International Journal of Psychiatry in Clinical Practice
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Post-marketing surveillance of sertindole Mondher Toumi To cite this article: Mondher Toumi (2002) Post-marketing surveillance of sertindole, International Journal of Psychiatry in Clinical Practice, 6:1, 33-35 To link to this article: http://dx.doi.org/10.1080/13651500215968
Published online: 12 Jul 2009.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [University of Lethbridge]
Date: 08 November 2015, At: 22:35
#
2002 Martin Dunitz Ltd International Journal of Psychiatry in Clinical Practice 2002 Volume 6 (Suppl 1) Pages S33 ± S35
S33
Post-marketing surveillance of sertindole MONDHER TOUMI
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
ICR ± Health Economics, Lundbeck SA, Paris, France
Correspondence Address Mondher Toumi MD, ICR ± Health Economics, Lundbeck SA, 37 Avenue Pierre 1er de Serbie, F-75008, Paris, France Tel: +33 1 5367 4200 Fax: +33 1 4723 4510 E-mail: [email protected]
The atypical antipsychotic drug, sertindole, like several other drugs, causes QT interval prolongation. Prolongation of the QT interval on the electrocardiogram has been associated with an increased risk of ventricular arrhythmia, including the more serious form, torsades de pointes, and is thus a safety concern for the authorities. In the case of sertindole, however, the available pharmacoepidemiological studies gathering data from about 10 000 patients documented the lack of increased risk associated to sertindole in comparison to other atypical antipsychotics. On the basis of these data, as well as non-clinical and clinical safety data, the CPMP expert group concluded that, although sertindole has the potential to prolong the QT interval, ``QT interval prolongation does not seem to be a reliable proxy for the risk of severe cardiac arrhythmias’’, and there are no clinical data suggesting that sertindole is more arrhythmogenic than are other atypical antipsychotics. To further substantiate this conclusion, two post-marketing surveillance studies have been initiated. One is a randomized comparison of sertindole and risperidone under normal conditions of use. Randomization minimizes selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. While the two drugs will be given in an open-label fashion, all safety data will be blinded and reviewed by an independent safety committee. The other study is an observational study that includes all patients prescribed sertindole who, for whatever reason, will not be included in the randomized study. In all, 10 000 patients are expected to take part in the studies, which will run for at least 1 year. (Int J Psych Clin Pract 2002; 6 (Suppl 1): S33 ± S35) Keywords sertindole post-marketing surveillance
INTRODUCTION
S
ertindole is an effective and well-tolerated antipsychotic drug.1 ± 4 It provides relief not only from the positive symptoms of schizophrenia but also from the negative symptoms. Patients who take sertindole are generally not burdened by extra-pyramidal symptoms or sedation, and serum prolactin levels are not significantly affected. Since sertindole causes QT interval prolongation and as this characteristic has long been linked with serious ventricular arrhythmias, including torsades de pointes, there was legitimate concern among regulatory authorities that sertindole could represent a serious cardiac risk to patients. In the face of evidence to the contrary, this concern with respect to sertindole was
schizophrenia atypical antipsychotic drugs
allayed and the European Committee for Proprietary Medicinal Products (CPMP) lifted the suspension of sertindole in October 2001, a decision that was ratified by the EU in June 2002. It was concluded that sertindole is no more arrhythmogenic than are many other atypical antipsychotic drugs. The CPMP decision was based on non-clinical and clinical studies of the safety and tolerability of sertindole, and on postmarketing studies comparing mortality rates and cardiac adverse event rates between sertindole and other atypical antipsychotics, including risperidone and olanzapine. Nonetheless, since sertindole does increase the QT interval, patients are required to undergo the sensible precaution of electrocardiographic monitoring prior to and during treatment, as stated in the drug’s summary of product characteristics (SPC). Such
S34
M Toumi
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
monitoring ensures that sertindole is not being prescribed to patients at high risk of ventricular arrhythmias. H. Lundbeck A/S has, in agreement with the CPMP, embarked on two large-scale, European, post-marketing surveillance (PMS) studies to further document the safety of sertindole. The two studies ± a comparative study and an observational study ± are being undertaken under the normal conditions of use of antipsychotic drugs. The studies began enrolment in July 2002 and the purpose of this article is to briefly outline the structure of the two studies. As part of the conditions for re-introducing sertindole, no patients will be prescribed sertindole without being included in one of these two studies. The studies will therefore generate safety data for every patient prescribed sertindole.
COMPARATIVE STUDY: SERTINDOLE RISPERIDONE One of the studies undertaken is a comparison of sertindole and risperidone. Since double-blind, randomized, controlled trials have already demonstrated the efficacy of sertindole, another trial assessing this parameter was not of interest. Instead, studies conducted under normal conditions of use were thought to be more likely to generate relevant safety data and to further document the low mortality risk of sertindole observed in clinical trials and post-marketing studies. Risperidone was chosen as the comparator because it has the longest market experience and because it is widely available across Europe; indeed, it is the most widely used atypical antipsychotic drug in the world today. Moreover, a large amount of efficacy and safety data is available on risperidone and regulatory safety concerns have not been raised regarding risperidone. Its clinical profile is also somewhat similar to that of sertindole in that both sertindole and risperidone require titration at the start of treatment. Risperidone also causes QT prolongation, although to a lesser extent than sertindole does.5 Unlike olanzapine, sertindole and risperidone do not induce sedation, anticholinergic side effects, type II diabetes, or excessive weight gain. The multinational study is randomized. All patients for whom sertindole or risperidone is an appropriate treatment and who meet the criteria set out in the national SPCs for both sertindole and risperidone are eligible for the study. Patients are being randomized to one of two parallel groups to avoid selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. Patients randomized to sertindole treatment are undergoing electrocardiographic monitoring according to the guidance given in the sertindole SPC. Since the aim of the study is to investigate the safety of sertindole under normal conditions of use, the study is only partially blinded; the drugs are prescribed in the usual, open-label
fashion, but an independent safety committee will evaluate cardiac and serious adverse events after these have been blinded. The open design ensures a high external validity of the result: the conclusion will be representative of the expected outcome under normal conditions of use of sertindole. The blinded assessment will ensure the objective review of the serious adverse events. The primary endpoint of the study is all-cause mortality, which is not biased by assessment methodologies or individual clinical judgement. Other endpoints are the incidence of cardiac adverse events, including arrhythmias (that lead to admission to hospital), cause-specific fatal events (such as cardiac deaths, suicide and non-suicide), admissions to hospital other than those related to patients’ psychiatric illness, and treatment duration. In all, approximately 10 000 patients will be enrolled, a number that is expected to provide 3800 patient-years of exposure to each drug. An extensive safety database will be generated by this study.
OBSERVATIONAL STUDY The other study is an observational study. Patients for whom sertindole is an appropriate treatment option but who for any reason do not participate to the comparative study will be entered into this study if they are prescribed sertindole. Thus, the study ensures that all patients who receive sertindole are included in the exhaustive postmarketing surveillance initiated by H. Lundbeck A/S. Essentially, the same eligibility criteria apply to this study as to the comparative study. The primary and secondary endpoints are also the same as in the comparative study.
EVALUATION Two independent committees ± a safety committee and a management committee ± will review the data from both studies. The safety committee will provide a blinded evaluation of the safety data while the management committee will also be able to classify the data according to treatment and will provide ongoing guidance on the organization and continuation of both studies. Specialties represented on the committees are epidemiology, cardiology, psychiatry, pharmacovigilance, statistics and internal medicine. For the comparative study, statistical analyses will include end-point analyses consisting of event rate ratios (adjusted for sex and age bands), calculated through Poisson regression with conventional confidence intervals, and also when relevant adjusted from interim analyses. Interim analyses will be conducted when a predefined number of deaths have occurred ± the procedure and timing being defined by the independent safety committee. The interim analysis will estimate the mortality rate for the primary endpoint and compare the
Post-marketing surveillance of sertindole
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
outcome against pre-specified boundaries using the Cox Proportional Hazards model. Reasons for withdrawal of treatment will be compared between treatment arms (w2 test). All demographic and baseline characteristics, treatment duration (reported by sex, age band and other relevant sub-groups) will be reported using descriptive statistics. Statistical analyses for the observational study will include a study end-point calculation of event rates with confidence intervals and, if the data allows, by sex and by age groups. Descriptive statistics will be provided for demographic and baseline characteristics, and for treatment duration by sex, age bands and other relevant subgroups. Extensive sensitivity analyses will be conducted for both studies to verify the robustness of the results.
LOGISTICS The studies are taking place across the European Union (EU) and have begun in the first wave of countries (UK, Germany, France, Finland, Norway, Spain, Belgium and Austria). A second wave comprising the remaining EU countries and Eastern European countries is to follow soon.
S35
CONCLUSION Sertindole is generally well tolerated by patients with schizophrenia. The two PMS studies described in this brief article will provide valuable comparative data on the safety of the drug, in particular on its cardiac safety and mortality risk. This exhaustive safety programme will accompany the re-introduction of Serdolect1 for patients with schizophrenia in Europe.
KEY POINTS . An estimated 10 000 patients will be enrolled in two sertindole PMS studies . One study is a randomized comparison of sertindole and risperidone (aim to include all sertindole treated patients in this study) . The other is an observational study to include sertindole treated patients not included in the comparative study . The primary end point of the studies is all-cause mortality
REFERENCES 1. Hale A, Azorin J-M, Kasper S, et al (2000) Sertindole improves both the positive and negative symptoms of schizophrenia: results of a phase III trial. Int J Psych Clin Pract 4: 55 ± 62. 2. Daniel DG, Wozniak P, Mack RJ, et al (1998) Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. Psychopharmacol Bull 34: 61 ± 9. 3. Tamminga CA, Mack RJ, Granneman GR, et al (1997) Sertindole in the treatment of psychosis in schizophrenia: efficacy and safety. Int Clin Psychopharmacol 12 (suppl 1:) S29 ± 35.
4. Zimbroff DL, Kane JM, Tamminga CA, et al (1997) Controlled, dose ± response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 154: 782 ± 91. 5. Haddad PM, Anderson IM (2002) Antipsychotic-related QTc prolongation, Torsade de Pointes and sudden death. Drugs 62(11): 1649 ± 1671.
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Post-marketing surveillance of sertindole Mondher Toumi To cite this article: Mondher Toumi (2002) Post-marketing surveillance of sertindole, International Journal of Psychiatry in Clinical Practice, 6:1, 33-35 To link to this article: http://dx.doi.org/10.1080/13651500215968
Published online: 12 Jul 2009.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [University of Lethbridge]
Date: 08 November 2015, At: 22:35
#
2002 Martin Dunitz Ltd International Journal of Psychiatry in Clinical Practice 2002 Volume 6 (Suppl 1) Pages S33 ± S35
S33
Post-marketing surveillance of sertindole MONDHER TOUMI
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
ICR ± Health Economics, Lundbeck SA, Paris, France
Correspondence Address Mondher Toumi MD, ICR ± Health Economics, Lundbeck SA, 37 Avenue Pierre 1er de Serbie, F-75008, Paris, France Tel: +33 1 5367 4200 Fax: +33 1 4723 4510 E-mail: [email protected]
The atypical antipsychotic drug, sertindole, like several other drugs, causes QT interval prolongation. Prolongation of the QT interval on the electrocardiogram has been associated with an increased risk of ventricular arrhythmia, including the more serious form, torsades de pointes, and is thus a safety concern for the authorities. In the case of sertindole, however, the available pharmacoepidemiological studies gathering data from about 10 000 patients documented the lack of increased risk associated to sertindole in comparison to other atypical antipsychotics. On the basis of these data, as well as non-clinical and clinical safety data, the CPMP expert group concluded that, although sertindole has the potential to prolong the QT interval, ``QT interval prolongation does not seem to be a reliable proxy for the risk of severe cardiac arrhythmias’’, and there are no clinical data suggesting that sertindole is more arrhythmogenic than are other atypical antipsychotics. To further substantiate this conclusion, two post-marketing surveillance studies have been initiated. One is a randomized comparison of sertindole and risperidone under normal conditions of use. Randomization minimizes selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. While the two drugs will be given in an open-label fashion, all safety data will be blinded and reviewed by an independent safety committee. The other study is an observational study that includes all patients prescribed sertindole who, for whatever reason, will not be included in the randomized study. In all, 10 000 patients are expected to take part in the studies, which will run for at least 1 year. (Int J Psych Clin Pract 2002; 6 (Suppl 1): S33 ± S35) Keywords sertindole post-marketing surveillance
INTRODUCTION
S
ertindole is an effective and well-tolerated antipsychotic drug.1 ± 4 It provides relief not only from the positive symptoms of schizophrenia but also from the negative symptoms. Patients who take sertindole are generally not burdened by extra-pyramidal symptoms or sedation, and serum prolactin levels are not significantly affected. Since sertindole causes QT interval prolongation and as this characteristic has long been linked with serious ventricular arrhythmias, including torsades de pointes, there was legitimate concern among regulatory authorities that sertindole could represent a serious cardiac risk to patients. In the face of evidence to the contrary, this concern with respect to sertindole was
schizophrenia atypical antipsychotic drugs
allayed and the European Committee for Proprietary Medicinal Products (CPMP) lifted the suspension of sertindole in October 2001, a decision that was ratified by the EU in June 2002. It was concluded that sertindole is no more arrhythmogenic than are many other atypical antipsychotic drugs. The CPMP decision was based on non-clinical and clinical studies of the safety and tolerability of sertindole, and on postmarketing studies comparing mortality rates and cardiac adverse event rates between sertindole and other atypical antipsychotics, including risperidone and olanzapine. Nonetheless, since sertindole does increase the QT interval, patients are required to undergo the sensible precaution of electrocardiographic monitoring prior to and during treatment, as stated in the drug’s summary of product characteristics (SPC). Such
S34
M Toumi
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
monitoring ensures that sertindole is not being prescribed to patients at high risk of ventricular arrhythmias. H. Lundbeck A/S has, in agreement with the CPMP, embarked on two large-scale, European, post-marketing surveillance (PMS) studies to further document the safety of sertindole. The two studies ± a comparative study and an observational study ± are being undertaken under the normal conditions of use of antipsychotic drugs. The studies began enrolment in July 2002 and the purpose of this article is to briefly outline the structure of the two studies. As part of the conditions for re-introducing sertindole, no patients will be prescribed sertindole without being included in one of these two studies. The studies will therefore generate safety data for every patient prescribed sertindole.
COMPARATIVE STUDY: SERTINDOLE RISPERIDONE One of the studies undertaken is a comparison of sertindole and risperidone. Since double-blind, randomized, controlled trials have already demonstrated the efficacy of sertindole, another trial assessing this parameter was not of interest. Instead, studies conducted under normal conditions of use were thought to be more likely to generate relevant safety data and to further document the low mortality risk of sertindole observed in clinical trials and post-marketing studies. Risperidone was chosen as the comparator because it has the longest market experience and because it is widely available across Europe; indeed, it is the most widely used atypical antipsychotic drug in the world today. Moreover, a large amount of efficacy and safety data is available on risperidone and regulatory safety concerns have not been raised regarding risperidone. Its clinical profile is also somewhat similar to that of sertindole in that both sertindole and risperidone require titration at the start of treatment. Risperidone also causes QT prolongation, although to a lesser extent than sertindole does.5 Unlike olanzapine, sertindole and risperidone do not induce sedation, anticholinergic side effects, type II diabetes, or excessive weight gain. The multinational study is randomized. All patients for whom sertindole or risperidone is an appropriate treatment and who meet the criteria set out in the national SPCs for both sertindole and risperidone are eligible for the study. Patients are being randomized to one of two parallel groups to avoid selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. Patients randomized to sertindole treatment are undergoing electrocardiographic monitoring according to the guidance given in the sertindole SPC. Since the aim of the study is to investigate the safety of sertindole under normal conditions of use, the study is only partially blinded; the drugs are prescribed in the usual, open-label
fashion, but an independent safety committee will evaluate cardiac and serious adverse events after these have been blinded. The open design ensures a high external validity of the result: the conclusion will be representative of the expected outcome under normal conditions of use of sertindole. The blinded assessment will ensure the objective review of the serious adverse events. The primary endpoint of the study is all-cause mortality, which is not biased by assessment methodologies or individual clinical judgement. Other endpoints are the incidence of cardiac adverse events, including arrhythmias (that lead to admission to hospital), cause-specific fatal events (such as cardiac deaths, suicide and non-suicide), admissions to hospital other than those related to patients’ psychiatric illness, and treatment duration. In all, approximately 10 000 patients will be enrolled, a number that is expected to provide 3800 patient-years of exposure to each drug. An extensive safety database will be generated by this study.
OBSERVATIONAL STUDY The other study is an observational study. Patients for whom sertindole is an appropriate treatment option but who for any reason do not participate to the comparative study will be entered into this study if they are prescribed sertindole. Thus, the study ensures that all patients who receive sertindole are included in the exhaustive postmarketing surveillance initiated by H. Lundbeck A/S. Essentially, the same eligibility criteria apply to this study as to the comparative study. The primary and secondary endpoints are also the same as in the comparative study.
EVALUATION Two independent committees ± a safety committee and a management committee ± will review the data from both studies. The safety committee will provide a blinded evaluation of the safety data while the management committee will also be able to classify the data according to treatment and will provide ongoing guidance on the organization and continuation of both studies. Specialties represented on the committees are epidemiology, cardiology, psychiatry, pharmacovigilance, statistics and internal medicine. For the comparative study, statistical analyses will include end-point analyses consisting of event rate ratios (adjusted for sex and age bands), calculated through Poisson regression with conventional confidence intervals, and also when relevant adjusted from interim analyses. Interim analyses will be conducted when a predefined number of deaths have occurred ± the procedure and timing being defined by the independent safety committee. The interim analysis will estimate the mortality rate for the primary endpoint and compare the
Post-marketing surveillance of sertindole
Downloaded by [University of Lethbridge] at 22:35 08 November 2015
outcome against pre-specified boundaries using the Cox Proportional Hazards model. Reasons for withdrawal of treatment will be compared between treatment arms (w2 test). All demographic and baseline characteristics, treatment duration (reported by sex, age band and other relevant sub-groups) will be reported using descriptive statistics. Statistical analyses for the observational study will include a study end-point calculation of event rates with confidence intervals and, if the data allows, by sex and by age groups. Descriptive statistics will be provided for demographic and baseline characteristics, and for treatment duration by sex, age bands and other relevant subgroups. Extensive sensitivity analyses will be conducted for both studies to verify the robustness of the results.
LOGISTICS The studies are taking place across the European Union (EU) and have begun in the first wave of countries (UK, Germany, France, Finland, Norway, Spain, Belgium and Austria). A second wave comprising the remaining EU countries and Eastern European countries is to follow soon.
S35
CONCLUSION Sertindole is generally well tolerated by patients with schizophrenia. The two PMS studies described in this brief article will provide valuable comparative data on the safety of the drug, in particular on its cardiac safety and mortality risk. This exhaustive safety programme will accompany the re-introduction of Serdolect1 for patients with schizophrenia in Europe.
KEY POINTS . An estimated 10 000 patients will be enrolled in two sertindole PMS studies . One study is a randomized comparison of sertindole and risperidone (aim to include all sertindole treated patients in this study) . The other is an observational study to include sertindole treated patients not included in the comparative study . The primary end point of the studies is all-cause mortality
REFERENCES 1. Hale A, Azorin J-M, Kasper S, et al (2000) Sertindole improves both the positive and negative symptoms of schizophrenia: results of a phase III trial. Int J Psych Clin Pract 4: 55 ± 62. 2. Daniel DG, Wozniak P, Mack RJ, et al (1998) Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. Psychopharmacol Bull 34: 61 ± 9. 3. Tamminga CA, Mack RJ, Granneman GR, et al (1997) Sertindole in the treatment of psychosis in schizophrenia: efficacy and safety. Int Clin Psychopharmacol 12 (suppl 1:) S29 ± 35.
4. Zimbroff DL, Kane JM, Tamminga CA, et al (1997) Controlled, dose ± response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 154: 782 ± 91. 5. Haddad PM, Anderson IM (2002) Antipsychotic-related QTc prolongation, Torsade de Pointes and sudden death. Drugs 62(11): 1649 ± 1671.
