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I was consulted on the following clinical case:

An elderly woman (over 65 years old) on Plavix due to 2 CVAs in the last few years. Six months ago treatment was changed to a generic Clopidogrel product, and during this period she developed diffuse hematomas. With Aspirin she also had hematomas, but not with the original Plavix. Therefore, her doctor recommended putting her back on Plavix. This, of course, seems like the right thing to do, and I'm not asking about that.

My question is: What could be the reason for developing hematomas on a generic formulation of Clopidogrel and not on the brand formulation?

A few points should be taken into consideration:

  • As a generic drug, the manufacturer obviously proved bioequivalence, so we won't go there.
  • The dosage with both formulations was the same.
  • The inactive ingredients are very similar in both formulations. I won't elaborate about them right now, unless you ask for it in the comments.
  • I found two articles on that topic, without much help:
    • This article says that "The innovator product of clopidogrel (Plavix/Iscover*) is a hydrogen sulfate salt. [...] Following the expiration of the above name-brands’ patent, a number of generic clopidogrel salt formulations were developed and approved for the treatment of CVD patients. [...] it should be stated that even minor differences in the pharmacokinetic/pharmacodynamic properties of various generic clopidogrel salts could have serious clinical consequences..."
      The active ingredient in Plavix is formally stated as Clopidogrel hydrogen sulphate, whereas the generic is stated as Clopidogrel bisulphate. After some online research I found that these are two names for the same chemical composition. It did leave me with some confusion - are these two descriptions truly identical, or do we have here two different salts?
    • This article is a systematic review about branded against generic Clopidogrel in CVD. The conclusions section states that: "There are a limited number of small studies comparing Plavix and generic clopidogrel in nonhealthy volunteers, reporting hard clinical end points. Taking these limitations into account, the available data did not suggest any difference in cardiovascular events, adverse events, and withdrawals among patients receiving branded and generic clopidogrel."

Any thoughts will be much appreciated.

edit: After some further research I found two more points that should be considered:

  1. I stated that the generic formulation of Clopidogrel I found was essentially identical to the brand name in terms of active ingredient, since Clopidogrel hydrogen sulphate and Clopidogrel bisulphate are two names for the same compound. However, I realized today that we have another generic formulation which contains a different salt, Clopidogrel besylate. According to the study I cited above, different salt formulations can affect the pharmacokinetics and the pharmacodynamics of the drug, so that's a new lead.

  2. This study attempted to compare the antiplatelet effect of clopidogrel hydrogen sulphate and clopidogrel besylate. According to its conclusion "no overall significant difference in the antiplatelet effect of clopidogrel hydrogen sulphate as compared to clopidogrel besylate [was observed]. However, it is important to note that besides high interindividual there is also high intraindividual variability between the two different clopidogrel formulas".

![Clopidgrel salts

Regarding the clinical case, I have yet to find out which generic formulation the patient received, but I wanted to update the question with this new information and ask if anyone witnessed this kind of clinical difference with different salts of Clopidogrel (sharing experiences with different reactions to different salts of other drugs is also welcome).

  • I know it's not what you are asking about, but are all other factors completely excluded? The thing I would suspect first would be a concomitant use of another medicine coincidentally introduced around the same time as the generic drug. Variations in metabolism and plasma protein binding may be an explanation if that is the case. Take a look at this: ncbi.nlm.nih.gov/pubmed/23116430 – Lucky Dec 16 '16 at 12:26
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    @Lucky, thanks for your comment. Of course your suggestion could explain the situation. However, I do not have all the details about the entire treatment plan of the patient. At any rate, since the discussion focuses on the difference of clinical result between different formulations of Clopidogrel, let's assume this is the only medication she receives (or that no significant drug interactions were identified). – Don_S Dec 16 '16 at 13:51

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