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WHO PHARMACEUTICALS NEWSLETTER

prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring

New cases of primary pulmonary hypertension reported

Belgium. The Belgian Centre for Pharmacovigi lance has recently been informed by a pulmonologist working in a university hospital of the diagnosis of 9 cases of primary pulmonary hypertension (PPH) associ- ated with previous use of amfepra- mone (diethylpropion) with or without fenfluramine or phentermine. This report has been triggered by the re-authorization of amfepramone in Belgium, and the prolongation of this authorization for a period of 12 months on 27 November 2000. These 9 cases were diagnosed since 1995 with the following time distribution: 1995: 1, 1996: 1, 1997: 1,1998: 2,1999: 2, 2000: 2. Age and sex distribution: 6 females, 2 males, 1 unknown gender; mean age: 41 years (range: 28-57). Suspec- ted drugs: fenfluramine + amfepramone: 5 cases; phenter- mine + amfepramone: 1 case; amfepra- mone alone: 3 cases. Mean duration of treatment in 4 cases where this information has been ascertained: 12.5 months. No other risk factor has been identified. The pulmonologist who reported the cases was the main investigator for the International Primary Pulmonary Hypertension Study in Belgium and has extensive experience in the diagnosis of PPH. In three of the nine cases, amfepramone was the only risk factor identified. These reports confirm that the authorization of amfepramone for marketing is associated with a serious public health problem. The Centre considers that this information is also highly relevant to the other countries in the world where amfepramone is still marketed. These cases show that primary pulmonary hypertension (PPH) can also occur with previous use of amfepramone alone. All previous cases were associ- ated with fenfluramine/dexfenflura - mine. Fenfluramine/dexfenfluramine have been withdrawn worldwide by the marketing authorization holder in 1997. PPH is a rare but very severe and often fatal disease. The results of the International Primary Pulmonary Hypertension Study were published in the New England Journal of Medicine in 1996. In Belgium, the decision to re-authorize amfepramone and other related anorectic agents will be re-assessed. Source: EU Rapid Alert dated 6 February 2001, Belgian Centre for Pharmaco- vigilance, Brussels. Reference: Abenhaim L, Moride Y, Brenot F et al. Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hyper- tension. New England lournal of Medicine, 29 Aug 1996, 335(9): 609-16.

BUFEXAMAC
An eczema therapy which can itself induce contact eczema

Germany. The Drug Commission of the German Medical Profession has issued a cautionary statement concerning bufexamac, an anti- inflammatory agent intended especially for topical use. Initially bufexamac was indicated for the relief of skin inflammation due to endogenous eczema (neurodermatitis) and chronic eczema. Subsequently, bufexamac was additionally indicated as a substitute for glucocorticoid therapy to treat atopic dermatitis, but it was also used for the treatment various types of eczema (e.g. congestion dermatitis in Status varicosus, perianal eczema due to haemorrhoids) and even undetermined dermatoses. It has been known for some time that bufexamac can provoke contact dermatitis. Since 1987, 25 cases have been published in the literature. Such cases of contact eczema have often persisted for several months, sometimes because the symptoms were erroneously attributed to eczema. Since the allergic potential of bufexamac was often not suspected, its extent was not recognized - these allergies were always cited as "rare". In recent years, not only spontaneous reports but also the results of epidemiological studies have given an indication of the number of cases of allergy due to bufexamac. Data collected from 14 dermatological clinics (showing a rate of 1.7% per 8,163 patients) suggest that bufexamac allergy has been very much under- rated and under-reported and that the real figure could be some 10,000 cases a year, or in the worst case, from 28,000 to 68,000 cases. Conclusion. Bufexamac can itself provoke contact eczema. This sub- stance is indicated for skin diseases (eczemas) which are deceptively similar to the adverse reactions. Thus there is a real danger that bufexamac allergy may not be recognized. For indications such as congestion derma- titis or perianal eczema, available therapy should be used that is indicated for the causative underlying affliction (Status varicosus or haemor- rhoids). Before making a critical assessment of bufexamac- containing topical products, alternative (and effective) eczema therapies should be taken into account. In therapy- resistant eczemas which have been treated with bufexamac, the causative role of the active pathogen should also be taken into consideration. Source: Pharmazeutische Zeitung 145(49): 4185, 2000.

CISAPRIDE
Restricted indications

Australia.Cisapride has been associated with serious cardiac arrhythmias and has been subjected to regulatory actions in many countries. In early 2000, the Australian Adverse Drug Reactions Advisory Committee (ADRAC) conducted a comprehensive review of the safety of cisapride. There had been 343 reports to ADRAC of adverse reactions involving cisapride and it was the only suspected drug in 210 of the cases. Five of the reports were associated with a fatal outcome but cisapride toxicity did not seem to play a major role in any of them. Approximately 12% of the reports concerned patients aged 12 years or less. There were 52 reports describing cardiac reactions. Many of these described minor effects such as palpitations or tachycardia but there were 12 reports of serious arrhythmias including prolonged QT interval or torsades de pointes. In 10 cases, cisapride was suspected of interaction with another drug, resulting in an adverse effect. Four of these involved concomitant erythromycin and in 3 of these cases I the combination resulted in a prolonged QT interval. After reviewing the results from several postmarketing studies and other information, the Committee concluded that the benefit/risk balance of cisapride is less favourable than had previously been considered. It was also noted that other drugs such as proton pump inhibitors were now available to treat some of the indications for cisapride. Following the review, the indi- cations have been revised by the Therapeutic Goods Administration as follows:

• Gastroparesis where the diagnosis has been made or confirmed by a specialist physician.

• Severe reflux oesophagitis in adults where other available treatment including acid suppression with proton pump inhibitor drugs has failed.

• Severe, proven gastro-oeso- phageal reflux in children.

The company has sent a "Dear Doctor" letter to all Australian pres- cribers and pharmacists advising them of these changes and a boxed warning has been added to the Product Information to highlight the cardiac and interaction issues. Source: ADR/AC Bulletin Vol 19, No 4, December 2000. [See also Pharmaceuticals Newsletter Nos. 1,2, 3, 4, 2000; 7/8, 1999]

DROPERIDOL
Voluntary withdrawal : prolongation of the QT interval

United Kingdom. The Medicines Control Agency (MCA) has issued a safety notice concerning droperidol (Droleptan�) to inform health professionals of the decision of the company, Janssen-Cilag, to dis- continue medicinal products containing droperidol from 31 March 2001. This means that shortly after this date, droperidol will no longer be available in pharmacies. This action has been taken by the company following an extensive risk-benefit assessment. The company concluded that the oral formulations should be discontinued to prevent use in chronic conditions and that the injectable form would no longer be commercially viable. The MCA had raised concerns about the potential effect of droperidol on the cardiac QT interval and requested the risk-benefit assessment. Droperidol is currently indicated for use in psychiatry to rapidly calm the manic, agitated patient. The injec- tion is also indicated for use in anaes- thesia in the technique of neurolept- analgesia; for premedication; for post-operative nausea and vomiting; i and for treatment of chemotherapy- induced nausea and vomiting.

Prescribers are advised as follows:
• Droperidol can continue to be used for its licensed acute use, whilst supplies are available.
• No new patients should be initia- ted on droperidol for chronic use.
• No patient should have droperidol stopped until a suitable alternative treatment plan has been identified for them.
• Existing patients currently receiving droperidol as a chronic therapy should be recalled for review by their psychiatrist and switched to an alternative treatment.

Chronic droperidol therapy may be tapered off by a stepwise reduction over a period of one to two weeks whilst the replacement antipsychotic therapy is initiated. Source: Medicines Control Agency, Important Safety Messages, 1 / January 2001. [http://www.open.gov.uk/ mca/ourwork/monitorsafequalmed/ safety messages/droleptan. htm] Reference: Reilly 1C, Ayis SA, Ferrier IN et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 354; 1048-52.

HERBAL MEDICINE
Warning : found to
contain chlordiazepoxide

NuMeridian, USA. The California State Health Director has warned consumers to immediately stop using the herbal product Anso Comfort capsules because the product contains the undeclared prescription drug, chlordiazepoxide. Chlordiazepoxide, available by prescription either by its generic name or the trade name Librium�, is used for anxiety and as a sedative and can be dangerous if not taken under medical supervision. The distributor, NuMeridian (formerly known as Top Line Project), is voluntarily recalling the product nationwide. An investigation by the California Department of Health Services' (DHS) Food and Drug Branch and Food and Drug Laboratory found that the product contains chlordiazepoxide. The ingredients for the product were imported from China and the capsules manufactured in California. A San Francisco woman was hospitalized in January 2001 with life-threatening low blood sugar after consuming Anso Comfort capsules. The woman has a history of diabetes and high blood pressure. The hospital ization may have been necessitated by a drug interaction of chlordiazepoxide,and the prescribed medications for her other medical conditions. She is expected to fully recover. Her physician referred the case to DHS for investigation by the California Poison Control System. The Health Director advised consumers to stop using Anso Comfort capsules and seek medical advice, especially if they are currently using prescribed medication. Chlor- diazepoxide, a controlled substance, adds to the effects of alcohol and other central nervous system depressants. It may also be habit-forming. Advertising for the product claims that the capsules are useful for the treatment of a wide variety of illnesses, including high blood pressure and high cholesterol, in addition to claims of being a natural herbal dietary supplement. The advertising also claims that the product only contains Chinese herbal ingredients and that consumers may reduce or stop their need for pres- cribed medicines. No clear medical evidence supports any of these claims. Anso Comfort capsules were available by mail or telephone order from the distributor. The capsules, available in 60-capsule bottles, are clear with dark green powder inside. The label is.yellow with green English printing and a picture of a plant. The UPC number is 7-63148-58798-6. The US Food and Drug Administration will assist in the follow-up investigation to monitor the recall throughout the United States. Reference: Anso Comfort Capsules recalled by distributor: Ingredient poses danger if not medically supervised. News Release from NuMeridian, 13 February 2001. [http://www.fda.gov/oc/po/firm -recalls/anso2_01.html]

ISOTRETINOIN
Medication guide and
informed consent documents

Roche, USA. Roche, the manufac- turer of isotretinoin (Accutane�), has announced the release of a medication guide, which was developed in conjunction with the US PDA, together with revised informed consent documents regarding the use of isotretinoin. These documents are to be distributed to prescribers and pharmacies in the United States.
The medication guide for isotretinoin must be distributed by the pharmacist to every isotretinoin patient each time an isotretinoin prescription is dispensed. It emphasizes key safety issues that patients should know about concerning the use of isotretinoin and pharmacies in the United States. The medication guide for isotretinoin must be distributed by the pharmacist to every isotretinoin patient each time an isotretinoin prescription is dispensed. It emphasizes key safety issues that patients should know about concerning the use of isotretinoin and summarizes the approved indication for isotretinoin and major adverse events reported in the package insert.
The informed consent document is to be completed and signed by the patient before receiving isotretinoin and female patients will be required to initial and sign an informed consent document that is currently part of the Pregnancy Prevention Program included in the professional package insert. Isotretinoin users are urged to report any adverse events potentially associated with isotretinoin to Roche or the FDA.
Reference: Letter to health care providers, Roche, 22 January 2001.
[http:llwww. fda.gov/medwatch/ safety/2001 faccutane.htm]

LABELLING REQUIRE- MENTS
Proposed rule

United States of America. The Food and Drug Administration (FDA) is proposing to amend its regulations governing the format and content of labelling for human prescription drug and biological products. This proposal would revise current regulations to require that the labelling of new and recently approved products include a section containing highlights of prescribing information and a section containing an index to prescribing information; reorder currently required information and make minor changes to its content; and establish minimum graphical requirements.
These revisions would make it easier for health care practitioners to access, read, and use information in prescription drug labelling and would enhance the safe and effective use of prescription drug products. This proposal would also amend pres- cription drug labelling requirements for older drugs to require that certain types of statements currently appearing in labelling be removed if they are not sufficiently supported. Finally, the proposal would eliminate certain unnecessary statements that are currently required to appear on prescription drug product labels and move other, less important information to labelling, for example:

• The names of all inactive ingredients will not have to appear on the product's container label (e.g. the box, vial or bottle in which the product is physically held for shipment to the pharm- acy/hospital and subsequent storage). Instead, this information is required to appear in labelling under the "Description" section.
• The currently required statement that tells the pharmacist the type of container that should be used in dispensing the product will not have to appear on the container label. Instead, it should be included in labelling in the section "How Supplied/Storage and Handling."

These changes would simplify drug product labels and reduce the possibility of medication errors.
Reference: Federal Register 65(247): 81082-81131 (2000).
[http://www.accessdata.fda.gov/scripts/ oc/ohrms/dailylist.cfm?yr=2000&mn =1 2&dy = 22]

LEVACETYLMETHADOL (Orlaam�)
Life-threatening cardiac
rhythm disorders: update

EMEA. The Committee for Proprietary Medicinal Products (CPMP) of the European Medicines Evaluation Agency has been made aware of 10 case reports of life-threatening cardiac disorders Including ventricular rhythm disorders such as torsade de pointes in patients treated with levacetylmethadol (Orlaam�). Levacetylmethadol (Orlaam�: Sipaco) is indicated for the substitution maintenance treatment of opiate addiction in adults previously treated with methadone, as part of a comprehensive treatment plan including medical, social and psycho- logical care. Orlaam� is currently marketed in the EU in Denmark, Germany, Netherlands, Portugal, Spain and the United Kingdom. It has been available in the USA since 1994.
These 10 cases of life-threatening cardiac rhythm disorders have been reported since 1 July 1997. They include 5 cases of cardiac arrest associated with ventricular arrhythmias, 3 cases of cardiac arrhythmia and 2 cases of syncope. The QT interval was prolonged in 7 of the patients (from 525 msec to 800 msec) and 4 of these patients had an episode of torsade de pointes. Three patients required a pacemaker insertion. This raises a major concern given the fact that these life-threaten- ing cases occurred in young patients (median age 39 years, range from 23 to 57 years), a population at low risk of developing these cardiac disorders, and given the relatively low exposure to the product. Furthermore, these cardiac disorders might have been under-recognised or under- reported.
Following a preliminary review of this new safety information, as an interim and precautionary measure while the CPMP performs a full comparative risk/benefit reassessment of Orlaam�, the EMEA wishes to draw attention to the following:

• Prescribers are advised not to introduce any new patients to Orlaam� therapy.
• Patients currently taking Orlaam� should contact their doctor for advice regarding their treatment. They must not stop Orlaam� suddenly without seeking medical advice.

The attention of prescribers is drawn to the special warnings and precautions for use concerning the assessment of the risk of torsade de pointes. The full text of the Summary of Product Characteristics and Package Leaflet is available on the EMEA's website: http://www.eudra.org/ emea. html.
Note: The EMEA issued a public statement on 15 December 1999 concerning life-threatening ventricular rhythm disorders associated with levacetylmethadol after 3 reports were received including 1 with fatal outcome (see Alert No. 94 dated 17 December 1999).
Reference: EMEA Public Statement on Levacetylmethadol (Orlaam�) - life threatening cardiac rhythm disorders, 19 December 2000. (Ref.: EMEA/ 38918/00/en)

MOFEZOLAC
Revised data sheet: gastrointestinal
haemor- rhage, abnormal hepatic
function and thrombo- cytopenia

Japan. Mofezolac (Disopain� Tablet 75: Welfide) was approved in July 1994 as a nonsteroidal anti- inflammatory analgesic agent which exerts its effects by inhibition of prostaglandin synthesis.
The data sheet has now been revised to include "Peptic ulcer" in the section on "Serious Adverse Reactions". In addition, with respect to abnormal hepatic function, the section on Contraindications has been extended to include patients with serious hepatic disorders and the section on Precautions has been extended to include patients with hepatic disorders or a history of hepatic disorders. The section on "Other adverse reactions" now includes "Increased AST(GOT), ALT(GPT) and Al-P", and since February 1998, "Petechiae" has also been added under thrombocytopenia.
Fifteen cases of gastrointestinal haemorrhage, 5 cases of abnormal hepatic function and 5 cases of thrombocytopenia were reported to MHLW. A causal relationship between mofezolac and these reactions could not be excluded. The Ministry directed its license holder to revise its package insert to add "Gastrointestinal haemorrhage, abnormal hepatic function, jaundice and thrombocytopenia" in the section on "Serious Adverse Reactions".
These cases are presented in a summary to alert medical pro- fessionals to these adverse reactions. Reference: Pharmaceutical and Medical Devices Safety Information No. 164, January 2001, Ministry of Health, Labour & Welfare.

MONOETHANOL - AMINE OLEATE
Revised data sheet : gastrointestinal
adverse reactions

Japan. Monoethanolamine oleate (Oldamin� Injection : Fuji) was approved in June 1996 with the indication of "Haemostasis in oeso- phageal varices, haemorrhage and sclerosis in oesophageal varices".
With respect to gastrointestinal disorders associated with the use of the drug, the contraindications have been extended to include patients with haemorrhage due to gastric/duo- denal ulcer, or haemorrhage due to gastric erosion, and the section on "Other adverse reactions" has been revised to include haemorrhagic gas- tritis and haemorrhage due to gastric/duodenal ulcer in order to alert medical professionals to these reactions.
Recently, 4 cases of giant gastric ulcer have been reported in associ- ation with the use of monoethanol- amine oleate for which a causal relationship could not be excluded. The Ministry of Health, Labour & Welfare therefore directed its license holder to include "Gastric ulcer" in the section of "Serious Adverse Reactions". In this section, reported cases are summarized in order to further alert medical professionals to these reactions.
Reference: Pharmaceuticals and Medical Devices Safety Information No. 164, lanuary 2001, Ministry of Health, Labour & Welfare.

PROPOFOL
Dosing advice : potentially
serious undesirable effects

Netherlands. The Medicines Evaluation Board has issued a press release concerning an article published in The Lancet on 13 January 2001 which describes 7 cases of Dutch patients with serious head injury who were sedated with high dosages of propofol (Diprivan�: AstraZeneca) for prolonged ventilatory support (more than 48 hours) in an intensive care unit. Most of these patients developed muscle decay, acidosis and acute heart failure with fatal outcome. In all of these cases the dosage used exceeded 5mg/kg/hour during more than 58 hours. This is higher than the dosage of 0.3-4mg/kg/hour which is usually sufficient to sedate patients for ventilation according to the Dutch product information.
On the basis of the available information it is not possible to draw definite conclusions concerning a causal relationship between prolonged use of higher dosages of propofol and the cardiovascular complications in these seriously ill patients. However, prescribers are reminded if possible not to exceed the dosage of 4mg/kg/hour which is usually suffici- ent for sedation of ventilated patients in the ICU situation (more than one day). Propofol is currently not recommended for sedation of patients younger than 16 years.
The conclusion of the Medicines Evaluation Board remains that the use of propofol in accordance with the instructions in the product information for the sedation of ventilated patients is effective and safe. A "Dear Doctor" letter was also sent by the company to anaesthetists, internists and hospital pharmacists. References:

1. Press Release. Dosing advice for propofol due to possible serious undesirable effects. Medicines Evaluation Board, 12 January 2001.
2. Cremer OL, Moons KG, Bouman EA et al. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 357(9250): 2001.

QUIXIL� HUMAN
SURGICAL SEALANT
Revised product information : update
on fatal neurotoxic reactions

United Kingdom. Prescribers were previously alerted to 2 reports of fatal neurotoxic reactions associated with the use of Quixil�, a human plasma- derived fibrin sealant kit, in neuro- surgical procedures. Studies in rabbits have since shown that Quixil� is neurotoxic when directly applied to the cerebral cortex or dura mater. The tranexamic acid component of the product appears to be the neurotoxic agent.
The product information for Quixil� has now been updated to state that it should not be used in surgical operations where contact with the CSF or dura mater could occur.
Prescribers are reminded that Quixil� is only licensed for use to facilitate haemostasis and to reduce operative and post-operative bleeding and oozing during liver surgery such as liver resection and reduced-size liver transplantation. The safety of Quixil� remains under close review. [See also Information Exchange System Alert No. 90 dated 11 November 1999.]
Reference: Current Problems in Pharmacovigilance Vol. 26, September 2000.

RIVASTIGMINE
Revised product information:
dosage instructions

Novartis, USA. Novartis has informed health professionals of recent changes to the WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for rivastigmine (Exelon�), which is indicated for Alzheimer's disease. These changes provide guidelines for reinitiating therapy in patients who have interrupted treatment with rivastigmine in order to reduce the risk of severe vomiting.(1)
There is limited experience related to restarting rivastigmine after an interruption in therapy at doses higher than the recommended starting dose. However, to reduce the possibility of severe vomiting in patients who have interrupted rivastigmine therapy for longer than several days, treatment should be reinitiated with the lowest daily dose. After reinitiating therapy, patients should be titrated back to their maintenance dose as described in the DOSAGE AND ADMINISTRATION section of the product information. There has been one post-marketing case of severe vomiting with esophageal rupture reported to have occurred after re-initiation of treatment at an inappropriate single dose of 4.5 mg following an interruption of treatment for eight weeks.(2)
Healthcare professionals should report all serious adverse events suspected to be associated with use of Exelon� to the company or the appropriate authorities. References:

1. Letter to health care providers, 26 January 2001. [http://www. fda.gov/medwatch/ safety/2001 fexelon.htm]
2. Babic T, Banfic L, Papa I et al. Spontaneous rupture of oesophagus (Boerhaave's syndrome) related to rivastigmine [letter]. Age and Aging 2000,lul;29(4):370-1.

SARPOGRELATE
Revised data sheet: serious
haemorrhage, thrombocytopenia
and abnormal hepatic function

Japan. Sarpogrelate (Anplag� Tablet 50mg, 100mg; Anplag� Fine Granules 10%: Mitsubishi-Tokyo) was approved in July 1993 and March 1999, and is indicated as a platelet aggregation inhibitor to improve peripheral circulation for the treatment of ischaemic symptoms observed in chronic arterial obstruction.
At the time of its approval, gastro- intestinal haemorrhage associated with the use of sarpogrelate was included in the section "Other Adverse Reactions". In May 1996, haematemesis, epistaxis, etc. and thrombocytopenia were added to the same section.
With respect to hepatic function disorders, at the time of approval the section on Other Adverse Reactions included "Increased bilirubin, AST(GOT), ALT(CPT), Al-P, etc.". This section was extended to include "Hepatic disorders" and "Increased gamma-CTP" in May 1996 and June 1998 respectively.
Reports of cerebral haemorrhage (4 cases), gastrointestinal haemorrhage (2), thrombocytopenia (5) and hepatic dysfunction (6) were received in association with sarpogrelate. Because causality could not be excluded, the MHLW directed its license holder to establish in its package insert a new section on "Serious Adverse Reactions" to include "Cerebral haemorrhage, gastrointestinal haemorrhage, thrombocytopenia, hepatic function abnormal and jaundice". A summary of reported cases is presented in this section in order to alert medical professionals to these reactions.
Reference: Pharmaceuticals and Medical Devices Safety Information No. 164, January 2001, Ministry of Health, Labour & Welfare.

STAVUDINE AND
DIDANOSINE
Cautionary statement
regarding use in pregnant women

United States of America. The Food and Drug Administration (PDA) and Bristol Myers Squibb have warned health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine (Zerit�) and didanosine (Videx� or Videx� EC) with other antiretroviral agents.
Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of Videx� and Zerit�.
This new warning follows 3 reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking Zerit� and Videx� in combination with other drugs used to treat HIV. Two of the cases were reported from ongoing clinical trials of an investigational HIV drug, and one was identified through worldwide postmarketing surveillance. In addition, postmarketing surveillance identified several nonfatal cases of pancreatitis, with and without lactic acidosis or hepatic failure, occurring in pregnant women receiving stavudine plus didanosine. Although data have suggested that women may be at increased risk for the development of lactic acidosis and liver toxicity, it is unclear whether pregnancy potentiates these known adverse effects.
On 5 January 2001, Bristol Myers Squibb issued a letter to alert health care professionals to the potential for increased risk of lactic acidosis and liver damage in pregnant women treated with the combination of Zerit� and Videx�. Bristol Myers Squibb recommends that the combination of the two drugs should be prescribed for pregnant women only when the potential benefit clearly outweighs the potential risk. One situation where the benefit may outweigh the risk is the use of didanosine plus stavudine in women who have exhausted other treatment options. The letter points out that decisions about using the drugs for pregnant women should be made by health care professionals experienced in treating HIV infection.
Because of these reports, the FDA will strengthen the existing black box warnings to include this new prescribing information. Women who are prescribed the combination drug therapy should be closely monitored for clinical or laboratory signs of lactic acidosis and liver damage. This syndrome may develop abruptly, and in the absence of abnormal laboratory values in the weeks preceding its development. Therefore, it is imperative that healthcare providers maintain a high index of suspicion when monitoring these patients. Healthcare providers are encouraged to report any adverse events related to stavudine and didanosine.
Reference: PDA Talk Paper JOT-02, 5 January 2001.
[http://www. fda.gov/bbs/topics/ ANSWERS/2001/ANSO W63.html]

THIORIDAZINE
Restricted use

United Kingdom. Following a review by the Committee on Safety of Medicines, the Medicines Control Agency (MCA) has restricted the indications for thioridazine (Melleril�). The review was prompted by the publication of an article(1) that showed an increased risk of QT interval prolongation with thioridazine.
Since 1964, the CSM has received 42 reports of suspected heart rate and rhythm disorders associated with thioridazine. Of 39 cases where the outcome was known, 21 cases were reported as fatal. These reports included patients on low doses of thioridazine or with a history of dementia.
The CSM concluded that the risk:benefit ratio of thioridazine would be favourable only as a second-line treatment in schizophrenia in adults under specialist supervision. There was insufficient evidence of efficacy to justify a favourable risk:benefit ratio for use in the elderly for sedation and agitation. Thioridazine lowers the seizure threshold and is no longer recommended in children for behavioural disorders and epilepsy.

Advice on thioridazine.

• Clinically significant cardiac disorders including arrhythmias, conduction disorders or a history of QTc prolongation are contraindications to the use of thioridazine.
• Other drugs taken concurrently may increase the risk of serious ventricular arrhythmias. Interactions with thioridazine may occur with (a) drugs which inhibit its metabolism, or (b) additive effects with other drugs which prolong the QTc interval. Important examples are given in the prescribing information.

(See also Pharmaceuticals Newsletter No. 4, 2000).
Source: Current Problems in Pharmaco- vigilance Vol. 27, February 2001.
Reference: Reilly ]C, Ayis SA, Ferrier IN et al. Cnc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355; 1048-52.

ZAFIRLUKAST
Revised product information :
adverse reactions

AstraZeneca, USA. AstraZeneca maintains a current database on all postmarketing reports for its prescribed medications. These reports are analysed regularly and updates to labels are made when appropriate. Zafirlukast (Accolate�), a leukotriene receptor antagonist indicated for the prophylaxis and chronic treatment of asthma in adults and children 7 years of age and older, has been prescribed with increased frequency over the past three years. With this increased usage, additional events have been reported in association with the use of zafirlukast. Therefore, AstraZeneca has informed health professionals of revisions to the PRECAUTIONS and ADVERSE REACTIONS sections in the labelling for Accolate�. The changes have been incorporated in the package insert. The principal changes are as follows: PRECAUTIONS.
Hepatic Dysfunction. Since April 1997, the Accolate� labelling has contained a precaution stating that "if clinical signs or symptoms of liver dysfunction (e.g. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, and flu-like symptoms) are noted, it is reasonable to recommend that standard liver tests be obtained and the patient managed accordingly". Based on continued monitoring of postmarketing reports of liver dysfunction, the label has been revised to include more specific recommendations for patient management including the following:

• If liver dysfunction is suspected based upon clinical signs of symptoms, Accolate� should be discontinued. Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly.
• If liver function tests are consistent with hepatic dysfunction, Accolate� therapy should not be resumed.
• Patients in whom Accolate� was withdrawn because of hepatic dysfunction, where no other attributable cause is identified should not be re-exposed to Accolate�.
• Hepatic events have occurred predominantly in women.

Geriatric Use. This section has been revised according to the FDA Final Rule on 27 August 1997 for all prescription drug products. The approved product labelling for Accolate� has been revised to include the following information.

• No overall differences in adverse events were seen in the elderly patients, except for an increase in the frequency of infections among zafirlukast-treated elderly patients compared to placebo-treated elderly patients (7% vs 2.9%).
• In an open-label, uncontrolled, 4-week trial of 3,759 asthma patients comparing the safety and efficacy of Accolate� 20 mg given twice daily in three patient age groups, a higher percentage of elderly patients, when compared to adults and adolescents, reported adverse events. These elderly patients showed less improvement in efficacy measures. The elderly reported the lowest percentage of infections of all three age groups in this study.

Adverse Reactions
In addition to changes regarding hepatic dysfunction as described above, the ADVERSE REACTIONS section of the Accolate� labelling has been revised to include the following information:

• There have been reports of patients experiencing arthralgia and myalgia in association with Accolate� therapy.

Adverse Event Reporting AstraZeneca requests that all adverse events occurring in patients treated with Accolate� be duly reported.
Reference: Letter to health care providers, AstraZeneca, September 2000.

CLOPIDOGREL
Concerns over thrombotic
thrombocytopenic purpura

Canada. Following reports of thrombotic thrombocytopenic purpura (TIP) associated with clopidogrel (Plavix�), the Canadian Adverse Drug Reactions Monitoring Program (CADRMP) reviewed reports of adverse drug reactions (ADRs) associated with clopidogrel in Canada. From October 1998, when clopidogrel was first marketed in Canada, until August 2000, the CADRMP received 61 reports of suspected ADRs associated with clopidogrel. Of these reports, 17 cited haematological disorders, particularly disorders involving white blood cells and platelets. There were 11 reports of thrombocytopenia and 1 report of pancytopenia, but no reports of TTP. The majority of reports of haematological disorders involved elderly patients with underlying cardiovascular disorders who were receiving other concomitant medications, including anticoagulants and antiplatelets. In addition, 3 of the reports of thrombocytopenia involved concomitant use of HMC-CoA reductase inhibitors. The CADRMP says that confounding factors such as age, concomitant diseases and medications make interpretation of the ADR data difficult.
Source: Canadian Adverse Drug Reaction Newsletter 11 (1): 2-3, lanuary 2001. Reports in WHO-file: Purpura thrombopenic thrombotic 10.

COX-2 INHIBITORS
(1) CELECOXIB AND WARFARIN

Interaction

Australia. Since the introduction of celecoxib (Celebrex�) on the market in Australia in October 1999, the Australian Adverse Drug Reactions Committee (ADRAC) has received 2218 reports of suspected adverse drug reactions. Of these, there have been 21 cases describing an increase in the INR (international normalized ratio) of patients on treatment with warfarin. In the 16 cases where the value of the INR was specified, it rose from a stable value of around 2.0 to a peak ranging from 4.2 to 12.2 (median: 5.3). In two other cases the INR was described as "high" and "very high". While most of the reports did not describe complications, bleeding was reported in 6 cases. These included severe oral bleeding, intracranial haemorrhage, epistaxis and gastrointestinal haemorrhage. In most cases, the problem occurred within two weeks of the addition of celecoxib. Of the patients in whom the outcome was known, all recovered after withdrawal of celecoxib and, in some cases, withholding or reducing the dose of warfarin.
In addition to these 21 cases, there have been 11 cases of bleeding in patients taking concomitant celecoxib and warfarin. These reports described purpura (3 cases), gastrointestinal haemorrhage (2), haematuria (1), haematemesis (1), melaena (1), subdural haematoma (1), unspecified haemorrhage (1) and stroke (1). There was no reference to the INR in these reports except for one in which the INR was reported as unchanged. It is not clear in these cases whether the bleeding was the result of an interaction, an additive effect, an effect of celecoxib alone, or unrelated to the use of celecoxib. The product information for celecoxib states that, in postmarketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving celecoxib concurrently with warfarin. In the cases of increased INR and bleeding reported to ADRAC, 5 of the 26 patients in whom the age was stated were aged less than 50 years.
The product information also describes a study in healthy volunteer subjects given 2 mg to 5 mg warfarin daily in whom celecoxib had no effect on the prothrombin time. However, since warfarin is metabolised mainly by CYP2C9 and this enzyme can be inhibited by celecoxib, it is possible that in some individuals, inhibition of CYP2C9 may be significant, producing higher blood concentrations of warfarin. There have been two recent publications describing this interaction. (1,2)
Source: ADRAC Bulletin Vol 20, No 1, February 2001.
References:

1. Mersfelder TL, Stewart LR. Warfarin and celecoxib interaction. Annals of Pharmacotherapy 2000; 34: 325-7.
2. Hasse KK, Rojas-Fernandez CH, Lane L et al. Potential interaction between warfarin and celecoxib. Annals of Pharmacotherapy 2000; 34:666-7.

(2)ROFECOXIB AND CELECOXIB
Risk profile similar to other NSAIDs

Sweden.The Medical Products Agency (MPA) cautions that rofecoxib (Vioxx�) and celecoxib (Celebre�) seem to have a similar risk profile to other NSAIDs in patients with risk factors (such as advanced age) for adverse effects such as fluid retention, hypertension, heart failure and renal dysfunction. Therefore the agency advises that the same precautions and contraindications apply to rofecoxib and celecoxib as for other NSAIDs, particularly concerning patients with active peptic ulcers, gastrointestinal bleeding, severe heart failure and a history of heart failure, hypertension and oedema. Up to September 2000, no suspected cases of rofecoxib- or celecoxib-related thromboembolic cardiovascular reactions have been reported in Sweden; however, such cases have been reported elsewhere, mainly in patients with risk factors for cardiovascular disease. A number of other known adverse reactions have been reported with these drugs in Sweden, including 6 cases with fatal outcomes.
Source: Information from the MPA, Vol 11, No 7, 2000.
Reports in WHO-file: Rofecoxib: Jhrombo-embolic cardiovascular reactions 32 (thromboembolism 7); Celecoxib: thromboembolic cardiovascular reactions 67 (thromboembolism 6).

ERGOTAMINE AND ERYTHROMYCIN
Interaction

Australia. Ergotism is manifested by symptoms and signs of peripheral ischaemia due to constriction of vascular smooth muscle caused by direct action of an ergot derivative. Headache, intermittent claudication, muscle pain, numbness, coldness and pallor of the extremities may occur, and gangrene has been reported. Ergotism is usually associated with excessive dosing of ergot preparations but has also been reported with normal doses of ergotamine preparations when there was concomitant use of macrolides (particularly erythromycin). The mechanism of the interaction is not established but may involve an inhibition of ergotamine metabolism or an increased gut absorption resulting in an increase in serum ergotamine concentration.
In recent years, ADRAC has received two reports describing severe ergotism in association with the combined use of ergotamine and erythromycin. The first report described a 47-year old woman who developed loss of power and sensation in her feet, an acutely tender left gastrocnemius muscle, absent peripheral pulses and evidence of early gangrene. This followed the addition of erythromycin to her long-term Migral� therapy (ergotamine tartrate, cyclizine, caffeine). On the 4th day of the course of erythromycin, the patient experienced right arm claudication and left arm paraesthesia after she had taken 3 Migral� tablets over the preceding 48 hours. On the 5th day, a worsening of her symptoms of peripheral ischaemia followed within minutes of taking two Migral� tablets. The patient survived but the left leg required amputation below the knee.
The second report described severe peripheral ischaemia affecting both arms in a 55-year old man as a result of clinical ergotism. He was taking long-term ergotamine (2 x 2 mg per week) for migraine and the reaction occurred after also taking erythromycin for 2 weeks to treat an upper respiratory tract infection.
ADRAC has also received reports of ergotism arising from the combination of ergotamine with ritonavir or verapamil and has noted published reports of similar interactions with HIV protease inhibitors, particularly ritonavir/1/2) These reports suggest that the basis of the interaction is inhibition of either cytochrome P4503A4 in the liver or gut P-glycoprotein with subsequent increase in ergotamine concentrations. As most inhibitors of CYP3A4 also inhibit P-glycoprotein, the concomitant use of erythromycin and other known inhibitors of CYP3A4 with ergotamine preparations should be avoided.
Source: ADRAC Bulletin Vol 19, No 4, December 2000.
References:

1. Phan JC, Agaliotis D, White C et al. Ischaemic peripheral neuritis secondary to ergotism associated with ritonavir therapy. Medical Journal of Australia 1999; 171: 502-3.
2. Blanche P, Rigolet A, Gombert B et al. Ergotism related to a single dose of ergotamine tartrate in an AIDS patient treated with ritonavir. Postgraduate Medical journal 1999; 75:546-7.

GABAPENTIN
Interaction with warfarin

Sweden. The Medical Products Agency (MPA) urges physicians to report any cases of suspected interactions between gabapentin (Neurontin�) and warfarin (Waran�). The agency says that 2 such cases have been received by the Regional Centre for Spontaneous Reporting of Adverse Drug Reactions in Uppsala. In both cases, international normalised ratios (INR) decreased after gabapentin was added to warfarin therapy. The MPA says that 1 other case of a suspected interaction between gabapentin and warfarin has previously been reported in the Swedish adverse reaction register (SWEDIS), but the patient was also receiving phenytoin which is known to interact with warfarin.
Source: Information from the MPA, Vol 11, No 7, 2000.
Reports in WHO-file: Prothrombin increased 5, prothrombin decreased 8, therapeutic response decreased 1.

GENTAMICIN EAR DROPS
Ototoxicity

Canada. The Canadian Adverse Drug Reactions Monitoring Program (CADRMP) warns that aminoglycoside ear drops can cause Ototoxicity when used in patients with tympanic membrane perforation. Between 1981 and October 2000, the CADRMP received 18 reports of suspected Ototoxicity associated with use of gentamicin + betamethasone (Gara- sone�) ear drops in patients with tympanic membrane perforation or tympanoplasty tubes; 16 of these reports involved vestibular disorders and 2 involved hearing loss. At the time of reporting, 15 patients had not recovered from their Ototoxicity. In addition to these 18 reports, the CADRMP has received 1 report of dizziness and vertigo associated with use of gentamicin ear drops and another report of temporary hearing loss in a patient with Meniere's disease following treatment with gentamicin ear drops and high-dose gentamicin infusion. The CADRMP reminds prescribers that the labelling of Carasone� and gentamicin (Garamycin�) ophthalmic/otic solutions was changed in 1996 to limit the indications and clinical uses, to expand the contraindications to include patients with absent or perforated tympanic membranes, and to recommend patient monitoring during treatment.
Source: Canadian Adverse Drug Reaction Newsletter 11 (1): 2-3, lanuary 2001.
Reports in WHO-file: Deafness 338, ototoxicity 72.

MEFLOQUINE
Neuropsychiatric reactions

Sweden. The Medical Products Agency (MPA) reminds prescribers that for malaria prophylaxis mefloquine (Lariam�) should be started at least 3 weeks prior to travel in case adverse neuropsychiatric reactions occur, such as anxiety, depression, difficulty in sleeping, psychotic and paranoid reactions. The agency has received a total of 69 reports of such reactions associated with mefloquine. The most commonly reported reactions are dizziness (21 reports), anxiety (14), worry (8), depression (8), sleeping difficulties (8), nightmares (6), loss of balance (5) and muscle cramps (5). The MPA stresses the importance of informing travellers about the risk of such reactions occurring during the first weeks of mefloquine administration, and that they should discontinue the drug if such reactions occur. The MPA adds that mefloquine is contraindicated in patients with a history of psychiatric disease (particularly depression) or epilepsy. Source: Information from the MPA, Vol 11, No 7, 2000.
Reports in WHO-file: Most reported psychiatric reactions; Agitation 775, anorexia 626, anxiety 730, confusion 428, depression 800, insomnia 607.

METHYSERGIDE
Cardiac valvulopathy

Australia. Methysergide (Deseril�) is an ergot alkaloid used in the j prophylaxis of migraine. Its most well-known serious adverse effect is retroperitoneal fibrosis. It has also been reported to be associated with fibrotic changes to other organs including heart valves.(1) The Australian Adverse Drug Reactions Committee (ADRAC) has received two recent reports describing cardiac valvulopathy.
A 74-year old woman had been taking methysergide for cluster headaches since 1990. In 1995 she developed symptoms of cardiac failure and in July 1999 she had a triple valve replacement because of cardiac failure due to severe valvular regurgitation. Histological analysis showed pathological features in the aortic, anterior mitral and tricuspid valve that resembled changes described by the pathologist as methysergide dystrophy. A second report described a 43-year old man who developed extensive bilateral pleural fibrosis, atrial fibrillation and mitral incompetence after taking methysergide.
The prescribing information for methysergide states that continuous administration of the drug should not exceed 6 months and then methysergide should be withdrawn for 3-4 weeks before recommencement. It was of particular interest in the two ADRAC reports that the cardiac abnormalities occurred despite interrupted treatment according to directions. The valve damage reported in association with methysergide appears to be similar to that reported with carcinoid syndrome, with ergotamine and more recently with fenflura-mine/dexfenfluramine. Many of these reports describe the presence of a white surface plaque on the valves. These observed similarities suggest that a common factor may be causing the damage and may be related to the action of excess serotonin.
Prescribers should be aware that although methysergide "drug holidays" are generally recommended to prevent fibrotic changes, these changes can still occur and may affect cardiac valves.
Source: ADRAC Bulletin Vol 19, No 4, December 2000.
Reference: Redfield MM, Nicholson WJ, Edwards WD et al. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Annals of Internal Medicine 1992;117:50-2.

METOPROLOL
Galactorrhoea

Sweden. A case of galactorrhoea in a 61-year-old woman with diabetes receiving metoprolol (Seloken Zoc�) for hypertension has been reported to the Medical Products Agency (MPA). The woman initially developed excessive sweating after starting metoprolol and then, after 6 months, she developed galactorrhoea. Metoprolol was discontinued and the galactorrhoea resolved. The MPA says that this is the first case of galactorrhoea associated with a P-adrenoreceptor antagonist to be reported in Sweden.
Source: Information from the MPA, Vol 11 No 6, 2000.
Reports in WHO-file: Location nonpuerperal.

SEROTONIN REUPTAKE INHIBITORS (SSRIs)
(1) Increased ocular pressure

Australia. From November 1972 to January 2001, the Australian Adverse Drug Reactions Committee (ADRAC) had received 92 reports of raised ocular pressure. Since 1992, there have been 11 reports implicating selective serotonin reuptake inhibitors (SSRIs) involving sertraline (4 reports), fluoxetine (3), paroxetine (3) and citalopram (1). Ages of patients in these reports ranged from 32 to 70 years. Onset generally occurred within 6 months of commencing the SSRI but ranged from one week to 5 years. In 2 cases, the SSRI may have aggravated pre-existing glaucoma. In one case, the intraocular pressures which had previously been stabilised with treatment almost doubled. Presentations consisted of asymptomatic increases in intraocular pressures noted on routine testing (6 j cases), eye pain (2 cases), and blurred I vision (3 cases). At the time of reporting, 5 patients had not recovered and the outcome remained unknown for the other 6.
The major causes of raised intraocular pressure reported to ADRAC are shown in the table, with corticosteroids, antidepressants and mydriatics accounting for 53 of the total of 92 reports (more than half). The association with SSRIs is less well known and is probably very uncommon although there have been | several published case reports.

Reports of Raised Intraocular pressure

Drug	No. of reports
Corticosteroids	24
Systemic	13
Topical	6
Inhaled	5
Antidepressants	17
SSRIs	11
Tricyclics	4
Other	2
Mydriatics	10

Source: ADRAC Bulletin Vol 20, No 1, February 2001.

(2) Ocular adverse reactions

Sweden. Serotonin reuptake inhibitor antidepressants can cause ocular adverse reactions of an anticholinergic nature, warns the Medical Products Agency (MPA). The agency has received a total of 73 reports of 76 ocular adverse reactions associated with these antidepressants, including glaucoma, blurred vision, eye accommodation problems, diplopia, mydriasis, conjunctivitis, xerophthalmia and unspecified visual disorders. The agency stresses that there is a risk of acute narrow-angle glaucoma in predisposed patients, such as those with a history of glaucoma, hypermetropia, old age or family history of glaucoma.
Source: Information from the MPA, Vol 1 1, No 7, 2000.
Reports in WHO-file: Glaucoma 142, vision abnormal 1385, accommodation abnormal 111, diplopia 189, mydriasis 364, conjunctivitis 167, xerophthalmia 113.

STATINS
Rhabdomyolysis : Concomitant use with fibrates to be avoided

(1) CERIVASTATIN and gemfibrozil

Australia. Cerivastatin (Lipobay�) is the fifth of the HMG-CoA reductase inhibitors ("statins") to be marketed in Australia. Rhabdomyolysis is a known but rare effect of all the statins and is more likely to occur when a fibrate is taken concurrently. Its occurrence in association with cerivastatin appears greater than with other statins. Up to January 2001, the Australian Adverse Drug Reactions Committee (ADRAC) had received a total of 95 reports associated with cerivastatin, of which 17 (18%) have described rhabdo-myolysis. This can be compared with the other statins for which the percentages range from 0.3 to 1 .2%.
The 17 cases of rhabdomyolysis associated with cerivastatin occurred from just over a week to 18 months after the introduction of cerivastatin but most occurred in the first month of therapy. Seven of the 15 cases in which the dose was stated occurred with daily dosages of 400 micrograms or greater and two cases occurred shortly after the dose was increased to 800 micrograms daily.
Of particular interest is the fact that 1 0 of the 1 7 patients were taking gemfibrozil concomitantly. The sponsor has made the concomitant use of cerivastatin and gemfibrozil a contraindication. ADRAC wishes to alert prescribers to the possibility of rhabdomyolysis with all statins. Cerivastatin should not be used in combination with gemfibrozil.
Source: ADRAC Bu//et/n Vol 20, No 1, February 2001.

(2) PRAVASTATIN and bezafibrate

Sweden. The Medical Products Agency (MPA) cautions that rhabdomyolysis can occur during treatment with HMG-CoA reductase inhibitors (statins), especially when used in combination with fibrates. The agency reports details of the first Swedish case of rhabdomyolysis in a patient receiving both pravastatin (Pravachol�) and bezafibrate (Beza-lip�). In the WHO's international adverse reaction register, there are 33 suspected cases of rhabdomyolysis associated with pravastatin and 43 cases associated with bezafibrate; both of these drugs were suspected in 3 of the reports.
Source: Information from the MPA, Vol 11, No 7, 2000.
Reports in WHO-file: Statins; Rhabdomyolysis 987, fibrates; Rhabdomyolysis 426.

TETRACYCLINE THERAPY
Benign intracranial hypertension

New Zealand. Benign intracranial hypertension (BIH) is a rare but potentially serious condition. BIH has been documented in association with a variety of medications, particularly the tetracyclirfes.
The New Zealand Centre for Adverse Reactions Monitoring (CARM) has received its second report of benign intracranial hypertension (BIH) related to minocycline involving a 14-year old female who was being treated with minocycline for acne. Other prescribed medicines were fluticasone and salbutamol inhalers. She presented with headache unrelieved by analgesics, and had intermittent vomiting. Her signs on admission to hospital included slurred speech, reduced sensation and left-sided weakness, with mild lateral rectus palsy on the right. The minocycline, which she had taken for thirteen days, was discontinued. A diagnosis of hemiplegic migraine was made, and she recovered from this episode. The headache then recurred after restarting minocycline. Papilloedema was observed and the diagnosis of benign intracranial hypertension (with hemiplegic migraine) was made. Treatment included four lumbar punctures and acetazolamide. The patient had not fully recovered at the time of reporting.
Physicians should regularly enquire about headache in patients receiving tetracycline therapy, in view of the potential risk of benign intracranial hypertension (BIH). BIH has been reported in association with a variety of medications, particularly the tetracyclines. Minocycline is the agent most frequently reported in the literature to cause BIH. The lipophilic properties of minocycline may be the explanation for the higher number of reported cases.
The most common presenting feature of BIH is headache (90% of cases); however, BIH can be completely asymptomatic. Diagnostic criteria include an increased intracranial pressure (more than 200mm water), the presence of papilloedema and/or sixth nerve palsy, and also sometimes decreased visual acuity and visual defects. If associated with a drug, BIH may resolve completely after drug discontinuation. However, the condition is not always benign; some patients can develop irreversible visual field defects and, occasionally, blindness. If drug-induced BIH is suspected, the implicated drug should be discontinued.
Tetracyclines should not be prescribed concomitantly with retinoids (e.g. isotretinoin), another drug class associated with BIH, as this may result in an increased incidence of BIH.
Source: Kingston H. Tetracyclines and Benign Intracranial Hypertension - a headache rare but real.
Prescriber Update No. 21, January 2001. [http://www. medsafe.govt. nz/profs.htm] Reports in WHO-file: Hypertension
intracranial, doxycydine 28, minocycline 190, tetracycline 31.

---

Review of ADRs
ANTI-INFLAMMATORY ANALGESICS
Hepatic reactions

Finland. Liver damage caused by anti-inflammatory analgesics is very rare. The incidence of symptomatic liver damage is estimated at 0.001-0.05%. A symptom-free, mild increase in hepatic enzymes is more common and may occur in as many as 5-15% of patients. The frequency and pattern of liver damage vary between the different anti-inflammatory analgesics. The damage is classified as hepatocellular, cholestatic or a mixture of these. Hepatocellular damage is often associated with hepatocellular necrosis. The levels of hepatic enzymes (AST, ALT) are considerably increased, whereas the levels of serum alkaline phosphatase (ALP) and bilirubin show less increase. In the case of cholestatic damage the biliary secretion is decreased and the serum levels of ALP and bilirubin are increased. The increase in hepatic enzymes may be quite small. The prognosis of cholestatic damage is better than that of hepatocellular damage and the normal situation is often restored after withdrawal of medication. The diagnosis of hepatitis requires a histological lesion diagnosed with the aid of liver biopsy.
The mechanisms of liver damage caused by anti-inflammatory analgesics are not well known. The reactions may be idiosyncratic, host-dependent and lacking precise correlation with the dose. The damage may be caused by a reactive/toxic metabolite formed from the drug. Sometimes the liver damage may be associated with symptoms indicative of a hypersensitivity reaction (e.g. fever, eosinophilia, rash, arthralgia).
The register of adverse reactions maintained by the National Agency for Medicines has received a total of about 15,200 reports between 1973 and November 2000 concerning suspected adverse reactions in association with the use of drugs. About 1,000 (6.6%) of these reports involved a variety of effects on the liver. A total of 59 cases have been reported in association with the use of anti-inflammatory analgesics where the patient's liver was found to have been adversely affected (see Table). The majority of cases involved only a change in liver function tests.
Nimesulide
A total of 17 of the reports on adverse effects on the liver were linked with the use of nimesulide. Eight of these cases involved hepatitis and 9 increased hepatic enzyme levels. The majority of patients (14) were women. The average age was 61 years (ranging between 23 and 88 years), and 9 of the patients were over 60 years of age. The symptoms or findings of liver effects usually appeared after 1 -6 weeks of treatment In 11 patients the laboratory values had returned to normal at the follow-up after nimesulide was stopped. Six patients had still not recovered 2-8 weeks after withdrawal of medication, when the report on the adverse effect was made. Five patients were using concomitant drugs which have been reported to have hepatic reactions. According to published case reports, nimesulide can cause both hepatpcellular necrosis and pure cholestasis. Individual cases of fatal liver damage have also been reported.
Nimesulide is a relatively new drug, introduced on the Finnish market in January 1998. However, it is widely used and the number of daily doses (0.2 g) by September 2000 totalled over 14 million. One reason for the popularity of nimesulide is probably its selectivity - which, as a COX-2 inhibitor, is claimed to be higher than that of older anti-inflammatory analgesics - and the fewer cases of gastrointestinal tract ulcers it causes.
Due to its adverse effects on the liver, the product information on nimesulide was updated at the beginning of 2000. Hepatic insufficiency was added to the contraindications and additional text was included in the section on warnings according to which patients with abnormal values in their liver function tests and/or patients with symptoms indicative of liver damage (anorexia, nausea, vomiting, jaundice) j during nimesulide therapy must be closely monitored and medication stopped. These patients should not be re-exposed to nimesulide. Increased hepatic enzyme values were included in the section on rare adverse effects in the SPC, and cholestasis and rapidly i developing hepatitis were included in j the list of very rare adverse effects.
Diclofenac
Among anti-inflammatory analgesics, the second largest number of reports on adverse effects on the liver received by the register on adverse reactions are those associated with the use of diclofenac (11 cases). The average age of the patients was 53 years (ranging between 31 and 80 years) and 9 of the patients were women. According to the reports, liver values returned to normal in 7 patients after withdrawal of medication and 1 case of liver damage proved fatal. Diclofenac has been in clinical use since 1977. The reports of adverse hepatic effects are distributed rather evenly in the years between 1978 and 2000. A hepatic reaction associated with diclofenac may not appear until after several months of treatment. The liver damage is usually of a hepatocellular or mixed type and less than 10% of cases have features of cholestatic damage. Predisposition to liver damage caused by diclofenac appears to increase with advancing age.
Other anti-inflammatory analgesics
According to the literature, the use of sulindac is associated with liver reactions. The drug is no longer available on the Finnish market. Hepatic reactions associated with other anti-inflammatory analgesics currently in use are very rare. This would appear to be true also according to the reports received by the register of adverse effects of the National Agency for Medicines (see Table).
Conclusion
The risk of liver damage associated with anti-inflammatory analgesics is very small compared with the symptoms of gastric irritation, ulcer and gastrointestinal haemorrhage that they cause. However, the risk of hepatic reactions caused by these products may increase with age. The risk of liver damage is also greater in patients on concomitant therapy with some other hepatotoxic medication. Patients with rheumatoid arthritis, for example, use many drugs which have been associated with liver damage. These include gold salts, sulfasalazine, penicillamine, methotrexate and ciclosporin. There is no information based on studies regarding underlying hepatic disorders or excess consumption of alcohol, but care should be exercised when treating : these patients.
Table
Hepatic reactions caused by anti-inflammatory analgesics and included in the register of adverse effects of the National /Agency for Medicines during 1973 to November 2000

Drug	No.of Cases
Hepatitis
nimesulide	8
diclofenac	3
naproxen	2
acetylsalicylic acid	1
ibuprofen	1
piroxicam	1
Other liver damage (no evidence of hepatitis)
diflunisal	1
indometacin	1
Increased hepatic enzymes
nimesulide	9
diclofenac	8
ibuprofen	5
tolfenamic acid	5
indometacin	4
ketoprofen	2
acetylsacylic acid	1
phenylbutazone	1
mefanamic acid	1
naproxen	1
oxypenbutazone	1
piroxicam	1
sulindac	1
tiaprofenic acid	1

Source: Drug Information from the National Agency for Medicines (TABU), No. 6, p.37-8, 2000.

VACCINES

Sweden. During 1998 and 1999, the Medical Products Agency (MPA) received over 600 reports of adverse reactions possibly associated with vaccines, with the majority of reports involving children aged 4 years or less. The MPA says that compared with the large number of doses given to children, few adverse reactions have been reported were local reactions, involving approximately 50% of reports. Other common adverse reactions were fever (123 cases), exanthema (44) and urticaria (31). Additionally, the MPA received reports of angioneurotic oedema (3 cases), nausea/vomiting (22), rash (18), cramps/seizures (7), ataxia (3), anxiety/irritation/sleeping disorders (5), continuous crying (33), joint pain/inflammation (8) and thrombocytopenia (1).
Source: Information from the MPA, Vol 11, No 6, 2000.

ALFACALCIDOL
Potential for medication errors with
new high-strength formulation

United Kingdom. The potential for error in prescribing and dispensing alfacalcidol drops (One-Alpha) has been highlighted this week. In a letter from Dr Pat Troop (deputy chief medical officer) and Mrs Jeannette Howe (acting chief pharmacist), health professionals, including pharmacists, are asked to be aware of a potential problem that has arisen following a change in formulation.
A high-strength formulation of alfacalcidol, One-Alpha� drops, was launched in July, 2000. This formulation is 10 times stronger than the former presentation, One-Alpha� solution, which was discontinued in September 2000. The letter states that if a prescription for alfacalcidol is written in "mls" (millilitres) rather than "ng" (micrograms), there is potential for a patient to be given a dose 10 times that intended.
The Medicines Control Agency has advised doctors and pharmacists to be vigilant when prescribing, dispensing and administering alfacalcidol drops. It adds that doses should be given in micrograms (ng) and that any suspected adverse reaction to alfacalcidol, including overdoses, should be reported through the yellow card scheme.
The most recent edition of the British National Formulary (number 40, September 2000) states that the strength of alfacalcidol drops is 2 micrograms/ml and includes a sentence noting that the concentration of One-Alpha� drops is 10 times stronger than that of the former presentation One-Alpha� solution.
Reference: The Pharmaceutical lournal, Vol.265, p. 347, 9 December 2000.

INSULIN FORMULATIONS
Humalog� and Humalog
Mix25 : potential for confusion

Australia. The names of the wide range of insulin products can cause confusion. The most recent example concerns Humalog� and Humalog Mix25�.
Humalog� is the product name for lispro insulin, a fast-acting analog of human insulin. Humalog Mix25� contains 25% lispro insulin and 75% lispro insulin protamine suspension. The Australian Adverse Drug Reactions Advisory Committee (ADRAC) has been notified of a small number of instances where the similarity of the two product names has led to dispensing or transcribing errors. No serious consequences have been reported but the potential for harm is clear. Prescribers and dispensers need to be aware of the potential for confusion. Humalog� is a clear, rapidly acting insulin. Humalog Mix25� is cloudy and combines rapid with intermediate actions. The sponsor, Eli Lilly, is aware of the problem and has distributed educational material to health professionals. It also intends soon to amend the packaging of the products to help differentiate the two insulins.
Source: ADRAC Bulletin Vol 20, No 1, February 2001.

METHOTREXATE
Serious dispensing errors reported

United Kingdom. Problems with the prescribing and o dispensing of methotrexate are highlighted in September's Current Problems in Pharmacovigi lance. Once-daily treatment has been prescribed or dispensed when weekly treatment was intended, and 10-mg tablets have been dispensed instead of 2.5-mg tablets. In addition, a dose for a patient with cancer has been prescribed for patients with rheumatoid arthritis or psoriasis.
The Committee on Safety of Medicines and the Medicines Control Agency suggest that when dispensing methotrexate, pharmacists should check the dose regime and indication, and if there are any doubts, consult the prescribing doctor. Reference: The Pharmaceutical lournal, Vol.265, p. 347, 9 December 2000.

MMR vaccine and its public image
Dr CJ Clements, Medical Officer, Department of Vaccines and Biologicals, WHO

Introduction
The combined measles, mumps and rubella vaccine was included in the WHO Model List of Essential Drugs in 1990 and is recommended by WHO for use in national immunization programmes. Since 1998, various reports have emerged in the professional and lay press that question the safety of the triple (MMR) vaccine resulting in loss of confidence and reduction in uptake. It is in the United Kingdom that the issue has the highest profile. Some are predicting a measles outbreak soon as a result. This article serves to provide an independent assessment of the situation.

Adverse events known to be associated with MMR
Much is known about MMR in terms of its composition, safety, efficacy and impact. The MMR vaccine is a combination of live attenuated virus vaccines for measles, mumps and rubella. This was first introduced in the USA in 1971, and is now widely used on a global scale. Studies have shown that the combination of the vaccines shows the same high rates of seroconversion seen with each component individually and that there is no increased risk of reaction m. The reasons for promoting the triple vaccine are to raise measles vaccination coverage, to interrupt the transmission of rubella amongst young children and to prevent mumps. Since the licensing and introduction of the MMR vaccine in several countries around the world, adverse events following immunization have been monitored, with additional studies confirming the safety of the vaccine. As with all vaccines, there have been documented cases of mild and severe reactions. These are:

Mild
Local reactions are not uncommon following administration of measles-containing measles vaccines. They include rash (5%), and pain and tenderness at the injection site. These reactions are generally mild and transient. In most cases, they
spontaneously resolve within two to three days. Mild systemic reactions include moderate fever (39 �C or less) in 5%-15% of recipients.

Severe
Severe reactions may also occur. Of the five mentioned below, all are rare and for one (Guillain-Barre Syndrome), there is insufficient evidence to be sure whether there is an association with administration of vaccine or not.

• Allergic Reactions, including anaphylaxis
• Encephalitis
• Guillain-Barre Syndrome (CBS)
• Seizures
• Thrombocytopenia

Table 1 highlights the fact that natural measles is a serious disease with frequent complications, whereas vaccination with live attenuated virus is remarkably benign.121 This stark contrast is consistently missing from the remarks of those who would decry the safety of MMR .

Table 1.
Risk of complications from natural measles infection compared to known risks of vaccination with a live attenuated virus in immunocompetent individuals

Complication	Risk after natural disease(a)	Risk after vaccination(b)
Otitis media	7-9%	0
Pneumonia	1-6%	0
Diarrhoea	66%	0
Post-infectious encephalomyelitis	0.5-1 per 1000	1 per 1 000 000
SSPE	1 per 100 000	0 (cases likely to be related to other causes)
Thrombocytopenia	c	1 per 30 000(d)
Death	0.1-1 per 1000 (up to 5-15% in developing countries)	0 (some case reports, but likely to be related to other causes)

1. Risks after natural measles are calculated in terms of events per number of cases
2. Risks after vaccination are calculated in terms of events per number of doses
3. Although there have been several reports of thrombocytopenia occurring after measles including bleeding, the risk has not been properly quantified.
4. This risk has been reported after MMR vaccination and cannot only be attributed to the measles component.

MMR = measles, mumps and rubella
SSPE = subacute sclerosing pan-encephalitis.

The type and rate of severe adverse reactions following administration of combination vaccines do not differ significantly from those following their separate administration.

Unsubstantiated adverse reactions
Inflammatory bowel disease and autism

In recent years, certain researchers have hypothesized that measles vaccine may be associated with inflammatory bowel diseases (IBD), including Crohn's Disease. (3-8) One research group speculated that measles vaccine could be related to the development of IBD and autism.(9) Within the scientific community, concerns have been raised about the methodological limitations in the studies upon which these hypotheses are based. (10-14) Other research does not support an association between the administration of MMR vaccine and IBD or autism - the alleged associations are based upon weak science and have been refuted by a large volume of scientifically sound work. (2, 15-19) However it is not possible to prove a lack of these j associations conclusively, only to ascertain their great rarity should an association exist at all.
The early signs of autism, a condition generally accepted as starting before a child is born, are usually first noticed by parents at or around the time MMR is given. This is known as a "temporal" association one that links two events in time. But it does not denote any "cause and effect". The link between autism and administration of MMR was speculated by Wakefield et al. (9) who described anecdotally 12 children with autism, most of whom reported disease onset just after MMR vaccination. A paper by Singh et al.(20) describes the existence of certain anti-measles antibodies in autistic childpen, but their titers do not differ significantly from normal controls; the results are consistent with the general hypothesis that a virus-induced autoimmune response could play a causal role in autism.
With the above exceptions, all other studies have found no association. Typical are the results of Taylor et al, in 1999(19) who investigated 498 cases of autism in the UK in children born after 1979 and did not find an association between MMR vaccine and autism. A study in 1998 followed up 14 years of MMR vaccination in Finland. No evidence was found for an increase in autism associated with MMR(1). A study of the same database searched for severe adverse events - again no evidence was forthcoming to prove an association with inflammatory bowel disease or autism.(21)

WHO's response

Along with the majority of the medical profession and official organizations, WHO has issued statements indicating that it (and its advisors) do not accept a likely causal association between the administration of MMR and onset of autism or inflammatory bowel disease. Moreover, if a causal association were to exist for autism and inflammatory bowel disease, it is so rare that it is hard to identify on the basis of currently available information.
The combination vaccine MMR and each of the three component vaccines separately are very safe and highly effective in preventing disease, complications and death. The effectiveness of the vaccine in preventing a potentially fatal disease outweighs the risks. The decision as to which to use should be determined solely on epidemiological grounds. WHO continues to recommend the use of these vaccines in national immunization programmes.

References:

1. Peltola H, Patja A, Leinikki P et al. No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet 351, 1998;1327.
2. Duclos P, Ward Bj (1998). Measles vaccines: A review of adverse events. Drug Safety, 6:435-54.
3. Ekbom A, Adamf HO, Helmick CC et al. Perinatal risk factors for inflammatory bowel disease: a case-control study. American Journal of Epidemiology 1990: 132: 1111-9.
4. Wakefield A), Pittilo RM, Sim R et al. Evidence of persistent measles infection in Crohn's Disease. Journal of Medical Virology 1993; 39: 345-53.
5. Ekbom AJ, Wakefield AJ, Zack MM et al. Perinatal measles infection and subsequent Crohn's disease. Lancet 1994; 344:508-10.
6. Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 1995; 345: 1071-4.
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8. Ekbom A, Daszak P, Kraaz W et al. Crohn's disease after in-utero measles exposure. Lancet 1996; 348: 515-7.
9. Wakefield AJ, Murch SH, Anthony A et a!. lleal-lymphoid-nodular hyper-plasia, non-specific colitis, and regressive developmental disorder in children. Lancet 1998; 351: 637-41.
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11. Farrington P, Miller E. Measles vaccination as a risk factor for inflammatory bowel disease [letter]. Lancet 1995; 345: 1362. 12.
    
12. MacDonaldTT. Measles vaccination as a risk factor for inflammatory bowel disease [letter]. Lancet 1995; 345: 1363-4.
13. Miller D, Renton A. Measles vaccination as a risk factor for inflammatory bowel disease [letter; comment]. Lancet 1995; 345: 1363.
14. Chen RT, DeStefano F. Vaccine adverse events: causal or coincidental? [comment]. Lancet 1998; 351: 611-612.
15. Liu Y, van Kruiningen HJ, West AB et al. Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn's disease. Gastroenterology 1995: 108: 1396-404.
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18. Haga Y, Funakoshi O, Kuroe K, et al. Absence of measles viral genomic sequence in intestinal tissues from Crohn's disease by nestedpolymerase chain reaction. Cut 1996; 38: 211-5.
19. Taylor B, Miller E, Farrington CP, Petropoulos M-C, Favot-Mayaud I, Li I, Waight PA. Autism and measles,
    mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026-29.
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21. Patja A, Davidikin I, Kurki T, Kallio M, Valle M, Peltola H. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatric Infectious Disease journal, 19(2000); 1127-1134.