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Australian Adverse Drug Reactions Bulletin, Vol 17, No 3

August 1998

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

Contents

Bruising and bleeding with SSRIs

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Erocap, Lovan, Prozac, Zactin), paroxetine (Aropax) and sertraline (Zoloft) have become widely used in Australia. Over the past few years their use in the treatment of depression and other disorders has increased considerably and ADRAC has been able to develop a comprehensive adverse effect profile. One effect which has emerged is bruising and bleeding, which in the majority of cases is not associated with thrombocytopenia but with platelet dysfunction. The numbers of reports of purpura/bruising, thrombocytopenia, bleeding and platelet dysfunction with these three SSRIs are shown in Table 1.

Table 1 - Bruising and Bleeding with SSRIs*
  Fluoxetine Paroxetine Sertraline
Total Reports 919 1036 2023
Purpura/Bruising 20 38 16
Bleeding 10 16 41
Thrombocytopenia 9 10 5
Platelet dysfunction 5 5 4
* more than one reaction may be present in a report

The most common bleeding site was vaginal (24 cases) and other more commonly reported bleeding episodes were epistaxis (19), haematuria (10) and rectal haemorrhage (8).

Purpura appears to be an important adverse effect for the SSRIs. With 38 reports submitted to ADRAC, paroxetine is one of the most commonly reported causes of purpura. Only seven of these cases occurred in the context of thrombocytopenia.

Of the 14 reports documenting platelet abnormalities, 11 occurred in association with purpura or bleeding. Five of the reports documented abnormal platelet aggregation which is consistent with the postulate that fluoxetine may diminish granular storage of serotonin in platelets, creating a haemostatic defect which disrupts the platelet aggregation process, resulting in bleeding.1,2,3 It has been suggested that this is probably a rare situation which only occurs in individuals with an underlying platelet disorder or an altered platelet serotonin reuptake system.2,3

References

  1. Alderman CP, Moritz CK, Ben-Tovim DI. Abnormal platelet aggregation associated with fluoxetine therapy. Ann Pharmacother 1992; 26: 1517-19.
  2. Humphries JE, Wheby MS, Vandenberg SR. Fluoxetine and the bleeding time. Arch Pathol Lab Med 1990; 114: 727-8.
  3. Pai VB, Kelly MW. Bruising associated with the use of fluoxetine. Ann Pharmacother 1996; 30: 786-8.

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Worldwide withdrawal of mibefradil

Mibefradil (Posicor) is the first of a new class of calcium antagonists which blocks both T and L type channels. In Australia it had been approved for treatment of hypertension and/or chronic stable angina pectoris. Early in June the drug's sponsor announced a worldwide withdrawal of the drug because of its interactions with many other drugs.

Up until this time, ADRAC had received 55 reports of suspected adverse reactions associated with mibefradil. Bradycardia was the single most common reaction and accounted for almost half the reports. Three other reports documented interactions of mibefradil with other drugs. Two reports described rhabdomyolysis with gross elevation of creatine kinase after mibefradil was added to long term simvastatin therapy and the other report of a suspected interaction involved a 36 year old man whose cyclosporin level became elevated after mibefradil was added to his other therapy.

At the time of the withdrawal, more than 25 drugs were suspected of interacting with mibefradil. It was considered by the sponsor that this number and diversity of drugs could not be practically addressed by standard warning labels. Included in the potentially interacting drugs are amiodarone, astemizole, cisapride, cyclosporin, erythromycin, quinidine, simvastatin and terfenadine.

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Drugs that make you forget

An elderly man taking allopurinol, diclofenac and gemfibrozil was prescribed simvastatin to help control his hypercholesterolaemia. After a couple of weeks he noticed a loss of memory for recent events. This problem resolved within two weeks of stopping simvastatin and recurred within a week of restarting the drug. In another report, a middle aged woman took an indomethacin capsule for back pain and developed amnesia for the 3 hour period prior to the ingestion of the capsule and for two hours afterwards. She then recalled that she had experienced a similar effect (which she did not associate with the drug at the time) two years previously after she had taken an indomethacin capsule.

Table 2 - Reports of Drug-Induced Amnesia*
Drug Reports of Amnesia Percentage of
Total Reports
for the Drug
Sertraline 19 0.9
Simvastatin 14 0.8
Paroxetine 8 0.8
Midazolam 5 2.1
Dothiepin 5 1.6
Moclobemide 5 1.0
Fluoxetine 5 0.5
Ranitidine 5 0.4
* The drug with the highest proportion of reports (7: 3.4%), dexfenfluramine, has recently been withdrawn.

Amnesia or memory impairment in association with drug therapy is a rare occurrence and of the 73,000 reports received by ADRAC over the past ten years, this adverse reaction is documented in only 219. There are some drugs such as the benzodiazepines which are established as a cause of amnesia which would not normally be the subject of a report to ADRAC because of the well-known association. Table 2 lists those drugs most commonly reported to ADRAC in association with this effect over the past 10 years. The table also lists the reports of amnesia as a percentage of the total number of reports for each drug. Since amnesia occurs in about 0.25% of the reports in the database, the reaction might be important for those drugs in which it occurs at a considerably higher percentage than 0.25%.

Of the 219 reports of drug-induced amnesia analysed, there was a single drug suspected in the majority (84%) of the reports. Ages of the patients ranged from 5 to 98 (median: 48) years and the onset of the reaction varied from the day drug therapy was commenced to many years afterwards with most occurring during the first week of therapy. Over a quarter occurred on the day the drug was started. The reaction occurred on rechallenge in 16 of the reports and most of the patients had recovered at the time the report was submitted. A number of these cases were reminiscent of transient global amnesia suggesting that a drug cause should be considered in such instances.

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Depression with isotretinoin

There has been recent publicity linking isotretinoin (Accure, Roaccutane) with depression. From 1985 to June 1998, ADRAC has a received a total of 129 reports of suspected adverse reactions in association with isotretinoin. Of these, 12 have described depression. All the patients involved were young (age range: 15-40 years, median: 19 years, M:F = 9:3) and taking the drug for treatment of acne.

Two reports described the re-emergence of depression and in the other 10 reports, depression was noted for the first time. Two cases were described as severe and 4 cases had psychotic features. Three patients developed suicidal thoughts and two patients attempted suicide. One of these had a fatal outcome. Of the other 11 patients, 3 had recovered after withdrawal of isotretinoin, one was improving with the use of an antidepressant, and the other 7 had not recovered at the time the report was submitted.

The product information for isotretinoin states that "depression has been reported in some patients on isotretinoin therapy" and ADRAC advises prescribers to be alert for any adverse mood changes in their patients taking isotretinoin and to withdraw the drug if these occur.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Acarbose (Glucobay)
  • Alendronate (Fosamax)
  • Atorvastatin (Lipitor)
  • Carvedilol (Dilatrend, Kredex)
  • Citalopram (Cipramil)
  • Diclofenac/misoprostol (Arthrotec)
  • Dicloxacillin (Diclocil, Distaph)
  • Dolasetron (Anzemet)
  • Fexofenadine (Telfast)
  • Fluvoxamine (Luvox)
  • Irbesartan (Avapro, Karvea)
  • Losartan potassium (Cozaar)
  • Nefazodone (Serzone)
  • Nicorandil (Ikorel)
  • Olanzapine (Zyprexa)
  • Tiagabine (Gabitril)
  • Topiramate (Topamax)

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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: ADR.Reports@tga.gov.au.

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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