• Rosiglitazone
  Increased risk of fractures in women receiving long-term treatment
• Piroxica
  Restrictions in use 
• Sixteenth Meeting of the Global Advisory Committee on Vaccine Safety, 12-13 June 2007, Geneva 
• Exenatide
  Reports of acute pancreatitis; label to be updated  

• Lumiracoxib
  Risk of serious hepatotoxicity
• PDES Inhibitors
  Reports of sudden decreases in or loss of hearing
• Tramadol
  Seizures and serotonin syndrome 
• Nimesulide: national and Eu review and regulatory outcome
  Niamh Arthur & Kevin Blake,
  Irish Medicines Board 

1. Dear Health-care Provider' letter from GlaxoSmithKline, February 2007 , (www.fda.gov).
   
2. Dear Health-care Professional' letter from GlaxoSmithKline, 23 February 2007 (www.hc-sc.gc.ca).
   
3. Dear Health-care Provider' letter from GlaxoSmithKline, 8 March 2007 (www.swissmedic.ch).
   
4. Dear Health-care Provider' letter from GlaxoSmithKline, 22 March 2007 (www.mhra.gov.uk).

-----------------------------------------------------------------------------------------------------

2. Piroxica
Restrictions in use 

Europe. The European Medicines Agency (EMEA) has recommended restrictions on the use of piroxicam-containing medicinal products because of the risk of gastrointestinal side effects and serious skin reactions. The Agency's Committee for Medicinal Products for Human Use (CHMP) has determined that piroxicam should no longer be used for short-term painful and inflammatory conditions. Piroxicam can still be prescribed to relieve the symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, but should not be used as a first-line treatment for these disorders. Piroxicam should be initiated by a physician with experience in the treatment of such conditions and the drug should be used at the lowest dosage (no more than 20 mg/day) for as short a time as possible. Treatment should be reviewed after 14 days. Topical medications containing piroxicam are not included in the new restrictions.  

Reports in the WHO database: Gastrointestinal system disorders (General) 6692* (for whole GI system)
gastritis                         224
GI haemorrhage            1167
haematemesis               568
melaena                        1003
abdominal pain             764
dyspepsia                     503
nausea                         472
gastric ulcer                  522
gastric ulcer
haemorrhagic                413
skin disorder                 26

Reference: Press Release. EMEA, 25 June 2007 (www.emea.europa.eu).  

-------------------------------------------------------------------------------------------------------

3. Sixteenth Meeting of the Global Advisory Committee on Vaccine Safety, 12-13 June 2007, Geneva 

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 sixteenth meeting in Geneva, Switzerland, on 12-13 June 2007. Issues discussed were: vaccine safety monitoring; the safety of vaccine formulations; a mumps vaccine strain repository; the safety of BCG, human papillomavirus (HPV), rotavirus and influenza vaccines; and the safety of the meningococcal vaccine Menactra®.  

Safety of HPV vaccines
Current evidence of the safety of HPV vaccines is reassuring. As with the introduction of any new vaccine, it will be important to conduct surveillance to identify possible, rare, unexpected events, especially as good quality information on pre-vaccination rates of a variety of diseases is generally lacking in the target age group for HPV vaccination (9 to 26 years). In addition, careful surveillance for specific adverse events in or around pregnancy will be important as the target group for vaccination includes females of reproductive age.  

Safety of rotavirus vaccines
Data were presented on the Merck vaccine Rotateq^TM and the GSK vaccine Rotarix™. GACVS concluded that with regard to intussusceptions, which had been identified as associated with a previous rotavirus vaccine, the data, particularly those from developed countries, are reassuring. It was noted, however, that the present data relate for the most part to vaccines administered to young children at the recommended age. Intussusceptions should be monitored in developing countries as rotavirus vaccines are introduced, especially as infants are likely to present for their first dose of vaccine at slightly older ages, on average, than is the case in developed countries.  Information was also presented on rare cases of Kawasaki disease observed following rotavirus vaccination. While the evidence is at best a hint of a signal, the data do not yet permit a full evaluation of a possible risk. There is a need for careful assessment of Kawasaki disease in the existing data and to ensure that ongoing and future studies incorporate surveillance for Kawasaki disease following vaccination.

Influenza vaccines
Among other issues discussed, a brief description of allergic events occurring after administration of Grippol, a polyoxidonium adjuvanted split influenza vaccine produced in the Russian Federation, was presented. There is a paucity of information regarding these events and WHO has not been able to secure additional information on the investigation. As such, it is unclear if events reported in the media were compatible with expected rates of allergic reactions or represented an increase, and possibly some manufacturing problems. GACVS nevertheless recommends that countries using this vaccine put in place a surveillance system for the upcoming season so that its safety profile can be better characterized. Improved information sharing regarding the safety profile of influenza vaccines is critical for pandemic influenza preparedness.  The report of the meeting was published in the WHO Weekly Epidemiological Record on 20 July 2007. Both this report and additional material on specific topics have been posted on the GACVS web site at http://www.who.int/vaccine_safety/en/

 -------------------------------------------------------------------------------------

4. Exenatide
Reports of acute pancreatitis; label to be updated  

USA. The United States Food and Drug Administration (US FDA) is advising that some postmarketing reports suggest an association between acute pancreatitis and exenatide (Byetta) use. Exenatide is the first of a new class of medications (incretin mimics) approved in the treatment of type 2 diabetes. It is used as an injection (s.c), with either sulfonylureas, metformin or with thiazolodinediones and increases insulin synthesis and secretion in the presence of glucose. The US FDA has reviewed 30 postmarketing reports of acute pancreatitis in patients treated with exenatide (Byetta), 27 of the 30 patients had at least one other risk factor for acute pancreatitis such as gallstones, severe hypertriglyceridaemia, and alcohol use. In six patients the symptoms of pancreatitis began or worsened soon after the dose of exenatide was increased from 5 micrograms twice daily to 10 micrograms twice daily. Twenty-one patients were hospitalized. There were no reports of hemorrhagic or necrotizing pancreatitis. However, five patients developed serious complications including dehydration and renal failure; suspected ileus; phlegmon; and ascites. Twenty-two of the 30 reports indicated that the patients improved after discontinuing exenatide (Byetta).  

Details in three reports indicated that the symptoms of acute pancreatitis returned when exenatide was restarted. Nausea and vomiting returned in two patients when exenatide was restarted. In a third patient, abdominal pain returned when exenatide was restarted and abated after exenatide was permanently discontinued. The Agency advises health-care professionals to instruct patients taking exenatide to seek prompt medical care if they experience unexplained persistent severe abdominal pain which mayor may not be accompanied by vomiting. If pancreatitis is suspected, exenatide should be discontinued. If pancreatitis is confirmed, exenatide should not be restarted unless an alternative etiology is identified.  The US FDA has asked the manufacturer (Amylin Pharmaceuticals, Inc) to include information about acute pancreatitis in the Precautions section of the product label.  Reference: Information for health-care professionals. US FDA, 16 October 2007 (www.fda.gov).

 -----------------------------------------------------------------------------------------

5. Lumiracoxib
Risk of serious hepatotoxicity  

Lumiracoxib (Prexige), is a COX"2 selective non-steroidal anti-inflammatory drug (NSAID) used to treat painful symptoms of osteoarthritis of the knee and hip at a dose of 100 mg once daily. It is approved in more than 50 countries worldwide and was first launched in Brazil in 2005. Concern was raised worldwide after rare reports of serious liver reactions, mostly relating to daily doses that were higher than licensed for use in osteoarthritis. Some post­marketing reports of severe hepatic adverse effects have been reported in some countries around the world. Some countries have reacted with specific regulatory measures:  

Australia (1). In August 2007 Australia's Therapeutic Goods Administration (TGA) cancelled the registration of lumiracoxib due to reports of serious liver adverse effects associated with the use of the drug. As of 10 August this year, the TGA had received eight reports of serious liver adverse reactions related to lumiracoxib, including two deaths and two liver transplants. These reports were "urgently investigated" by the TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC). ADRAC subsequently recommended the cancellation of registration for lumiracoxib, "due to the severity of the reported side effects associated with this drug". The TGA is advising patients to discontinue lumiracoxib use immediately, and to discuss alternative treatments with their physician. 

Canada (2). Health Canada has reviewed all safety and efficacy data for lumiracoxib from Novartis and has concluded that the risk of serious hepatotoxicity associated with the use of lumiracoxib cannot be safely and effectively managed. Health Canada has thus requested that Novartis stop the sale of lumiracoxib in Canada. Consistent with this decision to cease sales and marketing of lumiracoxib, Novartis is asking Canadian pharmacists and distributors to return the product to the company. Patients taking lumiracoxib have been advised to discontinue its intake and contact their physician for advice about alternative therapies.  Prescribers are advised: not to initiate treatment of new patients; to advise patients to discontinue lumiracoxib; review treatment options for patients currently taking lumiracoxib.  Pharmacists are advised: not to dispense further prescriptions for lumiracoxib; to tell patients to discontinue lumiracoxib and contact their physician if they have any concerns.  Consumers are advised to return the product to their pharmacy.  

New Zealand (3). The regulatory agency has withdrawn the market authorization for 200 mg and 400 mg lumiracoxib tablets for acute use, but kept the licenses of 100 mg once daily for osteoarthritis.  

Turkey (3). Turkey has suspended the marketing authorization for 100 mg lumiracoxib tablets pending further review.  

United Kingdom (3). Concern was raised worldwide after rare reports of serious liver reactions mostly relating to daily doses of lumiracoxib that are higher than licensed in the EU. Following consultation with the MHRA and other European regulators, the manufacturer of the osteoarthritis drug, lumiracoxib (Prexige), has written to health professionals to inform them of new restrictions on the prescribing of lumiracoxib.  

A summary of the latest advice from MHRA includes the following: Lumiracoxib should not be used in patients with current or past liver disease, those taking other medicines that may cause liver problems, or who have had previous drug-induced liver reactions. Blood tests to check liver function are needed before treatment, at monthly intervals during treatment, and at any stage if patients are unwell with possible liver problems. Patients already taking lumiracoxib should have their treatment reviewed at the next convenient opportunity. Blood tests should be taken if continued treatment is considered appropriate. Do not exceed 100 mg once daily and use only for the shortest duration necessary to control symptoms.  

Reports in WHO database: Hepatic function abnormal - 3  

Reference:

1. Media Statement. Therapeutics Goods Administration, 11 August 2007 (www.tga.gov.au)
2. 'Dear Health-care Professional' letter from Novartis Pharmaceuticals Canada Inc. 3 October 2007 (www.hc-sc.gc.ca )
3. Lumiracoxib and liver adverse reactions: MHRA, updated 24 October 2007 (www.mhra.gov.uk)  

---------------------------------------------------------------------------------------------

6. PDES Inhibitors
Reports of sudden decreases in or loss of hearing 

USA. The US FDA informed health-care professionals of reports of sudden decrease in, or loss of hearing following the use of phosphodiesterase type S enzyme (PDES) inhibitors sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis) for the treatment of erectile dysfunction, and sildenafil citrate (Revatio) for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited, which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labelling for Viagra, Levitra, and Cialis were revised. FDA is working with the manufacturer to revise the labelling for Revatio.

 Reference: Health-care Professional Information. US FDA, 10 October 2007 (www.fda.gov).  

------------------------------------------------------------------------------------------

7. Tramadol
Seizures and serotonin syndrome 

New Zealand. Tramadol is a centrally-acting analgesic indicated for moderate to severe pain. It stimulates opioid receptors, and inhibits noradrenaline and serotonin reuptake. Seizures and serotonin syndrome are amongst the more commonly reported serious adverse reactions attributed to tramadol in the CARM and in the WHO Global Individual Case Safety Report (ICSR) database.

Serotonin syndrome: The CARM database holds three reports of serotonin syndrome occurring in patients taking tramadol. In each case serotonin syndrome occurred after extra serotonergic medicine was taken as follows: tramadol dose increased in a patient taking tramadol, paroxetine and thioridazine; tramadol added to long-term treatment with amitriptyline and high-dose fluoxetine (60mg daily); citalopram recommenced after patient started tramadol. In the latter case, the tramadol was commenced in hospital where the patient's history of citalopram use was not recorded. Symptoms and signs of serotonin syndrome include at least three of the following: agitation, ataxia, increased sweating, diarrhoea, fever, hyperreflexia, myoclonus, or shivering. The syndrome usually occurs after initiating or increasing the dose of a serotonergic medicine. Medicines known to cause serotonin syndrome include antidepressants (such as selective serotonin reuptake inhibitors (SSRIs), mirtazapine), antiparkinson agents (amantadine, bromocriptine etc), migraine therapy (dihydroergotamine, sumatriptan), and other agents such as bupropion, carbamazepine etc. 

Seizures: Tramadol can induce seizures especially at high doses. In the last five years, tramadol has been the most commonly implicated medicine in reports of seizures to CARM. A total of ten reports were received up to December 2006, involving eight females and two males with an age range of 15 to 49 years. Seizures have been reported in patients receiving tramadol at recommended dose levels. However, reports to CARM indicate that high doses, co-prescribed medicines and a history of epilepsy may increase the likelihood of seizures with tramadol. Other medicines or history of seizures may further increase seizure risk with tramadol. In the CARM reports, three patients were taking a tricyclic antidepressant (TCA) as well as tramadol. One was also taking an antipsychotic medicine, and one an SSRI. Two of these patients experienced seizures when the dose of tramadol was increased. Prescribers are reminded that seizures can occur with tramadol, particularly if high doses are used, when tramadol is used with other serotonergic medicines or with medicines that lower the seizure threshold. Physicians should prescribe the lowest effective dose of tramadol and avoid its use in patients with a history of seizure disorders. In patients with risk factors for seizures or serotonin syndrome, it may be prudent to consider other analgesics instead of tramadol.  

Reference: Prescriber Update, Volume 28(1): 11-12, November 2007.  

------------------------------------------------------------------------------------- 

8. Nimesulide: national and EU review and regulatory outcome
Niamh Arthur & Kevin Blake,
Irish Medicines Board 

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID), with weak Cox-2 selectivity, which was first authorized in Italy in 1985 and is currently marketed in more than 50 countries worldwide. In common with other NSAIDs, a potential for hepatotoxicity associated with Nimesulide was identified and in view of concerns regarding this risk, experience with use of nimesulide was closely monitored by a number of countries, with articles published in national bulletins to highlight the issues among healthcare professionals. In addition, the product information was updated on a number of occasions to include strengthened warnings regarding the risk of hepatotoxicity.  

In April 2002, in accordance with European legislative provisions, a formal referral procedure was initiated to review the benefit/risk profile of systemic nimesulide products across European Union (EU) Member States, following suspension of the national marketing authorisations in Finland and Spain due to concerns regarding hepatotoxicity. Following its assessment of the data at that time, the Committee for Proprietary Medicinal Products (CPMP) concluded that the benefit/risk profile of nimesulide for systemic use remained positive subject to a number of restrictions, including limiting the maximum daily dose to 100 mg twice a day for as short a duration as possible, limiting its use to the treatment of acute pain, osteoarthritis and dysmenorrhoea, contra-indicating its use in patients with hepatic disorders and the inclusion of warnings relating to the risk of serious hepatic reactions. The CPMP Opinion was endorsed by the European Commission in April 2004 and the product information was subsequently amended in line with the legally binding European Commission Decision. 

On 9 May 2007, the Irish Medicines Board (IMB) received new data provided by representatives from the Irish National Liver Transplant Unit, based on a retrospective review of all cases of fulminant hepatic failure (FHF) of unknown cause (non-A, non-B, non-paracetamol overdose) transplanted at the unit from January 1994 until February 2007. Of the 29 evaluable cases of FHF included in the review, nine patients had recently commenced taking a nonsteroidal anti-inflammatory drug (NSAID) and of these, six were taking nimesulide. The treating clinician considered nimesulide as the probable cause of FHF in five of the six cases and a possible cause in the remaining case, based on the Naranjo scoring system. Two patients died following transplantation. The transplant cases occurred predominately in females (5/6) and the age range was from 23 to 61 years. The duration of use was reported as ranging from one week to four months. The data presented suggested that the development of FHF in association with nimesulide is unpredictable in nature and that it is difficult to define an at-risk population.  

A cumulative review of all spontaneous reports of adverse reactions associated with the use of nimesulide on the IMB's pharmacovigilance database identified a total of 53 hepatic adverse reactions since nimesulide was first authorized in Ireland in 1995, including nine cases of hepatic failure, four of which resulted in fatal outcomes.

These data, in conjunction with a comprehensive literature review, informed the IMB decision on 15 May 2007 to suspend the marketing authorisations for all nimesulide-containing medicinal products for systemic use in Ireland and to again refer the issue to the CHMP for further consideration. This referral was initiated under Article 107 of Directive 2001/83/EC, as amended, which requires that EU Member States, the Agency (EMEA) and the MAH must be notified of national regulatory action taken and in the case of suspension/revocation, for the CHMP to prepare an opinion on the issue.  

The CHMP initially considered the new safety data from Ireland on the risk of fulminant hepatic failure associated with nimesulide, as well as data available from published literature at its May 2007 meeting. In addition, the innovator MAH, Helsinn Birex Ltd., attended this meeting to provide explanation. The CHMP concluded that the hepatic profile of nimesulide, since the time of the previous referral, should be reviewed in an expedited manner with an opinion issued in July 2007. France was appointed rapporteur with Belgium and Ireland as co-rapporteurs. The procedure required assessment of pharmacovigilance data from individual member states and the responses from the MAHs to the list of questions agreed by CHMP. At the June 2007 meeting of the CHMP, the timetable for the procedure was extended with an opinion scheduled for September 2007.  

Data provided by other EU-Member States where nimesulide is authorized (excluding Ireland) identified a total of 206 hepatic-related adverse reactions associated with nimesulide reported in the period since the previous referral, from 12 of the 14 Member States where nimesulide is authorized, including 15 hepatic­related fatalities. Limited data were received from national liver transplant units, although a further six liver transplants associated with nimesulide were identified in Italy. Overall, these data confirm that serious and unpredictable hepatic reactions to nimesulide, including fatalities, continue to occur in a sustained manner despite extensive warnings in the current product information.

A review of the data available from the EudraVigilance database also suggested a higher reporting of hepatobiliary disorders (cholestasis and jaundice, hepatic failure and associated disorders and hepatocellular damage and hepatitis NEC) for nimesulide than for the coxibs. These data also suggest that nimesulide is associated with a higher case-fatality rate for hepatocellular damage and hepatitis and for cholestasis and jaundice.  A review of the MAHs' sales data indicated that in the period since the 2002 referral, while sales and prescriptions in the EU have fallen overall by approximately 10%, there have been marked increases in sales, particularly in newly established markets (example Austria, Czech Republic). In France and Ireland the indications for use were expanded post-referral and marked decreases were noted in other member states, including Italy and Portugal. This suggests that prescribing and usage practices are influenced predominately by local factors, including marketing. The data also show that in the EU, nimesulide is increasingly prescribed for 'musculoskeletal' indications, particularly low back pain and arthritic conditions, which are likely to be associated with chronic use.  

Specific analysis of the safety profile of nimesulide in the context of hepatic-related adverse reaction reports indicates a doubling of reporting in the last five years compared to the previous 17 years. The innovator MAH suggests this increase may be attributable to the reporting of old cases in the post referral period due to an increased awareness by health-care professionals of the risks associated with nimesulide. Serious hepatic adverse reactions, however, accounted for a higher proportion of hepatic reports in the post-referral period indicating that the increase in reporting rates following the referral is not solely attributable to reporting bias. Furthermore, in newly established markets there was an increase in hepatic adverse reaction reports with increasing exposure independent of the proceedings of, or the measures taken after, the Article 31 referral. This is despite market research undertaken by the innovator MAH suggesting that the majority of patients are now taking the recommended dosage of 200 mg daily for a period of less than 15 days. Of particular concern, the proportion of hepatic reactions that occur with short-term treatment has increased, with 39.8% and 28.9% of cases occurring within 15 and 7 days duration of therapy, respectively, clearly demonstrating that there is no 'safe' duration of use for nimesulide. The data also suggests that amendments to the product information arising from the referral resulted in a shift in the demographics of the cases of hepatic adverse reactions rather than any meaningful impact on the incidence of cases. 

While some cases of hepatic failure associated with nimesulide have occurred in patients who either had pre-existing liver disease or in whom nimesulide was continued despite liver dysfunction, avoiding such potential cases is not straightforward. Firstly, because a portion of the cases occurred in patients who to all appearances were previously well and who had consumed the drug at therapeutic doses and, furthermore, were appropriately dechallenged at the time of presentation. Secondly, neither radiological imaging nor prior medical history would detect any evidence of underlying hepatic cirrhosis. Without microscopic evidence, therefore, a prescribing physician would assume a normal liver at the time of prescription of the drug. This illustrates the difficulty in real clinical situations in separating the potential 'high-risk' group of patients from the 'normal-risk' ones.  

Recent literature supports the finding of the 2003 publication of Traversa et al of an increased risk of severe hepatotoxicity associated with nimesulide compared with other NSAIDs. Non-clinical data also supports the unpredictable nature of nimesulide's hepatotoxicity.  

In conclusion, because of their common use, NSAIDs contribute significantly to the overall burden of drug-induced liver injury. However, the importance of any drug as a cause of liver injury lies not in the overall number of cases, but in the severity of some reactions. Based on the review of the data presented, nimesulide is a NSAID with a higher and less predictable risk of severe hepatotoxicity than other NSAIDs and the data available indicate that previous measures taken to mitigate this risk have had limited effect.  

The Rapporteur's assessment reports were discussed at the September CHMP meeting and the innovator MAH gave an explanation to the CHMP on 18 September 2007 centred on the list of outstanding issues identified in relation to hepatotoxicity. In addition, the innovator MAH proposed measures to improve the benefit/risk profile of nimesulide and to assess how the impact of these measures could be monitored and assessed. For this purpose, a Risk Management Plan (RMP) was submitted, the main proposals of which are a review of epidemiological data; a non-interventional study in European transplant centres to characterize acute hepatic failure attributed to drug therapy and requiring liver transplantation, a monitoring activity to evaluate the effectiveness of risk communication and a survey to clarify the modes of use of nimesulide in selected EU Member States to identify potential misuse, in particular dispensing without prescription. 

Having considered the available data, the CHMP concluded that nimesulide is associated with an increased risk of hepatotoxicity. However, the magnitude of this increased risk was considered slight and as such, the CHMP considered that marketing authorisations could be maintained, subject to restriction and amendment. In reaching its conclusion, the CHMP also considered the gastrointestinal toxicity profile of nimesulide as compared to other NSAIDs, and the possible consequences of switching to other NSAIDs with a higher gastrointestinal risk.

On 20 September 2007, the CHMP adopted an opinion recommending maintenance of the Marketing Authorisations for nimesulide-containing medicinal products for systemic use, subject to restricted use, amendment of the product information and conditions for the Marketing Authorisations. A European Commission Decision on this opinion is awaited at this time.