Clinical Pharmacy News summary

A shortage of fluorouracil is causing problems for hospitals, according to Maxwell Summerhayes, principal oncology pharmacist at Guy's and St Thomas's Hospital in London...[more]

One of the most effective interventions for reducing the majority of preventable adverse drug events is to have full-time, ward-based clinical pharmacists, say American researchers...[more]

Debriding agents for difficult-to-heal surgical wounds should be chosen on the basis of comfort, odour control, type and location of wound, and total costs, according to new guidance from the National Institute for Clinical Excellence...[more]

Concerns over the safety of amfebutamone (bupropion, Zyban) have been expressed following an inquest into the death of a patient who was taking the drug...[more]

Experts from around the world met last week to discuss preparations for an influenza pandemic...[more]

A family history of thromboembolism is not a predictor of the risk of venous thromboembolism among women taking oral contraceptives, say researchers from Italy...[more]

Decreased prescribing of sulphonamides has not reduced resistance to them, microbiologists from London have found...[more]

Novartis has launched its new antidiabetic agent nateglinide (Starlix)...[more]

Losartan (Cozaar) could improve sexual dysfunction in men with high blood pressure, according to research undertaken in Spain...[more]

The National Institute for Clinical Excellence said last week that the earliest that it would be issuing guidance on drug treatments for multiple sclerosis would be September this year, but that it could be November...[more]

Lack of fluorouracil causing problems

A shortage of fluorouracil is causing problems for hospitals, according to Maxwell Summerhayes, principal oncology pharmacist at Guy's and St Thomas's Hospital in London.

Speaking to The Journal on April 30, he said that the lack of stock of Faulding Pharmaceuticals's fluorouracil 25mg/ml (see PJ, April 28, p601) was a “big problem” for hospitals. He commented that an alternative product was available from another supplier, Medac UK, but it was a double-strength solution and there would be problems switching from one to the other. Worksheets and labels would have to be amended and stability issues would have to be considered, he explained.

Tony Johnson, director of sales and marketing at Faulding told The Journal that the company was doing all it could to get supplies back to normal and it expected new supplies to be released by early June. He said that Faulding currently had a limited stock of the 50mg/ml solution and that this would be distributed as soon as the necessary documentation had been released by the Medicines Control Agency.

Mr Johnson acknowledged that it was not easy to switch between the 25mg/ml and 50mg/ml solutions but he expected that the higher strength solution would be available sooner. When asked why pharmacists had not been informed of the situation before it reached such a critical level, Mr Johnson said that Faulding had thought it could obtain stocks from other parts of the world. “When this avenue of investigation dried up we issued the press release,” he said.

Mr Johnson suggested that pharmacists could approach compounding companies, such as Baxter and Faulding Compounding, to acquire stock, but added that, unless they were regular customers, the companies were unlikely to agree to requests.

David Maybury, Medac UK's hospital business development director, told The Journal on May 1, that he was “confident of the continued supply of fluorouracil”. He added that the following single-pack presentations of fluorouracil were available from Medac: 500mg/10ml, 1,000mg/20ml, 2,500mg/50ml and 5,000mg/100ml.

Commenting on the supply problems, Allan Karr, pharmacy purchasing and business manager, University College London Hospitals NHS Trust, said that the situation had to be seen in context. “The shortage situation in general has never been worse, and there is currently a huge list of shortages, not just fluorouracil.”

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Pharmacists can reduce preventable ADEs

One of the most effective interventions for reducing the majority of preventable adverse drug events is to have full-time, ward-based clinical pharmacists, say American researchers.

Dr Rainu Kaushal of the Children's Hospital in Boston, Massachusetts, and colleagues assessed the rates of medication errors, adverse drug events (ADEs) and potential ADEs in a prospective study of 1,120 patients (most of whom were children) admitted to two teaching hospitals over a six-week period. They reviewed 10,778 medication orders and found 616 medication errors (errors in drug ordering, transcribing, dispensing, administering, and monitoring), 26 ADEs and 115 potential ADEs. Potential ADEs were medication errors that were considered to have significant potential for injuring a patient but were intercepted, or those which would have been harmful had they occured.

As part of the study, independent reviewers assessed the potential impact of prevention strategies. They judged that ward-based clinical pharmacists could have prevented 94 per cent of the potential ADEs and that computerised order entry by hospital doctors could have prevented 93 per cent. The researchers comment that the presence of clinical pharmacists on ward rounds could lead to more informed clinical decision-making by doctors, as well as increased interception of errors before medication orders were finalised. “Their presence on the wards should facilitate communication between clinical staff and the pharmacy. In addition, clinical pharmacists could independently monitor the transcription process, assist nurses with drug preparation and administration, and monitor the drug preparation, storage, and distribution systems,” they said (JAMA 2001; 285:2114).

Anthony Cox, adverse drug reaction pharmacist at the West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital NHS Trust, Birmingham, welcomed the study.

Speaking to The Journal on May 1, he said: “This study is a welcome addition to the relatively unstudied area of adverse drug events and medication errors in paediatrics.” He added that medication errors were common occurrences and that the study highlighted the need to find solutions, such as electronic prescribing, and ward-based clinical pharmacists. “A large study, based in the United Kingdom, is required to quantify the problem here and to investigate effective interventions to reduce the risk posed to this vulnerable group of patients,” he said.

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NICE guidance on debriding agents and brain cancer drug

Debriding agents for difficult-to-heal surgical wounds should be chosen on the basis of comfort, odour control, type and location of wound, and total costs, according to new guidance from the National Institute for Clinical Excellence.

The guidance, which was issued on April 27, states that “there is no randomised, controlled trial evidence to support any particular method of debridement”.

It adds that some studies have suggested that modern dressings (eg, hydrocolloids, hydrogels, polysaccharide beads or paste, foam dressings, and alginate dressings) as well as bio-surgical techniques (use of sterile maggots) might reduce pain and could be more acceptable to patients.

On the same day, the institute also issued guidance that says that, in certain circumstances, temozolomide, an antineoplastic agent, should be offered as second-line chemotherapy treatment for patients with recurrent malignant glioma. (Temozolomide is currently only indicated as first-line chemotherapy for patients taking part in clinical trials.)

Both guidance documents are available on the NICE website (www.nice.org.uk).

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Increased vigilance needed to avoid interactions with amfebutamone

Concerns over the safety of amfebutamone (bupropion, Zyban) have been expressed following an inquest into the death of a patient who was taking the drug.

A spokeswoman for GlaxoSmithKline, manufacturer of Zyban, told The Journal on April 30: “It is important to note that suspected adverse events are not necessarily caused by the drug and may relate to other factors, such as concurrent illnesses, other medicines a patient may be taking or, more importantly, the effect of smoking-related diseases and smoking cessation.”

The inquest highlighted the need for vigilance to prevent interactions between amfebutamone and other drugs. The patient concerned was also taking chloroquine and diphenhydramine.

The GSK spokeswoman said that a review would take place regarding the
inclusion of interactions between amfebutamone and these drugs in the summary of product characteristics (SPC) for amfebutamone.

She also said the patient had a predisposition to seizures, which is a contraindication for amfebutamone.

With regard to a specific list of all drugs with which amfebutamone may potentially interact, the spokeswoman said that pharmacists should refer to the SPC. The company had no further information available. However, if pharmacists had specific queries about amfebutamone, she recommended that they contact the medical information department at GSK. She agreed that there was a potential for amfebutamone to interact with some over-the-counter (OTC) products, if they fell into one of the categories listed in the SPC (see
Panel).

The medical information department does not hold a list of OTC drugs that interact with amfebutamone and enquiries need to be made for individual products.

Data from the Yellow Card Scheme until March 31, 2001, show that there have been 4,986 reports of adverse reactions caused by amfebutamone, of which 35 were fatal. Between its launch last June and February 28, 2001, an estimated 360,000 patients have taken the drug.

Professor Alasdair Breckenridge, chair, Committee on the Safety of Medicines (CSM), said in a press statement: “About 2 per cent of adverse reports for all medicines are associated with a fatal outcome. For amfebutamone, the proportion of reports [of fatalities] is much lower — less than 1 per cent.” The CSM considers the reports to be in line with the known safety profile of amfebutamone, which is reflected in the product information, Professor Breckenridge added.

“Amfebutamone is used in a population of patients who are put at risk because of smoking and, therefore, reports of deaths of patients receiving amfebutamone are to be expected.” The majority of patients who had died had underlying conditions that provided an alternative explanation for the deaths. In eight cases, the patients were not, in fact, receiving amfebutamone at the time of death, he said.

Potential interactions

Drugs that amfebutamone has a potential to interact with (based on information from amfebutamone's SPC and product information, the British National Formulary and 'Drug interactions', 5th edition, by Ivan Stockley):

• Drugs that lower seizure threshold
• Drugs that are metabolised by the cytochrome P450 isoenzyme CYP2D6 (because amfebutamone is an inhibitor of CYP2D6)
• Drugs that affect cytochrome P450 isoenzyme CYP2B6 (because amfebutamone is metabolised by CYP2B6)
• Drugs that are enzyme inducers
• Drugs that are enzyme inhibitors

Drugs that fall into these categories are specified in 'Drug interactions'. Some examples are antiarrhythmics (type 1c), antidepressants (selective serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricylics), antipsychotics, beta-blockers, carbamazepine, systemic steroids and theophylline.

The following OTC drugs might interact because they fall into one of the drug categories listed above: chloroquine, cimetidine, codeine, dextromethorphan, diphenhydramine and fluconazole.

The Journal will publish a list of specific products when available.

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Planning for an influenza pandemic

Experts from around the world met last week to discuss preparations for an influenza pandemic. Concerns were raised over the uncertainty of when a pandemic would happen and how drug companies would cope with increased demands for vaccines and antivirals. The meeting was held at the Royal Society in London.

Speaking at the meeting Dr Douglas Fleming, Royal College of General Practitioners, Birmingham, said that during the last pandemic in 1969, influenza had most affected people aged between 15 and 64 years. However, recently, more elderly people had been affected. He also said that between 1989 and 1998, on average, 9 per cent of all respiratory illnesses per winter were attributed to influenza and those most affected were children.

See also Forum, p629

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OC thromboembolism risk not predicted by family history

A family history of thromboembolism is not a predictor of the risk of venous thromboembolism among women taking oral contraceptives, say researchers from Italy.

Dr Benilde Cosmi, division of angiology, University Hospital, Bologna, and colleagues say that inherited defects can potentiate the risk from oral contraceptives but that a policy of selective screening could miss “a substantial number” of women at increased risk. They evaluated 324 women who had never had a thromboembolism, of whom 34 had a family history of venous thromboembolism.

The researchers found that the proportion of women with thrombophilia was similar among those with a positive family history and those without (6 per cent, 95 per cent confidence interval 3 to 8 per cent in both groups). (BMJ 2001;322:1024.)

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No decrease in sulphonamide resistance despite prescribing restrictions

Decreased prescribing of sulphonamides has not reduced resistance to them, microbiologists from London have found. Dr Virve Enne, of the department of medical microbiology, St Bartholomew's and the Royal London School of Medicine and Dentistry, and colleagues investigated the effect that a national restriction on the prescribing of sulphonamides, including sulfamethoxazole (in co-trimoxazole) had had on the prevalence of resistance to the drug in Escherischia coli.

The licensed indications for co-trimoxazole were restricted in 1995 after it was found that trimethoprim alone was as effective in urinary tract infection as the combination, and caused fewer side effects. Consequently, the number of prescriptions for sulphonamides dropped from 320,000 in 1991 to 7,000 in 1999.

The authors compared the rates of resistance to sulfamethoxazole in E coli isolates taken in 1991 with rates found in isolates taken in 1999.

They found that 39.7 per cent of isolates taken in 1991 were highly resistant to the drug, compared with 46 per cent of those taken in 1999.

“After a sustained and large decrease in the use of sulphonamides, the prevalence of resistance among E coli from east London has not declined,” they said.

Reasons for this might include not enough time having elapsed for a reduction to show, a pool of resistance arising from use of sulphonamides in animals and, most likely, the gene conferring resistance to sulphonamides being closely linked to other resistance genes and coincidentally maintaining sulphonamide resistance.

The authors noted that resistance to six out of eight other antimicrobial agents tested occurred significantly more often in sulphonamide-resistant isolates than in sulphonamide-susceptible isolates in both 1991 and 1999 (Lancet 2001;357:1325).

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New diabetes drug targets postprandial glucose

Novartis has launched its new antidiabetic agent nateglinide (Starlix). The drug restores normal “early phase” insulin secretion after a meal and so controls postprandial glucose levels in patients with type 2 diabetes. The company hopes that this effect will be shown to reduce cardiovascular disease, the major cause of morbidity and mortality in patients with diabetes.

Nateglinide is taken just before a meal. It has a fast onset and short duration of action. The short duration of action means that the drug is associated with less risk of hypoglycaemia than sulphonyl ureas, the company says.

Nateglinide is licensed for use with metformin in patients inadequately controlled on metformin alone (see p631), as the two drugs have complementary actions. Nateglinide (like sulphonylureas) acts on beta cell dysfunction and reduces postprandial glucose levels, whereas metformin improves insulin sensitivity and reduces fasting plasma glucose. Novartis says that clinical trials have shown the two drugs to have an additive effect on glycosylated haemoglobin levels (HbA_1c). Efficacy has not been directly compared with sulphonylurea/metformin combinations.

At the launch of nateglinide on May 1, Dr Melanie Davies, head of services, diabetes and cardiovascular medicine, Leicester Royal Infirmary, said that the two basic defects in diabetes — insulin resistance and beta cell dysfunction — were both important but there had been a tendency to ignore the latter. She said that in healthy individuals there was a burst of insulin secretion within minutes of eating. This “early phase” insulin response was lost in patients with type 2 diabetes, and the resulting postprandial glucose peaks contributed significantly to HbA_1c levels. There was, she said, increasing evidence now of a link between postprandial hyperglycaemia and cardiovascular disease.

Dr Davies added that the gradual decline in glycaemic control in type 2 diabetes could be attributed to progressive beta cell failure. “If we want to change the natural history of diabetes we have got to protect the beta cell.” In theory, use of a short-acting drug might help by avoiding the constant beta cell stimulation that occurred with sulphonylureas, she said.

No long-term outcome studies have yet been carried out. Novartis is, however, planning a study to test nateglinide's effect on progression of impaired glucose tolerance into type 2 diabetes, and to monitor the impact on cardiovascular disease. Studies of a nateglinide/rosiglitazone combination are also under way.

Novo Nordisk's repaglinide (NovoNorm) has a similar action to nateglinide on postprandial hyperglycaemia. No “head to head” study has compared the two drugs. At the nateglinide launch, Dr John Andrews, senior consultant physician, Whiteabbey Hospital, Co Antrim, said that the drugs differed structurally and in their kinetic properties. Nateglinide was an amino acid derivative whereas repaglinide was a sulphonylurea derivative. Nateglinide had a more rapid “on-off” action at beta cell receptors, and so might produce less hypoglycaemia.
— Contributed.

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Losartan can improve sexual dysfunction in hypertensive men

Losartan (Cozaar) could improve sexual dysfunction in men with high blood pressure, according to research undertaken in Spain.

Dr Carlos Ferrario (University of Valencia School of Medicine) and colleagues asked 82 men with hypertension and sexual dysfunction about sexual problems (such as decreased libido, impotence and poor sexual satisfaction) both before and after 12 weeks of treatment with 50 or 100mg losartan
daily.

At the end of the trial period, 88 per cent of the men reported improvement in at least one area of sexual function (American Journal of the Medical Sciences 2001;321:336).

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Further delay for MS treatment decision?

The National Institute for Clinical Excellence said last week that the earliest that it would be issuing guidance on drug treatments for multiple sclerosis would be September this year, but that it could be November. The institute said that it was still considering the evidence for beta-interferon and glatiramer acetate as treatments for the disease.

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