Prescriber Update
Vol. 41 No. 2 June 2020 www.medsafe.govt.nz ISSN 1179-075X (online)
Contents
Spotlight on tramadol, including updated advice for use in children 25
Ondansetron and oral cleft defects 27
Alerting the Medical Warning System can save lives! 29
MARC’s Remarks: March 2020 meeting 30
Antipsychotic medicines: monitor cardiovascular risk 31
Gathering knowledge from adverse reaction reports: June 2020 32
Recent approvals: new active ingredients or new indications 34
Anticholinergic burden – a cause of adverse reactions for older patients 35
Quarterly summary of recent safety communications 36
Flucloxacillin – sometimes bad news for kidneys 37
Medicines Monitoring: fluoxetine and levothyroxine 38
Medicines associated with fistulas 38
Medicinal Cannabis Scheme – now operational 40
Subscribe to Medsafe updates and alerts 42 Spotlight on tramadol, including updated advice for use in children
Key messages
§ Tramadol is now contraindicated in children aged under 12 years and should be used with care in patients aged over 75 years.
§ Patients who are CYP2D6 ultra-rapid metabolisers may be more sensitive to adverse reactions.
This article informs healthcare professionals of updated advice on the use of tramadol in children. It is also a reminder of tramadol’s metabolism, use in patients aged over 75 years, and some serious adverse reactions.
What is tramadol? Tramadol is a centrally-acting synthetic analgesic that exerts its effect by1,2:
binding to μ-opioid receptors inhibiting the reuptake of noradrenaline and serotonin.
Tramadol is used to relieve moderate to severe pain when paracetamol and/or a non- steroidal anti-inflammatory drug (NSAID) is not adequate1,2.
The importance of CYP2D6 Tramadol is similar to codeine in that CYP2D6 is important for producing metabolites that have a greater affinity for the μ-opioid receptor than the parent drug3.
Tramadol’s principal active metabolite is O-desmethyltramadol (M1)1. Animal models show M1 to be six-times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding1.
Patients with a deficiency of CYP2D6 may have reduced benefit from tramadol3. On the other hand, patients who are ultra-rapid metabolisers may be more sensitive to adverse reactions, even at commonly prescribed doses3. The frequency of poor metaboliser and ultra-rapid metaboliser phenotypes varies between populations4.
Tramadol is contraindicated in children Following review of their safety data, the companies have now contraindicated the use of tramadol in:
children aged under 12 years children aged under 18 years for post-operative pain management following tonsillectomy and/or adenoidectomy.
The tramadol data sheets are in the process of being updated with these contraindications.
Use with caution in patients aged over 75 years Serum concentrations of tramadol are slightly elevated, and the elimination half-life is slightly prolonged in patients aged over 75 years1. Their tolerance of adverse reactions is expected to vary more widely. Therefore, use a lower maximum daily dose of 300 mg in these patients1.
Prescriber Update 2020; 41(2) June 25 Serious adverse reactions Tramadol is associated with adverse reactions seen for both opioid and antidepressant medicines2. Tramadol should be administered cautiously in patients at risk of respiratory depression1. Avoid concomitant use with benzodiazepines or other central nervous system (CNS) depressants unless there are no suitable alternative treatment options1.
Tramadol may cause serotonin syndrome when taken alone or if the dose is increased, and more frequently when taken with another serotonergic medicine. Avoid concomitant use with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants and mirtazapine. For more information about serotonin syndrome, see the September 2015 edition of Prescriber Update (medsafe.govt.nz/profs/PUArticles/Sep2015/InteractionsSerotoninSyndrome.htm).
Seizures have been reported in patients taking tramadol even at the recommended dose1. Tramadol may also increase the seizure risk in patients taking other medicines that lower the seizure threshold1. Avoid using tramadol in patients with epilepsy or those susceptible to seizures.
Please refer to the medicine data sheet for full prescribing information (search for data sheets at: medsafe.govt.nz/Medicines/infoSearch.asp).
Adverse reactions reported in New Zealand over the last five years The Centre for Adverse Reactions Monitoring (CARM) has received 83 adverse reaction reports relating to tramadol from 1 January 2015 to 31 December 2019. The most frequently reported reactions were rashes (12), vomiting (10) and nausea (9).
Serotonin syndrome was reported in five cases (CARM IDs: 115985, 116267, 121427, 129817, 134414). Four of these cases reported a SSRI or SNRI as co-suspects. Convulsions were reported in five cases (CARM IDs: 121427, 124017, 129062, 129605, 133745).
Of the 83 reports, six were in children aged under 12 years and seven were in patients aged over 75 years.
References 1. Seqirus (NZ) Ltd. 2018. Tramal New Zealand Data Sheet 17 December 2019. URL: medsafe.govt.nz/profs/Datasheet/t/TramalcapSRtabinjoraldrops.pdf (accessed 21 April 2020). 2. BPAC NZ. 2018. Prescribing tramadol appropriately 23 February 2018. URL: bpac.org.nz/2018/tramadol.aspx (accessed 17 April 2020). 3. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. 2015. Acute Pain Management: Scientific Evidence (Fourth edition). URL: fpm.anzca.edu.au/documents/apmse4_2015_final (accessed 17 April 2020). 4. Medsafe. 2018. Spotlight on codeine. Prescriber Update 39(2): 18–19. URL: medsafe.govt.nz/profs/PUArticles/June2018/SpotlightOnCodeine.htm (accessed 23 April 2020).
Prescriber Update 2020; 41(2) June 26 Ondansetron and oral cleft defects
Key messages
§ Use of ondansetron during the first trimester of pregnancy is increasing.
§ Epidemiological study data suggest a small increase in the risk of oral cleft defects (such as cleft lip or cleft palate) associated with first trimester xposuree to ondansetron.
§ With informed consent, ondansetron should only be used during the first trimester of pregnancy if the benefits of use clearly outweigh the risks of harm to the woman and fetus.
Ondansetron Ondansetron is a selective serotonin (5-HT3) receptor antagonist. The approved indications are the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and the prevention of post-operative nausea and vomiting. Ondansetron is also used off-label during early pregnancy1.
New Zealand National Collections data show that first trimester use of ondansetron is increasing (Figure 1). The proportion of women who were dispensed ondansetron during the first trimester of pregnancy increased from 0.5 percent in 2009 to 9.6 percent in 2018.
Risk of cleft palate with ondansetron Two recent epidemiological studies investigated the risk of orofacial cleft defects and other congenital malformations in infants who were exposed to ondansetron in utero, using data from large administrative claims databases in the United States2,3.
The first was a retrospective cohort study of 1,816,414 pregnancies from 2000 to 2013, in which 88,467 (4.9 percent) pregnancies were associated with a prescription for ondansetron in the first trimester. Oral cleft defects occurred in 14.0 per 10,000 exposed infants compared to 11.1 per 10,000 unexposed infants (adjusted relative risk 1.24, 95% CI: 1.03–1.48)2.
The second was a nested case-control study of 864,083 mother-child pairs registered from 2000 to 2014, in which 5,557 mother-child pairs were administered ondansetron in the first trimester. Ondansetron exposure was associated with a numerical increase in oral cleft defects, although this increase did not reach statistical significance (adjusted odds ratio 1.30, 95% CI: 0.75–2.25)3.
The Medicines Adverse Reactions Committee (MARC) discussed the risk of oral cleft defects associated with first-trimester exposure to ondansetron at the March 2020 meeting (see MARC’s remarks on page 30). The Committee noted that although the effect sizes in the recently reported studies were small and there is some uncertainty in the data, the current evidence suggests a small increase in the risk of oral cleft defects associated with the use of ondansetron in the first trimester4.
Clinical implications The recent studies suggest an approximate 25 percent increase in the risk of oral cleft defects with first trimester use of ondansetron, amounting to an additional 3 cases per 10,000 exposed pregnancies.
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.
Prescriber Update 2020; 41(2) June 27 In line with the Code of Health and Disability Services Consumers’ Rights, authorised prescribers must advise the patient when the use of ondansetron in pregnancy is unapproved (off-label) and obtain informed consent5,6.
The possible benefit of using ondansetron during the first trimester of pregnancy must be weighed against the risk of harm. As with all medicines, benefit-risk assessment needs an individualised approach7.
Figure 1: Use of ondansetron during the first trimestera of pregnancy in New Zealand, public hospitalisations data, 2009–2018