• Obese patients committed to weight loss can be given orlistat, says the NICE
• Elderly patients find zanamavir Diskhaler easy to use, says GSK
• Second oral fluoropyrimidine launched for metastatic colorectal cancer
• NICE endorses pioglitazone use
• HIV treatment based on viral load could miss vulnerable women
• Slower infusion of amphotericin safer than rapid infusion
• Serious liver reactions with leflunomide
• Mixed results for Parkinson's disease foetal cell transplants
• Risk of cardiovascular events with sildenafil is not increased
• MMR and other matters

Obese patients committed to weight loss can be given orlistat, says the NICE

Obese patients can be prescribed orlistat (Xenical) as part of their weight loss plan, says the National Institute for Clinical Excellence (NICE) in guidance published last week. But it does not recommend its use in patients who cannot show their commitment to losing weight.

The NICE has advised the National Health Service that orlistat should be made available to patients between the ages of 18 and 75 years who are either:

• over weight (body mass index of 28kg/m² or more) if they have another serious illness, such as type 2 diabetes, high blood pressure and/or high cholesterol, which persists despite standard treatment
• or obese (body mass index of 30kg/m² or more) with no associated illness

The guidance states that when treatment with orlistat is offered, arrangements should be made to offer advice, support and counselling on diet, physical activity and behavioural strategies.

Under the NICE recommendations, patients will only be eligible for treatment with orlistat if they have attempted long-term control of body weight using diet and exercise without success. In addition, they must have lost 2.5kg in weight in the month before treatment starts. The NICE says that therapy should only continue for more than three months if the patient has lost at least 5 per cent of their body weight from the start of drug treatment and for more than six months if weight loss has been at least 10 per cent of body weight. It adds that treatment should not usually continue beyond 12 months, and never beyond 24 months.

Dr Ian Campbell (chairman, National Obesity Forum) said in a press release issued on behalf of Roche (manufacturer of Xenical): “By treating obesity and overweight, we can reduce the burden of disease linked to obesity, such as coronary heart disease and diabetes. The guidance from NICE will reassure health care professionals that they should continue to treat obese and overweight patients with prescription medicines if appropriate, benefiting their health in the longer term.”

Mrs Irene Gummerson (a pharmacist on three national diabetes committees) told The Journal on March 12: “Losing weight can help decrease insulin resistance and improve blood glucose control in overweight people with type 2 diabetes. Orlistat reduces the amount of fat absorbed from the intestine, and may also help people adhere to a low fat diet. Once a capsule has been taken, a person may be discouraged from eating fatty food by the thought of a more frequent bowel action and passing fatty stools.” She added that it was important for pharmacists to be aware that the concomitant use of orlistat with metformin, acarbose and fibrates was not recommended by orlistat's manufacturer. This was possibly because of the potential for additional abdominal problems, she said.

The guidance was welcomed by Diabetes UK. A spokesman told The Journal: “Anything that can help people with diabetes manage their weight is a good thing.” Asked about the difficulties that patients with type 2 diabetes might have in meeting the strict criteria laid down by the NICE, he said: “In an ideal world we would have liked to see orlistat recommended for use in weight management rather than weight loss, but this is not a huge issue.”

Cost-benefit analysis

At the launch of the guidance on March 9, Ms Anne-Toni Rodgers (executive director, NICE) said: “Some people who would benefit from this medicine are not getting it.” Prescribers can now be clear on the cost-benefit analysis which should stop variations in prescribing practice, she said. The NICE guidance states that over the past year there was a 16-fold variation in the number of prescriptions written for orlistat between different health authorities in England and Wales.

Also speaking at the launch of the NICE guidance, Professor Peter Littlejohns (clinical director, NICE) said: “Orlistat has been shown to be cost-effective, given the groups we have targeted, in terms of health of the individual and NHS resources.” He added that the NICE was recommending the treatment only as a part of a managed weight loss plan. The guidance would stop the prescribing of this drug to people who “just wanted to lose a few pounds”.

Commenting on the criteria set by the NICE for patients to be eligible for treatment with orlistat, Ms Rodgers said: “We want people to help themselves and if patients are not losing weight whilst taking the drug then the money can be better spent helping a patient who may be more committed.” She added that not all obese patients would need to take the drug as many would just need the support of a health care professional.

Before publication of the NICE guidance on orlistat, the treatment options for obesity available on the National Health Service included dietary advice, behavioural modification and exercise. The direct costs to the NHS for the treatment of obesity have been estimated to be £50m per year, and the indirect costs of treating associated conditions, such as diabetes and cardiovascular disease, have been estimated as a further £1,700m to £1,900m.

The guidance applies only to England and Wales and will be reviewed in February, 2004. The full guidance is available at the NICE website (www.nice.org.uk).

Orlistat — how it works

Orlistat works by preventing the absorption of fat molecules in the intestinal tract. About 30 per cent of fat that would otherwise have been absorbed passes straight through the bowel and is excreted in the faeces.

Patients taking orlistat might require vitamin supplements because of mal-absorption of fat-soluble vitamins.

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Elderly patients find zanamavir Diskhaler easy to use, says GSK

A number of studies have shown that elderly patients find the zanamivir (Relenza) Diskhaler easy to use, according to GlaxoSmithKline, manufacturer of the product. The company has released a statement in response to a study published in the British Medical Journal last week on the use of zanamivir in elderly patients (see PJ, March 10, 2001, p306).

A spokeswoman for GlaxoSmithKline told The Journal on March 12 that there were no plans to change the inhaler used to deliver zanamivir. “The Diskhaler is already widely used to deliver drugs for the treatment of asthma and has proved to be fine,” she said. In its statement the company highlighted a number of Diskhaler handling studies, carried out in patients who have had Relenza prescribed, which show that elderly patients find the device easy to use. “These studies showed that 94 per cent of patients found the Diskhaler instructions easy to understand and 89 per cent found the device easy to use.”

In the BMJ study, Dr Paul Diggory and colleagues (Mayday hospital, Croydon) comment that, in elderly patients, treatment with zanamivir is unlikely to be effective unless the delivery system used is improved. Seventy-three patients aged over 65 years were given either a placebo Diskhaler or placebo Turbohaler to use. The researchers found that 50 per cent of those allocated the Diskhaler were unable to load and prime the device after 15 minutes of inhaler technique tuition and that 66 per cent were unable to do so 24 hours later.

The Canterbury & Coastal Primary Care Group has implemented a patient group direction for pharmacist supply of Relenza. As part of the implementation, pharmacists involved with the scheme were trained in the use of the Diskhaler. Mr Jonathan Mason (prescribing adviser, Canterbury & Coastal PCG) told The Journal on March 13 that he was confident that pharmacists would be able to demonstrate use of the inhaler to patients prescribed Relenza. He added that he did not foresee any additional problems over and above those associated with other Diskhalers, such as manual dexterity problems.

Pharmacists can access detailed information (abbreviated in panel below) on how to use the Relenza Diskhaler at www.relenza.com. A Royal Pharmaceutical Society registration number is required to access the website.

Further information concerning Relenza can be obtained by contacting GlaxoSmithKline's medical information department (tel 0800 371891).

Instructions for using the diskhaler

A. To load a medicine disk into the Diskhaler device

1. Remove the blue cover from the Diskhaler device and check that the mouthpiece is free of foreign objects
2. Pull out the white mouthpiece by the edges and extend the tray fully
3. Once the tray is fully extended, press the raised edges on each side of the tray at the same time and pull the whole tray out of the Diskhaler body
4. Place a medicine disk, containing four blisters of zanamivir 5mg, on to the device's wheel, flat side up. The blisters on the underside of the disk will drop into the four holes in the wheel
5. Push the tray in as far as it will go

B. To puncture the medicine disk blister

1. Lift the half-circle flap that is on top of the Diskhaler until it cannot go any further. (The flap must be straight up for the plastic needle to puncture both the top and bottom of the blister inside.)
2. Keep the Diskhaler level so the medicine does not spill out and click the flap down into place

C. To inhale the medicine

1. Before putting the mouthpiece in the mouth, breathe all the way out
2. Keep the Diskhaler level and close the lips firmly around the mouthpiece. Make sure that the small holes on either side of the mouthpiece are not covered
3. Breath in through the mouth steadily and as deeply as possible. Hold the breath for a few seconds

D. To take another inhalation

1. Pull the mouthpiece out to extend the white tray without removing it
2. Push it back until it clicks. This will rotate the medicine disk to the next blister
3. Repeat steps B and C

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Second oral fluoropyrimidine launched for metastatic colorectal cancer

A second oral fluoropyrimidine has been marketed for treating metastatic colorectal cancer. Bristol-Myers Squibb has introduced Uftoral capsules, just one month after the launch of Roche's Xeloda (capecitabine) (PJ, February 17, p232). Both drugs are 5-fluorouracil (5-FU) prodrugs and are licensed for first-line use in metastatic colorectal cancer [see p370].

Oral 5-FU is erratically absorbed from the gut and so the drug is generally given by IV bolus injection or continuous infusion. The new drugs provide an oral alternative to this treatment, and have been reported to be as effective as, and better tolerated than, 5-FU given by the standard IV bolus regimen.

Uftoral contains a combination of two drugs, tegafur and uracil. Tegafur is the 5-FU prodrug, and uracil acts to slow the breakdown of 5-FU by reversibly inhibiting the catabolic enzyme dihydropyrimidine dehydrogenase.

Treatment is given with calcium folinate, which potentiates the cytotoxicity of 5-FU.

At the launch of Uftoral on March 8, Dr Paul Mainwaring (consultant oncologist, St Thomas's hospital, London) commented on the benefits to patients of an oral treatment that could be taken at home and emphasised the importance of improvements in patient comfort in palliative treatment.
— Contributed.

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NICE endorses pioglitazone use

Patients with type 2 diabetes should be offered pioglitazone combination therapy as an alternative to insulin, according to guidance issued on March 9 by the National Institute for Clinical Excellence (NICE).

The NICE says that patients should be offered pioglitazone on National Health Service prescription if they are unable to take metformin and sulphonylurea as a combination therapy, or if their blood glucose levels remain high despite adequate trial of this combination. The guidance is in line with the NICE's previous recommendations for the use of rosiglitazone, issued in August, 2000 (see PJ, August 26, 2000, p288). The new guidance states that when a glitazone is prescribed, either pioglitazone or rosiglitazone can be considered. The full guidance is available on the NICE website (www.nice.org.uk).

Pioglitazone in combination with either metformin or sulphonylurea could provide a more cost-effective option than insulin in type 2 diabetes, says the NICE. The maximum number of patients who would be eligible for treatment with a glitazone is estimated to be about 70,000 in England and Wales and this would result in eventual cost savings of approximately £12m, it says. (In the NICE's previous guidance on rosiglitazone, annual insulin costs were estimated to be £230 per patient. A more recent estimate of £611 per patient per year was adopted for the appraisal of pioglitazone.)

A spokesman for Diabetes UK told The Journal that the charity welcomed the NICE guidance on pioglitazone. “Pioglitazone and other tablets in the glitazone class may well provide the advantage of allowing those who would otherwise be considered for insulin therapy to delay this, thus avoiding the difficulties which having to inject insulin can bring.”

In a press release issued on behalf of Takeda (manufacturer of Actos) Professor John Betteridge (professor of endocrinology and metabolism, University College, London) said: “Treatment of type 2 diabetes must not only focus on high blood sugar but must tackle other major risk factors that are part of the highly complex insulin resistance syndrome. Several studies have demonstrated the ability of pioglitazone not only to reduce sugar levels but also to reduce the raised triglyceride and increase the low HDL cholesterol levels that are characteristic of the dyslipidaemia that is present in the majority of patients with type 2 diabetes.”

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HIV treatment based on viral load could miss vulnerable women

Guidelines for HIV treatment based on viral load may lead to differences in eligibility between the sexes. Researchers have found that the median initial viral load of women who progressed to AIDS was almost five times lower than that in men but that there was no difference in rate of progression to AIDS.

American researchers investigated the relationship between initial viral load and rate of progression to AIDS in 156 men and 46 women. The median initial viral load after HIV seroconversion was significantly lower in women — 15,103 copies/ml compared with 50,766 copies/ml in men. Among men who progressed to AIDS, the median initial viral load was 77,822 copies/ml compared with 40,634 copies/ml among those who did not progress to AIDS. The corresponding figures were much lower for women: 17,149 copies/ml in women who progressed to AIDS and 12,043 copies/ml in those who did not.

The differences seen are important because the cut-off value used in current US guidelines for initiation of antiretroviral therapy is the same for both men and women at 20,000 copies/ml. This means that fewer women in the study would have been eligible for treatment, and raises questions over whether or not therapy should be initiated at a lower viral load in women. However, the difference in viral load is greatest in the first few years after HIV infection when the risk of progression to AIDS is lowest.

Ms Liz Davies (principal pharmacist, HIV/genitourinary medicine, Chelsea and Westminster hospital, London) told The Journal on March 13 that there were no differences for when to start treatment for men and women in UK guidelines. However, viral load was only one indicator used to assess when to initiate treatment. For example, if someone had a low CD4+ count, treatment would be started regardless of their viral load. The study showed no significant difference in the proportion of men and women who were eligible for treatment on the basis of CD4+ counts (New England Journal of Medicine 2001;344:720).

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Slower infusion of amphotericin safer than rapid infusion

Continuous, rather than rapid infusion of amphotericin B decreases nephrotoxicity and side effects, Swiss researchers say.

Lipid formulations of amphotericin are known to reduce toxicity, possibly because of a slower delivery of amphotericin to tissues, the researchers suggest. Therefore, they assessed whether or not slow, continuous infusion was less toxic than rapid infusion. In total, 80 patients (most with neutropenia) with suspected or proved invasive fungal infections were randomised to receive either 0.97mg/kg amphotericin B by continuous infusion over 24 hours or 0.95mg/kg by rapid infusion over four hours.

Patients receiving the slow infusion had fewer side effects than those who had rapid infusion, including fewer cases of fevers, chills or rigors, vomiting and headache. Mortality was also higher in the group that received rapid infusions of amphotericin B.

A noticeable reduction in nephrotoxicity was seen in the slow, continuous infusion group. The mechanism by which amphotericin causes nephrotoxicity is not fully understood, but it is known to have pretubular and tubular effects, the researchers say. Giving amphotericin by continuous infusion was found primarily to reduce pretubular toxicity.

The researchers say that amphotericin B triggers a proinflammatory response by activating different cytokines. Continuous infusions might be better tolerated than rapid infusions because of delayed induction or release of such mediators, as reflected by differences seen in concentrations of C reactive protein and fever.

They conclude: “We, therefore, recommend continuous infusions of amphotericin B, where practical, as an effective and well tolerated alternative to the usual rapid infusions.” (British Medical Journal 2001;322: 579.)

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Serious liver reactions with leflunomide

A statement regarding serious liver injury associated with leflunomide (Arava) has been issued this week by the European Agency for the Evaluation of Medicinal Products (EMEA).

The EMEA says that it has been made aware of reports of serious liver injuries, including hepatitis, hepatic failure and very rare cases of acute hepatic necrosis, in patients treated with leflunomide. A total of 296 cases of hepatic reactions have been reported to the EMEA, of which 129 were considered serious, and there were nine fatal outcomes. Most of the cases occurred within six months of initiation of treatment. The EMEA says that although confounding factors were present in many cases, a causal relationship with leflumonide cannot be excluded. Confounding factors included previous history of alcohol abuse, liver function disturbance, acute heart failure, severe pulmonary disease and pancreatic cancer. In 78 per cent of the serious reports, concomitant hepatotoxic medicines were being taken. The EMEA says that concomitant treatment with methotrexate or other hepatotoxic medication is associated with an increased risk of serious hepatic reactions and is not advisable.

In addition, the EMEA emphasises the need for strict adherence to monitoring recommendations. Preliminary data suggest that monitoring of liver function tests and wash-out procedures might not have been fully adhered to in some of the reported cases of hepatic reactions.

As a result of the EMEA findings, the prescribing and patient information has been modified. The information for patients includes the following paragraph: “Tell your doctor without any delay if you develop symptoms such as unusual tiredness, abdominal pain, or jaundice (yellow discolouration of the eyes or skin). Such symptoms may indicate the development of liver disorders which may need special action by your doctor.” The summary of product characteristics includes new information on monitoring of liver enzymes and administration of the drug following recent or concurrent treatment with other disease modifying antirheumatic drugs. The EMEA statement is available on its website.

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Mixed results for Parkinson's disease foetal cell transplants

Treating Parkinson's disease by transplantation of foetal cells into the brain has been successful in patients aged 60 or under but has serious side effects, a study has found.

Dr Curt Freed (University of Colorado school of medicine, Denver, United States) and colleagues say that this was the first double-blind, controlled trial of transplantation of embryonic dopamine neurones. In the study, 40 patients were randomised to receive transplantation or sham surgery (where holes were drilled in the skull but no cells transplanted).

After one year, subjective disease rating scores for patients aged under 60 years in the transplantation group were significantly improved, compared with the control group, when assessed before the patient had had their morning dose of levodopa. Improvement occurred in rigidity and, in younger patients, bradykinesia. Tremor did not improve in either group. Activities of daily living scores improved significantly in the transplantation group — the change was equivalent to about half the effect of levodopa. The fact that there was no improvement in older patients could be explained by a lower degree of plasticity of the brain or more diffuse brain diseases, the researchers say.

However, longer-term follow-up (as long as three years in some patients) revealed that 15 per cent developed dystonia and dyskinesia. The patients were all 60 years old or younger at the time of surgery and symptoms had improved in all patients during the first year after transplantation. The researchers say that this implies that continued growth of the transplanted cells led to an excess of dopamine and that the simplest response to this outcome would be to transplant less tissue in the future. They conclude that these side effects indicate that the surgical technique might need further refinement (New England Journal of Medicine 2001;344:710).

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Risk of cardiovascular events with sildenafil is not increased

There is no evidence of a higher incidence of fatal myocardial infarction or ischaemic heart disease among men taking sildenafil (Viagra), prescription event monitoring has shown.

Dr Saad Shakir (director, drug safety research unit, Southampton) and colleagues sent questionnaires to general practitioners in England five months after they had first prescribed sildenafil. Information about cardiovascular events was obtained from 5,601 questionnaires. In patients who were taking sildenafil, there were nine cases of angina, 19 cases of chest pain, five cases of ischaemic heart disease and seven cases of non-fatal myo-cardial infarction. There were 10 cardiovascular fatalities associated with treatment. The standardised mortality ratio indicated no evidence for a higher incidence of fatal myocardial infarction or ischaemic heart disease among patients taking sildenafil, the researchers say. They conclude that although the results are reassuring it is inappropriate to accept these comparisons as definite evidence of equivalence between sildenafil users and the general population (British Medical Journal 2001;322:651).

A researcher has suggested that information is inadequate in sildenafil's package insert. Complete and well-defined product information is fundamental for appropriate usage of medicines, says Dr Jay Cohen (University of California, San Diego). He reviewed data for sildenafil, including package inserts, descriptions from the Physicians’ Desk Reference, unpublished data from Pfizer (manufacturer of sildenafil) and relevant articles. For example, more data on sildenafil's effect on blood pressure are needed, he says (Annals of Pharmacotherapy 2001;35:337)

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MMR and other matters

The latest edition of Current Problems in Pharmacovigilance covers MMR vaccine, blockage of CFC-free inhalers, a safety reminder about amfebutamone (bupropion, Zyban) and the availability of emergency hormonal contraception.

Other topics covered include a reminder about QT interval prolongation with antipsychotics and the fact that COX-2 selective non-steroidal anti-inflammatory drugs lack platelet activity (2001;27:1-8).

Current Problems is available as a PDF file on the internet.

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