1. INFLIXIMAB
Clinical alert: worsening congestive heart failure 

Canada, Europe, USA.  Infliximab      is a biological therapeutic product indicated for the treatment of rheumatoid arthritis and Crohn's disease. Schering Canada and Centocor have issued a 'Dear Healthcare Professional' letter for infliximab (Remicade) through Health Canada's website warning about the use of the drug in patients with congestive heart failure (CHF)⁽¹⁾. The letter advises that

• Infliximab therapy should not be initiated in patients with CHF
• Existing infliximab recipients with CHF should discontinue treatment if their CHF is worsening
• Treatment discontinuation should be considered for existing infliximab recipients with stable CHF and, if a decision is made to continue treatment, close monitoring of cardiac function should be undertaken.

The letter is based on the preliminary results of an ongoing phase II trial assessing the use of infliximab in patients with moderate to severe CHF which demonstrated higher incidences of mortality and hospitalisation for worsening heart failure in patients treated with the higher dose of 10mg/kg. Centocor will continue to acquire follow-up data from the study to provide more definitive recommendations to healthcare professionals in the future. The above safety information has also been disseminated via the website of the US FDA(2). The European Agency for the Evaluation of Medicinal Products (EMEA) reinforced the above concerns through its public statements issued first in October 2001 and later, again in February 2002^(3,4).  

Reports in WHO-file: cardiac failure 10.  

Reference:

1. Media Release, 23 Oct 2001. Available from URL: http://www.hc-sc.gc.ca
2. 'Dear Healthcare Professional' letter from Centocor, 18 Oct 2001. Available from URL: http://www. fda.gov/medwatch
3. EMEA Public Statement (CPMP/3257/0l), 24 Oct 2001. Available from URL: http://www.emea.eu.int
4. EMEA Public Statement (CPMP/32/02), 1 Feb 2002. Available from URL: http://www.emea.eu.int

 

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2. INFLIXIMAB
Risk of infections 

Worldwide. In 'the post­marketing spontaneous reporting for infliximab (Remicade), infections are the most common serious adverse event. Some of the cases have resulted in fatal outcome, Up to the middle of 2001, 202 deaths had been reported. Nearly 50% of these were associated with infections, Up to 31 October 2001 approximately 130 cases of active tuberculosis with extra­pulmonary location were reported worldwide in patients treated with infliximab (Remicade). A 'Dear Healthcare Professional' letter from Centocor, the Marketing Authorisation Holder for infliximab (Remicade) was posted on the US FDA's website in October 2001 detailing labelling revisions for infliximab (Remicade) about tuberculosis (TB) and other serious infections including histoplasmosis, listeriosis and pneumocystosis reported with the use of infliximab. Centocor has added a black box warning about these opportunistic infections and revised the Warnings and Adverse Reactions sections in the product label. Centocor advises physicians to review the revised labelling for infliximab and to carefully assess the risks and benefits of initiating treatment with infliximab in patients who have lived in endemic regions.  

The latest EMEA Public Statement on Infliximab issued in February 2002 also informs health professionals about the risk of infections including tuberculosis in patients under­going treatment with inflixmab. The statement advises that:  

• infliximab is contraindicated in patients with tuberculosis or other severe infections such as sepsis, abscesses or opportunistic infections;
• patients should be closely monitored for infections including tuberculosis before, during and after infliximab (remicade) therapy, in accordance with local recommendations;
• treatment with infliximab (remicade) must be discontinued if the patient develops serious infections or sepsis and that before starting treatment with infliximab all patients must be evaluated for both active and inactive (latent) tuberculosis. If active tuberculosis is diagnosed, infliximab therapy must not be initiated; if inactive (latent) tuberculosis is diagnosed, prophylactic anti­tubercular therapy must be started before initiating infliximab therapy.  

The statement also informs patients that while infliximab (Remicade) continues to be an effective and safe medicine, it increases the risk of getting infections, including tuberculosis. Patients should inform their physician if they have had TB or have been in close contact with a TB patient. In addition, patients receiving infliximab should report symptoms such as shortness of breath, swelling in the feet etc. as these may be signs of heart failure. In general, patients with a severe infection and/or moderate or severe heart failure may not be treated with infliximab. 

Reports in WHO-file: infection (various kinds) 46; sepsis 39  

Reference:

1. 'Dear Healthcare Professional' letter from Centocor, 5 Oct 2001. Available from URL: http://www. fda.gov/medwatch

2.        EMEA Public Statement (CPMP/32/02), 1 Feb 2002. Available from URL: http://www.emea.eu.int

 

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3. TRADITIONAL MEDICINES
Adulterants/ undeclared ingredients pose safety concerns 

New Zealand. Betamethasone in the range of 0.lmg to 0.3 mg per capsule, has been detected in Cheng Kum and Shen Loon, two herbal medicines popular for their benefits in joint pain, skin problems, colds, menopausal symptoms and dysmenorrhoea. Over exposure to betamethasone can result in typical signs of corticosteroid excess such as plethoric moon face, hyper­tension, easy bruising, purple abdominal striae, truncal obesity and hirsutism. The rec­ommended daily dose of Cheng Kum is 1 to 3 capsules per day (less in children). Most people will only be exposed to a small amount of corticosteroid with this dose. However there have been reports of corticosteroid­induced side effects in patients taking Cheng Kum and Shen Loon, even in the absence of other exogenous corticosteroid consumption. The New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE) has notified that the further importation of these herbal products into New Zealand will be stopped at Customs. However, because of the risk of adrenal suppression with corticosteroid use, consumers have been sent a letter advising them against abruptly discontinuing the use of these products. They should continue with the treatment and see their general practitioner as soon as possible for instructions on how they may be safely weaned off the products. The Director General of Health has reinforced these points through a privileged statement on Cheng Kum/Shen Loon under section 98 of the Medicines Act 1981. Medsafe has also issued a letter to doctors advising them to determine if patients taking Cheng Kum or Shen Loon are at risk of adrenal suppression by estimating the potential total dose of corticosteroid (from Cheng Kum or Shen Loon plus any exogenous steroid) and duration of use, examining the patient for signs of corticosteroid excess and by ascertaining if other risk factors for adrenal suppression are present (such as Addison's disease, AIDS etc). In the event of excess exposure or the presence of a risk factor for adrenal suppression, the patient should be transferred to an equivalent dose of prednisone (reducing to zero over 2 weeks or longer) and Cheng Kum or Shen Loon should be stopped^(1-3) .  

UK. The United Kingdom's MCA continues to find potentially dangerous and illegal ingredients in traditional Chinese medicines. Recently traditional Chinese medicines have been found to include aristolochia, mercury, arsenic compounds and prescription-only steroids. The Chairman of the UK Committee on the Safety of Medicines has cautioned that the public should not take traditional Chinese medicines that are not labelled or do not include a list of ingredients in English. Represen­tatives from the Chinese medicines sector have pledged their co-operation for improving the safety standards of traditional Chinese medicines⁽⁴⁾.  

Reference:

1. 'Dear Doctor' letter from Medsafe, 14 Dee 2001. Available from URL: http://www.medsafe.govt.nz
2. 'Dear Consumer' letter from Medsafe, 14 Dee 2001. Available from URL: http://www.medsafe.govt.nz
3. Media Release (Director General of Health privileged statement under section 98 of the Medicines Act 1981 - Cheng Kum/ Shen Loon), 17 Dee 2001. Available from URL: http://www.medsafe.govt.nz
4. Media Release, 27 Sept 2001. Available from URL: http://www.mca.gov.uk

 

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4. Interaction of Coxibs
(COX-2 inhibitors) with Warfarin  

(Australia) Interactions with warfarin are among the most important and clinically relevant of interactions because of their potential to cause bleeding and other sequelae. In Australia, up to August 2001 there had been over 4 million prescriptions with celecoxib following its introduction in 1999. Of these, 2.1 million were during the last 7 months of that period. There were 2940 reports of adverse drug reactions with celecoxib within which there were 31 reports of increased INR (International Normalised Ratio) in patients taking warfarin. There were 13 cases of associated bleeding and 12 reports of bleeding with no increase in the INR. For rofecoxib, which was marketed in July 2000 there had been 0.91 million prescriptions in the same 7 month period as for celecoxib. There were 373 rofecoxib-adverse drug reaction reports including 7 reports of increased INR in patients taking warfarin, 2 with associated bleeding and 1 report of bleeding with no increase in the INR. Pharmacokinetic studies had shown an 8% increase in INR in 15 subjects taking warfarin, whilst for celecoxib there was no increase in the INR in 24 subjects. The clinical relevance of these findings is not clear and there is uncertainty whether these reports are co-incidental, or whether they represent a real interaction. In the case of celecoxib there is a plausible pharmacokinetic mechanism as it is primarily metabolised by CYP2C9, but rofecoxib is not metabolised by CYP.  

Discussion: It was considered that a warning on the use of coxibs with warfarin should be included since the chance of bleeding from a peptic ulcer could be worsened in the presence of an anticoagulant.  

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5. HERBAL DIETARY SUPPLEMENTS (PC-SPES & SPES)
Adulteration with prescription only medicines precipitates regulatory action 

Canada, Ireland, USA. PC-­SPES and SPES are herbal medicines manufactured by Botanic Lab in the USA. The two products are marketed as 'herbal dietary supplements' for 'prostate health' and for 'strengthening the         immune system' respectively. These are sold through the internet, by mail and phone order as well as through various distributors and healthcare professionals. An analytical report from the California Department of Health, USA showed that samples of PC­SPES and SPES were adulterated with warfarin and alprazolam respectively. The Canadian medicines regulatory authority has also reported similar con­tamination. Warfarin is an anticoagulant (blood-thinning agent) which can cause serious bleeding, particularly if taken with other medications without prior supervision while alpra­zolam is a prescription only medicine used in the treatment of anxiety. In view of these reports Health Canada, the Irish Medicines Board and the State Health Director of California, USA have all warned consumers to immediately stop using these two products and to consult their health-care practitioners. Botanic Lab has also informed consumers of these laboratory findings and has issued a product recall of all lots of PC SPES pending further reports from additional testing of PC SPES in both commercial as well as academic laboratories.  

Reference:

1. Warning from the Office of Public Affairs, California Department of Health Services, 7 Feb 2002. Available from URL: http://www.fda.gov/medwatch/SAFETY /2002
2. 'Dear customer' letter from Botanic Lab, 8 Feb 2002. Available from URL: http://www.fda.gov/medwatch/ SAFETY/2002
3. Health Canada Warnings/Advisories, 8 Feb 2002. Available from URL: http://www.hc-sc.gc.ca
4. Current News and IMB Statements, 15 Feb 2002. Available from URL: http://www.imb.ie/

 

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6. KAVA-KAVA
Further investigations into Piper methysticum and liver injury  

New Zealand, Canada, Ireland, USA. Further to the precautionary warnings issued by the regulatory authorities in Germany, Switzerland, UK and USA (Pharmaceuticals Newsletter No.1, 2002), the follOWing actions have been recorded on the use of Kava.  

16 January 2002: The New Zealand Ministry of Health has stated that it is looking into concerns expressed by overseas authorities about a reported link between kava consumption and liver damage in some people. In New Zealand Kava is mostly consumed as a natural drink whereas in Europe it is consumed as a pre-packaged dietary supplement. Since factors other than kava consumption may have caused liver damage, it is difficult to draw a definite cause-effect relationship with the present evidence in New Zealand. However the ministry has been working closely with the Australia New Zealand Food Authority (ANZFA) since it became aware of this issue in early January to gather relevant information and is awaiting further information from Europe before reaching a conclusion on whether any action is warranted.  

16 January 2002: Health Canada has advised consumers not to use any product that contains kava although no cases of liver toxicity have been reported in Canada with Kava. Health Canada is conducting a comprehensive safety assess­ment of kava and will take further action, if required, on completion.  

4 February 2002: The Irish Medicines Board in consultation with the industry initiated a voluntary withdrawal of all products containing kava from the Irish market with immediate effect although the Medical Director at IMB stated that the current data are confounding. The IMB based its withdrawal on similar actions by other EU Member States.  

25 March 2002: The US FDA is advising consumers of the potential of liver injury with the use of kava -containing dietary supplements. Persons who have liver disease or liver problems, or persons who are taking drug products that can affect the liver have been advised to consult a physician before using kava­containing supplements. Consumers who use kava­containing dietary supplements and who experience signs of illness associated with liver disease should also consult their physician. The FDA has also issued a letter to health-care professionals informing them of the consumer advisory and has urged consumers and their health-care professionals to report any cases of liver and other injuries that may be related to the use of kava. In the meanwhile the FDA will continue to investigate the relationship, if any, between the use of dietary supplements containing kava and liver injury. 

Reference:

1. Media Release, 16 Jan 2002. Available from URL: http://www.ndp.qovt.nzlmedia
2. Health Canada Warnings / Advisories, 16 Jan 2002. Available from URL: http://www.hc-sc.qc.ca
3. Current News and [MB Statements, 4 Feb 2002. Available from URL: http://www.imb.ie/
4. Consumer Advisory, 25 Mar 2002. Available from URL: http://www.cfsan.fda.gov/
5. 'Dear Healthcare Professional' letter by US FDA, 25 Mar 2002. Available from URL: http://www.cfsan.fda.qov/
   

 

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7. TAMOXIFEN
Prevention in breast cancer versus risks of thromboembolic events 

UK. Tamoxifen is already a Widely used hormonal treatment for women following treatment for early and advanced breast cancer. Now, in addition to its use as a treatment in cancer, preliminary results from the International Breast Cancer Intervention Study (IBIS) provide evidence also for the use of ta moxifen to 'prevent' breast cancer in healthy women at high risk. The results so far show that the incidence of breast cancer was reduced by one-third in women at high risk, compared to women taking a placebo. The study also indicated, however, that tamoxifen can increase the risk of thromboembolism, par­ticularly during and immediately after major surgery or periods of immobility. The UK Department of Health has sent out an urgent communication with the above information to all directors of public health. The key messages in the communication may be summarised as under:  

1. It is clear that the benefits for women being treated for breast cancer with tamoxifen far outweigh the risks. It is important that women taking the drug as a treatment continue to do so as there is overwhelming evidence that tamoxifen saves life among women with breast cancer. There is evidence of some increase in risk from thromboembolism with tamo­xifen, especially during and immediately after major surgery or periods of immobility. Patients should be made aware of the symptoms of venous thrombo-embolism and if they have any sudden onset of breathlessness they should consult their doctor immediately.  

2. The IBIS study gives evidence of the preventative action of tamoxifen in breast cancer. However this is not a use of tamoxifen that has yet been licensed except in the context of a trial.  

3. A full analysis of all trials needs to be carried out to consider whether the benefits of preventative action outweigh potential risks.  

Reference:
Urgent Communication from Chief Medical Officer, 27 Mar 2002. Available from URL: http://www. mca.gov.uk

 

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8. ARISTOLOCHIA
Safety update from Oman  

Sultanate of Oman. The Directorate General of Pharma­ceutical Affairs & Drug Control (DGPA&DC) in the Sultanate of Oman has made a decision to prohibit the import and market­ing of any herbal product or traditional medicines containing aristolochic acid. The decision was made in light of information received by the directorate that aristolochic acid consumption has been associated with severe kidney toxicity and also the development of cancer of the urinary tract. 

Reference:
Directorate General of Pharmaceutical Affairs & Drug Control Pharmaceutical Newsletter 9: 1, No.3, 2001.

 

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9. EPHEDRINE / EPHEDRA
Products recalled following risk assessment  

Canada. Health Canada has requested a market recall of some products that contain ephedrine or ephedra following the conclusions of a risk assessment study that certain products containing these agents can pose a serious health risk. The voluntary recall affects products that have been marketed without approval and include those which meet the following criteria.  

• Products with a dose unit of >8mg of ephedrine, or labelling that recommends >8 mg/dose or >32 mg/day, and/or are labelled or implied for use of >7 days.
• Products that contain ephedrine or ephedra in combination with stimulants, such as caffeine, or other substances that could enhance the effects of ephedrine or ephedra.
• Products with labelling, or an implication for use, for appetite suppression, body­weight loss promotion and other stimulant effects.
• Fatality with caffeine/ ephedrine combination
  

The recall follows an advisory issued in June last year by Health Canada, in which the Canadian public was advised to avoid products containing' ephedra in combination with caffeine or other stimulants. This advisory was issued in response to 60 adverse events reported in Canada in association with such products. Adverse events associated with ephedrine and ephedra include stroke, heart attacks, arrhythmias, seizures and psychotic disorders. Some fatalities due to such events have also been reported. Since the advisory was issued, a product containing large doses of ephedrine with caffeine has been implicated as a contributing factor in 1 fatality in Canada. Health Canada has advised the Canadian public that anybody using the affected ephedrine-or ephedra-containing products should discontinue their use and return the product to the point of sale. The authority has also issued letters to companies involved in the manufacture, distribution, importation, and resale of affected products, and plans to undertake a random market survey within 6 months to assess if the recall has been effective. 

Reference:
Health Canada Warnings/ Advisories, 9 Jan 2002. Available from URL: http://www.hc-sc.gc.ca

 

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10. ROFECOXIB /  WARFARIN
Clinically significant interactions possible 

Australia. Since late 2000, the Australian Adverse Reactions Advisory Committee (ADRAC) has received 8 reports of increased International Normalis­ed Ratio (INR) in patients simultaneously using rofecoxib and warfarin. Of these, 2 reports described bleeding events (epistaxis and rectal haemor­rhage) and 1 described anaemia. The committee recommends increased monitoring of INR in patients taking warfarin and concomitant rofecoxib.  

Reference:
Australian Adverse Drug Reactions Bulletin 21(1): 3, Feb 2002.

 

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11. LORATADINE 

Loratadine is a tricyclic antihistamine with selective peripheral H 1 receptor antagonist activitiy. It is indicated for the treatment of allergic rhinitis and other hay fever symptoms. The total number of reports for loratadine is 7937.  

• Prostatic disorder

There were 5 reports of prostatic disorder and one of aggravated prostatism. All the reports were from the USA. Age was stated for 3 patients, two were aged 80 years and one 75 years. Three improved on withdrawal of loratadine and in one there was no recurrence on rechallenge. Dechallenge data was not recorded for the other patient. The only associated symptom was insomnia occurring in one patient. All were taking loratadine combined with pseudo-ephedrine.  

Recently there were 12 reports of glaucoma with loratadine. These reports as well as the reports of prostatism suggest that loratidine has anti-cholinergic effects. There are also some reports of prostatic disorder for other non-sedating anti­histamines and for dexchlor­pheniramine but not for promethazine and diphen­hydramine. The Physicians' Desk Reference lists the occurrence of urinary retention in at least one patient taking loratadine. Urinary retention is a good ma rker of a nti­cholinergic activity. The occurrence of urinary retention appears to vary between 0.1 % to 0.4% for sedating antihistamines and between 0.2 to 0.3% for 'non-sedating' anti-histamines, suggesting that there may be no difference in the cholinergic activity between preparations. For the long acting form of loratadine however the proportion of urinary retention reports was 1.1%. 

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12. CELECOXIB 
CLASS findings added to product label  

Canada, USA. Changes to the labelling for celecoxib (Celebrex) have been announced in Canada and the US and are based on the results of the Celecoxib Long­term Arthritis Safety Study (CLASS). Celecoxib is a non­steroidal anti-inflammatory drug (NSAID) approved for use in the acute and chronic treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) in adults. Health Canada is advising Canadians that, in the CLASS results:  

• There were no differences in the risk of ulcer compli­cations (gastrointestinal bleeding, perforation and obstruction) among the 3 groups of arthritis patients treated with celecoxib (Celebrex, 400 mg twice daily; 4-fold and 2-fold greater than the daily recommended OA and RA doses respectively), diclo­fenac and ibuprofen (75 mg twice daily and 800 mg thrice daily, respectively; common therapeutic doses for OA and RA). 

• In the indicated doses, the risk of ulcer complications and symptomatic ulcers (ulcers with abdominal pain, dyspepsia, nausea or vomiting) was lower for celecocib (Celebrex) than for ibuprofen, but not different from diclofenac.  

• The risk of ulcer compli­cations in patients taking celecoxib (Celebrex) and low dose aspirin was four times that of patients taking celecoxib (Celebrex) alone. 

The US FDA has advised that the following safety data from CLASS be included into the product label. 

• The overall safety of celecoxib used (400 mg twice a day) at twice the highest approved dose for rheumatoid arthritis was similar to commonly used doses of diclofenac and ibuprofen  

• The high doses of celecoxib used (400 mg twice a day) were not associated with an increased rate of serious cardiovascular events compared with diclofenac and ibuprofen  

• Patients receiving celecoxib had fewer clinically relevant reductions in haemoglobin
• compared with patients receiving diclofenac or ibuprofen  

• Patients receiving both low-­dose aspirin and celecoxib had a higher rate of gastrointestinal (GI) events than those receiving celecoxib alone. 

The new labelling will also include information regarding the risk of serious GI and renal effects in elderly patients.

 

Reference:

1. Gastrointestinal toxicity with celecoxib vs non-steroidal anti-­inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomised controlled trial. Celecoxib long-term arthritis safety study. JAMA 284(10): 1247-55, 13 Sep 2000.
2. Health Canada Warnings/Advisories, 23 May 2002. Available from URL: http://www.hc-sc.gc.ca
3. FDA Talk Paper, 7 Jun 2002. Available from URL: http://www.fda.gov

 

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13. KAVA-KAVA
More withdrawals due to hepatotoxic risks  

Australia, Germany, UK. Australia's Therapeutic Goods Administration (TGA) has initiated a voluntary recall of all complementary medicines containing the herb kava. TGA took this action following the death of a woman in Australia who used a medicine containing kava. Sponsors and retailers have been asked to remove all products containing kava from the market place immediately. Consumers have been advised to safely discard kava-containing products in their possession. In addition, the TGA will undertake further evaluation of the use of kava for any additional regulatory action.  

As of 17th June the Federal Institute of Germany withdrew all kava-kava and kavaine containing products from the German market due to hepatotoxic risks and insufficiently proven efficacy of these products. The regulation included homeopathic products with dilutions up to D4. The German regulation applies to all kava-containing pharmaceutical formulations.  

Following a provisional opinion from the UK Committee on Safety of Medicines (CSM), the Medicines Control Agency (MCA) is to consult on a proposal to prohibit the sale, supply or importation of unlicensed medicinal products containing kava in the UK. The CSM reviewed the issue of kava­associated liver toxicity in December 2001 following the emergence of safety concerns in Europe. At that time, stocks of kava were voluntarily withdrawn by the herbal sector while the safety concerns were under investigation. To date, the MCA is aware of 68 cases worldwide of suspected kava-associated liver problems, including 6 cases of liver failure which resulted in transplant, and 3 deaths. In the UK, there have been 3 reports of kava-associated liver toxicity. The CSM has advised consumers to stop taking medicinal products containing kava, and to seek medical advice if they feel unwell or have concerns about possible liver problems. The MCA's consultation will last until 27 September 2002.

Readers are referred to WHO Pharmaceuticals Newsletters No. 1 & No.2, 2002 for all kava- related safety measures adopted earlier in Switzerland, UK, Ireland, Canada and the USA.  

Reports in WHO-file: Liver and biliary system disorders, 22 case reports  

Reference:

1. Media Release from Australian Therapeutics Goods Administration, 15 Aug 2002. Available from URL: http://www.health.gov.au/tga
2. WHO Information Exchange System Alert No.105, 17 Jun 2002. Available from URL: http://www.who.int/medicines
3. http://www.mca.gov.uk
4. The WHO Pharmaceuticals Newsletter No.1, 2002.
5. The WHO Pharmaceuticals Newsletter No.2, 2002.

 

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14. DICLOFENAC &. OTHERS
ADR update from Singapore  

The Pharmacovigilance Unit of the Health Sciences Authority in Singapore received a 'record number' of adverse event reports in 2001; 561 reports were received by the agency, 24% of which were serious. There were 9 fatal cases in which the outcome was thought to be directly caused, or, precipitated by the suspected drug. Adverse events resulted in hospitalisation in 27% of patients, and a further 23% were already hospitalised at the time of the event. The majority (73.6%) of the reports were received from public sector hospitals, followed by private hospitals (14.4%) and general practitioners (6.4%). The most commonly reported events were rash (184 reports), periorbital oedema (142), urticaria (116), abnormal blood counts (28), acute respiratory distress (25) and liver disorders (22). Diclofenac, naproxen, iohexol, ceftriaxone, mefenamic acid, cotrimoxazole (trimethopriml sulfamethoxazole) and rofecoxib were the drugs most often associated with adverse events.

 

Reference: Adverse Drug Reaction News (Singapore) 4: 2-3, Mar 2002.

 

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15. CYCLO- OXYGENASE (COX) - 2
INHIBITORS
A summary of adverse drug reactions for COX-2 inhibitors from Canada, New Zealand and UK  

Cardiovascular/ cerebrovascular events:

Up to 12 October 2001, Health Canada had received 70 reports of suspected cardio-vascular/ cerebrovascular adverse re­actions in association with celecoxib and 68 in association with rofecoxibl marketed in Canada since April and November 1999, respectively. Of these, 7 celecoxib and 9 rofecoxib reports had a fatal outcome; most of these patients had presented with multiple adverse reactionsl had pre­-existing medical conditions or were receiving concomitant medication. The most commonly reported events were heart rate and rhythm disorders, increased BPI congestive heart failure myocardial infarction, cerebro-vascular events and thrombo-­embolic events. Health Canada cautions that factors such as pre-existing medical conditions the prevalence of cardiovascular disease in the drug target population and concomitant use of drugs that may cause cardiovascular adverse reactions or interactions, must be considered when interpreting these data. Of the 7 fatal cases of cardiovascular reactions reported in association with celecoxib, 2 were cases of cerebral haemorrhage in patients receiving concomitant warfarin. Health Canada says that caution should be exercised when prescribing COX-2 inhibitors to patients at risk of cardiovascular disease and that patients should be advised to report any symptoms of cardiovascular events to their physician immediately. 

Gastrointestinal (GI) toler­ability overview:

Although COX-2 inhibitors are associated with a reduced risk of GI adverse events compared with conventional NSAIDs, GI events still account for approximately 30% of COX-2 inhibitor-related adverse events reported in New        Zealand according to Dr Ruth Savage from the Centre for Adverse Reactions Monitoring (CARM), New Zealand. CARM has received 65 reports of GI adverse events attributed to celecoxib, of which 17 were serious; these included reports of melaena gastroduodenal ulcer, intestinal perforation and 3 deaths. All but 2 patients had > 1 risk factor for GI ulceration and 14 patients were aged > 75 years. GI adverse events have also been reported in association with rofecoxib, although it was noted that, at the time of analysis, the use of rofecoxib in New Zealand was half that of celecoxib. Dr Savage notes that, while the results of 2 large studies (the VIGOR and CLASS trials) showed a 50% reduction in risk of gastroduodenal ulcer complications with COX-2 inhibitors compared with conventional NSAIDs, the use of COX-2 inhibitors still confers a 2­fold increase in risk of gastro­duodenal ulcer complications compared with non-use. Reports received by CARM suggest that serious GI events occur predominantly in older patients and those with other risk factors but adds that this may be a reflection of preferential prescribing of COX-2 inhibitors to at-risk patients.  

Dr Savage says that COX-2 inhibitors should not be prescribed to patients with active gastroduodenal disease, and suggests that the concomitant use of a gastro-protective agent should be considered when prescribing COX-2 inhibitors to patients with a history of serious GI reactions to conventional NSAIDs. She also suggests that both conventional NSAIDs and COX-2 inhibitors should be prescribed at the lowest effective dose and preferably be restricted to short-term or intermittent use. Patients who develop pain, bleeding, signs of obstruction or altered bowel habits while using conventional NSAIDs or COX-2 inhibitors should discontinue treatment, pending investigation.  

The UK Medicines Control Agency (MCA) has issued updated advice regarding the safe use of NSAIDsfollowing a recent assessment of Yellow Card data, epidemiological studies and published literature' the results are consistent with a previous risk assessment for 7 non-aspirin NSAIDs issued by the agency in 1994 (see table). An analysis of Yellow Card reports of gastrointestinal (GI) perforation/obstruction, ulcer­ation or bleeding with diclofenac naproxen and ibuprofen for risk factors revealed that 71 % of patients were aged> 65 years, 28% were receiving concomitant aspirin, 6% were receiving another non-aspirin NSAID and 3% had a history of GI events. The agency notes that the risk of GI ulceration or bleeding is more than doubled when aspirin is combined with non-aspirin NSAIDs. Although the results of clinical trials suggest that the cyclo-oxygenase (COX)-2 in­hibitors, rofecoxib and celecoxib have a reduced risk of GI adverse events compared with non-selective NSAIDs, the MCA notes that Yellow Card reports of GI perforation/obstruction ulceration or bleeding have been received in association with these drugs. Up to September 2001, the reporting rates of these GI events with rofecoxib and celecoxib were 8.4 and 9 per 100 000 prescriptions, respectively. For the safe use of NSAIDs the MCA advises that:  

 

Psychiatric events with COX-­2 inhibitors:

Prescribers should be aware of the possibility of acute psychiatric-type reactions with COX-2 inhibitors as well as conventional NSAIDs, according to Dr. David Coulter, Director of CARM. During the first year of monitoring (up to February 2002) in the Intensive Medicines Monitoring Program (IMMP) 291 reports were received of adverse events associated with celecoxib and 149 reports with rofecoxib. 11 and 2 of these, respectively, were of acute psychiatric events. The reported psychiatric events included confusion, depression, hallucinations, anxiety and 'thinking abnormal'; 1 patient also experienced an exacerbation of manic-depressive psychosis.  

Most of the reports involved elderly patients and a higher proportion of patients were women. In all cases, the acute psychiatric reaction resolved rapidly upon withdrawal of the COX-2 inhibitor.  

Reference:

1. Vu D, Murty M, McMorran M. Selective COX-2 inhibitors: suspected cardiovascular/ cerebrovascular adverse reactions. Canadian Adverse Drug Reaction Newsletter 12: 1-3, Apr 2002.
2. Non-steroidal anti­-inflammatory drugs (NSAIDs) and gastrointestinal (GI) safety. Current Problems in Pharmacovigilance 28: 5, Apr 2002.
3. Prescriber Update, 23(2) Jul 2002. Available from URL:http://www.medsafe.govt.nz

 

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16. ACETYL-SALICYLIC ACID
New advice on aspirin use in children under 16  

UK. The Medicines Control Agency in UK has announced that the restrictions on aspirin, excluding its use in children under the age of 12, should now be extended to include children up to 16 years of age. All aspirin products will carry a warning to this effect. The announcement is based on the advice of the Committee on Safety of Medicines (CSM) that the risk of Reye's syndrome, however small, exists also in children under the age of 16. Although the causes of Reye's syndrome (a disorder found almost exclusively in children and adolescents) are not clearly understood, aspirin use, in the presence of a fever, has been implicated. Therefore, children of this age group, particularly those with a fever, should be given other analgesics not associated with Reye's syndrome such as paracetamol and ibuprofen. Aspirin should not be given except on the advice of a doctor.  

Reference:
Medicines Control Agency Statement 2002/0436/ 22 Oct 2002. Available from URL: http://www.mca.gov.uk

 

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17. ACETYL- SALICYLIC ACID
Warning about incorrect information on new approved uses  

Canada. Health Canada has issued a public advisory warning Canadians about the incorrect information issued by Bayer Inc. on new approved uses for Aspirin. The advisory points out that the Bayer announcement is inaccurate in stating that Health Canada has approved the use of acetylsalicylic acid (Aspirin) for primary prevention, to reduce the risk of first attacks and strokes in individuals deemed to be at sufficient risk. The approved new indication applies only to the reduction of risk of a first non-fatal heart attack and does not apply to primary prevention of stroke. This indication applies only to the products Aspirin Tablets 325 milligrams and Coated Aspirin Daily Low Dose 81 milligrams and not to the whole range of acetylsalicylic acid (Aspirin) products. Bayer Inc. has issued a letter to healthcare professionals for the above correction.  

Reference:
Health Canada Warnings/Advisories, 13 Aug 2002. Available from URL: http://www.hc-sc.gc.ca

 

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