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Australian Adverse Drug Reactions Bulletin, Vol 23, No 2

April 2004

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

Contents

The risks and benefits of HRT

The Women's Health Initiative (WHI) study, a large randomised trial comparing combination hormone replacement therapy (HRT) to placebo, found that the increase in risk associated with long term therapy exceeded the benefits.1 In particular the promise of cardiovascular benefit from HRT was unfulfilled and therapy was found to increase the risk of cardiovascular events (see Table below).

A further surprising result of the WHI study was an increase in the incidence of dementia with HRT using oestrogen plus progestogen, and a failure to enhance cognitive function.2 The WHI study did, however, demonstrate protection against fracture with oestrogen plus progestogen,1,3 but this protection, even in women with the highest risk of fracture in the study, did not outweigh the other negative effects.3

The Million Women Study (MWS), which had a prospective observational design, further emphasised the risks of HRT, indicating a higher risk of breast cancer with oestrogen plus progestogen than with oestrogen alone (see Table).4 The results indicated that the increase in the incidence of breast cancer with oestrogen plus progestogen (compared to oestrogen alone) was greater than the reduction in incidence of endometrial cancer associated with adding progestogen to oestrogen therapy.4 The MWS also reported a significant increase in the incidence of breast cancer with tibolone and with implanted and transdermal oestrogen-only preparations.

Table: Changes in incidences of adverse events with HRT found in WHI Study and Million Women Study
Adverse event Study Therapy Baseline rate
(events per 10,000
women-years)
Change in number of
events per 10,000
women-years
Cardiovascular disease
  Coronary heart disease WHI O+P 30 7 extra1
  Stroke WHI O+P 21 8 extra1
  Venous thromboembolism WHI O+P 16 18 extra1
Cognitive function
  Dementia WHI O+P 22 23 extra2
Fracture
  All fractures WHI O+P 199 47 fewer3
  Hip fracture WHI O+P 15 5 fewer1
Cancer
  Breast WHI O+P 30 8 extra1
  MWS O+P 21 12 extra4
  MWS O 21 3 extra4
  Endometrial MWS O   8 extra (estimate)4
  Colorectal WHI O+P 16 6 fewer1

Abbreviations: WHI, Women's Health Initiative Study; MWS, Million Women Study; O, oestrogen; P, progestogen.
Note: These event rates are age-dependent: mean age in WHI 63 years; mean age at recruitment for MWS 56 years

Following its comprehensive review of these studies and other available data, the Australian Drug Evaluation Committee has recommended:5

"The use of HRT for any long term disease prevention cannot be generally justified as the potential harm may out weigh potential benefits. This concern also applies to the use of HRT to prevent osteoporosis.

"HRT has an established place in the short term management of symptoms of the menopause. For treatment of established osteoporosis, the selection of HRT by the patient and doctor should be based on a careful consideration and discussion of risks and benefits for that individual."

In addition, ADRAC advises that HRT use be for as short a time as practical, and be reviewed regularly.

References

  1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33
  2. Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62
  3. Cauley JA, Robbins J, Chen Z et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density. The Women's Health Initiative randomized trial. JAMA 2003;290:1729-38
  4. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27
  5. Australian Drug Evaluation Committee. Update to ADEC statement on use of hormone replacement therapy. 17 Oct 2003.

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Macrolides and warfarin interaction

ADRAC has received reports of interactions between warfarin and all four macrolide antibiotics (azithromycin, clarithromycin, erythromycin, and roxithromycin) (see Table).1 Although most cases were asymptomatic, some reports documented substantial increases in INR. The haemorrhagic complications reported included haematoma, haemoptysis, haematuria, melaena, and retroperitoneal haemorrhage

The one fatality reported involved a 79 year old woman who was started on warfarin and roxithromycin simultaneously. By day 8 of treatment, her INR had risen to 11.6. She subsequently died from widespread bleeding, including subdural haemorrhage and haemopericardium.

Nearly all reactions occurred in the first week after starting the antibiotic; reactions reported later than this may reflect the frequency of INR monitoring.

Table: ADRAC reports of macrolide-warfarin interaction
Drug reports
(no. symptomatic)
onset in days
(median; range)
INR
(median)
azithromycin 3 (0) 3; 2-5 9.6
clarithromycin 6 (2) 7; 0-9 7.6
erythromycin* 19 (4) 5; 0-18 9.7
roxithromycin 56 (27) 6; 0-36# 8.8

* metronidazole was another potentially interacting agent in 2 cases.
# onset > 1 year in a further patient.

Close attention should be paid to INR monitoring in patients taking warfarin who are commenced on a macrolide antibiotic. Consideration could also be given to the use of an alternative antibiotic if possible. Azithromycin has a particularly long half-life (around 68 hours), so that an interaction with warfarin may theoretically persist for some days after azithromycin has been ceased.

Reference

  1. Interaction of warfarin with macrolide antibiotics. Aust Adv Drug Reactions Bull 1995;14:11.

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Bisphosphonates and ocular inflammation

A recent report to ADRAC described an elderly male with low bone mineral density in the hip who developed uveitis three weeks after beginning to take risedronate 35 mg once weekly. He later restarted risedronate but again developed eye pain. He then switched to alendronate 70 mg once weekly but eye pain occurred again.

The bisphosphonates have become important in the treatment and prevention of osteoporosis and are also used in the treatment of Paget's disease, hypercalcaemia and skeletal metastases. The Table lists the bisphosphonates available in Australia with their product names, number of PBS prescriptions and number of reports to ADRAC.

Predominant adverse effects of the bisphosphonates are those affecting the gastro-intestinal system such as nausea, dyspepsia, abdominal pain and oesophageal disorders, and musculoskeletal effects such as arthralgia and myalgia. A small number of reports describe eye disorders, some of which were serious including uveitis (13 reports), iritis (6), scleritis/episcleritis (7), haemorrhage (4), optic neuritis (2), visual field defect (2) and one case each of scotoma, glaucoma, blindness and macular degeneration. These reports were associated with alendronate and pamidronate in 18 cases each, and with risedronate and zoledronic acid in one case each.

Table: Bisphosphonates available in Australia
Bisphosphonate
(trade name)
PBS prescriptions since 1997 Reports to ADRAC
Alendronate
(Fosamax)
5,049,000 866
Clodronate
(Bonefos)
62,000 10
Etidronate
(Didronel; Didrocal)
260,000 124
Pamidronate
(Aredia)
6,600 223
Risedronate
(Actonel)
456,000 106
Tiludronate
(Skelid)
13,000 5
Zoledronic acid
(Zometa)
316 30

Of particular interest are the 28 reports that describe inflammatory reactions such as uveitis, iritis, scleritis, episcleritis and optic neuritis. Time to onset ranged from 2 days after the drug was commenced to over 3 years, with a median time of 3 weeks. As might be expected, most of the patients were female and almost half were elderly (range 48-79; median 63 years). Details of outcome were documented for 21 patients, of whom 15 had recovered at the time the report was submitted. Four of the six who had not recovered were reported to be improving although one of them required a trabeculectomy. Another patient had reduced visual acuity.

Inflammatory ocular disorders have been reported to ADRAC and in the literature only in association with alendronate, pamidronate, risedronate and zoledronic acid.1,2 The risk may be higher with bisphosphonates administered intravenously such as pamidronate and zoledronic acid but otherwise the number of reports probably relates to usage. Minor reactions such as blurred or abnormal vision or conjunctivitis have been reported to ADRAC or overseas with etidronate, clodronate and tiludronate.1,2

Inflammatory ocular disorders appear to be a rare effect of all bisphosphonates and prescribers should be aware that eye pain, redness and abnormal vision may be indicators of such disorders.

References

  1. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med 2003;348:1187-8.
  2. Uppsala Monitoring Centre. Bisphosphonates and ocular side effects. WHO Signal 2003;Dec:15-22.

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SSRI antidepressants in children and adolescents

Because of international concern about a possible increase in suicidal ideation and self-harm behaviour with SSRIs in the treatment of major depressive disorder in children and adolescents, ADRAC has reviewed the data on safety and efficacy. A statement by ADRAC is now available on the TGA website.

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Apomorphine (Uprima)
  • Aripiprazole (Abilify)
  • Ezetimibe (Ezetrol)
  • Fondaparinux (Arixtra)
  • Galantamine (Reminyl)
  • Lercanidipine (Zanidip)
  • Levetiracetam (Keppra)
  • Meloxicam (Mobic)
  • Pioglitazone (Actos)
  • Reboxetine (Edronax)
  • Rosiglitazone (Avandia)
  • Sibutramine (Reductil)
  • Tadalafil (Cialis)
  • Tegaserod (Zelmac)

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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 2004

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

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