suggestions for starting Norvir therapy - the times they are a-changing 5/96

Norvir, Abbott's protease inhibitor, was approved to be taken at 600mg bid (2x a day), based on a large study showing a survival benefit in PWAs with less than 100 CD4s. Abbott now recommends that everyone take Norvir at a low dose, and increase the dose over several days, "dosing up" to the full dose by Day 14. This may lessen the common side effects of Norvir: diarrhea, vomiting, bloating and cramping.

1. Why does the starting dose matter?
   One, we don't know if starting with a lower dose will lessen Norvir's side effects. It hasn't been studied. Lower doses were better tolerated in trials. There's a reason to be wary: this company stated repeatedly through the approval process that their new capsule form would be better tolerated than the original liquid form. They offered no data, and ignored the 30% dropout rate in their French trial with capsules.

   Two, we don't know if dosing-up gives you Norvir's maximum benefit, or what it means for resistance. It takes your liver a while to 'learn' to process Norvir, so for the first 3-4 days, your blood levels of Norvir are higher than ever again. By Day 14, your liver has learned to process an even amount of the drug, and taking the 600mg bid dose results in a smaller, steady amount of active drug in your blood. This is important, because right now we don't know if having high blood levels in the beginning few days is an advantage, or meaningless.

   In the Abbott trial, everyone took the prescribed 600mg bid dose, so everyone in that trial had the initial high burst of active drug. Within ten days, there was a significant difference in survival and new infections between the group that took Norvir and the group that didn't. This difference peaked at week 4, and remained constant through the next 5 months of the trial. Abbott researchers argue that the survival benefit happened because of the average viral suppression reached by Day 14. They say that since dosing-up will give you the equivalent of that average viral suppression, everything should be okay. This trial does not give us the answer either way. We don't know, and probably won't ever, as Abbott has no plans to compare dose escalation v. regular dosing. What a surprise.

   What was studied

   A - Phase II/III trials: PWAs started and took 600mg bid through the trials

   B - Earlier dose-ranging trials: Norvir has an extremely tiny 'therapeutic window'--there's not much leeway in how you can take this drug, in order to get its maximum benefit. 400mg bid didn't show enough clinical benefit, and more than 600mg bid wasn't tolerated. At all doses, some people had cramping, diarrhea, bloating and vomiting.

   Abbott's current recommendations (count 'em - three)

   A- In the package insert, they suggest taking 5 days to get up to full dose: Day 1-300mg bid; days 2&3-400mg bid; day 4-500mg bid; day 5 & on-600mg bid

   B - In their follow-up trial, they suggest taking 7 days to get up to full dose:

C- Abbott researchers are now suggesting in meetings to take up to 14 days to get to the full dose:

You must reach 600 mg bid by day 14. But then the instructions get confusing. "If you can't tolerate 600mg bid, you can stay at 500mg bid." The 500mg dose is not the approved dose. In dose-ranging studies, 500mg bid had a less sustained effect on both viral load and CD4 cells.

So, what's the take home message? Check your viral load, talk to your doctor, maybe take 600 mg bid from the first day to see if you can tolerate it (lots of people can), and if you can't tolerate it, dose up to full dose by Day 14.

This 4 day 'dose escalation' protocol may provide some relief, and help people stay on the drug, as opposed to quitting Norvir for good after feeling terribly sick. But neither this 'dose escalation' protocol, nor other protocol that escalates the dosage for up to two weeks, have been studied yet for Norvir.

In fact, it takes your liver a while to 'learn' to process Norvir, so the levels of the drug in your blood are initially higher than they would be eventually. We do not know what this means. One interpretation is that the lower initial doses are fine because blood levels are higher, translating into a clinical benefit similar to regular dosing. The second interpretation, based in the 1,000 person clinical endpoint study that got the drug approved, questions the efficacy of dose escalation, because the greatest benefit was seen within the first month of therapy. Would the benefit be lost with lower initial doses? We don't know, and unfortunately, we probably won't know, as Abbott doesn't have any studies planned to compare dose escalation and regular dosing.

The main problem is that Norvir has an extremely tiny 'therapeutic window.' This means that 400mg twice a day didn't seem to be of clinical benefit and more than 600mg twice a day was not tolerated (not that a lot of people can't even take 600mg). Norvir was approved by the FDA at 600mg bid, not because it was the most effective dose, but because it is the maximum that is tolerated. Abbott Labs was allowed by the FDA to include a strangely open-ended suggestion in in their package insert for Norvir:

"The recommended dosage of ritonavir is 600 mg twice daily by mouth. Some patients experience nausea upon initiation of 600 mg b.i.d. dosing; dose escalation may provide some relief: 300 mg b.i.d. dosing for 1 day, 400 mg b.i.d. dosing for 2 days, 500 mg dosing for 1 day, and then 600 mg b.i.d. thereafter. In addition, patients initiating combination regimens with NORVIR and nucleosides may improve gastrointestinal tolerance by intitiating NORVIR alone and subsequently adding nucleosides before completing two weeks of NORVIR monotherapy."

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last modified: 5/23/96