Psychosomatics 42:157-159, April 2001
© 2001 The Academy of Psychosomatic Medicine
Drug-Drug Interaction Update |
Consultation-Liaison Psychiatry Drug-Drug Interactions Update
Scott C. Armstrong, M.D., and
Kelly L. Cozza, M.D.
Key Words: Drug-Drug Interaction
This edition of the drug-drug interaction (DDI) update reviews three topics. First, we review what happened to thioridazine and mesoridazine with new warnings. At first, one might believe that these new warnings are not the result of DDI, but that is not entirely the case. In fact, these drugs along with the demise of the nonsedating antihistamines and cisparide are just the beginning—we expect more warnings for "old" drugs in the future.
Second, we review a strategy of using DDI to your advantage by reducing the cost of an expensive drug—clozapine. Although consultation-liaison (C-L) psychiatrists may not have the need to use this strategy often, it can be generalized to other medication regimens as long as it is safe and well monitored.
Finally, we review the question of whether bupropion inhibits Cytochrome P450 2D6. We had to dig deep to confirm this potential problem since the standard literature is silent on this issue.
1. Is the FDA picking on psychotropic drugs?
Recently, the manufacturer of Mellaril (thioridizine)1 and Serentil (mesoridazine)2 released a warning letter and a revision of the package inserts that includes a new "boxed" warning about their potential to prolong the QTc interval. The manufacturer warns that this potential may lead to a condition called torsade de pointes, an arrhythmia often associated with sudden death. The box also suggests that thioridizine and mesoridazine should be reserved for use only in schizophrenic patients who fail adequate trials of other, less potentially dangerous antipsychotics. You may ask, "Why all the fuss now? Thiorodizine and mesoridazine have been around a long time. Is this associated with similar warnings for chloropromazine, pimozide, and the clinically doomed sertindole?" Well, even seemingly safe risperidone has had reports of cardiac problems!3 Since we have reminded our readers to take serious heed of boxed warnings in previous columns, we thought a closer look at the recent flurry of manufacturer and FDA activity is in order.
We refer our readers to an excellent review of this topic by Welch and Chue.4 They remind us that the newer or novel antipsychotics have received significant attention in both pre- and postmarketing monitoring. For example, sertindole was withdrawn from the European market and was not marketed in the United States. The problem with many psychotropics, old (e.g., thioridazine) and new (e.g., sertindole) is their potential to increase the QTc. DePonti et al.5 note that that there are many noncardiac drugs that were found to prolong QTc after they were marketed years ago, stating that "although prolongation of the QT interval by non-cardiac drugs is not an unusual finding, potentially fatal arrhythmias, such as torsade de pointes, are uncommon and are unlikely to occur during the course of phase I-III studies, when relatively small numbers of subjects are exposed to the investigational drug."
Both reviews note that QT prolongation is associated with increased risk of arrhythmia, but the "critical QT interval," or specific duration at which fatal arrhythmia occurs, has not been well established. Welch and Chue4 list several diseases and disorders that are associated with altered repolarization of the ventricles and prolongation of the QT interval, but they state that drugs account for majority of the acquired causes that may lead to torsade de pointes. They list factors associated with drugs, such as gender, age, cardiac disease, electrolyte imbalance, metabolic/endocrine abonormalities, central nervous system insult, toxins and congenital long QT syndromes.
In addition, we believe that coadministration of metabolic inhibitors (causing DDIs) account for a significant portion of the arrhythmias attributed to drugs. In fact, the new drug warning for thioridazine included that it was contraindicated with drugs that inhibit Cytochrome P450 2D6, a major enzyme that metabolizes thioridazine. Terfenadine, astemizole, and cisapride have been reviewed in this column previously, and provide excellent examples of this DDI problem. Flockhart et al.6 provide a case report and review of clarithromycin and pimozide fatal interactions.
Welch and Chue4 discuss the antipsychotics at length. Haloperidol and sertindole seem to antagonize the human ether-a-go-go-related gene (HERG) which encodes for proteins associated with potassium channels that are involved in the rapid delayed rectifyer system. Sertindole binds the HERG channel to an extent equal to the class III antiarrhythmic medications, and Welch and Chue suggest that this binding is so potent, sertindole may have a role as an antiarrhythmic drug. Pimozide is a potent calcium channel antagonist, in a way similar to the classic calcium channel blockers diltiazem, nifedipine, and verapamil. Chlorpromazine can lead to atrial and ventricular tachycardia, premature atrial beats, heart blockage and ventricular fibrillation, in addition to blocking potassium-dependent channels and affecting QTc.
The more careful study of cardiac effects of the newest antipsychotics has slowed the process of releasing these newer, usually less toxic drugs. The newer understanding of the older antipsychotics has led to new boxed warnings. We wish to repeat what Welch and Chue close their review with, "conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used." Please heed the boxes!—KLC
REFERENCES
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Novartis Pharmaceuticals Corporation Drug Warning Letter to Physicians and Pharmacists on Mellaril (thioridazine HCL), July 7, 2000
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Novartis Pharmceuticals Corporation Drug Warning Letter to Physicians and Pharmacists on Serentil (mesoridazine besylate), September 22, 2000
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Ravin DS, Levensen JW: Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997; 31:867–870[Abstract]
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Welch R, Chue P: Antipsychotic agents and QT changes. J Psychiatry Neurosci 25(2):154–60, 2000[Medline]
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DePonti F, Poluzzi E, Montanaro N: QT-interval prolongation by noncardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000; 56:1–18[CrossRef][Medline]
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Flockhart DA, Drici MD, Kerbusch T, et al: Studies on the mechanism of a fatal clarithromycin-pimozide interaction in a patient with Tourette syndrome. J Clin Psychopharmacol 2000; 20:317–2324, 2000
2. Mong-Liang L, Hsien-Yuan L, Kun-Po C , et al: Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients.
J Clin Psychiatry 2000; 61:594–599
The strategy of using DDIs to decrease the cost of expensive medications has been discussed before in this column.7 Typically, the approach is to add a second drug that inhibits the metabolism of the first drug, thus lengthening the plasma half-life and reducing the dosage (and cost) necessary for the first drug. The strategy has been shown to work in nonpsychiatric settings with some success, but one must be aware of potential consequences of the added drug (i.e., side effects) or possible coordination problems if other clinicians are not aware that the two drugs must be continued in order to maintain therapeutic effectiveness of the first drug.
Despite these potential pitfalls, one such combination exists for chronic treatment resistant schizophrenia patients. For several years, it has been known that fluvoxamine strongly inhibits the metabolism of clozapine. In fact, one recent single-dose pharmacokinetic study indicated that 50 mg of fluvoxamine increased the clozapine plasma AUC by 2.58 and the mean plasma concentrations of clozapine increased by 2.87-fold!8
Clozapine is metabolized by Cytochrome P450s (CyP450) 1A2, 3A4, 2C9, 2C19, 2D6, and the flavin monooxgenase system. This diversity of metabolism would appear to make clozapine a very difficult drug to inhibit its metabolism. However, by coincidence, fluvoxamine is the "perfect" inhibitor of clozapine's metabolism because it inhibits CyP450 1A2, 2C9, 2C19 potently and 2D6 and 3A4 moderately.
Mong-Liang et al, provide the definitive clinical study on the use of combining fluvoxamine with clozapine in order to reduce the dosage (and, hence, cost) of clozapine. In a prospective design, they chose 18 treatment refractory schizophrenia patients. 10 were smokers and 8 nonsmokers (this was important to distinguish before the study since smoking induces CyP450 1A2 and tends to lower clozapine levels). All 18 patients were titrated to only a 100 mg qhs of clozapine. After steady state was reached, each patient had 50 mg/day of fluvoxamine added to their regimen. Plasma levels were obtained Days 14 and 28 after the combined treatment, as well as side effects and clinical efficacy with standardized instruments (GCI and GAF).
Their results were astounding. After 14 days of combined treatment, the mean plasma clozapine level increased 2.3-fold to 432.4±190.9 ng/ml, and this result was essentially unchanged on Day 28. Twelve of the 18 patients achieved concentrations of at least 350 ng/ml. Smokers had 34% lower levels on the combination, as one would expect. Overall, GCI and GAF scores improved significantly.
After reading this study, I went to my hospital pharmacy to do my own pharmacoeconomic assessment to see if we used such a strategy. On average, the final titrated dose of clozapine the past 3 years at my facility was approximately 500 mg/day. Unfortunately, I could not get complete serum levels from these patient records. However, if Mong-Liang et al.'s strategy for cost-sparing would work for my hospital, then switching to Clozaril (100 mg) Luvox (50 mg) would save $4,212 per year—assuming that the patient would be on 500 mg/day otherwise. If generic clozapine was prescribed, the savings would be $3,573 per year. There might be some added costs for following serum levels, but Mong-Liang et al.'s study indicates that the levels were unchanged from Day 14 to 28, which would argue that repetitive blood monitoring is unnecessary once steady state is achieved.
The short-term and long-term physiological effects of this strategy appear to be safe because patients have been on combinations of selective serotonin reuptake inhibitors (SSRI) and antipsychotics for years. However, there is a potential drawback to this strategy. Most patients who receive this regimen would eventually be in community settings. In rural settings many chronic schizophrenic patients are followed by family practice physicians. They receive occasional consultation to a psychiatrist when there is a crisis. The patient and the physician, if not properly educated, may not understand the combination strategy well, and they could discontinue the fluvoxamine with this simple reasoning: "it's a low dose and you don't have OCD or depression." Another adverse possibility would be for the physician to raise the clozapine dose if the patient begins to become symptomatic with the risk of then having toxic levels of clozapine, even with low to modest increase doses of the clozapine.
Nevertheless, with good clinical coordination and education in a highly motivated patient and provider, these potential hazards can be avoided. Based on Mong Liang et al.'s article, our facility is considering a protocol for the use of this strategy to reduce pharmacy costs. I recommend others should read this article and determine if developing a similar protocol with this combination would be helpful.—SCA
REFERENCES
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Armstrong SC, Cozza KL: Consultation-liaison psychiatry drug-drug interactions update. Psychosomatics 1999; 40:275–276[Free Full Text]
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Chang WH, Augsutin B, Lane HY et al: In-vitro and in-vivo evaluation of the drug-drug interaction between fluvoxamine and clozapine. Psychopharmacology 145(1):91–98, 1999[CrossRef][Medline]
3. Does Bupropion Inhibit Cytochrome P450 2D6?
In our readings and through our lectures, we have been asked "Are there clinically significant drug-drug interactions with bupropion?" Briefly, this drug is metabolized predominantly at Cytochrome P450 2B6, a very minor metabolic site in the liver. In addition, bupropion has many alternate sites of metabolism, including 1A2, 2A6, 2C9, 2E1, and 3A4 (Glaxo Wellcome product information). This plethora of metabolic sites makes inhibition of bupropion metabolism nearly impossible, and we are unaware of any clinical data to support the concern that potent inhibitors of 3A4 or other P450 enzymes could significantly raise bupropion levels to such a degree as to cause seizures. Seizures associated with this drug seem to be directly related to dosing/serum level and predisposing conditions, such as history of seizures, head trauma, CNS tumor, hepatic disease, and concomitant administration with seizure threshold-lowering drugs, not to metabolic drug interactions. There is a potential for bupropion's metabolism to be induced by the potent pan-inducers carbamazepine, rifampin, and others, but the clinical significance of this is not fully known. Potentially, lowering the serum level of bupropion could lead to a need for a higher dosage for clinical effectiveness. When the inducing agent is discontinued, over the course of 2–4 weeks, unless the dose of bupropion is lowered, the potential exists for toxic levels. Again, if providers maintain total dosage below the maximum recommended daily dose of 400 mg in divided doses, the risk of seizures after the withdrawal of inducing medications should be minimal.
There seems to be in vitro data to support that bupropion is an inhibitor of P450 2D6 (note that bupropion is not metabolized at 2D6). We could not find any published clinical data to suggest the extent of this inhibition. The manufacturer provided data from a study of 15 healthy volunteers with normal 2D6 activity where 150 mg bid of Wellbutrin SR increased the Cmax, AUC, and t1/2 of a single dose of desipramine (50 mg). The actual data were not provided for review (Glaxo Wellcome Inc. product information for Wellbutrin SR Tablets, May 2000). The manufacturer recommends initiation of treatment of drugs predominantly metabolized by 2D6 with narrow therapeutic windows (nortriptyline, desipramine, imipramine, beta-blockers, type 1C antiarrhythmics, and the potentially arrhythmogenic antipsychotics haloperidol, risperidone and thioridizine) be initiated at lower doses when coadministerd with bupropion. We would like to see more clinical data about this potential interaction.—KLC
FOOTNOTES
Dr. Armstrong is the Medical Director at Willmar Regional Treatment Center, Willmar, Minnesota; Dr. Cozza is an HIV Psychiatrist at the Department of Medicine, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Willmar Regional Treatment Center, 1550 Hwy 71 N, Willmar, MN 56201; e-mail Dr. Armstrong at scott.armstrong{at}state.mn.us
This article has been cited by other articles:
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M. L. Lu and H. Y. Lane
Adjunctive fluvoxamine with clozapine
The British Journal of Psychiatry,
January 2, 2003;
182
(1):
81 - 81.
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