Ministry of Health urges people using Felo ER to see their GPs

People taking Felo ER, a medicine being recalled by Pacific Pharmaceuticals Ltd, should see their GP about an alternative treatment as soon as possible, the Ministry of Health said today.

Dr Stewart Jessamine, spokesman for the Ministry's medicines safety authority (Medsafe), said patients should continue taking Felo ER until they can change to another treatment prescribed by their doctors.

Felo ER, which contains the active ingredient felodipine, is used for the treatment of high blood pressure and/or stable angina. About 50,000 people in New Zealand take the medicine. It is manufactured in Europe by Siegfried Ltd and supplied in New Zealand by Pacific Pharmaceuticals Ltd.

``The reason we're asking people to keep taking their medicine until they've seen their doctor is because the risks of untreated angina and/or high blood pressure are greater than the risks of continuing treatment,'' Dr Jessamine said.

He noted that there is no evidence from adverse reactions monitoring in Germany and New Zealand that Felo ER is harmful.

``Pacific Pharmaceuticals Ltd will reimburse doctors for one GP visit for each patient in relation to this recall. If further visits are required, these will have to be paid by the patient. Doctors and pharmacies have access to adequate supplies of alternative medicines, including a fully funded brand of felodipine, called Plendil ER.''

Pacific Pharmaceuticals Ltd, in co-operation with the Ministry of Health, issued a patient-level recall for all Felo ER tablets after the Ministry received new information questioning the effectiveness of the medicine.

Dr Jessamine said the German Regulatory Authority recently raised doubts about the integrity of the Felo ER bioequivalence studies. These studies were used by Pacific Pharmaceuticals Ltd to support an application to register it as a new medicine in New Zealand.

Medsafe reviewed the documentation provided by the German authority and concluded there were major problems with the quality of the original bioequivalence study information.

``The quality failures occurred in crucial clinical areas and are such that the Felo ER bioequivalence studies cannot be regarded as accurate and must be discarded,'' Dr Jessamine said.

``Without these studies there is no compelling evidence for the effectiveness of Felo ER, and there is concern that it may not offer the same degree of protection from the complications of high blood pressure and angina as other brands of felodipine.

``The European manufacturer has commissioned new studies, which will be completed early next year. Until Medsafe has assessed this data, Felo ER will not be sold in New Zealand.''

Felo ER can only be prescribed by a doctor and is dispensed monthly.

Letters and pamphlets outlining the product recall and the Ministry of Health's advice were sent to health professionals and patients today. An 0800 patient advice number -- 0800 18 18 16 -- has been set up by Pacific Pharmaceuticals Ltd, and will operate from 7am tomorrow. The recall notice will also be carried in newspapers on Thursday.

Questions and Answers

What is Felo ER? It is a calcium-channel blocker with the active ingredient felodipine. It has been approved for the treatment of hypertension and chronic stable angina.

When was it approved in New Zealand? February 2000.

How many people take Felo ER in New Zealand? An estimated 50,000 people.

Who are the people most likely to be taking Felo ER? Anyone with high blood pressure or angina. This is more likely to occur in people aged 40 years and over and generally in more men than women. Both high blood pressure and angina generally occur more frequently in older age groups.

What should anyone taking Felo ER do now that the drug has been recalled? Patients should see their GPs so their medication can be changed to a different product. Patients should not stop taking Felo ER tablets until this changeover is complete.

Will patients have to pay doctors' fees when they see their GP for alternative treatment? No, Pacific Pharmaceuticals Ltd will reimburse doctors for one GP visit per patient in relation to the recall. The General Medical Subsidy (GMS), a patient subsidy paid by the Ministry of Health for each visit an eligible patient makes to a doctor, will be provided for any visits made with respect to this medicines recall. To claim the GMS subsidy, doctors should submit claims in the normal manner for patients who visit them as part of the recall.

What about prescription costs at the pharmacy? As a result of the Felo ER recall, Pharmac will fully fund Plendil ER, an alternative medicine containing felodipine. Patients will still have to pay the usual prescription charge at the pharmacy, depending on their Community Services Card or High User Health Card status. This charge will range from no cost, $3 or up to $15.

How many products are now available in New Zealand with the ingredient felodipine? With the withdrawal of Felo ER, the AstraZeneca Ltd-supplied medicine Plendil ER is the only product in New Zealand.

Will there be enough Plendil ER to cover patients changing from Felo ER? Yes, AstraZeneca have assured Medsafe that they can supply the New Zealand market.

Why has Felo ER been recalled? Medsafe has received information indicating that the European bioequivalence study data used to establish the efficacy of Felo ER was not reliable. Until Medsafe is reassured about the data used, the product will not be sold in New Zealand.

Who conducted the Felo ER bioequivalence studies? European company Clin-Pharm Research Ltd (CPR) conducted several bioequivalence studies on felodipine in Switzerland. These studies form the basis of the approval for Felo ER in a number of markets.

How many countries sell Felo ER? Two, Germany and New Zealand. The German Regulatory Authority and Medsafe fully evaluated the bioequivalence studies and evidence of manufacturing quality before granting consent to market Felo ER. While Felo ER has only be sold in two countries (Germany and New Zealand), several other European countries have used the European mutual recognition scheme, to recognise the German Regulatory Authority decision and approve Felo ER for sale in their country.

Have there been any adverse reactions caused by Felo ER? To date there is no evidence in New Zealand or Germany that the drug has caused undue or unexpected harm to people taking it. Felo ER has been widely distributed in Germany for the last two or three years.

How were problems with the Felo ER bioequivalence studies discovered? Concerns were raised when the Dutch regulatory authorities reviewing an application to approve Felo ER under the European mutual recognition scheme noticed that the Swiss authority, which is responsible for licensing the CPR site, had not approved some aspects of CPR's research activities. Because of irregularities, the Dutch authorities asked Germany to audit the site. During this audit, which happened after CPR was declared bankrupt, it was discovered that much of the original documentation had been destroyed. The audit of the remaining material, however, showed there were a number of quality, accuracy and validity problems with the testing methods used in the bioequivalence studies to demonstrate the effectiveness of Felo ER.

What did Medsafe do after it learned of problems with the studies? Medsafe got a copy of the audit from the German authorities, evaluated the data and concluded that the effectiveness of Felo ER could not be assured. As a result of these findings, Medsafe instructed Pacific Pharmaceuticals to stop supplying Felo ER and recall the medicine.

What did the German Regulatory Authority do? It suspended marketing authorisation for Felo ER in Germany. In addition, the expert advisory committee of the European Medicines Evaluation Agency has recommended that the licences for any products approved under the mutual recognition scheme be revoked.

Who is responsible for checking the validity of the Felo ER bioequivalence studies? The company that commissioned CPR to do the studies was Swiss-based Siegfried Ltd. It is responsible for checking the validity, accuracy and quality of the studies.

Why didn't Medsafe pick up the problems with the bioequivalence studies? During its evaluation process Medsafe reviews the raw data that demonstrates the medicine's effectiveness. In this case, the problem is not necessarily that the results of the bioequivalence studies are wrong. The problem is that the quality of the testing system that generated the results cannot be guaranteed. In keeping with international practice, Medsafe does not actively review the quality systems used by the company performing a bioequivalence study during its evaluation process. Rather, it is assured that a company meets the required quality standards by requiring that the site is licensed and audited either by Medsafe or some other competent regulatory authorities. In the Felo ER case, the Swiss government licenced CPR as a company that met good research practice guidelines and had proper quality control systems. Because of this, Medsafe and the German authority accepted that CPR's quality control systems met international standards. The audit has revealed that while CPR had proper systems in place that met international standards when it was first issued with a licence, by the time it conducted the Felo ER studies it was not applying the quality controls appropriately.

Who is responsible for recalling the product? Pacific Pharmaceuticals Ltd, because it is the New Zealand distributor and owns the rights to the product in New Zealand.

What happens to the product now? The Director-General of Health has issued a formal notice under Section 36 of the Medicines Act 1981 seeking further information from Pacific Pharmaceuticals Ltd to establish the efficacy of the product. This is expected to be provided in the first quarter of 2003 after new European biostudies currently underway have been completed.

Can Felo ER be sold in the interim? No. Pacific Pharmaceuticals Ltd has been prohibited from selling or supplying all Felo ER tablets until Medsafe is satisfied of the safety and efficacy of the product, or a decision is made under Section 35 of the Medicines Act 1981 to revoke the approval of Felo ER.

What should patients do with unused tablets? All unused tablets should be given to pharmacists when patients pick up their replacement medicine.

Timeline of recent events relating to Felo ER Tuesday, September 24, 2002: Medsafe receives information that raises concerns about the bioequivalence study data relating to Felo ER. Friday, September 27: Medsafe faxes a written request to the German Regulatory Authority (BfArM) asking for more information. Wednesday, October 9: BfArM emails its report highlighting the deficiencies in quality control and quality assurance in the biostudy operation to a Medsafe employee who is on leave. Consequently, Medsafe officials do not receive the report until October 18. Friday, October 25: Medsafe receives response from the company that commissioned the bioequivalence studies, Siegfried, via Pacific Pharmaceuticals Ltd, to the BfArM audit report. Wednesday, October 30: Medsafe finishes evaluating the BfArM report on the German audit findings relating to Felo ER. Friday, November 1: Pacific Pharmaceuticals advised of Medsafe concerns. Monday, November 4: Health Minister Annette King, under Section 36 (3) of the Medicines Act, sends a notice to Pacific Pharmaceuticals prohibiting it from continuing to supply Felo ER. Tuesday, November 5: Director-General of Health Dr Karen Poutasi issues a formal notice under Section 36 (1) seeking further information from Pacific Pharmaceuticals to establish the efficacy of the product. Tuesday, November 5: Medsafe sends a letter to Pacific Pharmaceuticals under regulation 50 (1) (b) of the Medicines Regulations, advising it to recall Felo ER. Tuesday November 12: Letters advising doctors and pharmacists of the recall are sent out.

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