• Lumiracoxib
  Withdrawn
• Glucosamine
  Interaction with warfarin
• Seventeenth meeting of the Global Geneva, 12-13 December 2007
• Injectable colchicine
  Action against unapproved injectable colchicin

• Oseltamivir
  Label to include information on neuropsychiatric events
• Zanamivir
  Reports of delirium and abnormal behaviour
• Colchincine
  Adverse events prompt advice on drug choice
• Review of Oseltamivir Reports in Vigibase is reassuring but vigilance for hepatic and skin disorders recommended.

New Zealand: Lumiracoxib [Prexige] has now been withdrawn from the New Zealand market (see WHO
Pharmaceuticals Newsletters Nos. 5 and 6, 2007 for withdrawals in other countries.) Medsafe, the medicines
and medical devices safety authority in New Zealand has reviewed the latest safety data for lumiracoxib and
found reports of liver damage associated with prolonged use of low­dose lumiracoxib. The Agency has advised
current lumiracoxib users to stop taking the drug and to consult their doctor if they develop nausea, vomiting,
stomach pains, loss of appetite, yellowing or pruritus of skin, or dark urine.

Reference:

Reactions weekly, 1184: 4, 12 January 2008.

Australia. The TGA in Australia has received 12 reports suggesting an interaction between warfarin and glucosamine. Most of the cases described changes in the international normalised ratio (INR) after patients previously stable on warfarin started taking glucosamine. The INR fell slightly in two of the cases but in 10 others the INR value increased. Potentiating effect of glucosamine on warfarin activity is also reported in the WHO Individual Case Safety Reports (ICSR) Database, the Vigibase. The mechanism of this interaction is unknown. ADRAC recommends that patients taking warfarin should have their INR assessed within a few days and no later than two weeks after commencing or changing the dose of a complementary medicine.  Reference:

Australian Adverse Drug Reactions Bulletin,
Vol. 27(1): 3, February 2008 (www.tga.gov.au).

3. Seventeenth meeting of the Global Geneva, 12-13 December 2007

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body established in 1999 to respond, independently from WHO, promptly, efficiently, and with scientific rigour to vaccine safety issues of potential global importance, held its seventeenth meeting in Geneva, Switzerland, on 12-13 December 2007. Issues discussed were: Guillain-Bam§ Syndrome and vaccination; the safety of immunization for immunocompromised individuals; yellow fever vaccine safety; hepatitis B vaccination and rheumatoid arthritis; the safety of the live 14-14-2 Japanese encephalitis vaccine; the safety of meningococcal B vaccines; and rotavirus vaccines and Kawasaki disease.

Hepatitis B vaccination and rheumatoid arthritis
The Committee considered the potential association between hepatitis B vaccination and rheumatoid arthritis. Prior to previous discussions on this topic held in June 2006, the Committee had commissioned a
comprehensive literature review. At this meeting, the Committee reviewed more recent information,
particularly on genetic issues.

Safety of meningococcal B vaccines

Guillain-Barre Syndrome (GBS) and vaccination

GACVS recommended large-scale studies of the incidence of GBS before and after immunization. All cases
would need to be carefully ascertained and documented. Improved understanding of the pathogenesis of all
forms of GBS will help in the determination of possible associations between GBS and immunization. Such
studies would be particularly helpful for the investigation of such neurological adverse events following
immunization with pandemic or pre­pandemic influenza vaccines.

The report of the meeting was published in the WHO Weekly Epidemiological Record on 25 January and has been posted on the GACVS web site at http://www.who.in/vaccine_safety/en/  

4. Injectable colchicine

Reference:

Reference:

USA. The WARNINGS AND PRECAUTIONS sections of the prescribing information for zanamivir (Relenza) has been updated with information from postmarketing reports (mostly from Japan) of delirium and abnormal behaviour leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including zanamivir. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of zanamivir to these events has not been established. Influenza can be associated with a variety of neurologic and behavioural symptoms which can include seizures, hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. Health professionals are advised to monitor patients for signs of abnormal behaviour. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.

'Dear Health-care Professional' letter from GlaxoSmithKline, 11 March 2008 (www.fda.gov).

Australia. The Therapeutic Goods Administration (TGA) has advised that, in most cases, colchicine should be used for short-term periods and only where non-steroidal anti-inflammatory drug (NSAID) therapy is contraindicated or has failed. So far the Agency has received 243 reports for colchicine, including 53 describing blood dyscrasias such as neutropenia (15), thrombocytopenia (10), pancytopenia (10), leukopenia (8) and agranulocytosis (4), and an additional report describing sepsis and extensive severe maculopapular rash. Of these cases, 21 had not recovered at the time of reporting and nine described a fatal outcome associated with renal failure, multi-organ failure or overwhelming sepsis. Colchicine was the sole suspected drug in 16 of the reports of blood dyscrasias but other drugs were also suspected in all of the reports that described a fatal outcome.Colchicine is used to treat acute gout, but it has a narrow therapeutic index with significant potential for toxicity and severe drug interactions.In mid-2007, the Agency required updates to (the Colgout and Lengout) product information to limit colchicine use to only where NSAID treatment is contraindicated, has failed or has caused unacceptable side effects; and to limit the maximum cumulative dose to 6 mg over four days in otherwise healthy adults (with washout intervals of at least three days if additional treatment is needed). New Zealand's Medicines and Medical Devices Safety Authority (Medsafe) also advises that colchicine be limited to second-line treatment for acute gout, when NSAIDs are contraindicated. (See WHO Pharmaceuticals Newsletter No. 1,2006.)

Reports in WHO Global ICSR database, VigiBase:

1589 reports in total. Most reported relevant reactions: Anaemia 23 (1 fatal case) Anaemia aplastic 10 (3) Marrow depression 12 (6) Pancytopenia 42 (6) Sepsis 23 (7) Renal failure acute 68 (4) Renal failure chronic 12 (2) (more than one reaction may be mentioned in each report).

Reference:

8. Review of Oseltamivir Reports in Vigibase is reassuring but vigilance for hepatic and skin disorders recommended
Report from the WHO Collaborating Centre for International Drug Monitoring, Sweden.

Introduction
The antiviral agent oseltamivir is a selective inhibitor of influenza virus A and B neuraminidase. It is indicated for the treatment and prophylaxis of influenza virus infection types A and B although vaccination is preferred for prophylaxis. It should be commenced early in the course of illness to achieve maximum benefit. The WHO has recommended its use for treating Avian influenza A (H5Nl) (1). In 2007 the Uppsala Monitoring Centre (UMC) undertook a review of the international adverse reaction reports attributed to oseltamivir in the WHO Global Individual Case Safety Report Database, Vigibase, as well as the relevant literature and product information. This review did not identify any clearly defined signals of unsuspected serious adverse reactions not already in the product information or regulatory authority alerts, the latter concerning neuropsychiatric reactions.

Reports of serious skin disorders
Reports of Stevens Johnson Syndrome and toxic epidermal necrolysis had been reported in Vigibase. These disorders are listed under adverse reactions in product information for Tamiflu® (oseltamivir) but with causality not established (2). The Vigibase reports did not provide additional information on causality

Oseltamivir and reports of hepatic disorders
Despite the lack of a clear signal, reports in Vigibase of serious hepatic disorders occurring in association with oseltamivir use were of concern. Reports of hepatic failure, hepatic necrosis, hepato-renal syndrome, jaundice and bilirubinaemia were statistically disproportionate to the background data. Product information for oseltamivir (Tamiflu®) indicated that hepatitis and abnormal liver function tests had been identified during post-marketing experience and that it was not possible to establish a causal relationship with oseltamivir exposure.

Patient Characteristics
At the time of the review Vigibase held 770 reports for oseltamivir. There were 46 non-duplicated reports of hepatic reactions including reports of hepatic failure and necrosis. Numbers of males and females affected were similar and the age range was 18 to 88 years apart from two infants aged 12 months.

Duration of oseltamivir use
Data provided in 25 reports showed patterns of use duration and reaction onset. Overall oseltamivir was used for one to five days in 17 patients. The longest periods of use were 8 days and 19 days. Onset of hepatic manifestations occurred up to one week after oseltamivir was discontinued in 16 patients. Hepatic reactions to medicines usually become evident between five and ninety days after first exposure (3). For this reason eight patients with onset one to two days after first exposure and one patient for whom onset was 120 days after exposure were excluded from further analysis.

Dechallenge and Rechallenge
No reports had valid dechallenge or rechallenge data.

Hepatic failure, hepatic necrosis and serious hepatocellular reactions
Five reports of hepatic failure and/or hepatic necrosis were identified that contained information on time to onset from first exposure that was appropriate for drug-induced hepatotoxicity. Oseltamivir was the only medicine considered suspect in two of these reports. There were no reports of cholestatic hepatitis occurring within five and ninety days of oseltamivir use. There were five reports of hepatocellular damage but these were poorly documented in terms of exposure duration and other medicines were often co-suspect. The originals of eight reports of jaundice and/or bilirubinaemia together with elevated hepatic enzymes or hepatitis were requested from the countries of origin in order to identify serious hepatocellular reactions that are likely to progress to hepatic failure (4). Three such reports were obtained. Two of these patients progressed to the hepatic failure group described above. The third patient had not taken other suspect medicines, only low dose paracetamol. Thus oseltamivir appeared to be the most likely causal medicine in two reports of hepatic failure and one serious hepatocellular reaction.It is of note that one patient with hepatic failure had pre-existing renal failure and was taking the maximum recommended daily dose of oseltamivir.

Causality
While oseltamivir appeared to be the most likely causal medicine in three reports of the most serious suspected hepatic reactions no details of investigations for other potential causes, eg viral studies, were provided. The other reports of serious hepatic disorders could not readily be assigned a causality classification.There are difficulties in assigning causality to hepatic reports with oseltamivir for the following reasons:

1. Prodromal symptoms of hepatic disorders may mimic influenza symptoms.
2. Dechallenge data is largely unhelpful as oseltamivir has usually been discontinued before the reaction is evident.
3. If patients have influenza symptoms they are likely to take other medicines that can be hepatotoxic eg nonsteroidal anti-inflammatory medicines and paracetamol.
4. A number of patients were also taking antibiotics as well as oseltamivir and many of these were also potentially hepatotoxic.

Summary and Recommendations
There are reports of hepatic reactions attributed to oseltamivir in Vigibase that are more serious than those described in the product information. Where identifiable the reports appeared to be predominantly of hepatocellular disorders. There is no clear evidence of causality because of difficulty in discriminating influenza and the early symptoms of hepatic disease, because of common concurrent use of other hepatotoxic medicines and because of the usual short duration of oseltamivir use.

1. Alerting patients to the possibility of hepatic and serious skin reactions as well as other documented adverse effects, at the time of prescription, and
2. Discontinuation of oseltamivir with hepatic function testing where patients are slow to recover from presumed influenza, or relapse. Such testing would identify both those patients whose hepatic disorder had not been diagnosed earlier because they were presumed to have influenza and those who are developing an adverse reaction to oseltamivir. Oseltamivir will not provide any benefit at this stage and discontinuation may avoid more serious outcomes.
3. Prompt discontinuation of oseltamivir if a serious skin disorder occurs.

References

1. World Health Organisation: Clinical management of human infection with avian influenza A (H5N1) virus. World Health Organisation, Geneva, Switzerland 2007. Available from URL:
2. http://www.who.int/csr/disease/avian_influenza/guidelines/Clinical Management07.pdf.  Accessed 11^th  July 2008.
3. Tamiflu capsules® (Roche). Physician's Desk Reference. Revised January 2008.
4. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349(5): 474-485.
5. Reuben A. Landmarks in Hepatology. Hy' s Law. Hepatology 2004; 39(2): 574-578.

* Note from the Uppsala Monitoring Centre. There are now 918 reports for oseltamivir in Vigibase including three additional reports of hepatic reactions. These reports do not alter the conclusions and recommendations of this article.