Revised: 1 June 2010

Publications

Questions and answers on the recall of Pacific Atenolol (atenolol) 50mg and 100mg tablets

1. Why have there been so many consumer recalls recently?

In January this year, Marevan 3mg tablets were recalled because a manufacturing error resulted in some high strength tablets being incorporated in a batch. In March, Respigen inhalers were recalled because a manufacturing error led to variability in doses in some of the inhalers. This month, Pacific Atenolol (Atenolol) tablets were recalled on two occasions because of manufacturing issues that resulted in dose variability. On 6 May 2010, Medsafe recalled four ostensibly "herbal" products for erectile dysfunction which contained an undeclared prescription medicine.

Consumer level recalls of medicines are not common and occur, on average, once a year. A recall may be for an over-the-counter medicine or for a prescribed medicine. There has been a cluster of consumer recalls recently. However, this should not be interpreted as a drop in the quality of medicines in general or that particular new issues have arisen to cause this effect. Medsafe's view is that this clustering is purely coincidental.

2. What is the criteria for conducting a consumer recall?

The risks to patients arising from each quality issue are fully assessed before any action is taken. The company responsible for the product and Medsafe assess whether or not the product defect is potentially life-threatening or could cause a serious risk to health. This is an internationally used test for determining the level of a medicine recall. Medsafe has internal processes in place that ensure clinical and technical staff are brought together to discuss potential recalls and more specialised clinical advice is accessible if required to assist with decisions.

3. How do we know that the quality systems at medicines manufacturers are acceptable?

Approval to supply a medicine in New Zealand will only be granted if evidence is supplied indicating that the manufacturing site meets an internationally recognised code of Good Manufacturing Practice (GMP) for pharmaceutical manufacture. GMP is an exacting requirement that requires systems and processes to be in place to ensure all batches of a medicine will be safe and effective, free from contamination, and meet specifications. Factories are inspected for compliance against the code of practice around the world by government regulators. Medsafe only accepts inspections and certifications issued by regulators known to require high standards of compliance with GMP.

4. What does Medsafe do with respect to investigating the circumstances giving rise to recalls?

Companies responsible for placing the product on the market in New Zealand and the manufacturer of the product are required to thoroughly investigate the issues and ensure solutions are implemented to prevent the problem from recurring. The investigations and solutions are assessed by Medsafe and anything that is found to be unacceptable is raised and challenged. Medsafe may visit the manufacturing site and conduct an audit of the relevant process and/or may join with other regulators in addressing the issues. The Medicines Act provides mechanisms for the withdrawal of approval to market a medicine should a manufacturer not meet the requirements.

5. Why was a consumer level recall necessary in this particular instance?

All recalls are different and Medsafe assesses the risk inherent in each individual situation and considers the clinical risk faced by patients. Medsafe recognises the disruption and cost involved with consumer recalls and the need to ensure acceptable clinical alternatives are available, however patient safety is the primary concern. Consumer recalls are only required when it is necessary for patients to stop taking the product in question.

Many issues are considered when making these decisions, however, the principal consideration is whether the issue is potentially life-threatening or could cause a serious risk to health. With regard to this recall, Medsafe took into consideration the facts as they were known at the time, the magnitude of the deviations from specifications and the likely clinical consequences should patients take faulty tablets.

The overweight Atenolol 50mg tablets, which were the subject of the initial recall on 13 May 2010, were found to contain 86 to 88mg (note that all estimates of tablet content were based on physical tablet measurements). At the time the recall was initiated, 5 tablets in the batch had been identified in this range. In some cases, more than one overweight tablet was found in a single bottle. There was no assurance as to the actual cause of the problem and therefore, the likely frequency of overweight tablets was unknown.

The second recall on 27 May 2010 was triggered following reports relating to the finding of smaller tablets. Medsafe again considered that the magnitude of deviation from the specification, the frequency of the problem and the possible consequences of continued distribution were unacceptable. Information assessed included the outcome of limited sampling of containers over 4 batches of the 100mg tablets where 17 tablets were found, measured and determined to contain doses ranging from 77mg to 86mg; with 12 of these faulty tablets ranging from 77mg to 81mg found in ten bottles of the partially distributed batch. The sampling of a limited number of containers of 50mg tablets across two batches that had been distributed or partially distributed (excluding the overweight batch) identified underweight tablets determined to contain doses varying from 31mg to 41mg. One bottle from one of these batches was found to contain three underweight tablets.

These figures (for both underweight and overweight tablets) were determined from a very small sample of tablets from the batches and were only obtained by visual sorting and subsequent measurement; with the possibility that tablets with significant variations could have been missed. Information about the manufacturing process indicated that faulty tablets were likely to have been evenly distributed throughout a batch leading to the conclusion that, with batch sizes of either 500,000 or 1,000,000 tablets, many faulty tablets could have been present.

It was also important to consider that, although sampling was limited, instances were detected where more than one tablet was found in a single bottle indicating there was an increased possibility for a patient to receive consecutive underweight or overweight tablets. Overall, the results indicated a widespread, significant problem for both strengths of the product.

The dose-response curve for Atenolol is such that an increase in the 50mg to 100mg range is significant with respect to therapeutic effect and possible side effects. Medsafe considered that a significantly higher dose administered to a patient stable on 50mg could result in an unexpected drop in blood pressure possibly resulting in, for instance, postural hypotension, fainting, etc. Scenarios such as the potential serious clinical consequences should an elderly person experiencing unexpected low blood pressure suffer a fall, were part of the consideration.

With respect to the under-weight tablets, under-treatment is likely to result in an increased potential for, for instance, severe exacerbations of arrhythmias, angina or potential for myocardial infarction.

Mylan undertook its own risk assessment regarding the underweight issue in which it concluded the following:

• There is an unknown, but real risk of a patient with underlying cardiovascular disease taking one or more underweight Atenolol tablets.
• If several underweight tablets are taken consecutively by a patient using Atenolol to manage angina pectoris or an arrhythmia, they may experience a sudden decrease in plasma concentrations of Atenolol, a loss of beta-blockade and a subsequent withdrawal reaction.
• Withdrawal reactions may include severe exacerbation of angina, myocardial infarction or arrhythmias.
• Consequently, there potentially is an unacceptable risk to the patient.

Medsafe concurred that there was a real risk to a patient's health. These conclusions were consistent with the established criteria for a recall of a medicine to consumer level.

In the context of the information and conclusions outlined above, it was evident that patients should not continue to take the defective products when a clinically acceptable alternative was available.