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Australian Adverse Drug Reactions Bulletin, Vol 18, No 4

December 1999

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


Methotrexate misadventures - a need for care and counselling

Methotrexate is a widely used drug that carries particular risks of serious illness and death through misadventure. Three brands of metho-trexate 2.5 mg tablets: Ledertrexate (Wyeth Lederle), Methoblastin (Pharmacia & Upjohn) and Methotrexate (DBL) are distributed in Australia. In addition, a 10mg tablet: Metho-blastin (Pharmacia & Upjohn) is available.

Currently, all of these tablets are small and yellow.1 Although each tablet is marked with a code, this has not prevented confusion between the 2.5mg and 10mg strengths. In cases known to ADRAC in both Australia and overseas, medication errors have been due either to the dispensing of the wrong strength or the patient taking the wrong strength.2,3 The risk of misadventure is increased when a patient has supplies of both strengths, as may be needed to provide a particular dose.

A separate source of risk is the dose frequency. Quite different dosage regimens are used for the treatment of different diseases. In the treatment of some diseases such as rheumatoid arthritis and psoriasis, the patient is often told to take a dose once each week. There are instances where this dose has, instead, been taken each day or on several days each week resulting in severe unwanted effects such as neutropenia, hepatotoxicity, and bone marrow depression.4

Whenever methotrexate tablets are prescribed or dispensed, it is imperative that there be no doubt that the patient understands the strength of tablets being supplied, any changes in the strength of tablets and when the tablets are to be taken. If the tablets are to be taken once each week, it is essential for the prescriber to nominate the day and for this to be included on the label at dispensing.


  1. The sponsor of Methoblastin 10 mg, Pharmacia & Upjohn, is believed to be giving consideration to a change in the shape of the 10 mg tablet.
  2. Davies J. Potential Problems with Methotrexate Prescribing. Br J Rheumatology 1994; 33: 991.
  3. Isadale AH, Hordon LD, Daly M. Methotrexate Mishap. Br J Rheumatology 1994; 33: 503-4.
  4. ADRAC. Low dose methotrexate therapy - toxic if not taken correctly. MJA 1994; 161: 152.

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Constipation .... it can be severe with clozapine

Some drugs such as the narcotic analgesics are well known to cause constipation. However, the major drug causes of constipation reported to ADRAC come almost exclusively from 5 drug classes - calcium channel blockers (CCBs), NSAIDs, tricyclic antidepressants, lipid lowering drugs and SSRIs. The two most commonly reported are the CCBs verapamil (76 reports) and amlodipine (35).

Fifteen reports of constipation with clozapine have also been reported to ADRAC. Of these, 9 were described as severe with faecal impaction noted in 4 reports. While most patients recovered when clozapine was stopped, subacute bowel obstruction was reported in 2 cases and another report described rectal prolapse requiring ileostomy. The outcome in 7 cases was unknown and one patient died.1 In this case, a 47 year old male had unreported constipation which developed into severe faecal impaction. He died suddenly in hospital, probably as a result of inhalation of faeculant vomitus. This case is very similar to another published report in which a 29 year old male died after aspiration of vomitus secondary to obstruction of the transverse colon.2

Earlier this year, the Medicines Control Authority in the UK published an overview of 20 reports of reactions with clozapine suggesting gastrointestinal obstruction including 3 fatalities.3 It was speculated that reactions of this type are due to the anticholinergic properties of clozapine and may be more likely to occur in patients also taking other drugs which have anticholinergic effects.

It is important for prescribers to recognise and treat constipation in patients taking clozapine to prevent the development of more serious complications.


  1. Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust NZ J Psychiatry 1997; 31: 149-50.
  2. Hayes G, Gibler B. Clozapine-induced constipation. Am J Psychiatry 1995; 152: 298.
  3. Committee on Safety of Medicines/Medicines Control Agency. Clozapine (Clozaril) and gastrointestinal obstruction. Curr Prob Pharmacovigilance 1999; 25: 1.

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TTP with ticlopidine

ADRAC recently received its first report of TTP (thrombotic thrombocytopenic purpura) in association with ticlopidine (Ticlid). TTP is a life-threatening syndrome of thrombocytopenia and microangiopathic haemolytic anaemia commonly associated with fluctuating neurological abnormalities, renal dysfunction, and fever. A central feature is widely disseminated platelet aggregates, which have been particularly observed in the adrenal glands, brain, heart, kidneys, and pancreas. The association of TTP with ticlopidine has been the subject of two recent publications.1,2

In the report to ADRAC, a 56 year old female was admitted to hospital with spontaneous bruising on the arms, chest and legs after about 3 weeks use of ticlopidine for coronary stenting. Laboratory investigations showed thrombocytopenia (platelets 9 x 109/L [reference range: 150-400 x 109/L]) and declining haemoglobin (haemoglobin 88 g/L [reference range: 115-165 g/L]). There were microangiopathic red cells consistent with TTP on full blood examination. The patient's highest recorded temperature was 38ºC and she had haematuria in addition to the spontaneous bruising. Neurological signs and symptoms included severe headaches and neck stiffness. She recovered after aggressive treatment which included plasmapheresis.

TTP is a rare and often fatal disorder with an estimated incidence of 3.7 cases per million people (0.0004%).3 Ticlopidine is one of several drugs that has been associated with the disorder and a recent estimate of the incidence amongst ticlopidine-treated patients is 0.02%.2 As mortality exceeds 20%, it is important that this complication is recognised promptly, the suspected drug ceased and treatment commenced rapidly.

Ticlopidine is likely to become more widely used because its indications have been broadened to include use in patients with coronary stents, and prescribers need to be aware of the possibility of TTP.


  1. Chen DK, Kim JS, Sutton DMC. Thrombotic thrombocytopenic purpura associated with ticlopidine use. Arch Intern Med 1999; 159: 311-4.
  2. Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA 1999; 281: 806-10.
  3. Török TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States: analysis of national mortality data, 1968-1991. Am J Hematol 1995; 50: 84-90.

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Thanks for your reports

Chart showing Reports to ADRAC over the past 4 financial years

The figure shows the number of reports received by ADRAC over the past 4 financial years. There has been a steady increase over that time and this has maintained Australia's reporting rate as one of the highest in the world. Much of this increase has come from the pharmaceutical industry and although ADRAC welcomes its support, the Committee encourages health professionals to send their reports direct to ADRAC using a blue card. ADRAC's ability to monitor the safety of drugs is dependent on your reports.

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Drugs of current interest

The Committee maintains a list of drugs for which reporting of all reactions - mild or serious, previously described or unexpected - is encouraged. Most of the drugs on the list have been registered in Australia recently and intensified reporting is helpful in showing whether postmarketing experience reflects the clinical trial experience on which registration was based. The Committee updates the list regularly.

Please report all suspected reactions to these Drugs of Current Interest

  • Acamprosate (Campral)
  • Candesartan (Atacand)
  • Carvedilol (Dilatrend, Kredex)
  • Celecoxib (Celebrex)
  • Clopidogrel (Iscover, Plavix)
  • Donepezil (Aricept)
  • Entacapone (Comtan)
  • Gelatin succinylated (Gelofusine)
  • Montelukast (Singulair)
  • Naltrexone (ReVia)
  • Naratriptan (Naramig)
  • Nefazodone (Serzone)
  • Raloxifene (Evista)
  • Sildenafil (Viagra)
  • Telmisartan (Micardis/Pritor)
  • Tiludronate (Skelid)
  • Tramadol (Tramal)
  • Zafirlukast (Accolate)
  • Zanamavir (Relenza)
  • Zolmitriptan (Zomig)

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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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