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Australian Adverse Drug Reactions Bulletin, Vol 14, No 4

November 1995

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


Nitrofurantoin and the lung

Nitrofurantoin is an antibiotic used for the treatment of urinary tract infections, especially for prolonged prophylaxis in patients with recurrent infection. Adverse respiratory reactions have been documented in almost a quarter (98) of the 400 reports received by ADRAC in the period from November, 1972 to the present time. These reactions fall into two categories, early and late onset, and reports to ADRAC clearly show this pattern. Of the 90 cases for which the information is available, 54 reactions occurred within 3 weeks of commencing therapy and 32 occurred after 6 months or longer.

In general, early onset reactions are less severe and recovery usually occurs shortly after the drug is withdrawn. The most common presenting respiratory symptom was dyspnoea or coughing and this was usually part of a multisystem hypersensitivity reaction which can include rash, fever, rigors, nausea and vomiting. It is often described as an "acute pulmonary hypersensitivity reaction" and may occur as soon as a few hours after the first dose. There have been, however, 9 reports described as pulmonary fibrosis (2) or infiltration (7). Recovery was documented in 6 cases but in one case where fibrosis was strongly suspected from the chest X-ray, the outcome was fatal, probably because of respiratory failure.

Late onset reactions are usually more severe and 22 of these featured major changes to lung function caused by pulmonary fibrosis and infiltration. The age (range: 51-88, median: 67 years) and sex distribution (F:M = 19:3) probably reflects the prescribing of the drug. Clinical presentation ranged from a dry cough with mild, but often insidiously progressive, dyspnoea on exertion to fatal respiratory failure. The most common clinical signs were bilateral 'crackles' or rales audible over most of the lung fields. In many cases histopathology reports documented chronic interstitial inflammatory changes with associated fibrosis. In at least 7 cases, patients were taking the minimum dose of 50 mg per day. Only 5 patients had recovered and 14 had not recovered at the time the report was submitted although of those 14, there was significant improvement in 5 patients after the drug was withdrawn. Three reports documented a fatal outcome, and there were also two fatalities in reports of intermediate character (2-3 months use). In at least three of these cases the cause of death appeared to be respiratory failure.

Pulmonary reactions to nitrofurantoin, although rare, are associated with significant morbidity and mortality. Withdrawal of nitrofurantoin is often followed by rapid regression of symptoms but especially with reactions arising from long term use, resolution may be incomplete or may progress to respiratory failure.

Omeprazole ...

Omeprazole (Losec) is a 'proton pump inhibitor' which is used to reduce gastric acid secretion in patients with peptic ulcers and reflux oesophagitis. Its use appears to be increasing and ADRAC has recently become aware of two unusual adverse reactions which have occurred in association with the drug.

... and musculoskeletal problems

ADRAC has received 19 reports (13 female) describing musculoskeletal problems associated with omeprazole. Ages ranged from 43 to 91 (median 55) years. Of the 16 patients for whom the information is available, 14 took 20 mg daily, 2 took 40 mg and the onset of symptoms occurred as early as one day and as late as 12 months after starting omeprazole. Eight reports documented joint pain and/or swelling including gout in two cases (one of which was confirmed by rechallenge). Nine reports described muscle pain and/or atrophy and symptoms recurred on rechallenge in two of these. Two reports documented both myalgia and arthralgia occurring simultaneously. One report documented a marked elevation of plasma creatine phosphokinase. Ten reports documented recovery, usually within a few days, 4 patients had not recovered a few months after the drug was stopped, and except for an elderly man who died from an unrelated cause, the outcome is unknown in the 4 other cases. Recent overseas reports1 have also documented similar problems and the product information has been updated to include mention of arthralgia, myalgia and muscular weakness.

Prescribers should be aware that the onset of muscle and/or joint problems may be related to omeprazole therapy and may resolve on its withdrawal.


  1. Beutler M, Hartmann K, Kuhn M, Gartmann J. Arthralgias and omeprazole. BMJ 1994; 309: 1620.

... and interstitial nephritis

Recently the Committee received a report of a 51 year old man who developed interstitial nephritis several months after commencing omeprazole (Losec) 20 mg daily as treatment for reflux oesophagitis. He had tolerated omeprazole well for the first two months but then developed marked fatigue and rigors. Urine microscopy revealed over 40,000 red cells and 8,000 white cells per mL. His serum creatinine peaked at 0.19 mmol/L and a peripheral eosinophilia of 4.7% was noted. Renal biopsy revealed a marked interstitial infiltrate with prominent eosinophils consistent with acute interstitial nephritis. Omeprazole was withdrawn, he was treated with prednisone and improved rapidly.

Two other Australian1,2 and four overseas3 case reports have similarly described interstitial nephritis in association with omeprazole therapy. In these 6 patients who ranged in age from 58 to 86 (median: 75) years, onset occurred from a few weeks to 6 months after commencement of omeprazole therapy and for 3 patients, the reaction recurred on rechallenge. The triad of fever, rash and eosinophilia, is described as the classical presentation of drug-induced interstitial nephritis, but this was observed in only one of these 7 cases. Prescribers should be aware that interstitial nephritis can occur within the first few months after starting omeprazole.


  1. Jones B, Hewson E, Price A. Acute interstitial nephritis due to omeprazole. Lancet 1994; 344: 1017-8.
  2. Lewis C R, Somerville C, Agar J W M. Omeprazole induced acute interstitial nephritis. Aust NZ J Med 1994; 24: 578.
  3. References available on request.

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Drug-induced pancreatitis

Table: Drugs Associated with Pancreatitis
Drug No. of Reports of Pancreatitis (*)
Azathioprine 11 (4.9%)
Didanosine 9 (52.9%)
Sodium valproate 8 (2.6%)
Simvastatin 8 (0.7%)
Enalapril 5 (0.3%)
Sulindac 5 (0.8%)
Cimetidine 4 (0.6%)
Captopril 3 (0.2%)
Clozapine 3 (1.5%)
* Reports of pancreatitis as a percentage of the total number of adverse reaction reports received by ADRAC for that particular drug

Pancreatitis is an unusual adverse reaction to a drug and since 1972 ADRAC has received only 109 reports describing this association. Those drugs most commonly reported to ADRAC in association with pancreatitis are listed in the Table and these 9 drugs account for over half (51%) of the cases received. In the majority (80%) of reports, the listed drug was the only suspected causative agent and in 3 cases, the reaction recurred on rechallenge. Although the details are not always available, most patients (60%) were documented as having recovered once the drug was withdrawn. However, in 3 patients taking sodium valproate and one patient on didanosine, there was a fatal outcome.

The possibility of pancreatitis is mentioned in the product information for all the drugs in the Table, except for captopril and clozapine. The relative importance of pancreatitis as an adverse drug reaction varies from drug to drug. For didanosine, pancreatitis is probably the most common serious reaction after myelosuppression and the fact that it is described in 9 of the 17 reports submitted to ADRAC is an indication of this. For drugs which have been used extensively over the past few years and for which ADRAC has received over 1,000 adverse drug reaction reports, such as captopril, enalapril and simvastatin, pancreatitis is probably quite uncommon. For azathioprine and sodium valproate, pancreatitis is a more frequent reaction. A drug cause should be considered in patients who develop pancreatitis when no other aetiological factors have been determined.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Azithromycin (Zithromax)
  • Clarithromycin (Klacid)
  • Enoxacin (Enoxin)
  • Famciclovir (Famvir)
  • Gabapentin (Neurontin)
  • Goserelin (Zoladex)
  • Lamotrigine (Lamictal)
  • Lansoprazole (Zoton)
  • Leuprorelin (Lucrin)
  • Nafarelin (Synarel)
  • Paroxetine (Aropax 20)
  • Piperacillin/tazobactam (Tazocin)
  • Pravastatin (Pravachol)
  • Salmeterol (Serevent)
  • Sertraline (Zoloft)
  • Tacine (Cognex)
  • Terbinafine (Lamisil)
  • Ticlopidine (Ticlid)
  • Vigabatrin (Sabril)
  • Zopiclone (Imovane)

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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 1999

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

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