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
-
Maximum impurity in Viracept batches: 2,300 ppm of EMS
-
Maximum duration of use of batches with impurity: 3 months
-
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:
-
A determination of the threshold level of induction of genetic damage by EMS
in steady state
-
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:
-
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)
-
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 ([email protected]) and Patricia Madoerin
([email protected]) copy Sandra Torriano
([email protected]).
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
