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Prescribing Advice for GPs

An NHS Prescribing Advisers' Blog

Ezetrol Side Effects Update

The Summary of Product Characteristics for Ezetimibe (Ezetrol) has been updated recently following notification of some rare adverse events in patients taking this drug.

There have been reports of myopathy and rhabdomyolysis, most of these were in patients who were also taking a statin although some were on monotherapy with Ezetimibe.

Additionally, hepatitis has been reported as well as interactions with Warfarin and Ciclosporin.

Action: Patients on Ezetimibe should be informed to notify a clinician of any unexplained muscle pain or weakness. If myopathy is suspected then all drugs likely to be causal should be stopped (including statins and Ezetimibe).

Patients who are on Warfarin or Ciclosporin should be carefully monitored (for INR and therapeutic blood level respectively) during treatment with Ezetimibe.

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A recommendation has already been made regarding changing statin therapy following the implementation of the new Pharmacy Contract.

There is much discussion at present about the likely changes to the GMS contract and the targets contained within it regarding cholesterol. Broadly speaking there are two sides to the argument, the "fire and forget" approach and the "treat to target" approach. The treat to target approach is firmly contained in the current contract and rumours abound that the target is likely to be lowered for next year. The evidence to support this approach is growing but as yet is not entirely persuasive.

It would be prudent in any eventually to take a stepped approach to treatment to ensure that whatever happens, prescribers are prepared to tailor treatments to gain maximum benefit for as many patients as possible. Using the most cost effective and evidence based statins as first line will help to achieve this goal.

The 4S1 and HPS2 studies have shown that Simvastatin is an effective and well tolerated drug. It reduces cholesterol by 30% at the 40mg strength and has evidence to prove its benefits in saving patients lives. Simvastatin is unprecedented as the choice for lipid lowering.

In situation where Simvastatin 40mg does not get the patient to the required target, first consider if the patient is taking the medication and if they are still eating a healthy diet before altering the treatment. Where a treatment alteration is required, Atorvastatin 40mg is a more potent cholesterol reducing agent albeit with a lower level of evidence in terms of cardiovascular event outcomes.

Finally, if Atorvastatin 40mg fails to attain prescribers should consider the most appropriate way forward for the patient in question. Options include accepting the current cholesterol level, increasing the dose of the statin, adding in another lipid lowering agent or referring to a specialist.

Action: Implement and use a stepped approach to lipid management as follows:

  • Simvastatin 40mg tablets, 1 each day
  • Atorvastatin 40mg tablets, 1 each day
  • Revert to Simvastatin 40mg tablets and add Ezetimibe 10mg tablets, 1 each day

    Or Increase to Atorvastatin 80mg tablets, 1 each day

    Or Refer for specialist advice


  1. The Scandinavian Simvastatin Survival Study Group. Randomized Trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 1994;344:1383-1389
  2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22M

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Antiplatelets should be prescribed to reduce the risk of a cardiovascular event. This risk reduction can be classified as primary or secondary prevention depending on whether the first or subsequent event is being prevented. The evidence for the most appropriate intervention differs between these two groups.

Secondary Prevention is the reduction of risk of a subsequent cardiovascular event, for example a heart attack or stroke. NICE have recently issued a Technology Appraisal on this topic.

The guidance states the following:

  • Low dose Aspirin (75mg [Dispersible]) is "standard care"
  • In patients who have had an ischaemic stroke or a transient ischaemic attack, the combination of modified-release dipyridamole and aspirin (Asasantin) is recommended for two years after the most recent event
  • Only in patients who are intolerant to aspirin should clopidogrel (Plavix) be used (within the product license)

Primary Prevention is the reduction of risk of a first event. The NICE Technology Appraisal detailed above does not cover this population. In this group of patients the expected risk reducing benefits must be weighed against the potential risks associated with the treatment. It is also important to pay due regard to product licenses. Neither Asasantin nor Plavix are licensed for Primary Prevention.

An article on Bandolier has provided a sensible and evidenced approach to balancing the risks and benefits. This article concludes that at a coronary risk of 1.5% per year (or 15% in 10 years, or a CVD risk of 20% in 10 years) the benefits outweigh the risks.

Patients who are at a greater than 20% risk of their first CVD event in the next 10 years should be offered antiplatelet therapy with Low Dose Aspirin (provided their blood pressure is controlled and there are no contraindication)

Action: Prescribers should use Aspirin 75mg Dispersible as first line treatment for prevention of cardiovascular events. Where compliance is to be affected by gastrointestinal symptoms an Enteric Coated formulation can be tried before the alternative strategies listed above.

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First Vioxx Case Complete

The first court case against Merck, the manufacturers of Vioxx (Rofecoxib) was concluded in Texas, USA on Friday. The jury found that Merck had been negligent and awarded a £140 million settlement. The BBC News website carries more detail.

Merck have already made clear their intention to appeal against this decision as their share price fell by almost 8%. The basis for the appeal appears to be that the patient in question died from cardiac arrhythmia according to the autopsy report and there is no link between Vioxx and this particular heart condition.

The jury are still out and are debating if the cardiac side effects of Cox-IIs is a class effect. It should be noted though that the Summary of Product Characteristics for both Arcoxia (Etoricoxib) and Celebrex (Celecoxib) carry warnings about cardiovascular risks and recommend using the drug, if clinically appropriate, at the lowest possible dose and for the shortest possible duration.

Pfizer are still promoting Celebrex to prescribers with a paper from the Archives of Internal Medicine1 that compared the effects of Celecoxib, Rofecoxib and Naproxen on 24 hour blood pressure. The paper found that while Rofecoxib did significantly elevate blood pressure from baseline over the 12 weeks study, Celecoxib and Naproxen did not.

In appraising this trial there are two key things to note. Firstly, the end point is 24 hour blood pressure and not a hard patient oriented outcome such as stroke or myocardial infarction. Secondly, the three comparators are all active as there is no placebo arm. The only conclusion we can arrive at from the paper is that Celecoxib is no better or worse than Naproxen in affecting 24 hour blood pressure.

Action: Prescribers should continue to follow the MHRA Advice when considering prescribing any NSAID.


  1. Sowers J et al. The Effects of Cyclooxygenase-2 Inhibitors and Nonsteroidal Anti-Inflammatory Therapy on 24-Hour Blood Pressure in Patients With Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus. Arch Intern Med. 2005; 165:161-168

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Algicon Stock Problems

You may recall that in June the use of Algicon or Peptac was recommended in place of Gaviscon following the decision to remove Gaviscon from Prescription.

It is therefore unfortunate that manufacturers of Algicon are having stock problems and are currently unable to supply Algicon. As yet, they have not made a decision to discontinue this product although this outcome seems increasingly likely.

Apologies to those of you who have already implemented the recommendation, obviously Algicon would not have been a recommended option if it had been known there would be future problems.

The manufacturers of Peptac have confirmed that are there are no current stock problems or any plans to discontinue the product. The recommendation that was originally made still applies with some minor revision.

Action: Any patient on an Alginate and concurrent GI medication for acid (PPI or H2RA) should have the Alginate (Gaviscon or Algicon) stopped and have their symptoms re-assessed. Patients on Gaviscon or Algicon only should be changed to Peptac.

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