Prepared by the Adverse Drug Reactions Advisory Committee (ADRAC) and the Office of Medicine Safety Monitoring (OMSM) of the TGA.

Contents

Emerging cardiovascular concerns with rosiglitazone

ADRAC draws to the attention of prescribers an emerging concern about the cardiovascular safety of the thiazolidinedione (TZD) drug rosiglitazone.

TZD drugs (rosiglitazone, pioglitazone) improve glycaemic control (mean HbA1c decrease of 0.8-1.5%) and are approved for the treatment of Type 2 diabetes mellitus. Whether they have long term benefits in reducing the chronic complications of Type 2 diabetes remains an open question. It is well established that TZDs cause fluid retention and can exacerbate or precipitate cardiac failure. These medicines are contraindicated in NYHA heart failure Grades 3 and 4 and are only to be used with caution in Grades 1 and 2.

Recently, three separate meta-analyses of data derived from pooled clinical trials of rosiglitazone have reported an increased risk of cardiac ischaemia.^1,2,3 The odds ratio for cardiac ischaemic events was in each case of the order of 1.40, conveying a 40% increase in the chance of a subject having such an event (and NOT that 40% of rosiglitazone treated patients will have such an event).

Some caution is needed in considering these results. Various comparator treatments have been used in the studies that were analysed, including placebo, metformin and sulphonylureas.

An interim analysis of the on-going RECORD study examining cardiovascular events with rosiglitazone was inconclusive (hazard ratio compared with control group 1.08, 95% CI 0.89 1.31).⁴

The product information for rosiglitazone (Avandia/Avandamet) has been amended to reflect these emerging results and the TGA has now required the following boxed warning: "The use of AVANDIA/AVANDAMET is not recommended in patients with known ischaemic heart disease, particularly in those taking nitrates. AVANDIA/AVANDAMET has been shown to be associated with an increased risk of myocardial ischaemia (angina, infarction) in pooled short-term clinical studies, particularly in those who needed several antidiabetic drugs or nitrates. See Precautions"

The TGA has commissioned an additional review of the information. Pending the outcome of this review, prescribers should include this potential additional risk in their consideration of appropriate drug therapy for Type 2 diabetes, taking into account that rosiglitazone should not be prescribed for patients with known ischaemic heart disease or those considered to be at high risk for ischaemic heart disease.

Reference

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1. Nissen SE & Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. NEJM 2007; 356: 2457-2471 (correction published in volume 357, p 100).
2. FDA Briefing Document (pdf,6.15Mb)*. Division of Metabolism and Endocrine Products and Office of Surveillance and Epidemiology. July 30, 2007
3. GlaxoSmithKline Clinical Trial Register. Rosiglitazone studies. Study No.: ZM2005/00181/01 and Study No.: HM2006/00497/00 / WEUSRTP866.
4. Home PD et al for the RECORD study Group. Rosiglitazone evaluated for cardiovascular outcomes - An interim analysis. NEJM 2007; 357: 28-38.

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Erythropoietins: aim for lower haemoglobin levels

Dosage instructions for the use of erythropoiesis-stimulating agents (erythropoietins) in patients with chronic kidney disease have been updated in line with evidence that higher haemoglobin levels may be associated with an increased risk of morbidity and mortality.

The three erythropoietins currently available in Australia are erythropoietin alfa (Eprex), erythropoietin beta (NeoRecormon), and darbepoetin alfa (Aranesp). They are approved for the treatment of anaemia associated with chronic renal failure and with the treatment of certain malignancies.

Recent studies and a meta-analysis have compared outcomes in patients with chronic kidney disease treated with an erythropoietin and randomised to achieve either a normal or subnormal haemoglobin level.^1,2,3

The larger of the two randomised studies showed a lower incidence of adverse cardiovascular outcomes (death, myocardial infarction, hospitalised heart failure, or stroke) in the subnormal (113 g/L) compared to the normal (135 g/L) target haemoglobin group.¹

The second study showed no difference in cardiovascular outcomes between the two groups,² and the meta-analysis of nine randomised trials showed a lower all-cause mortality and lower incidence of arteriovenous access thrombosis in patients in the lower target haemoglobin groups.³

Product information documents for the three erythropoietins have been amended to indicate a target haemoglobin not exceeding 120 g/L in patients with anaemia due to chronic kidney failure.

The dose of erythropoietin should be adjusted to maintain the lowest haemoglobin level needed to avoid the need for blood transfusions.

Reference

1. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan. Correction of anemia with epoetin alfa in chronic kidney disease. NEJM 2006; 355: 2085-2098
2. Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. NEJM 2006; 355: 2071-2084.
3. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007; 369: 381-388.

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Reports of hypersensitivity reactions to pregabalin

Case Report: Four and a half hours after her first dose of pregabalin for neuropathic pain, a woman woke during the night with breathing difficulty due to a swollen face, neck and tongue. She required emergency treatment with adrenaline, promethazine and prednisone before making a full recovery.

Pregabalin (Lyrica) is approved for use in the treatment of neuropathic pain in adults and as adjunctive therapy in adults with partial seizures with or without secondary generalisation. Post-marketing reports of hypersensitivity reactions to pregabalin comprise 13% of all the pregabalin adverse reaction reports in the ADRAC database, with a range of symptoms reported in 22 individuals (14F:8M). Presentations have included anaphylaxis and 7 reports of allergic skin rash. The others were angioedema of eyelids, tongue, mouth, face, lips or upper airway, with breathing difficulty when severe and widespread.

Of the 22 cases, 6 women developed symptoms within hours of their first dose of pregabalin. In 14 of the cases, pregabalin was the sole suspected drug. Four patients required emergency treatment, including adrenaline and/or parenteral steroids and IM or oral antihistamine. Three of the cases of skin reaction were confirmed by a positive dechallenge and subsequent rechallenge. There is insufficient information about the patients' histories of atopy or other allergies to comment on the predictive value of such a history.

The pregabalin Product Information includes a contraindication for patients who have demonstrated hypersensitivity to pregabalin or to any of the excipients.

Pregabalin prescribers should be alert to the fact that acute allergic reactions may present early after its introduction and after any dose increases, and counsel patients accordingly.

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Transdermal medications - look for the patch

The TGA has received a report of an inadvertent overdose of opioid medicines caused when subcutaneous morphine was administered pre-operatively to a patient who was wearing a Norspan transdermal patch, delivering buprenorphine 20 µg/hour. Despite a thorough medical history, the patient omitted to tell the anaesthetist and other medical staff that she was using Norspan patches, and she had applied a fresh patch on the day of surgery. Medical staff discovered the patch when the patient became comatose with significant respiratory depression after the conventional dose of morphine was given.

The patient recovered after naloxone was administered. Although a fatal outcome was averted, the patient remained drowsy for 24 hours despite naloxone and her surgery was delayed.

Doctors are advised to remind their patients to disclose use of all medications, including those administered by non-conventional routes such as transdermal patches and subcutaneous implants. Physical examinations should include a check for topically applied or superficially implanted medicines.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

• Atomoxetine (Strattera)
• Ezetimibe/Simvastatin (Vytorin)
• Moxonidine (Physiotens)
• Pregabalin (Lyrica)
• Ranibizumab (Lucentis)
• Rosuvastatin (Crestor / Viacor)
• Strontium ranelate (Protos)
• Varenicline (Champix)
• Ziprasidone (Zeldox)

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What to report?

(you do not need to be certain, just suspicious!)

ADRAC encourages the reporting of all suspected adverse reactions to medicines, including vaccines, OTC medicines, herbal, traditional or alternative remedies. ADRAC particularly requests reports of:

• ALL suspected reactions to new drugs (see drugs of current interest)
• ALL suspected drug interactions
• Suspected reactions causing
  • Death
  • Admission to hospital or prolongation of hospitalisation
  • Increased investigations or treatment
  • Birth defects

For blue cards

Reports of suspected adverse drug reactions are best made by using a prepaid reporting form ("blue card") which is available from the website or from the Office of Medicines Safety Monitoring (02 6232 8744).

Reports can also be submitted electronically, by clicking on "Report a problem" on this website, by fax: 02 6232 8392, or email: ADR.Reports@tga.gov.au.

ISSN 0812-3837

© Commonwealth of Australia 2007

All correspondence to be addressed to: The Secretary, ADRAC, PO Box 100, Woden ACT 2606

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