Basic Information
ID DDInter1298 and DDInter995
Interaction Coadministration with ketoconazole or itraconazole may significantly increase the plasma concentrations of nisoldipine. The proposed mechanism is decreased first-pass metabolism and hepatic clearance of nisoldipine due to inhibition of CYP450 3A4. Although not studied, itraconazole is expected to interact similarly, since it is a known potent inhibitor of CYP450 3A4.There have been case reports of leg and ankle edema in patients treated with itraconazole and dihydropyridine calcium channel blockers. Pharmacodynamically, itraconazole exhibits a dose-related negative inotropic effect, which may be additive to those of calcium channel blockers (CCBs). It is conceivable that coadministration may potentiate the risk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonary edema, particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disorder; edematous disorders such as renal failure).
Management Because the alterations in nisoldipine pharmacokinetics cannot be feasibly managed by dosage reduction, concomitant use with ketoconazole or itraconazole is considered contraindicated. Some authorities consider concomitant administration of nisoldipine and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.
References [1] "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceutica, Titusville, NJ. (1992): [2] Jalava KM, Olkkola KT, Neuvonen PJ "Itraconazole greatly increases plasma concentrations and effects of felodipine." Clin Pharmacol Ther 61 (1997): 410-5 [3] Rosen T "Debilitating edema associated with itraconazole therapy." Arch Dermatol 130 (1994): 260-1 [4] Cerner Multum, Inc. "Australian Product Information." O 0 [5] Tailor SAN "Peripheral edema due to nifedipine-itraconazole interaction: a case report." Arch Dermatol 132 (1996): 1374 [6] "Product Information. Sporanox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ. [7] Heinig R, Adelmann HG, Ahr G "The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine." Eur J Clin Pharmacol 55 (1999): 57-60 [8] Tailor SAN, Gupta AK, Walker SE, Shear NH "Peripheral edema due to nifedipine-itraconazole interaction: a case report." Arch Dermatol 132 (1996): 350-2 [9] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [10] Neuvonen PJ, Suhonen R "Itraconazole interacts with felodipine." J Am Acad Dermatol 33 (1995): 134-5 [11] Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in humans." Clin Pharmacol Ther 64 (1998): 248-56 [12] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [13] Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8 [14] Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77 [15] Bailey DG, Arnold JM, Munoz C, Spence JD "Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin." Clin Pharmacol Ther 53 (1993): 637-42 [16] "Product Information. Procardia (nifedipine)." Pfizer US Pharmaceuticals, New York, NY. [17] Yamreudeewong W, Henann NE, Fazio A, Lower DL, Cassidy TG "Drug-food interactions in clinical practice." J Fam Pract 40 (1995): 376-84 [18] Edgar B, Bailey D, Bergstrand R, Johnsson G, Regardh CG "Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine--and its potential clinical relevance." Eur J Clin Pharmacol 42 (1992): 313-7 [19] Josefsson M, Zackrisson AL, Ahlner J "Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers." Eur J Clin Pharmacol 51 (1996): 189-93 [20] "Product Information. Plendil (felodipine)." Merck & Co, Inc, West Point, PA. [21] Fuhr U, Muller-Peltzer H, Kern R, et al. "Effects of grapefruit juice and smoking on verapamil concentrations in steady state." Eur J Clin Pharmacol 58 (2002): 45-53 [22] Gunston GD, Mehta U "Potentially serious drug interactions with grapefruit juice." S Afr Med J 90 (2000): 41 [23] Fuhr U, Maier-Bruggemann A, Blume H, et al. "Grapefruit juice increases oral nimodipine bioavailability." Int J Clin Pharmacol Ther 36 (1998): 126-32 [24] "Product Information. Sular (nisoldipine)." Zeneca Pharmaceuticals, Wilmington, DE. [25] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [26] "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4 [27] Takanaga H, Ohnishi A, Maatsuo H, et al. "Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model." Br J Clin Pharmacol 49 (2000): 49-58 [28] Ho PC, Ghose K, Saville D, Wanwimolruk S "Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers." Eur J Clin Pharmacol 56 (2000): 693-8 [29] Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD "Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics." Clin Pharmacol Ther 54 (1993): 589-94
Alternative for Nisoldipine C08C
Clevidipine
Alternative for Itraconazole J02A
Caspofungin Micafungin Amphotericin B Oteseconazole Flucytosine Anidulafungin
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.