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Australian Adverse Drug Reactions Bulletin, Vol 21, No 2

June 2002

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

Contents

Sildenafil - three years experience

Sildenafil (Viagra) has now been available in Australia for over 3 years. During that time ADRAC has received 773 reports for sildenafil with it as the only suspected drug in 741. Most of these reports describe reactions that are relatively minor in nature and are consistent with the pharmacology of the drug and the adverse effects observed during clinical trials (see Table 1).

Table 1 Most Commonly Reported Reactions with Sildenafil
Adverse Reaction Number of Reports
Headache 233
Flushing 139
Abnormal vision 65
Therapeutic inefficacy 51
Rhinitis 42
Chest pain 34
Dizziness 31
Dyspepsia 28
Nausea 27
Myocardial infarction 20
Abdominal pain 16
Palpitation 16
Priapism 16

There have been, however, 20 reports describing myocardial infarction which included 4 with a fatal outcome. Nine of the 20 patients had established cardiovascular disease or diabetes, or were at high risk of cardiovascular disease, and one was taking concomitant nitrates. There have also been 26 other reports of chest pain and 10 other reports which described a fatal outcome: 6 sudden unexplained deaths, 2 strokes and 2 subarachnoid haemorrhages. The temporal relationship to the ingestion of sildenafil was often not reported and in only 23 of these 56 cases could it be inferred that the event occurred within 6 hours of the use of the drug.

Because ingestion of sildenafil occurs in the context of sexual intercourse and, in some cases, underlying coronary disease, the contribution of sildenafil to cardiac events is difficult to assess. Information on prior risk factors and accurate details on drug ingestion and timing of the adverse reaction are often lacking. Resolution of the role of sildenafil requires robust epidemiological studies, however a recent publication which shows no evidence for a higher incidence of fatal myocardial infarction or ischaemic heart disease among users of sildenafil provides some reassurance that sildenafil may not be a primary cause of cardiovascular events.1

Prescribers are reminded that the drug is contraindicated in men for whom sexual intercourse is inadvisable such as those with severe cardiovascular disease, established cardiac failure and unstable angina pectoris. The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing. Sildenafil has been shown to potentiate the hypotensive effects of both acute and chronic nitrate administration and, therefore, its coadministration with nitrates in any form, either regularly or intermittently, is contraindicated.

Reference

  1. Shakir SAW, Wilton LV, Boshier A, Layton D, Heeley E. Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England. BMJ 2001; 322: 651-2.

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Haemorrhagic cystitis with ticarcillin in cystic fibrosis patients

Only 58 reports of haemorrhagic cystitis, characterised by dysuria and haematuria, have been reported to ADRAC since 1972. The reaction is well known in association with cyclophosphamide (22 reports) and tiaprofenic acid (8) but it may not be appreciated that ticarcillin, a semisynthetic antibacterial agent derived from penicillin is also an important cause. Ticarcillin either alone (which is no longer available) or in combination with clavulanic acid (Timentin) is registered for intravenous administration in the treatment and prophylaxis of many infections including those that complicate cystic fibrosis. Fifteen reports of haemorrhagic cystitis with ticarcillin or ticarcillin-clavulanic acid have been received by ADRAC since 1980 and describe 9 males and 6 females aged 2 to 19 years. All had cystic fibrosis. Onset of the reaction occurred from four hours to 3 weeks after starting ticarcillin.

Three reports documented recurrence of the haemorrhagic cystitis on rechallenge. In one case, cystitis occurred 11 days after the first course in a girl at 13 years of age, 8 days after the second course at 16 years and 4 hours after the first dose of the third course at 18 years of age. Three reports included ultrasound evidence of bladder wall thickening. Ticarcillin is known to increase bleeding time and in the two patients where this was tested, it was normal in one and prolonged in the other. Almost all patients recovered quickly after withdrawal of ticarcillin. There are two publications in the literature describing 3 children with cystic fibrosis who developed this reaction after the use of ticarcillin.1,2

Ticarcillin is a rare cause of haemorrhagic cystitis. Health professionals should be aware that prompt recognition and withdrawal of ticarcillin usually results in rapid recovery. It appears from the reports to ADRAC and elsewhere that paediatric patients with cystic fibrosis are those most at risk.

References

  1. Marx CM, Alpert SE. Ticarcillin-induced cystitis. Cross reactivity with related penicillins. Am J Dis Child 1984; 138: 670-2.
  2. Relling MV, Schunk JE. Drug-induced haemorrhagic cystitis. Clin Pharm 1986; 5: 590-7.

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Venous thromboembolism with third generation oral contraceptives and cyproterone

Third generation oral contraceptives

Venous thromboembolism (VTE) is a recognised complication of oral contraceptives. For a number of years it has been debated whether "third generation" (containing desogestrel or gestodene) combined oral contraceptive pills (OCP) carry a higher risk of VTE than "second generation" OCP (containing levonorgestrel or norethist-erone). A number of independent studies addressing the issue have been published.1,2 The European Agency for the Evaluation of Medicinal Products (EMEA) released its final position statement in September 2001 which indicates a "small increased risk of venous thrombo-embolism" with OCPs containing desogestrel or gestodene compared with second generation OCPs.3 The overall conclusions of both the EMEA and an earlier statement from New Zealand Medsafe in 1996 4are as follows:

  • VTE is a rare adverse effect of all combined oral contraceptives. The level of risk is low (and lower than in pregnancy) and the benefits of the use of OCPs compare favourably with the risks. The risks of VTE are highest in the first year of use.
  • The risk of developing VTE with third generation OCPs is about twice that of second generation OCPs.
  • It has been estimated that for every 10,000 women on a second generation OCP for a year, 2 women would be expected to develop a clot. For third generation OCPs, that figure is estimated to be about 3 to 4 women per 10,000 per year.
  • Major risk factors for VTE include inherited thrombophilia, obesity, smoking, old age, trauma, pregnancy, surgery, and immobilisation. (see article in the Australian Prescriber accompanying this Bulletin).5

Third generation OCPs marketed in Australia are shown in Table 2. These products are not extensively used in Australia.

Combined cyproterone products

New Zealand Medsafe has also released a statement concerning oral contraceptives containing cyproterone.6 The conclusion of its review is that:

  • The risk of developing VTE with cyproterone OCPs is about 4 times that of second generation OCPs.
  • It has been estimated that for every 10,000 women on an OCP containing cyproterone, about 8 women per year would be expected to develop a clot.

In Australia, products containing low dose cyproterone (2 mg) combined with ethinyloestradiol (see Table 2) are not indicated for contraception but for treatment of signs of androgenisation in women. These include severe acne where prolonged oral antibiotics or local treatment alone has not been successful, and idiopathic hirsutism of mild to moderate degree. These products will also provide effective oral contraception in this patient group but they are not available on the PBS.

ADRAC suggests that all women being prescribed combined oral contraceptives or combined cyproterone products should be advised of the benefits and risks. Each woman should be assessed carefully for inherent or pre-existing risk factors, including family history. For cyproterone, the indications for use should be followed.

Table 2 Combined Oral Contraceptive and Cyproterone Products Available in Australia
Second Generation OCPs Levonorgestrel Norethisterone
Biphasil, Levlen, Loette, Logynon, Microgynon, Monofeme, Nordette, Nordiol, Sequilar, Trifeme, Triphasil, Triquilar Brevinor, Improvil, Norimin, Norinyl, Synphasic
Third Generation OCPs Desogestrel Gestodene
Marvelon Femoden, Minulet, Tri-Minulet, Trioden
Cyproterone Brenda, Diane, Juliet

References

  1. Committee on Safety of Medicines/Medicines Control Agency. Combined oral contraceptives containing deso-gestrel or gestodene and the risk of venous thrombo-embolism. Curr Problems Pharmacovigilance 1999; 25: 12.
  2. Spitzer W, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83-88.
  1. The European Agency for the Evaluation of Medicinal products, Committee for Proprietary Medicinal Products (CPMP). Position Statement: CPMP concludes its assess-ment of 'third generation' combined oral contraceptives and the risk of venous thromboembolism. Available from:
  2. Medsafe Editorial Team. The risk of venous thrombo-embolism with third generation oral contraceptives. Available from http://www.medsafe.govt.nz/Profs/PUarticles/contraceptivesJuly96.htm (viewed 4 March 2002).
  3. Weisberg E. Contraception, hormone replacement therapy and thrombosis. Aust Prescr 2002; 25: 57-59.
  4. Savage R. Venous thromboembolism with Diane 35 and Estelle 35. Available from http://www.medsafe.govt.nz/Profs/PUarticles/VTEwithCPA.htm (viewed 9 April 2002).

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Bupropion (Zyban)
  • Galantamine (Reminyl)
  • Gatifloxacin (Tequin)
  • Leflunomide (Arava)
  • Lercanidipine (Zanidip)
  • Meloxicam (Mobic)
  • Mirtazapine (Avanza, Remeron)
  • Moxifloxacin (Avelox)
  • Oseltamivir (Tamiflu)
  • Oxcarbazepine (Trileptal)
  • Pioglitazone (Actos)
  • Quetiapine (Seroquel)
  • Reboxetine (Tegaserod)
  • Risedronate (Actonel)
  • Rivastigmine (Exelon)
  • Rofecoxib (Vioxx)
  • Rosiglitazone (Avandia)
  • Sibutramine (Reductil)
  • Tegaserod (Zelmac)
  • Zolpidem (Stilnox)

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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 2002

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

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