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Norvir Advisory

Temperature Questions & Answers
from Presentation 1, Norvir Community Update

Exerpt from Presentation 1, Norvir Community Update - Eugene Sun, MD

QUESTION: I don't know if this is the time to address the temperature range in which the liquid must be maintained, but it's confusing to me. I know children who have been on the same liquid formulation and temperature was never before an issue. Is the liquid Norvir that we are taking now the same as the liquid Norvir that the children have been taking? Their virus was controlled by the same liquid that you're now saying needs to be maintained between 68 and 77 degrees. And that temperature range isn't even found in most normal environments. My house isn't 68 degrees. So I'm wondering how fragile ritonavir really is.

SUN: You raised several important issues which I will try to explain. First is that Norvir liquid is Norvir liquid. The liquid is what it was and remains what it is. The liquid formulation has not changed. What we did was change the recommended storage conditions from what was previously a refrigerated product that couldn't be stored at room temperature for a limited period of time to a product that we recommended not be refrigerated but stored at room temperature within a fairly narrow temperature range.

Why? We encountered Form II. Form II is a chemical form of ritonavir that exists regardless of formulation. It happened to rear its head in the semisolid capsule. But when we looked at forcing Form II into liquid ritonavir, we learned that it can live in there as well. As I said earlier, the crux of this problem is solubility. For example, if you take, two tablespoons of water and try to dissolve 16 grams of table sugar in it, the sugar won't dissolve unless you add more water. That is essentially what happened to the semisolid. With the liquid, we realized that at room temperature, that solution would be OK - just like the table sugar and water analogy you want to use. At lower temperatures, one could potentially have the risk of exceeding the solubility. In other words, one could be in a situation where the potential for crystallization was higher.

So the first thing that we did after discovering the crystal form of ritonavir was to make sure that the problem in the semisolid was not happening with the liquid. Then, in conjunction with the FDA, we made the very conservative recommendation that, if possible, people should store it at temperatures where we knew would decrease the possibility of crystallization. Now, does it mean that if you get at 77.5 degrees, something will happen to the Norvir liquid? No. But we have data to support our recommended storage conditions.

From a regulatory concern, we have data that allows us to guarantee certain things, such as the stability of the product for a given period of time. We know that if we exceed the recommended temperature and go to higher temperatures, and this is true for every drug since all drugs are chemicals, drugs start to degrade, and the molecules start to fall apart. Does that happen instantaneously? No. If I were in Tempe, Arizona in the middle of the summer and it was 120 degrees outside, I would put Norvir liquid in the refrigerator if I didn't have air conditioning.

QUESTION: So you're describing actually a very wide range of temperatures that you're saying you're approving.

SUN: No. I am not approving anything. I am only telling you that Abbott can back up the label recommendations with data. I am only commenting on the pragmatic realities that affect how some of us respond to drug labeling.

QUESTION: Why did you recommend such a narrow temperature range for Norvir liquid?

SUN: A 68 to 77 degree temperature range is very narrow and tight. This recommended temperature range is a maximally conservative position on our part. But as I said earlier, you have to accommodate label recommendations to the reality of your situation. What you have to know is that when you go above 77, you don't need to throw the drug away. But you should try to minimize the time and the excess temperature to which you expose the drug. We may have to marry the practicality of our lives with a drug label which is not always practical.

QUESTION: How can you change the label recommendations for temperature so easily without going through all many months of FDA review?

SUN: It is always easier to change to a more conservative recommendation than to a more liberal recommendation. If we had gone to the FDA and said that we wanted to widen the label recommendations, then we would have to go through a more rigorous and extensive review process.

QUESTION: Wouldn't you have to provide extensive clinical data to justify taking Norvir liquid out of the refrigerator and storing it at room temperature?

SUN: No. The previous label provided for storage at refrigeration or at room temperature. We kept the room temperature recommendation. We changed the label to recommend that Norvir not be stored in the refrigerator.

QUESTION: To your knowledge, has there ever been an instance of any crystallization of Norvir liquid under refrigeration?

SUN: There may have been isolated instances which is not unexpected because of what we know about ritonavir. When we first encountered Form II, we wanted to know exactly what situations one could possibly encounter crystals in the liquid, which is a large part of the reason why we opted to go to the room temperature storage. So it can theoretically happen and it has happened, and so we need to recognize that.

Posted 12/28/98

Notice: This is an IAPAC initiative that is under the sole direction of the IAPAC Norvir Advisory Committee. Contents of the Norvir Advisory section of the IAPAC Web site are subject to the approval of the chair of the advisory committee and will reflect the recommendations of the committee members. Abbott Laboratories has no input in the content of the Norvir Advisory section of the IAPAC Web site.