MedSafe- Health Authority of New Zealand government has released the below drug safety information in their latest issue-June-2020 to update public-(health care professionals & consumers) about the safe use of medicines.


Tramadol use Contradicted in children & elder patients (<75 y)

Oral cleft defects associated with ondansetron


Tramadol use Contradicted in children & elder patients (<75 y)

Tramadol is an opioid pain medication used to treat or relive from moderate to severe pain when the treatment with paracetamol and/or a non-steroidal anti-inflammatory drug (NSAID) like Ibuprofen are not adequate in relieving pain in patients.

How it reduces pain?

Tramadol molecule acts by binding to μ-opioid receptors (Receptors present in the body which sends signals to brain in controlling the feelings of reward and pain). After binding to these receptors, it inhibits the process of re uptake of nor adrenaline and serotonin (neurotransmitter responsible for transmitting information in the nervous system).

Tramadol is metabolized inside the body by an enzyme CYP2D6 to active metabolite- O‑desmethyltramadol which is 6 times more potent than tramadol. O‑desmethyltramadol has higher affinity for μ-opioid receptor than the tramadol.

Role of CYP2D6 enzyme in Tramadol Benefit-Risk analysis:

Tramadol has an overall favorable benefit-risk profile (Hence, continuing to find a space for it in the market). However, Physicians and other healthcare professionals are advised to monitor the level of CYP2D6 enzyme in patients (the key metabolizing enzyme for tramadol to its primary active metabolite), before initiating/prescribing treatment with tramadol. Since the Individual Benefit-Risk Profile might varies considering the metabolizing capacity of tramadol.

Key rationale for assessing Individual benefit-risk profiles:

Poor Metabolizes/Patients with deficiency of CYP2D6 enzyme– They might not get effective pain relief from tramadol (due to minimal/lack of conversion of tramadol to its active metabolite for pain relief). This implies that anticipated benefit of tramadol could not be expected for this category of patients.

Ultra-rapid metabolizers-They are exposed to higher levels of O‑desmethyltramadol and prone to serious adverse reactions even at commonly prescribed doses. The anticipated/unidentified risks are more expected for this category of patients.

The frequency of poor metabolizer/patients with deficient CYP2D6 enzyme and ultra-rapid metabolizer phenotypes varies between populations. The population group more prone to these variations are children and elder patients of age more than 75 y.

Case reports of Tramadol at Med Safe:

The New Zealand’s Centre for Adverse Reactions Monitoring (CARM) has received 83 adverse reaction reports relating to tramadol during the period 01-Jan-2015 to 31-Dec-2019. The most commonly reported adverse drug reactions were rashes (12), vomiting (10) and nausea (9).

Of the total case reports received, 6 case reports were pertaining to children aged under 12 years and 7 case reports were in elder patients aged over 75 years.

The significant safety findings for tramadol are-

  • Serotonin syndrome in 5 case reports (four cases with selective serotonin re-update inhibitors (SSRI) as co-suspect medications
  • Convulsions in 5 case reports.

Advice to health care professionals:

Tramadol use in contraindicated in below group of populations owing to the review of its safety data.

Pediatric population:

  • Children aged under 12 years
  • Children aged under 18 years for post-operative pain management following tonsillectomy and/or appendectomy.

Geriatric population:

Use with caution in patients aged over 75 years- a lower maximum daily dose of 300 mg is suggested to use, since the serum concentrations of tramadol are slightly elevated, and the elimination half-life is slightly prolonged in this category of patients. Their tolerance of adverse reactions is expected to vary more widely.

Concomitant use of tramadol with benzodiazepines or other central nervous system (CNS) depressants are advised to avoid unless there is no beneficial alternative treatment option.


Oral cleft defects associated with ondansetron

Ondansetron is a selective serotonin (5-HT3) receptor antagonist which is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery (post-operative nausea and vomiting). It is also used during early pregnancy which is not an approved use (off-label use).

As per the New Zealand’s National Collections data, the use of ondansetron in pregnancy (during the first trimester) is increasing significantly (from 0.5% use in 2009 to 9.6% use in 2018).

Risk of Congenital abnormalities:

There is a potential risk of fetal anomalies like oral cleft defect, as per the epidemiological studies which were conducted to assess the risk of congenital malformation with ondansetron use. A case-control study identified an association between prenatal exposure to ondansetron and cleft palate, and one cohort study found an increased risk of cardiovascular defects.

A retrospective cohort study by Krista F Huybrechts, found that first-trimester exposure to ondansetron was associated with a small increased risk of oral clefts and they found that it was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders. A nested case-control study in a large population from United State by April Zambelli-Weinerin, found a statistically significant association between early pregnancy ondansetron exposure and specific structural birth defects in offspring.

The New Zealand’s Medicines Adverse Reactions Committee (MARC) discussed risk of cleft palate with ondansetron exposure in utero during the first trimester of pregnancy. The Committee noted that although the effect sizes in the recently reported studies were small and there is some uncertainty in the available evidence of safety data, the current evidence suggests a small increase in the risk of oral cleft defects associated with the use of ondansetron in the first trimester. The MARC considered this small risk should be highlighted in New Zealand data sheets.

Three cases of congenital anomaly per 10,000 exposed pregnancies-The recent studies suggest an approximate 25% increase in the risk of oral cleft defects with first trimester use of ondansetron.


The data sheets of ondansetron-containing medicines are being updated with information on the increased risk of oral cleft defects associated with first trimester use.

Health care professionals in New Zealand are advised to obtain informed consent must advise the patient about the use of ondansetron in pregnancy which is unapproved (off-label).

Individual Benefit-Risk assessment: The possible benefit of using ondansetron during the first trimester of pregnancy must be weighed against the risk of harm.

Voluntary ADR reporting:

Every medicine present in market (Prescription & OTC medicines) are having their own benefits and risks. Marketing authorization for these medicinal products would be granted based on their overall benefit-risk profile in wide range of populations. However, the benefit-risk ratio for a medicine which is positive for patients might become negative for a certain group of patients (due to different age group, risk factors, underling medical conditions, special populations like pregnancy etc.,). It is always wise from a patient safety perspective to perform assessment for a medicine’s benefit-risk ratio for each individual patient. With respect to safety of a medicinal product (No medicinal product is having the complete information about its own safety data).

All health care professionals & consumers of pharmaceutical medicinal product(s) are strongly advised to observe, monitor, and become aware of the possible (not always) unusual experiences or adverse events after administration of medicinal product and voluntarily report the adverse drug experiences to respective national health authority. This would help in early identification of potential signals and risks of medicinal product which are not yet detected by pharmaceutical companies or regulatory bodies. Citizens of New Zealand are encouraged to voluntarily report the adverse drug reactions through online to the New Zealand’s Centre for Adverse Reactions Monitoring .

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