Published: May 2008
Publications
Watching Briefs - June 2008
Prescriber Update 29(1): 2-4
May 2008
Medsafe Pharmacovigilance Team
Omeprazole and headaches
Tamoxifen and visual changes – investigate
promptly
Amiodarone and lung toxicity – ongoing
patient monitoring required
Roxithromycin-warfarin interaction
of increased INR
Use of clozapine in older people requires
extra care
Myocardial infarction with glitazones
Update on cough and cold products
Imiquimod cream – skin pigmentation
changes and flu-like symptoms
Concomitant parenteral administration of
ceftriaxone and calcium
Memory loss and depression with lipid-lowering
agents
Codeine in breastfeeding – risk of fatal
infant morphine toxicity
Graseby syringe driver update
Omeprazole and headaches
Headaches are a common adverse effect of omeprazole. Headaches can be difficult to diagnose in children and may present as prolonged or worsening irritability. Therefore, prescribers should consider headaches as a possible explanation in children with non-specific irritability who are taking omeprazole.
Tamoxifen and visual changes – investigate promptly
Retinopathy and keratopathy are recognised adverse effects of tamoxifen. While retinal damage more usually occurs at high doses used for a long duration, it has been reported in patients receiving standard doses of tamoxifen for only nine months. Patients should be asked to report the following symptoms of ocular damage without delay: blurred vision lasting more than a week, or change in colour vision. Any patients taking tamoxifen, regardless of dose or duration, who develop changes in visual acuity should be referred for ophthalmological examination. If tamoxifen is withdrawn promptly, the vision usually returns to normal without permanent impairment.
Amiodarone and lung toxicity – ongoing patient monitoring required
Information on this subject has been updated. Read the most recent information.
Prescribers are reminded that lung toxicity is the most serious potential adverse reaction associated with amiodarone therapy, and has a fatality rate of about 10%. Medsafe is aware that CARM and ACC have received a number of reports of lung toxicity in association with amiodarone use, in the last few years.
Prescribers are reminded that pulmonary function assessment (including chest X-ray) should be carried out at baseline and at 6-monthly intervals thereafter. Prescribers are advised of the importance of ensuring that a lead carer (either specialist or GP) is identified whenever amiodarone is prescribed. Liaison between specialists and GPs is vital to ensure that patient monitoring is carried out and any adverse effects are appropriately managed.
Roxithromycin-warfarin interaction of increased INR
Prescribers are reminded that there is an established but unpredictable interaction between erythromycin and warfarin, resulting in an increased international normalised ratio (INR).
CARM has received several reports of a possible interaction between roxithromycin and warfarin, with a resultant increased INR. These reports suggest that roxithromycin may have a potentiating effect on warfarin, but to a considerably lesser degree than erythromycin. This effect may, however, become clinically significant in patients receiving polytherapy, or in those who are elderly or otherwise at risk of increased sensitivity to warfarin. Therefore, in patients receiving warfarin, the INR should be closely monitored during the addition and withdrawal of concurrent treatment with roxithromycin.
Use of clozapine in older people requires extra care
Clozapine is only licensed for treatment-resistant schizophrenia. Its use for other indications requires informed consent. Use of clozapine in older patients carries a higher risk of adverse reactions such as postural hypotension, falls, sedation, and constipation, compared to use in younger patients. Therefore, increased clinical monitoring of the elderly is necessary to ensure their safety.
Myocardial infarction with glitazones
Recent literature supports an association between rosiglitazone and myocardial infarction. As pioglitazone belongs to the same class of medicines, it is possible pioglitazone may have a similar effect. However, no increase in the risk of myocardial infarction has been demonstrated for pioglitazone in published studies. The data are limited and further studies are needed. Meanwhile, the possibility of myocardial ischaemia with glitazones should be borne in mind when prescribing rosiglitazone or pioglitazone.
Update on cough and cold products
Following the commencement of a review of the safety of cough and cold products in children, by the FDA in the United States, the Medicines Adverse Reactions Committee (MARC) discussed this issue at their December 2007 meeting. The MARC subsequently recommended that all cough and cold medicines be contraindicated in children under two years of age. The rationale being that there is very limited evidence for efficacy in this age group; an absence of evidence-based dosage advice; and evidence of significant toxicity in overdose. As a result, the risk-benefit profile for the use of cough and cold medicines in children under 2 years of age is considered to be unfavourable. Medsafe and the MARC are currently considering the safety and efficacy of cough and cold medicines in children over two years of age.
Imiquimod cream – skin pigmentation changes and flu-like symptoms
Use of imiquimod (Aldara) cream can cause intense local inflammatory reactions. While these are rare, they can occur after only a few topical applications. These reactions may be accompanied, or even preceded, by flu-like systemic signs and symptoms such as malaise, pyrexia, nausea, and myalgias. An interruption of imiquimod use should be considered. In two cases reported to CARM, the patients had applied imiquimod more frequently than recommended for the condition being treated, and subsequently developed ulceration at the site of application.
Localised hypopigmentation and hyperpigmentation following the use of imiquimod cream may also occur. Follow-up information suggests that these skin colour changes may be permanent in some patients.
Concomitant parenteral administration of ceftriaxone and calcium
Information on this subject has been updated. Read the most recent information.
Prescribers are reminded of the potential risk of intravascular or pulmonary precipitations occurring due to the concomitant parenteral administration of ceftriaxone with calcium or calcium-containing solutions. Isolated neonatal deaths associated with calcium-ceftriaxone precipitates in the lungs and kidneys have been reported internationally. Although no reports have been received for patients other than neonates, the theoretical possibility exists for this interaction in patients of any age.
Ceftriaxone and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition should not be administered to any patient, irrespective of age, within 48 hours of each other, even via different infusion lines at different sites. The data sheets for all ceftriaxone products available in New Zealand have been updated to include this warning. Prescribers are also reminded that ceftriaxone is contraindicated in hyperbilirubinaemic neonates.
Memory loss and depression with lipid-lowering agents
Prescribers are reminded that the risk of psychiatric reactions associated with lipid-lowering agents is not limited to statins. The symptomatic onset of psychiatric reactions, particularly memory loss and depression, can occur within days after initiation of treatment with statins, fibrates, or ezetimibe.1 Reports have been received where the symptoms occurred within four days after commencing treatment with ezetimibe.2 However, reactions can occur up to one year after initiation of treatment. In most reported cases, the symptoms resolved upon discontinuation of treatment. It is suspected that memory loss and depression are due to a reduction of brain cell membrane cholesterol, rather than direct adverse effects of the lipid-lowering agents themselves.1
It is important that patients are advised to inform their prescriber immediately if they experience symptoms suggestive of depression, memory loss, or other psychiatric reactions. Prescribers should consider the lipid-lowering agents as a possible causal explanation in patients presenting with psychiatric symptoms, particularly memory loss or depression.
References
- Tatley M, Savage R. Psychiatric reactions with statins, fibrates and ezetimibe. Drug Safety 2007:30(3):195-201.
- Australian Adverse Drug Reactions Advisory Committee (ADRAC). Ezetimibe and depression – a possible signal. Aust Adverse Drug React Bull 2006;25(5):19. www.tga.gov.au/adr/aadrb/aadr0610.htm
Codeine in breastfeeding – risk of fatal infant morphine toxicity
Codeine is commonly used by breastfeeding women to treat mild to moderate pain associated with delivery. A report published in the Lancet in 20061 detailed the death from a morphine overdose of an otherwise healthy 13-day-old breastfed baby whose mother had been prescribed codeine (60mg bd for 2 days and then 30mg bd thereafter) to treat episiotomy pain. The baby experienced feeding difficulties and lethargy at day 7, and was found dead on day 13. Analyses of the baby’s blood and the mother’s breast milk found toxic levels of morphine in both. Subsequent genetic testing of the mother determined that she was an ultra-rapid metaboliser (URM) of codeine, which explained the very high levels of morphine.1
The chance of being an ultra-rapid metaboliser of codeine varies amongst different racial groups.2 It is estimated that approximately 1-10% of Caucasians are URMs;2 it is unknown what proportion of Maori or Pacific people are URMs of codeine. However, in the absence of genetic testing, it is not possible to identify URMs prior to prescribing codeine.
Therefore, prescribers are advised to carefully consider the risks and benefits before prescribing codeine for breastfeeding mothers. If codeine is prescribed, the lowest dose should be used for the shortest period of time. Patients should be advised of the symptoms of morphine toxicity in themselves (nausea, vomiting, somnolence, constipation and/or difficulty caring for the baby) and their babies (increased sleepiness – i.e. sleeping for more than 4 hours in the neonatal period, difficulty breastfeeding, breathing difficulties, or limpness). Patients should be advised to discontinue codeine and to seek medical attention immediately if these symptoms occur.3
References
- Koren G, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:704.
- FDA Public Health Advisory: Use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies. August 2007. www.fda.gov/cder/drug/advisory/codeine.htm and www.fda.gov/CDER/Drug/InfoSheets/HCP/codeineHCP.htm
- Douglas Pharmaceuticals Ltd. Codeine Phosphate data sheet. 28 August 2007. www.medsafe.govt.nz/profs/datasheet/c/CodeinePhosphatetab.htm
Graseby syringe driver update
Information on this subject has been updated. Read the most recent information.
In October 2007, the supply of Graseby MS-Series Syringe Drivers was ceased in New Zealand, due to safety concerns. These syringe drivers are commonly used in palliative care and other situations to provide continuous ambulatory infusion of medicines. Spare parts and servicing for existing devices continues to be available through Smiths Medical.
Regulators in several countries, including Australia and the UK, have previously issued safety alerts in relation to the Graseby MS-Series Syringe Driver; and these have related to possibilities of over-infusion, tampering with the device, and confusion between the different models of Graseby device.
Medsafe is cognisant of the clinical implications of the decision to cease supply. It therefore did not require the existing devices to be recalled or withdrawn from clinical use where alternates are not available, provided the manufacturer's instructions for the Graseby MS-Series Syringe Drivers are carefully observed.
Medsafe also recognises that there are on-going risks associated with these devices and therefore advises users to give immediate consideration to sourcing alternative equipment which meets the Global Harmonisation Task Force (GHTF) "Essential Principles" of safety and performance (www.ghtf.org/documents/sg1/sg1n41r92005.pdf).
A Syringe Driver Advisory (SDA) group has been established in New Zealand to facilitate the safe and smooth transition from the use of Graseby syringe drivers to alternative device(s). The SDA group recognises the need to plan for changing over to a different device; and that current users are providing generalist or specialist palliative care in a variety of settings, or within a variety of pediatric and neonatal healthcare settings. This has practical, financial and educational implications. The SDA group wishes to provide a supportive, rather than a directive role. More details about the SDA Group, and background information about the reasons for ceasing distribution of Graseby syringe drivers, are available on the Medsafe web site (www.medsafe.govt.nz/profs/device-issues.asp).
