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Australian Adverse Drug Reactions Bulletin, Vol 20, No 3

August 2001

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


Extensive limb swelling and DTPa booster doses

The replacement of the whole cell pertussis antigens (Pw) with acellular pertussis antigens (Pa) in the combination diphtheria, tetanus and pertussis vaccines (DTPa) (Infanrix, Tripacel) has been an important recent development. Clinical studies have shown that DTPa causes fewer worrying reactions like inconsolable crying, high fevers, hypotonic-hyporesponsive episodes and convulsions than DTPw.

As clinical experience with the use of DTPa-containing vaccines has grown, it has been observed that there is an increase in the rate of occurrence and severity of injection site reactions with each successive dose.1 The fourth and fifth doses of DTPa sometimes cause extensive limb swelling which may be associated with redness and pain. These booster doses are recommended at 18 months (fourth dose) and four years (fifth dose) in Australia and may be given into the arm or the thigh. Of the 331 Australian reports of suspected adverse reactions to DTPa vaccines received by ADRAC between late November 1997 and mid-June 2001, 103 described injection site reactions in children aged 18 months or older. In contrast, only 37 described similar reactions in younger children. Of the 103 reports in the older children, forty-eight described extensive limb swelling or included measurements of the swelling with at least one dimension greater than 10 cm. Descriptions like "swollen, red, hot from groin to ankle" and "arm swollen from elbow to shoulder" are typical. Based on the children's ages, 37 of the reports are likely to relate to a fourth dose of DTPa and 11 to a fifth dose. The possibility of these reactions is mentioned in the Australian product information for the vaccines.

This reporting needs to be seen in the context of approximately 250,000 Australian children being eligible each year to be given either a fourth or fifth dose of DTPa. The estimated frequency of extensive limb swelling after booster doses of DTPa is about 2%.1 The frequency with which extensive limb swelling was encountered with whole cell pertussis-containing vaccines (DTPw) is less well documented as booster doses were introduced in many countries without prior clinical studies, but in one recent study was also 2%.2 Extensive local reactions involving most of the upper arm or thigh have also been described following booster doses of diphtheria-tetanus vaccine (DT) which does not contain pertussis.2 It has been proposed that DTPa-associated extensive limb swelling reactions occur more commonly with those vaccines which contain larger amounts of diphtheria antigens, but further study is needed.

In the forty-eight reports to ADRAC of extensive limb swelling reactions to DTPa, the outcome was "unknown" for 7 reports and "not yet recovered" for 14 reports. In all the other reports the child was said to have recovered without sequelae. This is consistent with a published report of twenty cases of such swelling, all of which subsided spontaneously, completely and without sequelae.1 To date there is insufficient information available about whether a child who has experienced extensive limb swelling after the fourth dose of DTPa would be likely to have a similar reaction to a fifth dose at four years of age.

DTPa generally causes far fewer local reactions than DTPw, but extensive limb swelling seems to occur with both vaccines with equal frequency. Parents should be warned of this possible adverse reaction. As the swelling resolves without sequelae, and pertussis continues to circulate in the community, it is recommended that a child who develops extensive limb swelling after a fourth dose of DTPa be offered a fifth dose of DTPa, with appropriate informed parental consent. This recommendation is endorsed by the Australian Technical Advisory Group on Immunisation (ATAGI).


  1. Rennels MB, Deloria MA, Pichichero ME et al. Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines. Pediatrics 2000; 105: e 1 - e 12.
  2. Miller E, Rush M, Ashworth LAE et al. Antibody responses and reactions to the whole cell pertussis component of a combined diphtheria/tetanus/pertussis vaccine given at school entry. Vaccine 1995; 13: 1183-86.

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P-glycoprotein - another way for drugs to interact

There have been several published case reports in which a macrolide antibiotic (eg erythromycin, roxithromycin), most commonly clarithromycin, has increased blood concentrations of digoxin. Initially the underlying mechanism was not understood as digoxin is renally excreted and not significantly metabolised by the liver. It is now known that digoxin is transported by, and clarithromycin is an inhibitor of, P-glycoprotein (P-gp). P-gp is perhaps better known for causing multidrug resistance in malignant tumours but it is also a drug transporter pump in the gut and kidneys and many other organs. P-gp in the gut pumps drug back into the gut lumen, therefore if the pump is inhibited, the result will be an increase in concentration of the substrate drug in the body.

ADRAC has received 2 reports of digoxin toxicity occurring in patients given roxithromycin. A 76 year old female, who had maintained digoxin concentrations in the therapeutic range, presented with nausea, vomiting, fatigue and malaise 4 days after starting roxithromycin 300 mg a day. Her digoxin level was 7.5 nmol/L. She recovered after the antibiotic was ceased and her digoxin level returned to the therapeutic range. This report has been published.1 An 80 year old woman, on daily digoxin, presented with malaise, vomiting and confusion after the addition of roxithromycin 300 mg daily for 9 days. Her digoxin level was 6.3 nmol/L. She had not recovered at the time the report was submitted.

Both these cases are consistent with roxithromycin inhibiting P-gp and hence increasing the net amount of absorption from the gut and reducing the renal excretion of digoxin. Both women were on a dose of 250 µg digoxin daily which is high for their age group and may have put them at greater risk of toxicity due to the interaction. Many, but not all, of the drugs which are transported by P-gp are also metabolised by cytochrome P4503A4 which can confuse the interpretation of interactions. This is not a problem with digoxin. Other common substrates for P-gp are cyclosporin, fluoroquinolones, HIV-protease inhibitors, lignocaine, quinidine and ranitidine. Common inhibitors are diltiazem, verapamil and macrolide antibiotics. Prescribers should be aware of the potential for interactions caused by this mechanism.


  1. Corallo CE, Rogers IR. Roxithromycin-induced digoxin toxicity. MJA 1996; 165: 433-4.

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Nitrofurantoin and peripheral neuropathy

A recent letter to the Medical Journal of Australia highlighted a case of peripheral neuropathy in association with nitrofurantoin, an antibiotic used for urinary tract infection prophylaxis.1 This is a well known effect of nitrofurantoin but awareness of it may be declining as nitrofurantoin is used less frequently.

ADRAC has received 18 reports of peripheral neuropathy since 1978. While there were no reports received between 1990 and 1997, there have been three in the last 4 years. Most (15/18) of the reports have involved elderly females. Daily dosages have ranged from 100 to 400 mg with a median of 250 mg. The time to onset has ranged from 3 weeks to over 12 months (median: 2-3 months) before the reaction was identified. Only 4 of the 18 patients were documented as having recovered at the time the report was submitted to ADRAC. Peripheral neuropathy can be both severe and irreversible.

Prescribers should take care with the use of nitrofurantoin in the elderly, those with renal impairment and those taking the drug for prolonged periods. Particular attention to the use of the minimum effective dose may reduce the possibility of occurrence of peripheral neuropathy and any suggestive symptoms should trigger cessation of the drug.


  1. Spring PJ, Sharpe DM, Hayes MW. Nitrofurantoin and peripheral neuropathy: a forgotten problem? MJA 2001; 174: 153-4.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Bupropion (Zyban)
  • Celecoxib (Celebrex)
  • Gatifloxacin (Tequin)
  • Leflunomide (Arava)
  • Mirtazapine (Avanza, Remeron)
  • Moxifloxacin (Avelox)
  • Oseltamivir (Tamiflu)
  • Oxcarbazepine (Trileptal)
  • Pioglitazone (Actos)
  • Quetiapine (Seroquel)
  • Raloxifene (Evista)
  • Repaglinide (NovoNorm)
  • Risedronate (Actonel)
  • Rivastigmine (Exelon)
  • Rofecoxib (Vioxx)
  • Rosiglitazone (Avandia)
  • Sildenafil (Viagra)
  • Tibolone (Livial)
  • Tramadol (Tramal)
  • Zolpidem (Stilnox)

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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:

ISSN 0812-3837

© Commonwealth of Australia 2001

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

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