- Email: [email protected]
Med-Psych Drug-Drug Interactions Update
Med-Psych Drug-Drug Interactions Update SCOTT C. ARMSTRONG, M.D. KELLY L. COZZA, M.D.
This edition of the column briefs three drugs. The first two relate to a topic that appears to have no end—that of drugs lengthening the QTc interval. We have commented in previous columns that as older drugs are reviewed, some drugs previously presumed to have a safe cardiac profile may be found not to be so safe. Levomethadyl and loratadine are two drugs now thought to have potentially significant QTc problems that can be exacerbated by drug-drug interactions (DDI). The third review updates our knowledge of grapefruit juice and the use of clozapine. Unlike the expanding problem of drugs enhancing QTc, the combination of grapefruit juice and clozapine may be safer than once thought.—SCA and KLC 1. Levomethadyl Acetate HCL (Orlaam娂) FDA Talk Paper T01-15. FDA announces labeling changes following cardiac adverse events with addiction drug. April 20, 2001. Orlaam娂 package insert, Roxane Laboratories Inc., Columbus, OH. Revised May 2001. Levomethadyl is a drug used to treat opiate addiction and has been available since 1993. It was approved in record time because of its unique efficacy profile. Unfortunately, under a warning from the FDA in March 2001, it has Psychosomatics 43:2, March-April 2002
now been relegated to second-line use with restrictions. The reason is that out of 33,000 patients treated with levomethadyl, 10 severe arrhythmia cases had been reported to the FDA MedWatch program. The problem is the same as with many other drugs we have written about in previous columns, that of lengthening the QTc and the risk of Torsade de Pointes. The manufacturer recommends that an EKG be obtained before using the drug, and that if the baseline QTc is greater than 430 ms (men) or 450 ms (women), levomethadyl not be used. Drugs that potentially affect the cardiac conduction system (i.e., antiarrhythmics) are contraindicated with levomethadyl. To add to this complexity, levomethadyl is metabolized by CYP450 3A4; thus, concomitant use with drugs that inhibit CYP450 3A4 (ciprofloxacin, itraconazole and ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir, and cimetidine are some of the major inhibitors) should be avoided. Interestingly, because CYP450 3A4 metabolizes the parent drug to active metabolites, the manufacturer also recommends against its use with drugs that induce CYP450 3A4, including carbamazepine, phenobarbital, phenytoin, rifampin, and possibly St. John’s Wort.—SCA and KLC 2. Loratadine (Claritin娂) Abernethy DR, Barbey JT, Franc J, et al: Loratadine and terfenadine interaction with nefazodone: both
antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2000; 69:96–103 Renwick AG: The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(suppl 3):116–124 Claritin娂 package insert, Schering Corporation, Kenilworth, NJ, September 2000. In keeping with the QTc theme, we discuss loratadine, the ‘‘safe,’’ nonsedating antihistamine that survived the QTc/DDI problems of terfenadine and astemizole. Loratadine may not be as safe as once thought. As recently as 1999, Renwick wrote a review indicating that loratadine’s parent compound and its metabolites (from metabolism of CYP450s 3A4 and 2D6) lack cardiac effects on the conduction system. The package insert does state that CYP450 3A4 inhibitors can increase levels of loratadine, but that CYP450 2D6 does take over when this occurs. The package insert does not mention that the drug may affect the QTc. However, a recent study by Abernethy et al. (2001) indicates that this may not be so. Abernethy et al. studied healthy volunteers who received nefazodone (a potent 3A4 inhibitor) 300 mg every 12 hours (a high dose, but it is the recommended maximum dose by the manufacturer) with terfenadine (60 mg twice a day), or loratadine (20 mg 169
Drug-Drug Interaction once a day). For comparison, each of the three drugs was used alone. Blood levels of parent compounds and metabolites were measured, as were EKGs in each permutation. As expected, terfenadine’s levels were increased and the average QTc increased 42.4 ms when used with nefazodone. Interestingly, the QTc was unchanged when terfenadine was used alone. The concomitant use of nefazodone with loratadine yielded an average increase of the QTc of 21.6 ms. Loratadine alone did not increase the QTc. For comparison, this change in QTc for the loratadine-nefazodone combination is similar to the change noted with ziprasidone used alone. Abernethy et al. astutely point out that loratadine is often used past 20 mg/day and that this study had only healthy volunteers. In addition, we wonder whether other potent CYP450 3A4 inhibitors (see levomethadyl review above) may have the same effect when used with loratadine. Stay tuned for more about loratadine and potential warnings.—SCA and KLC 3. Grapefruit Juice and Clozapine Revisited Lane H-Y, Jann MW, Chang Y-C, et al: Repeated ingestion of grapefruit juice does not alter clozapine’s steady-state plasma levels, effectiveness, and tolerability. J Clin Psychiatry 2001; 62:812–817 Grapefruit juice has been shown to significantly raise levels of several drugs dependent on CYP450 3A4 for clearance. Grapefruit juice has also been theorized to raise clozapine levels. Three-fold to 12-fold increases have been noted when grapefruit juice is used with CYP450 3A4 substrates such as alprazolam, midazolam, triazolam, buspirone, some calcium channel 170
blockers, cyclosporine, and lovastatin. Grapefruit juice may also inhibit CYP450 1A2 and inhibit the transport enzyme P-glycoprotein. Lane et al. (2001) looked at the use of grapefruit juice with clozapine. Clozapine is metabolized in part by CYP450 3A4, as well as by CYP450s 1A2, 2D6, and 2C19. The concern, of course, was that grapefruit juice could markedly increase clozapine levels to toxicity because it has a narrow therapeutic index. For example, many studies have shown that fluvoxamine drastically raises clozapine levels because fluvoxamine inhibits CYP450s 1A2, 2C19, and, to some extent, 3A4. Lane et al. found that 250 cc twice a day of 100% pure grapefruit juice did not significantly raise clozapine levels in 15 patients with schizophrenia who had been titrated to a therapeutic dose of clozapine. Lane et al. did find that clozapine levels increased modestly (about 15%), but that this increase persisted 3 weeks after the grapefruit juice had been withdrawn. Lane et al. hypothesized that CYP450s 1A2 and 2C19 were more than adequately able to handle clozapine’s metabolism. Indeed, the authors commented that they have had similar results (unpublished) with ketoconazole (a potent 3A4 inhibitor) and clozapine. In addition, the inhibition of CYP450 3A4 by grapefruit juice occurs at the gut wall, which might have less effect if the liver was affected by a grapefruit juice chemical. The researchers also concluded that their study agreed with other studies indicating that grapefruit juice is, at best, a weak inhibitor of P-glycoprotein. The only drawback of this study is that it did not include a control group. For example, no group received a similar-flavored juice. If such a control group existed and the results did not indicate an increase in clozapine levels of 15%, then one could argue that there
was an effect, albeit modest, by grapefruit juice. So far, this study is the best examination of grapefruit juice and clozapine. Unfortunately, it is not yet, in our opinion, the definitive answer. This is because it was done in Taiwan and, according to the researchers, all the patients were Chinese. The cytochrome P450 system and other metabolic enzymes are potentially different in their activity, their phenotype, or both in other races. Pharmacogenetic profiles ought to be done in future studies. If you have read previous editions of this column, you know that we are advocates for pharmacogenetic research. We hope that in the near future, the clinician can predict potential DDI (or metabolic enzyme food-drug interactions) through individual genetic profiles. In the case of grapefruit juice and clozapine, such bedside pharmacogenetics may help us advise which (if any) of our clozapine patients should avoid grapefruit juice.—SCA and KLC Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are coauthors of The Cytochrome P450 System: Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Press, Inc., 2001. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or scott. [email protected]. Psychosomatics 43:2, March-April 2002
This edition of the column briefs three drugs. The first two relate to a topic that appears to have no end—that of drugs lengthening the QTc interval. We have commented in previous columns that as older drugs are reviewed, some drugs previously presumed to have a safe cardiac profile may be found not to be so safe. Levomethadyl and loratadine are two drugs now thought to have potentially significant QTc problems that can be exacerbated by drug-drug interactions (DDI). The third review updates our knowledge of grapefruit juice and the use of clozapine. Unlike the expanding problem of drugs enhancing QTc, the combination of grapefruit juice and clozapine may be safer than once thought.—SCA and KLC 1. Levomethadyl Acetate HCL (Orlaam娂) FDA Talk Paper T01-15. FDA announces labeling changes following cardiac adverse events with addiction drug. April 20, 2001. Orlaam娂 package insert, Roxane Laboratories Inc., Columbus, OH. Revised May 2001. Levomethadyl is a drug used to treat opiate addiction and has been available since 1993. It was approved in record time because of its unique efficacy profile. Unfortunately, under a warning from the FDA in March 2001, it has Psychosomatics 43:2, March-April 2002
now been relegated to second-line use with restrictions. The reason is that out of 33,000 patients treated with levomethadyl, 10 severe arrhythmia cases had been reported to the FDA MedWatch program. The problem is the same as with many other drugs we have written about in previous columns, that of lengthening the QTc and the risk of Torsade de Pointes. The manufacturer recommends that an EKG be obtained before using the drug, and that if the baseline QTc is greater than 430 ms (men) or 450 ms (women), levomethadyl not be used. Drugs that potentially affect the cardiac conduction system (i.e., antiarrhythmics) are contraindicated with levomethadyl. To add to this complexity, levomethadyl is metabolized by CYP450 3A4; thus, concomitant use with drugs that inhibit CYP450 3A4 (ciprofloxacin, itraconazole and ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir, and cimetidine are some of the major inhibitors) should be avoided. Interestingly, because CYP450 3A4 metabolizes the parent drug to active metabolites, the manufacturer also recommends against its use with drugs that induce CYP450 3A4, including carbamazepine, phenobarbital, phenytoin, rifampin, and possibly St. John’s Wort.—SCA and KLC 2. Loratadine (Claritin娂) Abernethy DR, Barbey JT, Franc J, et al: Loratadine and terfenadine interaction with nefazodone: both
antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2000; 69:96–103 Renwick AG: The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(suppl 3):116–124 Claritin娂 package insert, Schering Corporation, Kenilworth, NJ, September 2000. In keeping with the QTc theme, we discuss loratadine, the ‘‘safe,’’ nonsedating antihistamine that survived the QTc/DDI problems of terfenadine and astemizole. Loratadine may not be as safe as once thought. As recently as 1999, Renwick wrote a review indicating that loratadine’s parent compound and its metabolites (from metabolism of CYP450s 3A4 and 2D6) lack cardiac effects on the conduction system. The package insert does state that CYP450 3A4 inhibitors can increase levels of loratadine, but that CYP450 2D6 does take over when this occurs. The package insert does not mention that the drug may affect the QTc. However, a recent study by Abernethy et al. (2001) indicates that this may not be so. Abernethy et al. studied healthy volunteers who received nefazodone (a potent 3A4 inhibitor) 300 mg every 12 hours (a high dose, but it is the recommended maximum dose by the manufacturer) with terfenadine (60 mg twice a day), or loratadine (20 mg 169
Drug-Drug Interaction once a day). For comparison, each of the three drugs was used alone. Blood levels of parent compounds and metabolites were measured, as were EKGs in each permutation. As expected, terfenadine’s levels were increased and the average QTc increased 42.4 ms when used with nefazodone. Interestingly, the QTc was unchanged when terfenadine was used alone. The concomitant use of nefazodone with loratadine yielded an average increase of the QTc of 21.6 ms. Loratadine alone did not increase the QTc. For comparison, this change in QTc for the loratadine-nefazodone combination is similar to the change noted with ziprasidone used alone. Abernethy et al. astutely point out that loratadine is often used past 20 mg/day and that this study had only healthy volunteers. In addition, we wonder whether other potent CYP450 3A4 inhibitors (see levomethadyl review above) may have the same effect when used with loratadine. Stay tuned for more about loratadine and potential warnings.—SCA and KLC 3. Grapefruit Juice and Clozapine Revisited Lane H-Y, Jann MW, Chang Y-C, et al: Repeated ingestion of grapefruit juice does not alter clozapine’s steady-state plasma levels, effectiveness, and tolerability. J Clin Psychiatry 2001; 62:812–817 Grapefruit juice has been shown to significantly raise levels of several drugs dependent on CYP450 3A4 for clearance. Grapefruit juice has also been theorized to raise clozapine levels. Three-fold to 12-fold increases have been noted when grapefruit juice is used with CYP450 3A4 substrates such as alprazolam, midazolam, triazolam, buspirone, some calcium channel 170
blockers, cyclosporine, and lovastatin. Grapefruit juice may also inhibit CYP450 1A2 and inhibit the transport enzyme P-glycoprotein. Lane et al. (2001) looked at the use of grapefruit juice with clozapine. Clozapine is metabolized in part by CYP450 3A4, as well as by CYP450s 1A2, 2D6, and 2C19. The concern, of course, was that grapefruit juice could markedly increase clozapine levels to toxicity because it has a narrow therapeutic index. For example, many studies have shown that fluvoxamine drastically raises clozapine levels because fluvoxamine inhibits CYP450s 1A2, 2C19, and, to some extent, 3A4. Lane et al. found that 250 cc twice a day of 100% pure grapefruit juice did not significantly raise clozapine levels in 15 patients with schizophrenia who had been titrated to a therapeutic dose of clozapine. Lane et al. did find that clozapine levels increased modestly (about 15%), but that this increase persisted 3 weeks after the grapefruit juice had been withdrawn. Lane et al. hypothesized that CYP450s 1A2 and 2C19 were more than adequately able to handle clozapine’s metabolism. Indeed, the authors commented that they have had similar results (unpublished) with ketoconazole (a potent 3A4 inhibitor) and clozapine. In addition, the inhibition of CYP450 3A4 by grapefruit juice occurs at the gut wall, which might have less effect if the liver was affected by a grapefruit juice chemical. The researchers also concluded that their study agreed with other studies indicating that grapefruit juice is, at best, a weak inhibitor of P-glycoprotein. The only drawback of this study is that it did not include a control group. For example, no group received a similar-flavored juice. If such a control group existed and the results did not indicate an increase in clozapine levels of 15%, then one could argue that there
was an effect, albeit modest, by grapefruit juice. So far, this study is the best examination of grapefruit juice and clozapine. Unfortunately, it is not yet, in our opinion, the definitive answer. This is because it was done in Taiwan and, according to the researchers, all the patients were Chinese. The cytochrome P450 system and other metabolic enzymes are potentially different in their activity, their phenotype, or both in other races. Pharmacogenetic profiles ought to be done in future studies. If you have read previous editions of this column, you know that we are advocates for pharmacogenetic research. We hope that in the near future, the clinician can predict potential DDI (or metabolic enzyme food-drug interactions) through individual genetic profiles. In the case of grapefruit juice and clozapine, such bedside pharmacogenetics may help us advise which (if any) of our clozapine patients should avoid grapefruit juice.—SCA and KLC Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are coauthors of The Cytochrome P450 System: Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Press, Inc., 2001. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or scott. [email protected]. Psychosomatics 43:2, March-April 2002