The Malaysian Health Authority-National Pharmaceutical Regulatory Agency (NPRA), Ministry of Health Malaysia released the following new drug safety alerts during the month of June.

Restriction of domperidone use in pediatric patients less than 12 years of age

Risk of oculogyric crisis associated with metoclopramide use (a reminder)

 

Restriction of domperidone use in pediatric patients less than 12 years of age

Domperidone is a medicine which is used in the treatment of nausea and vomiting (ant-emetic drug) caused by other drugs. This drug is also used to treat Parkinson’s Disease. Domperidone exerts its anti-emetic effect through antagonism of dopamine receptors (dopamine antagonist) in the gut and the chemoreceptor trigger zone present in the central nervous system. Domperidone also shows some effects like increasing lower oesophageal pressure, improves antroduodenal motility and accelerates gastric emptying by increasing the movements or contractions of the stomach and bowel.

Benefit-Risk assessment for domperidone use in children (age: <12 years)

Domperidone shows a favorable benefit-risk profile in the context of relieving nausea and vomiting symptoms in adult group of population. This assessment is based on the evident safety and efficacy data obtained from the studies conducted in the adult population. However, the benefit-risk profile for the use of this drug for the same intended indications in the children of age less than 12 years is not assessed due to lack of adequate data for evaluation. In the year 2014, European Medicines Agency (EMA) reviewed the safety of domperidone and domperidone-containing combination products due to its association with the following significant safety concerns:

-Risk of serious and potentially life-threatening cardiovascular adverse effects such as ventricular arrhythmias and sudden cardiac death

Also, due to Insufficient data on the efficacy and safety of domperidone in children group, EMA had requested the marketing authorization holders (drug manufacturers) to perform a study for confirmation of efficacy and safety in children group.

A randomized controlled study was performed by the manufacturers as per EMA request. In the year 2019, the results of the study showed that domperidone is not much effective in showing its intended therapeutic effect in the children group of patients (Lack of drug efficacy). There is no significant difference in efficacy of domperidone in comparison to group of patients treated with placebo (a dummy drug). This led to the identification of an “un-favorable benefit-risk profile for domperidone in pediatric patients” (children of age less than 12 years).

In response to this, the marketing authorization holders of domperidone has updated their product information documents (package information leaflets) to reflect this safety information-restricted use of domperidone in in pediatric patients (children of age less than 12 years).

Advice for Healthcare Professionals:

Domperidone should not be used in infants and children less than 12 years of age who weighs less than 35 kg due to lack of efficacy evidence in this population.

Domperidone is contraindicated in the following group of patients:

• Patients with known existing prolongation of cardiac conduction intervals
• Patients with significant electrolyte imbalances or disturbances or underlying cardiac diseases
• Patients with concomitant use of drugs which are having QT-prolonging potential or drugs which are CYP3A4 inhibitors.

Be cautious and alert on the risk of significant and serious cardiac adverse drug reactions associated with the use of domperidone.

Domperidone should be taken at the lowest effective dose for the shortest duration possible. The usual maximum treatment period should not exceed one (1) week. 

 

Risk of oculogyric crisis associated with metoclopramide use (a reminder)

Metoclopramide is also a dopamine receptor antagonist which acts centrally in blocking dopamine receptors. This medicine is generally used for the prevention of nausea and vomiting associated with chemotherapy or radiotherapy and symptomatic treatment of nausea and vomiting in adults.  Metoclopramide is also used in treating the symptoms of slow stomach emptying (gastroparesis) in patients with diabetes. It increases the movements or contractions of the stomach and intestines. It relieves symptoms heartburn, a feeling of fullness after meals, and loss of appetite. It is also used in the treatment of heartburn in patients suffering with gastroesophageal reflux disease (GERD). GERD is esophageal irritation from the backward flow of gastric acid into the esophagus.

Metoclopramide is a lipophilic molecule having the capacity to cross the blood-brain barrier (BBB). It is associated with serious neurological adverse events, especially oculogyric crisis and other related symptoms which are of particular concern in children.

Oculogyric crisis is spasmodic movements of the eyeballs into a fixed position, usually upwards (characterized by a marked involuntary deviation of the eyes) which is due to uncontrolled ocular muscles. These episodes usually last for minutes, which can range from seconds to hours. And sometimes there would be an often-increased blinking of the eyes frequently accompanied by pain.

Owing to the benefit-risk profile of metoclopramide based on the available scientifically evident safety data, NPRA has issued order for product registration holders to update the product information documents like package inserts with the below significant information of restrictions in its indication and dose-

• Restricted use/new contraindication of metoclopramide use: In patients aged below one year old
• Limitation of metoclopramide usage as a second-line treatment option in patients aged between 1-18 years old.

Case reports at NPRA:

National Malaysian health authority (NPRA) has received 897 case reports having 1,591 adverse events suspected to be related to metoclopramide. The total number of neurologic adverse events reported are 361. The total number of cases reported with the adverse reaction, oculogyric crisis are 241 (66.7%). There was one case report pertaining to a six (6) months old infant who experienced oculogyric crisis associated with metoclopramide use.

Advice for Healthcare Professionals

Contraindicated use:

Metoclopramide (oral and injection) use is contraindicated in children aged below one (1) year old

Metoclopramide suppository is contraindicated in children aged below 18 years old.

Limitations in usage:

The duration of treatment in children should not exceed five (5) days for the prevention of post-chemotherapy nausea and vomiting and should not exceed 48 hours for the prevention of post-operative nausea and vomiting.

Alert on Significant Safety Concern:

Be cautious when prescribing metoclopramide to alert patients, especially in paediatric patients on the risk of oculogyric crisis.

Consider for an alternative treatment if it is indicated and available.

Voluntary ADR Reporting:

Health care professionals and consumers are advised to report any suspected adverse reactions or experienced with the use of domperidone or domperidone-containing products and metoclopramide to the Malaysian health authority by online voluntary reporting facility through ADR web form. This will facilitate in accumulation of the more evident safety data which could help in taking early regulatory actions by NPRA.