ANNEX I LIST OF THE NAMES OF THE MEDICINAL PRODUCTS, MARKETING AUTHORISATION HOLDERS, PHARMACEUTICAL FORMS, STRENGTHS, ROUTE OF ADMINISTRATION, PACKAGING AND PACKAGE SIZES IN THE MEMBER STATE 1
SERTINDOLE CONTAINING MEDICINAL PRODUCTS WITH MARKETING AUTHORISATION IN THE EUROPEAN UNION Member State Austria Serdolect 4 mg Filmtablettten 4 mg film coated tablet blister Austria Serdolect 8 mg Filmtabletten 8 mg film coated tablet blister Austria Serdolect 12 mg Filmtabletten 12 mg film coated tablet blister Austria Serdolect 16 mg Filmtabletten 16 mg film coated tablet blister 2
Austria Serdolect mg Filmtabletten mg film coated tablet blister Austria Serdolect 24 mg Filmtabletten 24 mg film coated tablet blister Belgium Serdolect 4 mg film coated tablet blister Belgium polypropylen container Serdolect 8 mg film coated tablet blister polypropylen 3
Belgium container Serdolect 12 mg film coated tablet blister Belgium polypropylen container Serdolect 16 mg film coated tablet blister Belgium polypropylen container Serdolect mg film coated tablet blister polypropylen container 4
Belgium Serdolect 24 mg film coated tablet blister polypropylen container Serdolect 4 mg film coated tablet blister Serdolect 8 mg film coated tablet Not applicable since is not marketed Serdolect 12 mg film coated tablet blister Serdolect 16 mg film coated tablet blister 5
Serdolect mg film coated tablet blister Finland Finland Finland Ottiliavej 9 20 Copenhagen Ottiliavej 9 20 Copenhagen Ottiliavej 9 20 Copenhagen Serdolect 24 mg film coated tablet Not applicable since is not marketed Serdolect 4 mg film coated tablet blister polypropylen container Serdolect 8 mg film coated tablet Not applicable since is not marketed Serdolect 12 mg film coated tablet blister polypropylen container 6
Finland Finland Ottiliavej 9 20 Copenhagen Ottiliavej 9 20 Copenhagen Serdolect 16 mg film coated tablet blister polypropylen container Serdolect mg film coated tablet blister polypropylen container Finland Germany Germany Germany Ottiliavej 9 20 Copenhagen Serdolect 24 mg film coated tablet Not applicable since is not marketed Zerdol 4mg 4 mg film coated tablet blister Zerdol 8mg 8 mg film coated tablet blister Zerdol 12mg 12 mg film coated tablet blister 7
Germany Zerdol 16mg 16 mg film coated tablet blister Germany Zerdol mg mg film coated tablet blister Germany Zerdol 24mg 24 mg film coated tablet blister Germany Serdolect 4mg 4 mg film coated tablet blister 8
Germany Germany Serdolect 8mg 8 mg film coated tablet blister Serdolect 12 mg 12 mg film coated tablet blister Germany Serdolect 16mg 16 mg film coated tablet blister Germany Serdolect mg mg film coated tablet blister Germany Serdolect 24 mg 24 mg film coated tablet blister 9
Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect 4 mg film coated tablet blister Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect 8 mg film coated tablet blister Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect 12 mg film coated tablet blister Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect 16 mg film coated tablet blister Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect mg film coated tablet blister 10
Greece Lundbeck Hellas Kifisias 64 15125 Marousi Serdolect 24 mg film coated tablet blister Ireland Serdolect 4 mg film coated tablet blister polyproylene container Ireland Serdolect 8 mg film coated tablet blister Ireland polyproylene container Serdolect 12 mg film coated tablet blister 11
Ireland polyproylene container Serdolect 16 mg film coated tablet blister Ireland polyproylene container Serdolect mg film coated tablet blister polyproylene container 12
Ireland Serdolect 24 mg film coated tablet blister Italy polyproylene container Serdolect 4 mg film coated tablet blister Italy polypropylene container Serdolect 8 mg film coated tablet blister Italy polypropylene container Serdolect 12 mg film coated tablet blister 13
Italy polypropylene container Serdolect 16 mg film coated tablet blister Italy polypropylene container Serdolect mg film coated tablet blister polypropylene container 14
Italy Serdolect 24 mg film coated tablet blister Luxembourg Lundbeck S.A. 225 Avenue Molière B 10 Brussels Belgium polypropylene container Serdolect 4 mg film coated tablet blister Luxembourg Luxembourg Luxembourg Lundbeck S.A. 225 Avenue Molière B 10 Brussels Belgium Lundbeck S.A. 225 Avenue Molière B 10 Brussels Belgium Lundbeck S.A. 225 Avenue Molière B 10 Brussels Belgium Serdolect 12 mg film coated tablet blister Serdolect 16 mg film coated tablet blister Serdolect mg film coated tablet blister 15
Netherlands Serdolect 4 mg 4 mg film coated tablet blister polyproylene container Netherlands Serdolect 8 mg 8 mg film coated tablet blister Netherlands polyproylene container Serdolect 12 mg 12 mg film coated tablet blister polyproylene container 16
Netherlands Serdolect 16 mg 16 mg film coated tablet blister Netherlands polyproylene container Serdolect mg mg film coated tablet blister Netherlands polyproylene tablet container Serdolect 24 mg 24 mg film coated tablet blister Portugal polyproylene container Serdolect 4 mg coated tablet blister 17
Portugal Portugal Serdolect 12 mg coated tablet blister Serdolect 16 mg coated tablet blister Portugal Spain Spain Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Serdolect mg coated tablet blister Serdolect 4 mg film coated tablet blister Serdolect 8 mg film coated tablet blister 18
Spain Spain Spain Spain UK UK Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Lundbeck España Avda. Diagonal, 605, 9, 1ª 080 Barcelona Serdolect 12 mg film coated tablet blister Serdolect 16 mg film coated tablet blister Serdolect mg film coated tablet blister Serdolect 24 mg film coated tablet blister Serdolect 4 mg film coated tablet blister Serdolect 12 mg film coated tablet blister 19
UK Member State Serdolect 16 mg film coated tablet blister UK Serdolect mg film coated tablet blister
ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR SUSPENSION OF THE MARKETING AUTHORISATIONS PRESENTED BY THE EMEA 21
SCIENTIFIC CONCLUSIONS PRESENTED BY THE EMEA OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF SERTINDOLE CONTAINING MEDICINAL PRODUCTS Data from spontaneous adverse drug reactions reported in the first two Periodic Safety Update Reports suggested a relative risk of sudden or cardiac death higher for sertindole than for comparable compounds (risperidone and olanzapine). Analysis of data from the ADROIT database of UK spontaneous adverse drug reaction (ADR) reports showed that in terms of the number of reports of sudden unexplained death plus fatal cardiac arrhythmia as a percentage of the total reactions reported, sertindole differed from olanzapine and risperidone by several fold. Interim data from the EPOS study (pan European Post-marketing Observational Study) also suggested that sertindole had a significantly worse safety profile than comparable compounds. Furthermore the use of sertindole did not present advantages over the use of comparable compounds. Due to these data the Netherlands decided on 2 November 19 to suspend the marketing of sertindole containing medicinal products in its territory with effect from 1 December 19. The Netherlands referred the matter to the CPMP, under article 15a of Council Directive 75/319 as amended, on 2 November 19. The CPMP at their meeting of 22-23 June 1999 considered the matter and reached the following conclusions, based on the Assessment Reports prepared by the Rapporteur and the Co-Rapporteur. SAFETY The overall safety profile of sertindole was reviewed. The main safety concerns discussed were serious cardiac adverse effects, such as QT prolongation, arrhythmia and sudden death. Cardiac Adverse Effects QT prolongation Preclinical data Preclinical data on QT prolongation were reviewed. In vitro data show a prolongation of QT interval by sertindole, but this effect is less potent than for haloperidol. The in vivo data in beagle dogs show a small increase in QT interval at high dosages of sertindole, but effects are difficult to interpret due to marked changes in heart rate, possibly related to α1-receptor blocking properties of sertindole. An electrophysiological study comparing the effects of sertindole and risperidone in rabbit purkinje fibres was assessed. The results confirmed that sertindole has the potential to prolong the QT interval at concentrations that may be relevant for clinical doses. However, sertindole did not induce early after depolarisations (EADs), whereas risperidone did. EADs are thought to be precursors of Torsades de Pointes. The results of pre-clinical data indicate a difference in response between species. Their relevance to use in man is not clear. Clinical data Data from clinical trials and the EPOS study confirm that sertindole causes a definite and dose dependent increase in QT, which is more frequent and severe than with other antipsychotics. Analysis of these data shows that a significant proportion of patients (10-15%) with a normal baseline QT had a QT prolongation of more than 60 msec which was much higher than the placebo 22
or reference population (3%). When the patients with a borderline baseline QT were taken into account, still a substantial number of patients showed a prolongation between and 60 msec (clinical trials 6-13%, EPOS 18-36%). These results suggest an inverse relation between pretreatment QT and QT prolongation after treatment. In a significant number of patients (5-6%) the QT prolongation was above the limit at which concerns are raised about the potential for an active substance to induce arrythmias, including Torsade de Pointes, according to the document Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-cardiovascular Medicinal Products (CPMP/6/96). The following risk factors regarding QT prolongation in patients treated with sertindole were identified: increasing dose of sertindole, active substances known to affect the metabolism of sertindole, obesity and diabetes. Arrhythmia Clinical trials found that the rate of cardiac arrhythmia in sertindole treated patients was comparable to that in patients treated with haloperidol. Analysis of the EPOS data revealed that the frequency of arrhythmias in the sertindole cohort (3,5%) was higher than in the reference cohort (1,3%). However, if tachycardias were excluded the frequency was similar in sertindole and non-sertindole treated patients. The overall available post marketing surveillance (PMS) data do not indicate a high incidence of ventricular arrhythmias. However, due to the type of patients and the disease itself, data can often be missing and the true incidence of ventricular arrhythmia in a post registration population remains to be established. Mortality Analysis of clinical trials data suggest that sertindole is associated with an increased incidence of sudden cardiac deaths as compared to olanzapine and risperidone, although all cause mortality rates are comparable. In the UK there has been a much higher rate of spontaneous reporting of sudden unexplained death and fatal cardiac ADRs compared with other atypical antipsychotics. Although some of this difference could be explained by reporting bias, these data remain a cause for concern. The CPMP was also concerned by reports of fatal ADRs occurring elsewhere in Europe and by the characteristics of many of the reported cases, which were suggestive of a causal role for sertindole. Having considered the evidence available as a whole, the CPMP concluded that it is highly probable that sertindole is associated with increased mortality as a consequence of its effect in prolonging the QT interval. Other ADRs Apart from the cardiovascular adverse reactions discussed above the following adverse events were significantly different in the sertindole group compared to placebo: rhinitis, dizziness, postural hypotension, peripheral oedema, abnormal ejaculation, weight gain, dry mouth, dyspnoea and paresthesia.the incidence of extrapyramidal symptoms in the sertindole groups were comparable to that seen in the placebo groups. 23
Data from studies M95-372 and 973 The two clinical trials recently submitted by the MAHs (M95-372 and 973) provided similar data to that seen above. These studies are two comparative trials in which the efficacy and safety of sertindole were compared to that of risperidone. Both studies were stopped prematurely due to the withdrawal of the application for sertindole in the USA (M95-372) and to the suspension of the marketing of sertindole containing medicinal products in the European Union (973). Study M95-372 examined the efficacy and safety of sertindole compared to risperidone in patients with therapy resistant schizophrenia and study 973 in patients who were treatment naive or responsive. These studies reinforce that sertindole has unfavourable effects on QT interval. No new aspects emerged, except that study 973 included assessments of QT dispersion and did not detect any differences between sertindole and risperidone in this respect. However, the value of this parameter as a predictor of cardiotoxicity is still investigational and no conclusions can be drawn. In these studies a greater proportion of patients in the sertindole group withdrew prematurely due to ECG abnormalities, QT prolongation and tachycardia than in the risperidone group. EFFICACY From the data on efficacy it can be concluded that sertindole is effective in the treatment of schizophrenic patients. However, sertindole can not be used in acute situations, as it needs to be phased in over one to two weeks due to side effects especially postural hypotension. The effect of sertindole seems to be maintained over the time. The optimal dose is unclear but effect of higher doses (-24 mg/daily) seems more consistent. Results from studies M95-372 and 973 did not find statistical differences in efficacy between sertindole and risperidone. In study M95-372, in patients who were treatment resistant, the effect of risperidone tended to be larger, especially during the first few weeks, even though it was assumed that risperidone would not be effective in this population. In these studies neither drug showed consistently superior efficacy in the treatment of secondary negative symptoms. In both studies the doses were high: in M95-372 study 52% of patients were treated with mg/day of sertindole or more and in study 973 these dosages were used in 45% of patients. RISK-BENEFIT ANALYSIS Regarding safety, sertindole is associated with a dose dependent increase in QT and has the potential to cause cardiac arrhythmias, which can be fatal. Sertindole is associated with reports of sudden cardiac death and unexplained sudden death. The role of monitoring QT interval in clinical practice for the prevention of these serious adverse reactions is doubtful. Furthermore the feasability of regular ECG is questionable in terms of availability of equipment, reliability of QT interval measurement and acceptability on behalf of patients. Regarding efficacy, sertindole is effective in the treatment of schizophrenic patients but does not present a specific therapeutic benefit in relation to other antipsychotic agents. Furthermore sertindole seems to be more effective at higher doses whereas QT prolongation is dose dependent. 24
The s proposed, in view of the safety concerns associated to QT prolongation, to restrict the indication for sertindole. Their first proposal for an indication was in patients who have not tolerated other antipsychotics. During the oral explanation in the June 1999 CPMP meeting the s proposed to further amend the indication to patients who have failed to respond at least for two other antipshycotics or who have not tolerated other antipsychotics. However, these proposals were not supported by any clinical data in such a population. Therefore, the CPMP, based on present evidence, considered that sertindole containing medicinal products have an unfavourable risk/benefit balance. GROUNDS FOR SUSPENSION OF THE MARKETING AUTHORISATIONS Whereas - the Committee considered the referral made under article 15a of Council Directive 75/319/EEC as amended for sertindole containing medicinal products - the Committee agreed that there were concerns related to the safety profile of sertindole containing medicinal products regarding the risk of serious cardiovascular adverse reactions, such as prolongation of QT interval, sudden cardiac death and unexplained sudden death - the Committee agreed that sertindole containing medicinal products are effective in the treatment of schizophrenia, but do not present a specific therapeutic benefit in relation to comparable compounds and that sertindole containing medicinal products seem to be more effective at higher doses whereas QT prolongation is dose dependent - the Committee, based on present evidence, considered the risk/benefit balance of sertindole containing medicinal products to be unfavourable and concluded that these medicinal products should not be maintained on the market, the CPMP has recommended the suspension of the s for sertindole containing medicinal products (see Annex II) for one year period. 25