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Drug Interactions between itraconazole and Revatio

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

itraconazole sildenafil

Applies to: itraconazole and Revatio (sildenafil)

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of sildenafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of sildenafil should be considered. In 14 healthy volunteers, the potent CYP450 3A4 inhibitor ritonavir (500 mg twice a day for 7 days) increased mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of sildenafil (100 mg single dose) by 300% and 1000%, respectively, compared to sildenafil given alone. At 24 hours, sildenafil plasma levels were still approximately 200 ng/mL as opposed to about 5 ng/mL with sildenafil alone. In a parallel study, saquinavir (SGC 1200 mg three times a day for 7 days) increased single-dose sildenafil Cmax and AUC by 140% and 210%, respectively, in 14 healthy volunteers. No change in safety or tolerability of sildenafil was observed with either protease inhibitor. In six HIV-infected patients stabilized on triple antiretroviral therapy containing indinavir (800 mg three times a day), the AUC of a single 25 mg dose of sildenafil was 4.4 times higher than dose-normalized data from historical controls. The patients experienced headache, flushing, dyspepsia and rhinitis, and there was a mean maximal decrease in blood pressure of 14/10 mmHg. The interaction was also suspected in the death of a 47-year-old man who used sildenafil (25 mg) during treatment with ritonavir and saquinavir. Another CYP450 3A4 inhibitor, erythromycin (500 mg twice daily for 5 days), increased single-dose sildenafil AUC by 182%.

MANAGEMENT: Caution is advised if sildenafil is coadministered with potent CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. For the treatment of erectile dysfunction, an initial sildenafil dosage of 25 mg should be considered in patients treated concomitantly with potent CYP450 3A4 inhibitors. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours). For the treatment of pulmonary arterial hypertension, a dosage adjustment for sildenafil should be considered during coadministration with some CYP450 3A4 inhibitors such as erythromycin, saquinavir, telithromycin, and nefazodone. However, use with more potent CYP450 3A4 inhibitors such as ritonavir, ketoconazole, itraconazole, or clarithromycin is not recommended. Some authorities consider the use of very potent CYP450 3A4 inhibitors with sildenafil to be contraindicated in patients with pulmonary arterial hypertension. When sildenafil is used for the treatment of pulmonary hypertension, the manufacturer of itraconazole recommends avoiding concomitant use during and for 2 weeks after treatment with itraconazole.

References

  1. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  2. "Product Information. Viagra (sildenafil)." Pfizer U.S. Pharmaceuticals PROD (2001):
  3. Nandwani R, Gourlay Y "Possible interaction between sildenafil and HIV combination therapy." Lancet 353 (1999): 840
  4. Hall MCS, Ahmad S "Interaction between sildenafil and HIV-1 combination therapy." Lancet 353 (1999): 2071-2
  5. Merry C, Barry MG, Ryan M, Tjia JF, Hennessy M, Eagling VA, Mulcahy F, Back DJ "Interaction of sildenafil and indinavir when co-administered to HIV-positive patients." AIDS 13 (1999): f101-7
  6. Warrington JS, Shader RI, vonMoltke LL, Greenblatt DJ "In vitro biotransformation of sildenafil (Viagra): Identification of human cytochromes and potential drug interactions." Drug Metab Disposition 28 (2000): 392-7
  7. Muirhead GJ, Wulff MB, Fielding A, Kleinermans D, Buss N "Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir." Br J Clin Pharmacol 50 (2000): 99-107
  8. Hyland R, Roe GH, Jones BC, Smith DA "Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil." Br J Clin Pharmaacol 51 (2001): 239-48
  9. "Product Information. Revatio (sildenafil)." Pfizer U.S. Pharmaceuticals Group (2005):
  10. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  11. Cerner Multum, Inc. "Australian Product Information." O 0
  12. "Product Information. Voquezna Dual Pak (amoxicillin-vonoprazan)." Phathom Pharmaceuticals, Inc ORIG-1 (2022):
  13. "Product Information. Voquezna Triple Pak (amoxicillin/clarithromycin/vonoprazan)." Phathom Pharmaceuticals, Inc ORIG-1 (2022):
View all 13 references

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Drug and food interactions

Moderate

itraconazole food

Applies to: itraconazole

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

References

  1. Van Peer A, Woestenborghs R, Heykants J, et al. "The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects." Eur J Clin Pharmacol 36 (1989): 423-6
  2. Wishart JM "The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal infection." J Am Acad Dermatol 17 (1987): 220-3
  3. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  4. Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers." Antimicrob Agents Chemother 37 (1993): 778-84
  5. Zimmermann T, Yeates RA, Albrecht M, Laufen H, Wildfeuer A "Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in japanese subjects." Int J Clin Pharmacol Res 14 (1994): 87-93
  6. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals (2022):
  7. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H "Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects." Int J Clin Pharmacol Ther 36 (1998): 306-8
  8. Barone JA, Moskotitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L "Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers." Pharmacotherapy 18 (1998): 295-301
  9. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M "Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers." Ther Drug Monit 21 (1999): 304-9
  10. Katz HI "Drug interactions of the newer oral antifungal agents." Br J Dermatol 141 (1999): 26-32
View all 10 references

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Moderate

sildenafil food

Applies to: Revatio (sildenafil)

GENERALLY AVOID: Coadministration with grapefruit juice may slightly increase the oral bioavailability and delay the onset of action of sildenafil. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a randomized, crossover study with 24 healthy male volunteers, ingestion of 250 mL of grapefruit juice one hour before and concurrently with a 50 mg dose of sildenafil increased the mean area under the plasma concentration-time curve (AUC) of sildenafil and its pharmacologically active N-desmethyl metabolite by 23% and 24%, respectively, compared to water. Peak plasma concentrations (Cmax) were unaltered, but the time to reach sildenafil Cmax was prolonged by 0.25 hour. The observed increase in sildenafil bioavailability is unlikely to be of clinical significance in most individuals. However, pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability and may be significant in the occasional susceptible patient. Indeed, one subject in the study had a 2.6-fold increase in sildenafil concentrations.

MANAGEMENT: It may be advisable to avoid administration of sildenafil with grapefruit juice to prevent potential toxicity and delay in onset of action.

References

  1. Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. "Effects of grapefruit juice on the pharmacokinetics of sildenafil." Clin Pharmacol Ther 71 (2002): 21-29

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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