in WHO Submitting or Supporting the Application. 3. Name of the Organization Supporting this Application. The World Fellowship for Schizophrenia and Allied Disorders supports this application. 4. International Nonproprietory Name(s) (INN, generic name) of the Medicine(s). We are proposing the inclusion of 6 antipsychotic and 3 antidepressant medications. Antipsychotic Medications clozapine olanzapine risperidone quetiapine aripiprazole ziprasidone Antidepressive Medications Although there are now 22 different antidepressants in 8 different classes of drugs (Preskorn, 1999) we selected 3 that are frequently used. fluoxetine paroxetine sertraline 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) 6. International availability sources, if possible manufacturers We were unable to trace the availability of the following medications internationally. All are available in the United States and, we think, in Canada and Europe.

2 Antipsychotic Medications clozapine olanzapine risperidone quetiapine aripiprazole ziprasidone Antidepressive Medications fluoxetine paroxetine sertraline Maker Sandoz; Ivax; Mylan; Zeneth Goldline Pharmaceuticals. Lilly Janssen; SmithKline Beecham Zeneca Otsuka America; BristolMeyers Squibb Pfizer Lilly SmithKline Beecham Pfizer; Roerig; Pratt 5. Individual Medicine or Example of Therapeutic Group These are individual medications for two disorder groups. 6. Public Health Relevance Schizophrenia, a psychotic disorder, has a prevalence of 1.4 to 4.6 per 1000 and incidence rates of from 0.16 to 0.42 per 1000 worldwide (Jablensky, 2000). Another study in the USA found a one-year prevalence for schizophrenia and schizophreniform disorders of 1.0% for all ages (Narrow, Rae. Robins & Regier, 2002). Abou-Saleh et al.(2001) obtained a prevalence of 0.7% for adults in the United Arab Emirates. In terms of disability-adjusted life years (DALYs) schizophrenia was number 8 on a long list of diseases affecting people from 18 to 54 years of age. Schizophrenia affects females and males alike, although females develop the disorder somewhat later and seem to have a better outcome. The lifetime risk of developing depression is approximately 15% worldwide although rates vary greatly from one country to another. One study found a one-year prevalence of 4.5% for a wide age range and both genders (Narrow et al., 2002). Abou-Saleh and associates (2001) obtained a rate of 3.4% in the United Arab Emiraes. Lifetime and annual prevalence estimates for other countries are as follows: Canada, 9.6%, 5.2%; France, Germany, 9.2%, 5.0%; Italy, 12.4%, NA; Korea, 2.9%, 2.3%; Lebanon, 19%, NA; New Zealand, 11.6%, 5.8%; Puerto Rico, 4.3%, 3.0%, Taiwan, 1.5%, 0.8%, United States, 5.2%, 3.0%. The Global Burden of Disease Study (Murray & Lopez, 1997) found that using the disability-adjusted life year (DALY) depression ranked number 4. The risk for suicide is much higher for people who are depressed. Of people with severe depression 15% commit suicide (Hirschfeld et al., 1997). Depression affects adults, adolescents and children. Across the lifespan, only infants are spared. In general, more women than men develop depression. 7. Treatment Details Antipsychotic Medications Recommended Dose Range (mg. per day) Clozapine Olanzapine Risperidone 2-8 Quetiapine Aripiprazole Ziprasidone These dose ranges are from American Psychiatric Association, 2003.

3 Antidepressive Medications Therapeutic Dose Range (mg. per day) Fluoxetine Paroxetine Sertraline Source: Depression Guideline Panel, Summary of Comparative Effectiveness in a Variety of Clinical Settings. Antipsychotic Medications The effectiveness of the drugs listed above in preventing relapse compared with placebo has been amply demonstrated. Superior effectiveness was demonstrated in a metaanalysis with six studies carried out by Leucht and associates (2003). However, when the new antipsychotics are compared with older, typical, antipsychotics, the results are somewhat different. The same authors made this comparison with 11 studies. The control in each case was haloperidol. The newer drugs were significantly better. Clozapine did better in 3 of 5 trials, olanzapine was better in 7 of 8 trials and risperidone was better in 6 of 6 trials. Geddes and associates (2000) also conducted a meta-analysis of many of the same studies. They obtained essentially the same results as Leucht et al. A recent study with 4 atypicals (olanzapine, quetiapine, risperidone, ziprasadone) had similar results when newer drugs were compared with an older antipsychotic, perphenazine (Lieberman, et al. 2005). Only olanzapine performed better than the control. It should be noted that in this study drop-out rates were very high placing results in uncertainty. Rabinowitz et al. (2001) found olanzapine and risperidone superior to conventional antipsychotics after 24 months. Aripiprazole was not included in these studies, but several studies of that drug have had comparable results. Trifiro et al. (2005) examined antipsychotic prescribing patterns in Italy from 1999 to They noted a rapid increase in prescribing atypicals. They also noted that medication adherence was better for atypicals. Hugenholtz and associates (2004) looked at antipsychotic medication switching in a large hospital in the Netherlands. They found that patients initially on typical medication were more likely to switch than those initially on atypical medications. Switching is commonly carried out when there is a poor response to treatment or adverse side effects have appeared. Atypicals cost more than typicals, but apparently there are some savings because patients are more likely to be adherent with atypicals and thus are less likely to require expensive rehospitalization (Glazer, 1998). Clozapine is especially important because it is effective with about one-third of cases who are not helped with other antipsychotic medications. Antidepressant Medications When an anti-depressant is prescribed for moderate or severe depression it should be an SSRI, because SSRIs are as effective as tricyclic anti-depressants and their use is less likely to be discontinued because of side effects. This quote is from an update published on December 6, 2004 by the United Kingdom National Institute for Clinical Excellence (NICE). In one sentence it makes a case for the addition of the drugs listed above, all of which are SSRIs. Preskorn (1999) has noted that SSRIs are now the most often prescribed antidepressants in the United States. 9. Summary of Comparative Evidence on Safety. All psychiatric medications have some side effects. The list below is remarkable in the kinds of side effects it has or does not have. Among the extrapyramidal side effects is akathisia which is especially troubling for patients and one of the main reasons for

4 discontinuing medication. The atypicals listed below, except for risperidone, do not cause akathisia in most patients, although it does appear in a few. Even for risperidone the effects are mild. Weight gain is a problem for several of the drugs, but it does not appear for aripiprazole or ziprasidone. A major side effect for clozapine is aggranulocytosis. This blood condition occurs in about 1 patient per 1000, and is therefore, quite rare, but because it may result in death patients who take clozapine must have their white blood cell counts checked at regular intervals, typically weekly in the early stages of treatment. Most health authorities change the blood tests to every two weeks or once a month after several months of early treatment. Apart from weight gain and glucose and lipid abnormalities in 4 of the drugs, the side effect profile is highly favorable and is much more favorable than for older typical antipsychotic drugs. Side Effects Extrapyramidal Side Effects/ Prolactin Weight Glucose Lipid Tardive Dyskinesia Elevation Gain Abnormalities Abnormalities Clozapine Olanzapine Risperidone Quetiapine Aripiprazole Ziprasidone QTc Sedation Hypotension Anticholinergic Prolongation Side Effects Clozapine Olanzapine Risperidone Quetiapine Aripiprazole Ziprasidone Note: O = not present; = degree of side effect. Source: American Psychiatric Association, Antidepressive Medications As may be seen in the table below, the side effect profile for the three antidepressant drugs listed is highly favorable. It is much more favorable than the older triclyclic drugs. Side Effects Anticholinergic Drowsiness Insomnia/ Hypo- Cardiac Weight Agitation tension Arrhythmia Gain Fluoxetine Paroxetine Sertraline Note: 0 = not present; 2 = moderate severity Source: Depression Guideline Panel, 1993.

5 10. Summary of Available Data on Comparative Cost and Cost-Effectiveness The International Drug Price Indicator Guide provided information on the following drugs. Prices are in US dollars. Clozapine BDS 50 Tab-Cap Median price: 0.59 Low: 0.24 High 1.31 Risperidone BDS 20 Tab-Cap Median price: 0.70 Low: High: 1.19 Quetiapine USA 100 Tab-Cap Annual cost is $2781 to $3176 in the United States. This was not listed in the IDPI Guide. Fluoxetine BDS 100Tab-Cap Median price: 0.02 Low: 0.01 High: 0.09 Paroxetine BDS 30 Tab-Cap Median price: 1.14 Low: 0.95 High: 1.34 The other drugs were not listed in the guide. 11. Summary of Regulatory Status of the Medicine The drugs listed above have all been approved by the United States Food and Drug Administration. 12. Availability of Pharmacopoeial Standards We made use of the American Psychiatric Association (2003). Practice guideline for the treatment of patients with schizophrenia, Second Edition, but other national formularies are available, but not on the internet, and thus, not available to us. 13.Proposed Text for the WHO Model Formulary 24.1 Medicines used in psychotic disorders Clozapine 100mg. Olanzapine Risperidone 20 mg. Quetiapine 100 mg. Aripiprazole Ziprasidone References Medicines used in depressive disorders Fluoxetine 100 mg. Paroxetine 30 mg. Sertraline Abou-Saleh, M. T., Ghubash, R., & Daradkeh, T. K. (2001). Al Ain community psychiatric survey. I. Prevalence and socio-demographic correlates. Social Psychiatry and Psychiatric Epidemiology, 36, American Psychiatric Association (2003). Practice guideline for the treatment of patients with schizophrenia, Second Edition. American Psychiatric Association Press. Depression Guideline Panel (1993). Depression in primary care: Vol. 2. Treatment of major depression. Rockville, MD: Agency for Health Care Policy & Research. Geddes, J., Freemantle, N., Harrison, P., et al. (2000). Atypical antipsychotics in the treatment of schizophrenia systematic overview and meta-regression analysis. British Medical Journal, 321,

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