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March 24, 1993, Vol 269, No. 12 >
ARTICLE | March 24, 1993

Understanding Consequences of Concurrent Therapies FREE

Carl C. Peck, MD; Robert Temple, MD; Jerry M. Collins, PhD
[+] Author Affiliations

Reprint requests to Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Ln, Rockville, MD 20857 (Dr Peck).


JAMA. 1993;269(12):1550-1552. doi:10.1001/jama.1993.03500120088033
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References

In 1989, the occurrence of a rare, life-threatening ventricular arrhythmia (torsades de pointes) in an otherwise healthy young woman led alert clinicians at the Naval Hospital in Bethesda, Md, to consider the possibility that the patient's near-fatal arrhythmia was triggered by a drug-drug interaction involving her antihistamine (terfenadine) and her antifungal (ketoconazole) medications.1 Consulting clinical pharmacologists from the Uniformed Services University of the Health Sciences and the US Food and Drug Administration (FDA) suggested that ketoconazole inhibited the oxidative metabolism of terfenadine. Analysis of blood samples revealed that the patient had high levels of unmetabolized terfenadine, a compound not usually detectable in blood because it is metabolized so quickly. Review of reports to the FDA's spontaneous reporting system revealed that among additional cases of torsades de pointes in patients receiving terfenadine, many were also receiving ketoconazole. This evidence led the FDA to ask Marion Merrill Dow, Kansas City, Mo,

REFERENCES

1 +
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR.  Torsades de pointes occurring in association with terfenadine use. JAMA . 1990;;264: 2788-2790.
2 +
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR.  Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA . 1993;;269:1513-1518.
3 +
Woosley RL, Chen Y, Freiman JP, Gillis RA.  Mechanism of the cardiotoxic actions of terfenadine. JAMA . 1993;;269:1535-1539.
4 +
Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR.  Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther . 1992;;52:231-238.
5 +
Oates NS, Shah RR, Idle JR, Smith RL.  Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther . 1983;;34:827-834.
6 +
Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF.  Impaired oxidation of debrisoquine in patients with perhexilene neuropathy. BMJ . 1982;;284:295-299.
7 +
Bergstrom RF, Peyton AL, Lemberger L.  Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther . 1992;;51: 239-248.
8 +
Preskorn JH, Barber JE, Faul JC, Hirschfeld RMA.  Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry . 1990;;147:532.
9 +
Westermeyer J.  Fluoxetine-induced tricyclic toxicity: extent and duration. J Clin Pharmacol . 1991;;31:380-392.
10 +
Edgar B, Bailey D, Bergstrand R, Johnsson G, Regarth CG.  Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine, and its potential clinical relevance. Eur J Clin Pharmacol . 1992;;42:313-317.
11 +
Soons PA, Vogels BA, Roosemalen MC, et al.  Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther . 1991;;50:394-403.
12 +
Bailey DG, Spence JD, Munoz C, Arnold JMO.  Interaction of citrus juices with felodipine and nifedipine. Lancet . 1991;;337:268-269.
13 +
Herbert MF, Roberts JP, Prueksaritanont T, Benet LZ.  Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme inhibition. Clin Pharmacol Ther . 1992;;52:453-457.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR.  Torsades de pointes occurring in association with terfenadine use. JAMA . 1990;;264: 2788-2790.
2 +
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR.  Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA . 1993;;269:1513-1518.
3 +
Woosley RL, Chen Y, Freiman JP, Gillis RA.  Mechanism of the cardiotoxic actions of terfenadine. JAMA . 1993;;269:1535-1539.
4 +
Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR.  Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther . 1992;;52:231-238.
5 +
Oates NS, Shah RR, Idle JR, Smith RL.  Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther . 1983;;34:827-834.
6 +
Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF.  Impaired oxidation of debrisoquine in patients with perhexilene neuropathy. BMJ . 1982;;284:295-299.
7 +
Bergstrom RF, Peyton AL, Lemberger L.  Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther . 1992;;51: 239-248.
8 +
Preskorn JH, Barber JE, Faul JC, Hirschfeld RMA.  Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry . 1990;;147:532.
9 +
Westermeyer J.  Fluoxetine-induced tricyclic toxicity: extent and duration. J Clin Pharmacol . 1991;;31:380-392.
10 +
Edgar B, Bailey D, Bergstrand R, Johnsson G, Regarth CG.  Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine, and its potential clinical relevance. Eur J Clin Pharmacol . 1992;;42:313-317.
11 +
Soons PA, Vogels BA, Roosemalen MC, et al.  Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther . 1991;;50:394-403.
12 +
Bailey DG, Spence JD, Munoz C, Arnold JMO.  Interaction of citrus juices with felodipine and nifedipine. Lancet . 1991;;337:268-269.
13 +
Herbert MF, Roberts JP, Prueksaritanont T, Benet LZ.  Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme inhibition. Clin Pharmacol Ther . 1992;;52:453-457.

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