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Australian Adverse Drug Reactions Bulletin, Vol 17, No 1

February 1998

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

Contents

Paradoxical reactions with midazolam in children

Midazolam (Hypnovel) is a short acting benzodiazepine which is used for sedation or as a premedication for anaesthesia. Of the 228 reports to ADRAC, 31 describe paradoxical reactions such as agitation (18 instances), aggression (11), abnormal crying (9), hallucinations (7) or emotional lability (3).

Twenty of these cases occurred in children 11 years and younger. The episodes were characterised by agitation, aggressive or violent behaviour and screaming or uncontrollable crying. Some typical examples included "confused behaviour, manic, running around the room, falling over, unsteady gait, screaming, unable to be pacified" or "extreme agitation, bordering on violent behaviour, screaming, very irritable, kicking, lashing out at parents". These events usually occurred within 30 minutes of the midazolam administration for either a premedication for general anaesthesia or as sedation prior to a procedure. Doses varied between 0.1 mg for a neonate and 17.5 mg for the 11 year old. Most doses were delivered orally but a few reports described intravenous or intranasal administration. All of the children recovered, usually after an hour or two, although in two cases the benzodiazepine antagonist flumazenil was used.

Prescribers should be aware that paradoxical reactions can occasionally occur after the use of midazolam, particularly in children.

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Venlafaxine: not just an SSRI?

Venlafaxine (Efexor), a new antidepressant drug was first marketed in Australia in mid 1996. It inhibits the neuronal reuptake of both serotonin and noradrenaline, has a weak effect on the reuptake of dopamine but has no affinity for muscarinic, histaminergic or adrenergic receptors. In this respect its adverse effect profile would be expected to be different to that of the tricyclic antidepressants which have a variety of effects on at least 5 of these neuro transmitters and more similar to that of the selective serotonin reuptake inhibitors (SSRIs) which are believed to affect only serotonergic transmission.

From marketing to December 1997, ADRAC has received 190 reports of suspected adverse reactions in association with venlafaxine. Most of these (145) implicated venlafaxine as the only suspected drug. Ages of the patients involved ranged from 21 to 84 (median 46) years. For those reports which provided the information the onset of the reaction was within the first week of therapy in over half of the reports with about half of those having their onset on the first day. In some cases the reaction occurred shortly after the daily dose had been increased.

The ten most reported reactions are shown in Table 1 together with the percentages of reports received for the SSRIs. The similarity to the SSRIs is clear. However, venlafaxine appears to have a greater association with nausea/vomiting/anorexia, headache, increased sweating, syncope and hypertension than the SSRIs. It may be that these differences, especially syncope and hypertension, are related to venlafaxine's effect on noradrenergic transmission.

Prescribers should be alert to the possibility of these reactions occurring especially in the early stages of therapy with venlafaxine.

Table 1 Most commonly reported adverse reactions with venlafaxine
  Number* Percentage of total Percentage for SSRIs
Nausea/vomiting/anorexia 54 28% 14%
Headache 25 13% 7%
Increased sweating 20 11% 5%
Rashes/urticaria/pruritus 20 11% 10%
Agitation/anxiety 18 9% 10%
Dizziness 14 8% 7%
Fatigue/weakness 13 7% 4%
Hyponatraemia 11 6% 3%
Syncope 10 5% 1%
Hypertension 9 5% 1%
Tremor 9 5% 7%
* More than one reaction can occur in a single report

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Depression - could it be the drug?

Just under 1% of all reports to ADRAC describe depression as a suspected adverse reaction to therapeutic medicines. In the seven year period from 1990 through 1996, 454 reports depression have been received. In 406 of these reports, there was no evidence suggesting pre- existing depression.

For these 406 reports, ages ranged from 4 to 95 (median: 50) years and onset varied from one day to 9 months. A single drug was implicated in 92% of the reports and in 36 of these the association was particularly convincing as the symptoms recurred on rechallenge. Recovery following withdrawal of the suspected drug(s) was documented in more than 70% of the reports. Ten reports noted that the patient had been hospitalised because of depression. Suicide attempts were described in 19 of the reports and two fatal outcomes were documented. The drugs most commonly reported in this context are listed in Table 2. As depression is common and association with commonly prescribed drugs may be coincidental, only those drugs with more than 2 reports per million prescriptions are included in the table.

Prescribers should be aware of the possibility of drug-induced depression which can sometimes be severe. If the temporal relationship is suggestive, withdrawal of a possible precipitating drug should be tried before the initiation of antidepressants.

Table 2 - Reports of Depression
  Reports per 106 prescriptions* Reports#
(minimum = 5)
Mefloquine 148.5 15
Vigabatrin 52.0 6
Dexfenfluramine** 21.3 14
Ciprofloxacin 9.3 6
Pravastatin 6.0 7
Simvastatin 4.0 53
Gemfibrozil 3.8 7
Nicotine transdermal 3.8 5

* Usage data was obtained from the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee and refers to prescriptions dispensed through community pharmacies

# Refers to those reports where the drug was the only drug suspected

** Dexfenfluramine has been recently withdrawn from marketing worldwide (see below)

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Withdrawal of fenfluramine and dexfenfluramine

In September 1997, the anti-obesity agents fenfluramine (Ponderax) and its stereoisomer dexfenfluramine (Adifax) were withdrawn worldwide following the association of valvular heart disease with these drugs. Initial reports were associated with the long term (12 ± 7 months) use of fenfluramine and phentermine but additional reports have described valvulopathy with the use of fenfluramine/dexfenfluramine alone.1,2,3 Most cases have involved aortic regurgitation, some have documented mitral regurgitation, with both occurring in a small percentage of cases.4 Although a causative effect of fenfluramine/dexfenfluramine has not been demonstrated, the association is striking. The histopathological features are also similar to those observed in carcinoid-induced valvular disease, a serotonin-related syndrome.

At the time of the withdrawal, ADRAC had received no reports of this problem but subsequently, 3 reports have been received of cardiac valve disease in association with dexfenfluramine. It would be reasonable for prescribers to investigate any of their patients who have been exposed to fenfluramine/dexfenfluramine for any length of time to determine the presence or absence of cardiopulmonary signs and/or symptoms.

ADRAC would be interested to receive reports of any such cases.

References

  1. Connolly HM, Crary JL, McGoon MD et al. Valvular heart disease associated with fenfluramine-phentermine. New Engl J Med 1997; 337: 581-8.
  2. Graham DJ, Green L. Further cases of valvular heart disease associated with fenfluramine-phentermine. New Engl J Med 1997; 337: 635.
  3. Cannistra LB, Davis SM, Bauman AG. Valvular heart disease associated with dexfenfluramine. New Engl J Med 1997; 337: 636.
  4. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: ... JAMA 1997; 278: 1729-30

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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)
  • Cilazapril (Inhibace)
  • Dicloxacillin (Diclocil)
  • Dolasetron (Anzemet)
  • Eformoterol (Foradile)
  • Famciclovir (Famvir)
  • Fexofenadine (Telfast)
  • Fluvastatin (Lescol, Vastin)
  • Fluvoxamine (Luvox)
  • Losartan potassium (Cozaar)
  • Meropenem (Merrem)
  • Nefazodone (Serzone)
  • Olanzapine (Zyprexa)
  • Sevoflurane (Sevorane)
  • Tiagabine (Gabitril)
  • Topiramate (Topamax)
  • 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: 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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