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Provig DOESN'T Induce Klon/And if Did, No Big Deal » 3 Beer Effect

Posted by Rick on February 9, 2002, at 6:28:22

In reply to Provigil induces metabolism of Klonopin :(, posted by 3 Beer Effect on February 8, 2002, at 17:08:36

3-Beer, there's no need to be disappointed. Your headline ("Provigil induces metabolism of Klonopin :(") is most likely incorrect. And even if it were accurate, it wouldn't matter much in terms of using those two meds together. Without realizing it, you've used what might seem like reasonable logic on the surface, but in reality has some big-time jumping-to-conclusions. I probably would have done the same a few years ago.

Explanaton:

--Most importantly, even if your logic and conclusions were true (and they're not), so what? Even if Provigil really DID cause an effective 30% reduction in Klonopin dose, would you expect me to convince myself, "damn, I guess I'm not really doing as well as I feel"? If there were safety issues, or if I were taking Klonopin for potentially-serious physical-consequences conditions like epilepsy or even severe panic, I might be a little more concerned (if your conclusion were true, that is). But let's say I'm taking 2 mg Klonopin. If it's "really" only 1.5 mg now, but still works better for my Social Phobia than any other med, why would I make any change other than a possible compensating increase in dosage to 2.5 mg? The best therapy is whatever works for you and is safe and affordable. Period. (Periodic liver checks advisable with any combo.)

--Even if Provigil really did induce Klonopin metabolism, your method for arriving at the magnitude of the effect ("30%") is just plain wrong. For some reason you're assuming that all inducers of CYP3A4 are *equally potent* inducers. It doesn't work that way. The induction potency of the drugs mentioned in the monograph just happened to be about the same vs. Klonopin. But the only way to attach a specific number is to do an actual test of impact. You can't just take a number from tests done with other inducers and assume it will be the same for *any* CYP3A4 inducers.

--Notice that the section you pointed out in the Provigil monograph -- which again did not cite any tests with Klonopin -- was entitled 'Precautions", NOT "Cotraindications".
Even if there were an induction effect against Klonopin (which there most likey *isn't*), that doesn't necessarily translate to a *theraputically* significant finding. For example, look at the Serzone monograph and you'll see that Serzone significantly reduces Propranolol levels, but that tests show that this DOESN'T cause reduction in Propranol effectiveness.

-- Along the same lines, there is significant inter-individual variability when a real interaction occurs, since some people are poorer metabolizers of any given enzyme than other people are.

-- The Provigil monograph states that Provigil can induce its own metabolism, to the tune of a 20% plasma reduction at 400 mg. Does this mean you shouldn't take Provigil with Provigil?

-- The induction studies cited in the Provigil monograph were done on a high 400 mg dose, and I believe they said the amount of induction of CYP3A4 was dose dependent. So even if Provigil really did cause 30% induction of Klonopin at 400 mg (and again, it doesn't), it would lkely be a significantly lower effect at the standard 200 mg dose and a much lower effect at my 100 mg. So it might be as if I'm taking .9 mg of Klonopin instead of 1.0. Big deal. And they *don't interact, anyway.

OK, now that I've explained some of the reasons why your conclusion had some flaws in logic, let me explain why there probably *isn't* any induction effect. (And even if it's later proven that there really IS, that wouldn't be of much import for me, for some of the reasons discussed above... especially the fact that the combo WORKS for me!).

I'm attaching links to two studies, the first study being a recent look some mechanisms behind Provigil CYP3A4 induction. The second looks at how Klonopin is metabolized.

The first study concludes that Provigil's CYP3A4 induction interactions affect CP3A4 substrates that have significant *gastrointestinal* first-pass metabolism. Then the second study notes that Klonopin's first-pass metabolism is primarily *hepatic* (via the liver), rather than gastrointestinal. Thus, Klonopin would not be susceptible to modafinal induction of CYP3A4.

Anyway, I didn't mean to pounce on this, but I was dismayed to see the "bad news" about this dynamite combo proclaimed to readers when there's really NOT any bad news. And for the 57th time (sorry), even if there WAS an interaction, that sure isn't sufficient reason to dismiss the combo as ineffective. Provigil's possible reduction of GABA in some areas of the brain is another thing that people read and then incorectly conclude, "hey this combo can't work, the Provigil's cancelling out Klonopin's pro-GABA effects!" It's just not that simple. And dammit, it's a helluva combo -- for me, at least. I went back to Klonopin alone when for awhile when my Blood Pressure was going up. And I was still doing MUCH, MUCH better SP-wise than pre-meds. Klonopin is still my mainstay. But when I added back the Provigil, the theraputic enhancement came roaring back. Klonopin's the meat, Provigil's the savory seasonings and condiments that add flavor and zing. (Pretty lame analogy, huh?)

Rick

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11823757&dopt=Abstract

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2057519&dopt=Abstract
-----------------

> I have done some research & have unfortunately found out some dissapointing news:
>
> Provigil (Modafinil, Alertec), it turns out induces metabolism of drugs such as Klonopin (clonazepam) that are metabolized through the Cytochrome-P450 CYP3A4 liver enzymes. According to the official Klonopin prescribing information inducers of this enzyme such as Provigil, Dilantin, Phenobarbital, & Tegretol result in faster Klonopin metabolism, & an approximately 30% decrease in plasma Klonopin levels (both of which reduce the effectiveness of Klonopin for social phobia).
>
>
> See PRECAUTIONS (drug interactions) for Provigil at--
> http://www.provigil.com/pi.htm
>
> Also see PRECAUTIONS (Drug interactions) at the revised (1999) official Roche Laboratories Klonopin Presribing information--
> http://www.rocheusa.com/products/klonopin/pi.html


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