Roche recognises that the recall of Viracept causes difficulty, particularly in countries that have limited alternative treatment options immediately available.
Written communications with NGO treatment providers in resource-limited countries commenced June 8. We remain absolutely committed to open dialogue with all humanitarian organizations and are pleased we are able to offer face to face meetings at the 2007 IAS conference for discussions on this important and challenging issue.
We would like to provide information on specific areas as follows:
Alternative treatments
One of the most challenging and difficult aspects of this recall is that it is not possible for Roche to suggest just one substitute medication for patients to switch onto. The nature of HIV means that treatments need to be tailored for the individual patient. With complex and complicated treatment regimes, even in resource limited settings, it is not ethically or medically possible for Roche to provide just one option for patients to switch to. Prior treatments, virological factors, CD4 count, prior medication and polypharmacy make it essential that Viracept patients seek advice and consultation with their treatment specialists in order to switch. We have also been concerned about the need for patients to stay on continuous suppressive treatments, and therefore did not advise patients to switch without first consulting their physician. To this end, Roche has prepared a table of alternative treatments to physicians in order to facilitate the switch.
Resumption of supply
Roche is doing everything possible to regain our marketing license and resume supply of Viracept to patients. We have been continuously working with the health authorities since the notification of the issue, and are working on the necessary quality assurance process changes to ensure manufacturing can be started again without risk of EMS impurity. It is not possible to indicate when the health authorities will reinstate the marketing authorisation.
Origin of contamination
While EMS is not found in nature, it can be found in pharmaceutical manufacture as a result of the manufacturing process of mesylate salts (such as Viracept). The origin of of EMS in some batches of Viracept is related to the accidental reaction of an ingredient called methane sulphonic acid (MSA) used in the synthesis of the API with ethanol,. MSA and ethanol react slowly to form ethyl methanesulphonate (EMS). In the meantime a thorough risk assessment of the complete API production process of Viracept was performed and corrective and preventive actions are being implemented.
Routine controls for EMS
At the time of receiving the marketing authorisation for Viracept (in 1998), the manufacturing process was considered safe and robust. Analysis of EMS levels was not included in the quality specifications. In 2001, upon request from the health authorities who were evaluating medicines that contained mesylate salts, Roche performed several tests which revealed the presence of EMS only at extremely low levels. As a consequence, no analysis of EMS was included in the quality specifications for the Active Pharmaceutical Ingredient (API) of Viracept. Obviously, this will now be included as part of our process improvements for all future batches of Viracept API.
Potential toxicity of EMS
We have conducted extensive literature searches regarding EMS, and consulted external toxicology experts in order to understand the risk associated with EMS impurity. There are no data about the impact of EMS in humans. We know from preclinical studies that high doses of EMS can cause cancer in animals. However, based on this very limited data, we can say that the levels used to produce tumours in animals was at higher amounts than the absolute maximum exposure of EMS possible from Viracept.
Maximum human exposure to EMS
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Maximum impurity in Viracept batches: 2,300 ppm of EMS
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Maximum duration of use of batches with impurity: 3 months
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Maximum calculated daily dose of EMS: 6.7 mg or 0.134 mg/kg
(based on daily dose 2.92g of nelfinavir base for a patient weighing 50 kg)
Lowest dose exposure in animal studies
Using the lowest reported dose that produces tumors in young rats when EMS is taken orally via drinking water
~40 mg/kg/day produces mammary tumors in 15% at 16 weeks and 100% at 32 weeks when delivered via drinking water (note the study did not include a non-tumourigenic dose)
- calculation based on 100 g body weight, 30 ml water intake/day, concentration: 1X10-3 M = 0.124 mg/ml
In addition, there is some evidence of a threshold amount of EMS. Under this threshold dose level, cellular repair mechanisms could act to repair DNA that has been alkylated by EMS. Our assessment is that the maximum theoretical exposure to humans of EMS from impurity in Viracept is likely to be below this threshold level. We are doing additional animal studies to understand this threshold level fully.
EMEA reaction to the toxicology report
As agreed with the EMEA, Roche is conducting additional animal studies to further explore the multiple dose effects of EMS. These studies are due to start in the next month with final results expected at the end of the year. We expect that the results from these studies will allow:
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A determination of the threshold level of induction of genetic damage by EMS in steady state
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The correlation with protein adduct to providing a more robust basis for risk assessment of any long-term toxicological implications for patients exposed to elevated EMS impurity levels
Information for doctors to provide patients
EMS is known to cause cancer to animals at high levels (much higher than the amount in some batches of Viracept). Roche has provided consistent information that patients should be switched from Viracept on to alternative treatments for their HIV. Our advice to doctors and healthcare professionals is:
The recall of all Viracept formulations has been triggered by the presence of an impurity called ethyl methanesulphonate (EMS, also called methane sulfonic acid ethyl ester) in the active substance. The effect of this substance in humans has not been studied; however, research in animals shows that methane sulfonic acid ethylester is mutagenic. However, our risk assessment reports show that potential exposure to patients and the subsequent risk is low. Nevertheless, in the interest of patient welfare, we have decided to recall all possibly affected Viracept formulations.
For pregnant patients, Roche provided additional information to health care providers in order to guide decisions about what to do.
We our unable to provide clear guidance on the use of batches with EMS levels less than 1ppm, but are unable to provide specific information while we are still in discussion with the EMEA and Swissmedic to agree an appropriate method and specification. Therefore, we could only provide factual information to make NGO treatment providers in resource-limited countries aware of which batches were affected by the elevated levels of EMS. As EMS was not analysed routinely in the past, we could only provide this information once we had retrospectively analysed our retention samples from the batches which had been supplied.
Viracept patient registries
Roche is in the process of establishing patient registries as part of the follow up measures being taken after the Viracept recall. We are meeting with an advisory board with external expert epidemiologists and physicians to help us with the process for establishing the registry. The registries will include the most vulnerable patients:
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Patients who may have been exposed to elevated levels of EMS (>1,000 ppm). This registry will be limited to countries where patients were dispensed Viracept tablets with >1000 ppm (March 2007 to June 2007)
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Women who took the medicine during pregnancy, and children who have taken Viracept at any time or were exposed in utero
Local destruction of Viracept
Roche will reimburse expenses associated with collection of Viracept packs, and with the cost of destruction. Our communication of June 21 advised NGO treatment providers in resource-limited countries that a consolidated list of the quantities, the invoiced prices and all other costs involved in the recall be sent to Gian von Planta (gian.von_planta@roche.com) and Patricia Madoerin (patricia.madoerin@roche.com) copy Sandra Torriano (sandra.torriani_cazzato@roche.com).
After having received the Certificate of destruction bearing the batch numbers and quantities or when the returned goods have reached our warehouse in Switzerland we will issue a credit note. In instances where NGOs have been unsure about a local destruction processes, we advise that it is then better to send the goods back to Roche.
We fully appreciate the urgency this challenge presents to patients and humanitarian organisations.
Alternative Protease Inhibitors for Patients Discontinuing Viracept
