Letter: Z

Zonisamide is licensed for use in monotherapy or as an adjunct for the treatment of partial seizures with or without secondary generalisation.

It is important that epilepsy remains well-controlled during pregnancy.

There is limited evidence regarding the safety of zonisamide use in pregnancy, with data provided by a small number of studies and case series/reports which collectively describe the outcomes of 616 exposed pregnancies.

Although the limited available evidence does not suggest that zonisamide is a major teratogen, data are conflicting and further studies are required to allow for a more accurate risk assessment. Weight loss is a recognised side effect of zonisamide, and some studies have indicated a possible association between zonisamide use in pregnancy and neonates that are small for gestational age at delivery. Although the available data do not clearly indicate increased risks of other adverse pregnancy or fetal outcomes following maternal zonisamide use in pregnancy, these data are highly limited and higher quality studies are required before a more accurate safety assessment can be provided. Additionally, no studies have investigated the risk of longer-term adverse outcomes such as childhood neurodevelopmental impairment.

Case series have described low Apgar score, hyperbilirubinemia, poor feeding/GI disturbance, and sedation following exposure to zonisamide during pregnancy. However, confounding due to concomitant medication exposure is likely. Use of any centrally acting drug throughout pregnancy or near delivery may be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should be planned in a unit with neonatal intensive care facilities.

Therapeutic use of zonisamide can cause metabolic acidosis, therefore pregnant women should be monitored for metabolic acidosis and treated as per the non-pregnant patient. Neonates of women treated with zonisamide should be monitored for possible transient metabolic acidosis following delivery.

Although not predicted from the recognised pharmacology of zonisamide, it is unknown whether use prior to conception or during pregnancy may impact upon maternal folate status. UK guidelines state that women who take any anti-seizure medication should be prescribed high-dose folic acid (5mg/day).

More research is required to define the pregnancy safety profile of zonisamide. Pregnant women and women of childbearing potential should be made aware of the limited data for most pregnancy outcomes, and highly limited data regarding exposure in late pregnancy. Zonisamide should only be used during pregnancy if there is no suitable alterative antiseizure medication (ASM) with a more favourable pregnancy safety profile. In view of the limited human pregnancy data, close monitoring of mother and fetus should be considered following zonisamide use in pregnancy. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Zolpidem is a hypnotic benzodiazepine receptor agonists (HBRAs) licensed for the short-term treatment of debilitating or distressing insomnia.

Zopiclone is a hypnotic benzodiazepine receptor agonists (HBRAs) licensed for the short-term treatment of debilitating or distressing insomnia.

CLINICAL SUMMARY
Teratogenicity/Fetotoxicity
Human data do not provide clear evidence of an increased risk of adverse fetal effects.

Evidence-base
Approximately 2,200 published pregnancy exposures, occurring at various stages of pregnancy.

Benefit-risk
Influenza in pregnancy is associated with adverse maternal and fetal outcomes. Zanamivir should not be withheld where clinically indicated.

Clinical recommendations
• Zanamivir is generally preferred over oseltamivir in pregnancy due to its low systemic absorption following inhalation
• Use with caution in women with asthma or COPD.

DETAILED SUMMARY: Zanamivir is an inhaled neuraminidase inhibitor used in the treatment of influenza infection (licensed for use within 48 hours of the first symptoms), for post-exposure prophylaxis in at-risk groups when influenza is circulating in the community, and in exceptional circumstances to prevent influenza in a pandemic. Currently, zanamivir is not recommended for prophylaxis against seasonal influenza.

The available data relating to zanamivir exposure in human pregnancy do not indicate increased risk of adverse pregnancy outcome but are too limited to rule out such a risk. Systemic absorption of zanamivir after inhalation is low and the risk of adverse fetal effects is therefore expected to be lower than any hypothetical risk posed by systemically administered neuraminidase inhibitors. Due to the established risks of influenza infection during pregnancy, zanamivir should not be withheld if indicated.

Exposure to zanamivir at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors which independently increase the risk of adverse pregnancy outcome may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.