Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Serdolect (Lundbeck)
4 mg, 12 mg, 16 mg and 20 mg tablets
Approved indication: schizophrenia
Australian Medicines Handbook section 18.2

Sertindole, an atypical antipsychotic drug, was marketed overseas in the 1990s (see 'New antipsychotic medications' Aust Prescr 1999;22:81-3). In 1998 the drug was withdrawn from the European market because of concerns that it could cause fatal arrhythmias. It returned to the market several years later after a review of its safety.

Sertindole blocks dopamine D2, alpha1 adrenergic and serotonin 5HT2 receptors. It has no significant anticholinergic effects and little effect on serum prolactin.

Although sertindole is well absorbed, the absorption is slow. Most of the dose is metabolised and then slowly excreted in the faeces. Severe hepatic impairment is a contraindication. The metabolism involves cytochrome P450 2D6 and 3A so there are potential interactions with drugs such as fluoxetine and erythromycin. Coadministration with inhibitors of P450 3A is contraindicated. The half-life of sertindole varies, because of interindividual variability in metabolism, but averages about three days. While it is suitable for once-daily dosing, there is a delayed onset of action so sertindole is not suitable for emergency treatment of psychosis.

There have been several trials of sertindole and these have been assessed in reviews by the Cochrane Collaboration. The first review included a placebo-controlled study and two comparisons with haloperidol involving a total of 1104 patients with schizophrenia. After 40 days the 54 patients given sertindole 20 mg had improved on a range of rating scales compared to the 48 patients randomised to placebo. The number of patients who needed to be treated for one to be 'very much improved' was approximately eight (confidence interval 4–41, 95% confidence interval). Lower doses were not significantly better than placebo. One of the comparisons with haloperidol only lasted for a few weeks, but the other continued for one year. After eight weeks the scores on the positive and negative symptoms scale (PANSS) were similar for both drugs. Although the mean improvement in the PANSS scores after a year was greater for sertindole, this difference was not statistically significant.1

The second review attempted to compare sertindole with other atypical antipsychotics but only included two low quality comparisons with risperidone. These studies involved 508 patients, but only lasted for 12 weeks. There was no clear difference in efficacy.2

The extrapyramidal adverse effects of sertindole were similar to those of placebo and less than with haloperidol.1 Sertindole caused less akathisia and parkinsonism than risperidone, but some of the patients had been given high doses of risperidone.2

Both reviews reported on prolongation of the QTc interval on the ECG. More patients taking sertindole had QTc prolongation than those taking placebo, haloperidol or risperidone.1,2 All patients should have an ECG at baseline before treatment as a prolonged QTc interval is a contraindication. ECG monitoring is mandatory during treatment, particularly around the time of changes in dose. Prolongation of the QTc interval is an indication to reduce or stop treatment. Many drugs can prolong the QTc interval, and they should not be used by patients taking sertindole. In addition to regular monitoring of the ECG, patients need to be checked for hypokalaemia and hypomagnesaemia. These electrolyte disturbances are contraindications to treatment with sertindole.

As sertindole blocks alpha1 adrenergic receptors it can cause postural hypotension. Treatment should therefore begin at a low dose and be increased slowly.

Patients taking sertindole are likely to put on weight. In trials where patients took 24 mg daily for 12 months, 21% gained at least 15% of their baseline weight.

Other adverse effects which occur significantly more often with sertindole than placebo include dizziness, paraesthesia, peripheral oedema and abnormal ejaculation. The safety of sertindole in pregnancy and lactation is uncertain.

Considering the concerns about safety, 8600 patients who had been treated with sertindole were followed up in a company-sponsored study. There were 3819 person-years of exposure with 35 deaths including 11 from cardiac causes and eight suicides.3 The all-cause mortality rate was 0.92 per 100 person-years of exposure. Cardiovascular and metabolic diseases (including diabetes) were associated with a higher risk of premature cardiac or unexplained death. Sertindole is therefore contraindicated in patients with cardiovascular disease.

An open-label prospective study followed approximately 10 000 patients treated with sertindole or risperidone. Although there was no significant difference in suicide, cardiac mortality was higher with sertindole. There were 31 deaths from cardiac causes in the sertindole group and 12 in the risperidone group.4

Although sertindole has been back on the European market for several years there are many limitations to its use. In view of the safety concerns sertindole should only be used by patients who cannot tolerate or do not respond to other antipsychotic drugs.

manufacturer provided the product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.