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Australian Adverse Drug Reactions Bulletin, Vol 16, No 3

August 1997

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


Alendronate oesophagitis - are precautions effective?

Alendronate is an aminobisphosphonate which specifically inhibits osteoclast-mediated bone resorption. The sodium salt (Fosamax) has recently been approved for treatment of osteoporosis in postmenopausal women and Paget's disease of bone. In the first half of 1997 ADRAC has received 67 reports describing suspected adverse reactions associated with the use of alendronate in 58 females and 9 males. Cases involving gastrointestinal and/or musculoskeletal symptoms accounted for 75% of the reports.

Of particular importance are 22 reports which documented early onset (mostly in the first week) of possible oesophageal problems variously described as oesophageal ulceration (3), oesophagitis (2), dysphagia (2), dyspepsia (3), indigestion (2), heartburn or epigastric pain (8), or retrosternal or other chest pain (2).Three of these reports were accompanied by the results of endoscopy. In one case these revealed "extensive ulceration of the lower half of the oesophagus", another documented "severe ulceration along the length of the oesophagus", and the third described "severe oesophagitis". Another report, which did not provide endoscopic results, described "severe total oesophageal ulceration". Three reports indicated that oesophageal problems had occurred despite compliance with the contraindications and precautions specified in the product information.

Prescribers should be aware that alendronate can cause oesophagitis which may be severe and/or extensive. The drug appears capable of causing damage to the whole length of the oesophagus. The precautions specified in the product information should be observed: in particular, the drug should be taken after getting up in the morning with a full glass of water and patients should not lie down for at least 30 minutes after the dose and until after their first food of the day.

Pethidine and convulsions

Pethidine is an opioid analgesic drug usually given parenterally for the management of severe pain. The recommended adult analgesic dose by intramuscular injection is from 25 to 100mg repeated as necessary every 3 to 4 hours. Although pethidine is similar to morphine in many pharmacological actions, its long-acting metabolite, norpethidine, can cause CNS excitation including convulsions, particularly when it accumulates with prolonged or multiple dosing, or if renal or hepatic function is impaired, or in neonates and the elderly.

Since 1975, ADRAC has received 35 reports describing convulsions in association with the administration of pethidine. Seven of these cases were confounded by the presence of the anaesthetic induction agent propofol, itself associated with the development of convulsions.1 In the 17 cases where pethidine was the only drug suspected, the age of the patients ranged from 12 to 79 (median: 35) years. In at least 10 cases, the total dose of pethidine administered was high due either to multiple intramuscular injections, or to a prolonged intravenous infusion of the drug. Another complicating factor was the presence of renal impairment in 3 individuals; a raised norpethidine level was documented in 1 patient with end-stage renal failure. In 9 patients, the convulsions were described as being of a generalised tonic-clonic nature; in the remaining 8 cases, a variety of clinical manifestations were documented such as myoclonic spasms or jerks, "minor epileptic fit" or dystonia. Following the episode of convulsions or myoclonic spasms, several patients underwent comprehensive neurological investigations but in no cases were any underlying causes found. In 15 of the 17 patients full recovery was documented.

Careful monitoring and adjustment of pethidine dosage, or the selection of an alternative analgesic agent are essential, if therapy needs to be prolonged. If convulsions occur, pethidine administration should be ceased and appropriate anticonvulsant treatment should be given if required.


  1. ADRAC. Propofol convulsions. Aust Adv Drug React Bull 1993; 12: 7.

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Drug-induced gynaecomastia

Reports of gynaecomastia (minimum 10 reports)
Drug Percentage* Total Number (sole suspected)
Spironolactone 16.1 77 (62)
Cimetidine 11.2 49 (39)
Famotidine 3.8 11 (6)
Ranitidine 2.5 32 (25)
Digoxin 2.4 22 (7)
Omeprazole 2.3 10 (8)
Verapamil 1.6 14 (7)
Simvastatin 1.2 19 (11)
Frusemide 1.1 13 (0)
Asprin 1.0 12 (0)
* percentage of all reports for that drug

Gynaecomastia is enlargement of male breast tissue which may be painful. Occasionally, this can occur as an adverse reaction to prescribed medicines. Since November 1972 ADRAC has received 332 reports (representing 0.3% of all reports received) of suspected drug-induced gynaecomastia in patients who ranged in age from 8 to 91 (median 62) years. In many cases a drug cause was not suspected initially and therapy was continued for several weeks (in some cases months) after the onset. Four reports were accompanied by the results of excision biopsies which confirmed no malignancy. In 102 reports which documented recovery, over 80% of patients recovered within 4 months of ceasing the suspected drug. The drugs most commonly reported are listed in the table below. These represent over 75% of all reports of gynaecomastia. The anti-ulcer drugs (cimetidine, ranitidine, famotidine and omeprazole) account for 30% of the total. Aspirin and frusemide must be considered unlikely causes as there have been no reports implicating either of these as the only suspected drug.

Drug-induced gynaecomastia is usually bilateral but often asymmetric. The development of gynaecomastia is considered to be related both to the daily dose and the duration of therapy. It is generally reversible after withdrawal of the drug although complete recovery may take several months. The condition is more than a cosmetic embarrassment as it is often painful and may result in concerns about the possibility of malignancy. A possible drug cause should always be considered before surgery.

Visual field defects with vigabatrin

Vigabatrin (Sabril) is a recently introduced drug which is approved for the treatment of epilepsy not satisfactorily controlled by other antiepileptic drugs. Early this year, Eke and coworkers reported visual field constriction in 3 patients in the United Kingdom who had taken vigabatrin from 2 to 3 years.1 These defects have persisted for periods up to a year after the drug was withdrawn. The mechanism is unknown at this stage.

ADRAC has received 5 Australian reports of visual field defects in association with vigabatrin. Four of these were described as concentric bilateral visual field constriction, and the other was of distorted peripheral vision. The 4 patients who developed visual field constriction had all been taking the drug long term (from 2 to 6 years) whereas the other patient had taken the drug for a month. All 5 patients had not recovered at the time the reports were submitted.

The sponsor of Sabril has recently amended the product information for the drug to include the following sentence:

Rare cases of visual field defect and retinal disorders (e.g. peripheral retinal atrophy) and very rare cases of optic neuritis or atrophy have been reported. ADRAC advises prescribers to be aware of the potential for these effects to occur with vigabatrin and the need for regular review of their patients.


  1. Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1997; 314: 180-181.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Acarbose (Glucobay)
  • Alendronate (Fosamax)
  • Cilazapril (Inhibace)
  • Dicloxacillin (Diclocil)
  • Eformoterol (Foradile)
  • Famciclovir (Famvir)
  • Fexofenadine (Telfast)
  • Fluvastatin (Lescol, Vastin)
  • Fluvoxamine (Luvox)
  • Losartan potassium (Cozaar)
  • Meropenem (Merrem)
  • Nefazodone (Serzone)
  • Olanzapine (Zyprexa)
  • Sevoflurane (Sevorane)
  • Valaciclovir (Valtrex)
  • Venlafaxine (Efexor)

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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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