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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by Elizabeth on November 8, 2001, at 20:48:15
Hey, I just saw the Paxil for GAD commercial on TV. Does anyone happen to know why they specifically recommend avoiding Mellaril (but not phenothiazines in general)?
Just curious.
-elizabeth
Posted by Cam W. on November 8, 2001, at 22:28:30
In reply to Paxil interaction?, posted by Elizabeth on November 8, 2001, at 20:48:15
Elizabeth - I wonder if it is the QT-prolongation with the Mellaril™ (thioridazine). You'd think that if they were worried about seizure risk (both lower seizure threshold) it would hold for all phenothiazines. - Cam
Posted by Sunnely on November 8, 2001, at 23:12:27
In reply to Paxil interaction?, posted by Elizabeth on November 8, 2001, at 20:48:15
> Hey, I just saw the Paxil for GAD commercial on TV. Does anyone happen to know why they specifically recommend avoiding Mellaril (but not phenothiazines in general)?
>
> Just curious.
>
> -elizabeth**************************************
Must be the concern for a serious and potentially deadly drug-drug interaction.
Thioridazine (Mellaril) is metabolized by cytochrome P450 2D6 (among other P450 enzymes) or CYP2D6 for short. Paroxetine (Paxil), as well as fluoxetine (Prozac) are potent inhibitors of CYP2D6. Inhibition of Mellaril metabolism by Paxil or Prozac via CYP2D6 leads to increased blood level of Mellaril, which in turn could lead to prolonged QTc which could lead to a serious heart beat irregularity called "torsades des pointes" and sudden death.
Last year, the US FDA and the manufacturer of Mellaril (Novartis) issued a warning that CYP2D6 inhibitors and thioridazine should not be coadministered. For the same reason, mesoridazine (Serentil), the active metabolite of Mellaril should not be combined with CYP2D6 inhibitors. The low-potency phenothiazines (e.g., Mellaril, Serentil, and Thorazine) are more prone to cardiac side effects and therefore, should not be combined with drugs that inhibit their metabolism or have the potential to cause prolonged QTc. High-potency phenothiazines (e.g., Stelazine, Prolixin, Trilafon) appear to cause less cardiovascular side effects than the low-potency phenothiazines.
For the same reason, but involving a different cytochrome enzyme (CYP3A4), pimozide (Orap) should not combined with CYP3A4 inhibitors, including grapefruit juice. Seldane, Hismanal and Propulsid are no longer available in the US market. Several deaths (heart) have been reported with the use of these drugs which tend to occur when combined with other drugs that inhibit their metabolism (via CYP3A4).
On a related note, ziprasidone (Geodon) can also cause prolonged QTc. Geodon's metabolism depends heavily on an enzyme called aldehyde oxidase and only partly on CYP3A4. Aldehyde oxidase has no known inhibitors and inducers. Therefore, combining Geodon with a CYP3A4 inhibitor (e.g., ketoconazole, grapefuit juice), will probably not lead to clinically significant elevation of Geodon's blood level and risk of prolonged QTc. However, Geodon should not be taken with drugs that themselves prolonged QTc including Mellaril, Serentil, Pimozide, the tricyclic antidepressants, certain antibiotics, certain heart medications, to name a few. Also, Geodon should not be given to those with recent heart attack, congested heart failure, heart block, and congenital long QT syndrome (born with this condition). The following people should have their potassium and magnesium levels, and electrocardiogram checked first, and should be normal before taking Geodon: eating disorders, alcoholics, dehydration, vomiting, diarrhea.
Posted by Elizabeth on November 9, 2001, at 13:26:39
In reply to Re: Paxil interaction? » Elizabeth, posted by Sunnely on November 8, 2001, at 23:12:27
I thought it was the EKG changes, yes. I just wondered why Mellaril only, and not the other phenothiazines that can also be dangerous.
-e
Posted by Cam W. on November 9, 2001, at 22:36:56
In reply to Re: Paxil interaction?, posted by Elizabeth on November 9, 2001, at 13:26:39
Elizabeth - I believe that the extent of the QT prolongation with Mellaril is significantly more than with other phenothiazines. I believe the delay is on the extent of double the time, if I am not mistaken. Still Mellaril is fairly safe; especially when you consider the number of doses that have been taken without incident since it was first released.
Today, more than ever, the motto of the business community is "Cover Thine Ass".
Also Novartis (formerly Sandoz), who made Mellaril could have released this info to keep the generic companies in the U.S. at bay. Don't want to make a generic form of a drug that kills, do they.
- Cam
Posted by Elizabeth on November 10, 2001, at 22:44:43
In reply to Re: Paxil interaction? » Elizabeth, posted by Cam W. on November 9, 2001, at 22:36:56
> Elizabeth - I believe that the extent of the QT prolongation with Mellaril is significantly more than with other phenothiazines. I believe the delay is on the extent of double the time, if I am not mistaken.
Ahh, well that explains it then.
> Still Mellaril is fairly safe; especially when you consider the number of doses that have been taken without incident since it was first released.
I even took it once (I think it was just 10 mg or so -- I was desperate to get to sleep!).
> Today, more than ever, the motto of the business community is "Cover Thine Ass".
Yeah, I was just interested in why Mellaril was singled out. (I think the ass-covering can be a good thing, in moderation.)
> Also Novartis (formerly Sandoz), who made Mellaril could have released this info to keep the generic companies in the U.S. at bay. Don't want to make a generic form of a drug that kills, do they.
That's pretty sleazy, but I have to give them points for cleverness if they really did it!
On a related note -- have you noticed how corporations (drug companies and others) are buying each other like crazy lately? Like, Glaxo Smithkline, AOL Time Warner, etc. Novartis seems to be this giant beast made up of a number of formerly independent drug firms (too many to combine all their names!).
-elizabeth
Posted by Sunnely on November 11, 2001, at 19:50:39
In reply to Re: Paxil interaction? » Elizabeth, posted by Cam W. on November 9, 2001, at 22:36:56
>Still Mellaril is fairly safe; especially when you consider the number of doses that have been taken without incident since it was first released.
Actually, there have been serious incidents of thioridazine (Mellaril)-induced arrhythmias. In 1992, Donatini et al., reviewed 22 cases in the literature of Mellaril-induced arrhythmias plus 155 cases reported to Mellaril's manufacturer, Sandoz.
They found out that cases of life-threatening arrhythmias and even deaths have occurred with the use of Mellaril. The most life-threatening are ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation and "torsades de pointes." These arrhythmias are more likely to occur with higher doses of Mellaril and not correlated with the duration of treatment. They also found out that patients who overdosed on Mellaril remained vulnerable to ventricular tachycardia or fibrillation for up to 10 days after Mellaril was discontinued. In patients who were on Mellaril 800 mg/day (maximum dose allowed/day), 14 cases of ventricular tachycardia or fibrillation occurred. Five of 10 patients who suffered complete heart block died. Six cases who developed first or second-degree heart blocks from doses of 800 mg/day, always led to ventricular tachycardia.
IMHO the seriousness of Mellaril-induced arrhythmias was not widely talked about until at least 2 events occurred: 1) several (heart) sudden deaths reported to the FDA from the use of Seldane, Hismanal, and Propulsid, and 2) the Geodon study. Like Seldane, Hismanal, and Propulsid, Mellaril can also prolong QTc on electrocardiogram (ECG) which could potentially lead to serious ventricular tachycardia, in particular, "torsades" and even death. Experts consider the presence of prolonged QTc on ECG as a "harbinger" for "torsades."
During clinical trials, Geodon was found to cause prolonged QTc. This was the reason why Geodon was delayed (about 2 years) in its release to the US market. To convince the FDA that Geodon is safe, Pfizer conducted a study comparing Geodon with other antipsychotics with regard to their potential to prolong QTc. Among the antipsychotics involved, only Mellaril was found to prolonged QTc to a clinically significant proportion. While Geodon was also found to prolonged QTc, it was considered not clinically significant to be of concern, hence, its subsequent FDA approval. Although doing a pre-treatment and maintenance treatment ECG is not required during Geodon treatment, the FDA required that Geodon's labeling include a "Warning" about QT prolongation and risk of sudden death.
Incidentally, as a consequence of the Geodon study, Mellaril got clocked. Subsequently, the US FDA required that Novartis (formerly Sandoz) revise Mellaril's labeling to include a "black box" about risk of serious heart arrhythmias and risk of sudden death. Also, the revised label now indicates that Mellaril is no longer considered a "first-line" drug for the treatment of schizophrenia and other psychoses. Finally, a pretreatment and maintenance treatment ECG should be done on patients who are on Mellaril. For patients who are already on Mellaril, if ECG shows prolonged QTc that is greater than 450 msec but less than less 500 msec, CONSIDER a switch to a different antipsychotic; if ECG shows prolonged QTc that is 500 msec or greater, MUST switch to a different antipsychotic.
This is the end of the thread.
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