jandekkers schreef op 18 oktober 2017 04:24:
Dr C:
Greetings,
Today I thought that it would be something of interest to discuss the following question passed on by Tony Castaldo, President of the HAEA:
“My doctor wants me to go on the Ruconest which is a recombinant C1 inhibitor. I recently read a social media post where someone stated that Ruconest caused blood clots. I did see, however, that this person used a port to take her medicine. Another patient posted that Ruconest causes allergic reactions because the C1 inhibitor medicine is derived from the milk of rabbits. Can you provide some expert advice?”
This is a very timely question for multiple reasons. As many of you are aware there have been recent manufacturing problems at Shire with Cinryze and resulting shortages. CSL has also announced that they will not be able to meet the demand for plasma derived C1 inhibitor (pdC1INH), with their available stocks. Patients are rightfully anxious about running out of medication. Recombinant C1 inhibitor (rC1INH) is identical to the plasma derived C1 inhibitor protein. It is expressed and purified from the milk of transgenic rabbits. Intravenous rC1INH, has been shown to be safe and effective for the treatment of acute attacks of angioedema in a pivotal phase III study. A Phase II study led by Marc Riedl demonstrating efficacy for prophylaxis of attacks has also been published this last year. Fortunately for patients there is no shortage of supply of rC1INH and the manufacturer, Pharming, is dedicated to facilitating availability to patients. As is the case for pdC1INH there have been no significant safety concerns. The questioner raises the issue of rabbit allergy. A warning about rabbit allergy is included in the package insert in the US, which stems from a single case of anaphylaxis during the trials in an individual with rabbit allergy -which had not been disclosed to the investigators. With the manufacturing process there are very low levels of host related impurities (HRIs) in the final product and such that the risk is very low of a reaction even in rabbit allergic patients. A large study in a rabbit allergic cohort has not been done however. In the event that rC1INH is the best option for a patient with a history of rabbit allergy everything has a risk benefit ratio. I would consider skin testing with rabbit and the rC1INH to check prior to use. If the testing for rC1INH is negative and the rabbit positive to err on the side of caution I would then give a test dose of rC1INH under observation in the office to see if it is safe to use. Marc, you have had a lot of experience with rC1INH, could you elaborate further on the rabbit issue?
Dr R: In order to address the question about allergic reactions to the recombinant human C1INH (rhC1INH/Ruconest), let’s quickly review the process by which it’s manufactured. rhC1INH is produced in rabbits that have been designed to generate the human C1INH protein in their milk. The rabbit milk goes through extensive complex processing to purify the human C1INH protein and remove all other materials. At the end of the process, the medication contains less than 0.002% rabbit-related proteins. So it is an incredibly pure human C1INH medication. To my knowledge, there has been only one confirmed case of an allergic reaction to rhC1INH due to rabbit allergy. This occurred during the early clinical studies with the drug when a young woman treated in the study did not mention to study physicians that she had previously had allergic reactions to rabbits. On receiving the medication, she developed symptoms of a serious allergic reaction, but was treated and recovered without complication. Since that time additional studies have carefully monitored for this potential allergy issue, but no additional allergic reactions related to rabbit allergy have been observed. For a while, the European regulatory agency required that all patients have rabbit allergy testing performed prior to using rhC1INH, but this requirement was removed in early 2016 due to the fact no additional issues with such allergic reactions had been seen. The FDA has never required such testing though of course warns of the possible risk in the medication label. Since FDA-approval, an additional study investigating this issue showed that 4 of 5 individuals with positive allergy tests to rabbit in fact tolerated rhC1INH treatment without any allergy issues. (The fifth individual was the aforementioned woman who had an allergic reaction in the study; she also had the strongest rabbit allergy test of the group.) All told, it appears that rabbit allergy issues related to rhC1INH are exceedingly rare. If someone has a history of allergic reactions to rabbit exposure, then it would be important for them to speak with their physician about rabbit allergy test (blood or skin test) prior to using rhC1INH. But for the vast majority of people, this is not going to be a significant risk or concern, since rabbit allergy is quite uncommon.