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Australian Adverse Drug Reactions Bulletin, Vol 22, No 6

December 2003

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

Contents

Meningococcal C vaccine: early experience is reassuring

Meningococcal serogroup C conjugate vaccines (NeisVac-C, Meningitec, Menjugate) have been included in a mass vaccination program in Australia, from early 2003.1 These vaccines are highly effective and have a low rate of adverse events. A single dose is recommended to confer long-term immunity in adults and children ≥ 12 months of age. Initial appraisals of efficacy against invasive meningococcal group C disease indicate the vaccine is 92% effective in toddlers and 97% effective in teenagers.2 It is estimated that meningococcal C conjugate vaccines have the potential to prevent over 100 cases of meningococcal infection and 5 to 10 deaths each year in Australia. No vaccine is available against group B meningococcus which causes almost 70% of all meningococcal infections. Individuals who are given meningococcal C vaccine continue to be susceptible to group B meningococcus.

Since March 2002, ADRAC has received 270 reports associated with the use of serogroup C conjugate vaccines. Commonly reported adverse events include injection site reaction (86), fever (48), rash (39), vomiting (32), urticaria (28) and headache (28). Serious events include anaphylaxis (2), angioedema (2) and convulsions (17). Seven of the cases of convulsions were associated with syncope and four with fever. Although it is not possible to develop group C meningitis from the vaccine, two reports have been received of meningitis-like symptoms. Such reactions may include headache, neck stiffness and soreness and photophobia. No deaths have been reported associated with the vaccine.

Up to 30 June 2003, around 2.5 million doses of meningococcal vaccine were distributed in Australia. Using this figure, the reported rate in Australia for convulsions is 7 per million doses. This is broadly consistent with the reported rate for convulsions in the United Kingdom, which is 16 per million doses.3

References

  1. National Meningococcal C Vaccination Program. Information for immunisation providers. Department of Health and Ageing, Australian Government, 22 May 2003.
  2. Meningococcal disease and vaccination. Frequently asked questions. Population Health Division, Department of Health and Ageing, Australian Government, 22 August 2002.
  3. Report of the Committee on Safety of Medicines Expert Working Group on Meningococcal Group C Conjugate Vaccines, 23 May 2002.

Harmful interactions

A recent article has highlighted the risks of prescribing drugs that can interact with effective, well-tolerated, long-term drug therapy in the elderly.1 The article focussed on three interactions involving addition of a new drug to long-term therapy:

  • hypoglycaemia with trimethoprim/sulpha-methoxazole added to glibenclamide
  • digoxin toxicity with clarithromycin added to digoxin
  • hyperkalaemia with potassium-sparing diuretic added to ACE inhibitor

The authors found use of each of the combinations to be associated with an increased risk of hospitalisation. Patients taking an ACE inhibitor who then took a potassium-sparing diuretic had a 20-fold increased risk of admission. Some patients were hospitalised for as long as 8 days, and several patients with each of the interactions died. No increased risk of toxicity was found in patients who received an alternative drug with a similar indication but no known interaction (amoxycillin, cefuroxime, indapamide, respectively).

Australian reports received by ADRAC illustrate these interactions.

Trimethoprim/sulphamethoxazole + glibenclamide

Two patients stabilised on glibenclamide for their diabetes became hypoglycaemic when they commenced trimethoprim/sulphamethoxazole for a bacterial infection. One patient had previously taken trimethoprim with glibenclamide without adverse effect. This interaction occurs because sulphonamides inhibit the hepatic metabolism of sulphonylureas by CYP2C9. In addition, high dose sulphonamides alone may, rarely, have a hypoglycaemic effect.

Clarithromycin + digoxin

A 75 year old female who had been taking digoxin 250 µg daily for almost four years was admitted with digoxin toxicity (4.2 nmol/L) on the third day after commencement of clarithromycin 250mg twice daily. The dose of digoxin was halved and clarithromycin stopped. She was discharged eight days later. Digoxin bioavailability is around 70% because p-glycoprotein in the gut wall pumps it back into the gut lumen, reducing absorption. Clarithromycin, and other macrolide antibiotics, inhibit the p-glycoprotein pump, increasing the amount of digoxin absorbed.

Spironolactone + ACE inhibitor

Three patients developed hyperkalaemia (two with renal failure) after the addition of spironolactone to long-term ACE inhibitor therapy. In one case serum potassium rose to 8.4 mmol/L. All three patients recovered fully following withdrawal of both medications and treatment to reduce potassium levels. Hyperkalaemia commonly occurs with ACE inhibitors alone, and adding a potassium-sparing diuretic, such as spironolactone or amiloride, exacerbates this effect by further impairing renal potassium excretion.

Prescribers are advised to be cautious about the risk of interactions when prescribing additional medication to patients on long-term drug therapy for chronic conditions. Besides potentially serious direct consequences from the interaction, the interaction may not be correctly identified and the long-term medication may be unnecessarily ceased. In the context of long-term therapy, increased surveillance is recommended in the weeks after starting or stopping other medication.

Reference

  1. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652-58.

Post-partum NSAIDs may cause hypertension

Recently ADRAC received a cluster of six reports of hypertension or hypertensive crisis in women given an NSAID (indomethacin, ibuprofen or diclofenac) post-partum. One woman, with a history of severe pre-eclampsia, died of hypertensive crisis and intracranial haemorrhage after Caesarean section. Three of the other women had a history of pre-eclampsia, but two, including one with an eclamptic seizure, had no prior hypertension. Four of the women were receiving no antihypertensive therapy at the time of the adverse event.

The efficacy and tolerability of NSAIDs for the treatment of post-partum pain following uncomplicated spontaneous delivery have been demonstrated in controlled prospective studies.1,2 However, there is a lack of data on the use of NSAIDs in the post-partum period in women with pre-eclampsia or premature delivery. Studies unrelated to pregnancy and delivery indicate that, although NSAIDs have a minimal effect on the blood pressure of normotensive individuals, they can cause major increases in hypertensive patients whose blood pressure was previously controlled by medication.3 Beta-blockers and ACE inhibitors are particularly susceptible to reduced efficacy in the presence of an NSAID.3,4 Limited data suggest that NSAIDs may also increase blood pressure in patients with uncontrolled hypertension.5 Different NSAIDs may have different degrees of effect on blood pressure.

The severe hypertension in the present cases may have been caused solely by the patients' underlying condition. It is plausible, however, that the NSAID administered in each case made a significant contribution.

ADRAC advises careful monitoring of blood pressure in women with a history of pre-eclampsia or essential hypertension given an NSAID in the post-partum period. ADRAC would be interested to hear from health professionals who observe similar rises in blood pressure following the use of an NSAID in this setting.

References

  1. Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomised controlled trial. Can Med Assoc J 2001;165:1203-9.
  2. Searles JA, Pring DW. Effective analgesia following perineal injury during childbirth: a placebo controlled trial of prophylactic rectal diclofenac. Brit J Obstetrics & Gynaecology 1998;105:627-31.
  3. Johnson AG. NSAIDs and increased blood pressure. What is the clinical significance? Drug Safety 1997;17:277-89.
  4. Palmer R, Weiss R, Zusman RM et al. Effects of nabumetone, celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors. Am J Hypertension 2003;16:135-39
  5. Lewis RV, McLay J, Maclean D, Tregaskis B. The effects of indomethacin and sulindac upon the blood pressures of individuals with untreated labile or mild hypertension. J Human Hypertension 1989;3:233-7.

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Apomorphine (Uprima)
  • Aripiprazole (Abilify)
  • Esomeprazole (Nexium)
  • Fondaparinux (Arixtra)
  • Galantamine (Reminyl)
  • Lercanidipine (Zanidip)
  • Levetiracetam (Keppra)
  • Meloxicam (Mobic)
  • Pioglitazone (Actos)
  • Pramipexol (Sifrol)
  • Reboxetine (Edronax)
  • Rosiglitazone (Avandia)
  • Sibutramine (Reductil)
  • Tadalafil (Cialis)
  • Tegaserod (Zelmac)

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 2003

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