Atypical Antipsychotics: Restless Legs Syndrome, Sleep Apnoea and Urinary Retention

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Overview

Atypical antipsychotics, also known as second generation antipsychotics, are used to treat mental disorders including schizophrenia, manic episodes associated with bipolar disorder, and in some cases, depression.
Currently there are nine different atypical antipsychotic agents with 112 products registered in Malaysia, namely olanzapine (32 products), risperidone (32), quetiapine (16), clozapine (9), aripiprazole (8), paliperidone (7), ziprasidone (4), asenapine (2), and amisulpride (2).


Background of Safety Issues


Restless Legs Syndrome1
Restless legs syndrome (RLS) is a sensory-motor disorder characterised by unpleasant leg sensations and an intense urge to move the legs. It occurs or worsens exclusively in the evening and is often associated with sleep disturbances and daytime sleepiness2.
The National Pharmaceutical Regulatory Agency (NPRA) has initiated a safety review to evaluate the risk of RLS with olanzapine-use following the recommendation by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC). NPRA subsequently extended the review to all atypical antipsychotics available in Malaysia.
A review of scientific literature suggested central dopamine dysfunctions as the plausible mechanism of RLS. A number of atypical antipsychotics with dopamine antagonism have been linked to RLS in literature case reports, including quetiapine, risperidone, clozapine, aripiprazole and asenapine. International reports of RLS suspected to be related to atypical antipsychotics have also been identified from the WHO global ADR database.


Sleep Apnoea3
Sleep apnoea is a respiratory disorder characterised by abnormal pauses in breathing or shallow breaths during sleep.
NPRA received new safety information from Health Canada on the risk of sleep apnoea with the use of atypical antipsychotics. Following the safety review on scientific literature, Canadian cases and international cases, Health Canada concluded that the available data suggested a possible link between the use of all atypical antipsychotics available in Canada and recommended an update of the product information for these products.


Urinary Retention4
Urinary retention is the risk of having difficulty urinating or not being able to fully empty the bladder. This can be an emergency that requires medical attention.
Health Canada’s safety review found evidence supporting a potential link between the use of atypical antipsychotics and the occurrence of urinary retention. Upon review of Canadian cases and those from published literature, it was noted that most patients recovered or were recovering from the side effects after stopping the antipsychotic medication (positive dechallenge). In some cases, urinary retention recurred after re-administration of the antipsychotic medication (positive rechallenge). These findings further support a potential link between the atypical antipsychotic and urinary retention.


Adverse Drug Reaction Reports5

  • Since year 1995, NPRA has received 1,671 ADR reports with 2,853 adverse events suspected of being linked to the nine registered atypical antipsychotics in Malaysia.

The most reported adverse events are tremor (89), salivary hypersecretion (77), weight increased (82), akathisia (62) and extrapyramidal disorder (51).

  • NPRA has received four (4) reports related to restless legs syndrome associated with olanzapine (2), risperidone and asenapine. There were also four (4) reports of urinary retention associated with clozapine (2), olanzapine and quetiapine.
  • NPRA has not received any reports of sleep apnoea associated with atypical antipsychotic use.

Advice for Healthcare Professionals

  • Atypical antipsychotics have been associated with cases of sleep apnoea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnoea, atypical antipsychotics should be prescribed with caution.
  • Inform patients about the signs and symptoms of restless legs syndrome, sleep apnoea and urinary retention. Advise patients to seek medical advice if the symptoms persist or worsen.

References:

  • European Medicines Agency (2017). PRAC Minutes of the meeting on 24-27 October 2016. EMA/PRAC/127425/2017.
  • Zucconi & Ferini-Strambi (2004). Epidemiology and clinical findings of restless legs syndrome. Sleep Medicine, Volume 5, Issue 3, 293 – 299.
  • Health Canada (2016). Summary Safety Review - Atypical antipsychotics - Assessing the Potential Risk of Sleep Apnoea.
  • Health Canada (2016). Summary Safety Review - Atypical antipsychotics - Assessing the Potential Risk of Urinary Retention.
  • The Malaysian ADR Database, NPRA [Accessed: February 2018]

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

 

National Pharmaceutical Regulatory Agency (NPRA)
Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia.
  • Email: npra@npra.gov.my
  • Phone: +603-7883 5400
  • Fax: +603-7956 2924, +603-7956 7075

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