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Drug Interactions between Prevpac and sildenafil

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

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Interactions between your drugs

Major

clarithromycin sildenafil

Applies to: Prevpac (amoxicillin / clarithromycin / lansoprazole) and 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 Dosage adjustments may be appropriate for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects.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. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. (2001) "Product Information. Viagra (sildenafil)." Pfizer U.S. Pharmaceuticals
  3. Nandwani R, Gourlay Y (1999) "Possible interaction between sildenafil and HIV combination therapy." Lancet, 353, p. 840
  4. Hall MCS, Ahmad S (1999) "Interaction between sildenafil and HIV-1 combination therapy." Lancet, 353, p. 2071-2
  5. Merry C, Barry MG, Ryan M, Tjia JF, Hennessy M, Eagling VA, Mulcahy F, Back DJ (1999) "Interaction of sildenafil and indinavir when co-administered to HIV-positive patients." AIDS, 13, f101-7
  6. Warrington JS, Shader RI, vonMoltke LL, Greenblatt DJ (2000) "In vitro biotransformation of sildenafil (Viagra): Identification of human cytochromes and potential drug interactions." Drug Metab Disposition, 28, p. 392-7
  7. Muirhead GJ, Wulff MB, Fielding A, Kleinermans D, Buss N (2000) "Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir." Br J Clin Pharmacol, 50, p. 99-107
  8. Hyland R, Roe GH, Jones BC, Smith DA (2001) "Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil." Br J Clin Pharmaacol, 51, p. 239-48
  9. (2005) "Product Information. Revatio (sildenafil)." Pfizer U.S. Pharmaceuticals Group
  10. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  11. Cerner Multum, Inc. "Australian Product Information."
  12. (2022) "Product Information. Voquezna Dual Pak (amoxicillin-vonoprazan)." Phathom Pharmaceuticals, Inc
  13. (2022) "Product Information. Voquezna Triple Pak (amoxicillin/clarithromycin/vonoprazan)." Phathom Pharmaceuticals, Inc
View all 13 references

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Moderate

clarithromycin lansoprazole

Applies to: Prevpac (amoxicillin / clarithromycin / lansoprazole) and Prevpac (amoxicillin / clarithromycin / lansoprazole)

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

References

  1. Ushiama H, Echizen H, Nachi S, Ohnishi A (2002) "Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol." Clin Pharmacol Ther, 72, p. 33-43
  2. Saito M, Yasui-Furukori N, Uno T, et al. (2005) "Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes." Br J Clin Pharmacol, 59, p. 302-9
  3. Miura M, Tada H, Yasui-Furukori N, et al. (2005) "Effect of clarithromycin on the enantioselective disposition of lansoprazole in relation to CYP2C19 genotypes." Chirality, 17, p. 338-344

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Minor

amoxicillin clarithromycin

Applies to: Prevpac (amoxicillin / clarithromycin / lansoprazole) and Prevpac (amoxicillin / clarithromycin / lansoprazole)

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

References

  1. Strom J (1961) "Penicillin and erythromycin singly and in combination in scarlatina therapy and the interference between them." Antibiot Chemother, 11, p. 694-7
  2. Cohn JR, Jungkind DL, Baker JS (1980) "In vitro antagonism by erythromycin of the bactericidal action of antimicrobial agents against common respiratory pathogens." Antimicrob Agents Chemother, 18, p. 872-6
  3. Penn RL, Ward TT, Steigbigel RT (1982) "Effects of erythromycin in combination with penicillin, ampicillin, or gentamicin on the growth of listeria monocytogenes." Antimicrob Agents Chemother, 22, p. 289-94

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Drug and food interactions

Moderate

sildenafil food

Applies to: 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. (2002) "Effects of grapefruit juice on the pharmacokinetics of sildenafil." Clin Pharmacol Ther, 71, p. 21-29

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Minor

clarithromycin food

Applies to: Prevpac (amoxicillin / clarithromycin / lansoprazole)

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

References

  1. Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) "Effect of grapefruit juice on clarithromycin pharmacokinetics." Antimicrob Agents Chemother, 42, p. 927-9

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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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.