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Australian Adverse Drug Reactions Bulletin, Vol 25, No 2

April 2006

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

Contents

Hepatotoxicity with black cohosh

Preparations of black cohosh (Cimicifuga racemosa) are used commonly for the relief of symptoms of menopause.1 Recently, reports have been received in Australia and overseas of serious hepatic reactions occurring in association with black cohosh use, and in four cases the patient experienced hepatic failure requiring liver transplantation.

Currently, ADRAC is aware of 49 cases of hepatotoxicity with black cohosh worldwide, including 11 Australian reports. The details of five cases have been published.2-5 One was an autoimmune hepatitis,5 but others have involved massive and sub-massive necrosis.2-4 Serious cases have occurred with use for less than a month.2,5

Many of the reports are confounded by use of other medication and by the range of ingredients in the herbal formulation being used. However, the lack of other identifiable causal substance/s and exclusion of viral infection in the serious cases suggests that there may be a causal association between black cohosh and serious hepatitis.

There are currently about 200 listed medicines containing black cohosh available in Australia. Considering the widespread use of black cohosh in Australia and around the world, the number of known cases of hepatotoxicity with this substance is very low. Because of the perceived safety of herbal products, it is possible that there have been cases for which the causal link has not been suspected. The proportion of cases reported may be considerably less than would be expected for a conventional medicine.

Patients presenting with hepatic dysfunction should be questioned about their use of alternative medicines, including herbal and other complementary medicines, as well as alcohol and conventional medicines. ADRAC asks that any cases suspected of being caused by black cohosh (or any other medicine) are reported.

References

  1. Osmers R, Friede M, Liske E, Schnitker J et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105:1074 83.
  2. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. MJA 2002;177:440-1.
  3. Lontos S et al. Acute liver failure associated with the use of herbal preparations containing black cohosh. MJA 2003;197:390-1.
  4. Levitsky J et al. Fulminant liver failure associated with the use of black cohosh. Digestive Diseases & Sciences 2005;50:538-9.
  5. Cohen SM et al. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 2004;11:575-7.

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Medical Alert devices

Patients with conditions including serious allergies, diabetes, epilepsy, specific heart diseases, warfarin therapy and asthma may benefit from the use of medical identification devices in the form of a bracelet, necklace or wallet card.1,2 Examples of medical alert devices available in Australia include 'Medic-Alert', 'Medic Tag' 'SOS Talisman' and 'Vial of Life' (see Table 1). They are imprinted with the person's identity, relevant medical condition, including allergies, and other details such as drugs required or specialised medical contact.

People with a serious condition that requires immediate medical attention in case of accidents and emergencies are encouraged to wear or carry with them some form of medical identification.

Table 1: Medical Alert Devices
Alert system Devices used Contact details
Medic Alert Bracelet, plastic wallet card, digital information fitted to a key Medic Alert Foundation
email: medic@medicalert.com.au
Medic Tag Digital information fitted to a key ring Retail pharmacies; MedicTag
SOS Talisman Locket Retail pharmacies; International Diabetes Institute; Alzheimer's Australia; Haemophilia support groups.
Vial of Life Small vial and plastic wallet Retail pharmacies; COTA National Seniors

References

  1. Morton L, Murad S, Omar RZ, Taylor K. Importance of emergency identification schemes Emer Med J 2002;19:584-586
  2. Baker R, Coughlin PB, Gallus AS, Harper PL, Salem HS, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. MJA 2004; 181 (9): 492-497

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Interactions with macrolides

The macrolide antibiotics (erythromycin, roxithromycin, clarithromycin and azithromycin) are well-known to interact with other medicines. In 10 years from 1995 to 2004, ADRAC received 31 reports of a suspected interaction out of the 597 reports involving erythromycin. The most commonly reported interacting drugs have been warfarin, statins, cisapride, anticonvulsants and ergot derivatives. The basis for these interactions is considered to be cytochrome P4503A, particularly 3A4, and also p-glycoprotein, particularly for digoxin.1 It is also possible that the interactions with warfarin have a mechanism which does not involve CYP3A4. Details of the most commonly reported interactions are shown in Table 2.

Roxithromycin is often considered to have less potential for interactions than erythromycin due to its much lower affinity for CYP3A4, but reports to ADRAC suggest otherwise. Of the 737 reports for roxithromycin in the past ten years, 80 have described interactions. The majority of these have described interactions with warfarin but there are also reports of interactions with anticonvulsants, statins, digoxin and cyclosporin (see Table 2). It is probable that the interaction with warfarin has a mechanism not involving CYP3A4.

Clarithromycin, a potent inhibitor of CYP3A4, has a similar level of reported interactions, with 18 out of 193 reports. Warfarin is again the most commonly suspected interacting medicine, and statins and anticonvulsants are also represented (Table 2).

Azithromycin is considered to have little potential for interactions but of the 111 reports received for this medicine, 6 have described interactions with either warfarin or tacrolimus (Table 2).

Prescribers should be aware of the potential for interactions with all of the macrolides, especially with those medicines known to be subject to interactions such as warfarin, digoxin, anticonvulsants, statins and immunosuppressants, many of which also have a low therapeutic index.

Table 2: Interactions with Macrolides from 1995 to 2004
Drug/Class No. of reports Reported clinical effect
Warfarin Roxithromycin - 53 Increase in INR in almost all reports, with bleeding reported in 1/3 of the cases
Clarithromycin - 7
Erythromycin - 6
Azithromycin - 4
Anticonvulsants Roxithromycin - 5 Increase in anticonvulsant levels or adverse effects - mainly carbamazepine and sodium valproate
Erythromycin - 3
Clarithromycin - 2
Statins Roxithromycin - 5 Rhabdomyolysis in 9 cases, all with simvastatin
Erythromycin - 4
Clarithromycin - 2
Cisapride Erythromycin - 4 Prolonged QT interval (2) with torsades de pointes in 1
Immunosuppressants Roxithromycin - 3 Increase in cyclosporin levels and renal impairment
Clarithromycin - 2
Erythromycin - 1
Azithromycin - 2 Increase in tacrolimus levels and renal impairment
Erythromycin - 1
Digoxin Roxithromycin - 3 Increase in digoxin levels, vomiting, confusion
Clarythromycin - 1
Ergots Erythromycin - 2 Peripheral ischaemia (ergotism) in both cases

Reference

  1. ADRAC. P-glycoprotein - another way for drugs to interact. Aust Adv Drug React Bull 2001; 20: 11.

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Changes to ADRAC membership

Long-standing Member, Professor David Isaacs has retired from the ADRAC. The ADRAC thanks David for his valuable contributions to the work of the ADRAC and wishes him well in his future endeavours.

ADRAC welcomes aboard new Member, Dr Michael Gold, specialist immunologist/paediatrician from the University Department of Paediatrics, Women's and Children's Hospital, SA.

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Atomoxetine (Strattera)
  • Ezetimibe (Ezetrol)
  • Fenofibrate (Lipidil)
  • Iron sucrose (Venofer)
  • Pimecrolimus (Elidel)
  • Pregabalin (Lyrica)
  • Teriparatide (Fortéo)

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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 2006

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

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