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Drug Interactions between azithromycin / trovafloxacin and Primatene Dual Action

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

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Interactions between your drugs

Moderate

azithromycin theophylline

Applies to: azithromycin / trovafloxacin and Primatene Dual Action (ephedrine / guaifenesin / theophylline)

MONITOR: Coadministration with certain macrolide antibiotics may increase the serum concentrations of methylxanthines such as theophylline, which may result in toxicity. In one case report, a pediatric patient developed seizures in association with theophylline toxicity shortly after the addition of erythromycin. The proposed mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of theophylline. Data from pharmacokinetic studies suggest that the magnitude of the interaction is generally greatest with troleandomycin, followed by erythromycin. The interaction with clarithromycin appears to be mild and inconsistent. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4, and most studies have not found a significant effect on the pharmacokinetics of theophylline. However, a case report describes an unusual interaction with azithromycin in an elderly patient whereby reduced serum theophylline levels were repeatedly observed after the discontinuation of azithromycin. The changes were transient and did not require an adjustment in the theophylline dosage. Theophylline has been reported to decrease plasma concentrations of erythromycin by increasing its renal clearance.

MANAGEMENT: Pharmacologic response and serum theophylline levels should be monitored more closely whenever a macrolide antibiotic is added to or withdrawn from therapy, and the methylxanthine dosage adjusted as necessary. For patients with theophylline levels at the upper end of the therapeutic range (15 to 20 mcg/mL), some clinicians suggest an initial reduction of the methylxanthine dosage by 25% when given with erythromycin and 50% with troleandomycin. Patients should be advised to contact their physician if they experience signs and symptoms of theophylline toxicity such as nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat.

References

  1. Branigan TA, Robbins RA, Cady WJ, et al. "The effects of erythromycin on the absorption and disposition kinetics of theophylline." Eur J Clin Pharmacol 21 (1981): 115-20
  2. Zarowitz BJ, Szefler SJ, Lasezkay GM "Effect of erythromycin base on theophylline kinetics." Clin Pharmacol Ther 29 (1981): 601-5
  3. Prince RA, Wing DS, Weinberger MM, et al. "Effect of erythromycin on theophylline kinetics." J Allergy Clin Immunol 68 (1981): 427-31
  4. May DC, Jarboe CH, Ellenburg DT, et al. "The effects of erythromycin on theophylline elimination in normal males." J Clin Pharmacol 22 (1982): 125-30
  5. Iliopoulou A, Aldhous ME, Johnston A, Turner P "Pharmacokinetic interaction between theophylline and erythromycin." Br J Clin Pharmacol 14 (1982): 495-9
  6. Paulsen O, Hoglund P, Nilsson LG, Bengtsson HI "The interaction of erythromycin with theophylline." Eur J Clin Pharmacol 32 (1987): 493-8
  7. Hildebrandt R, Moller H, Gundert-Remy U "Influence of theophylline on the renal clearance of erythromycin." Int J Clin Pharmacol Ther Toxicol 25 (1987): 601-4
  8. Renton KW, Gray JD, Hung OR "Depression of theophylline elimination by erythromycin." Clin Pharmacol Ther 30 (1981): 422-6
  9. Richer C, Mathieu M, Bah H, Thuillez C, Duroux P, Giudicelli JF "Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin." Clin Pharmacol Ther 31 (1982): 579-86
  10. Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part I)." Clin Pharmacokinet 20 (1991): 66-80
  11. Peters DH, Friedel HA, McTavish D "Azithromycin: a review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy." Drugs 44 (1992): 750-99
  12. Maddux MS, Leeds NH, Organek HW, Hasegawa GR, Bauman JL "The effect of erythromycin on theophylline pharmacokinetics at steady state." Chest 81 (1982): 563-5
  13. Descotes J, Andre P, Evreux JC "Pharmacokinetic drug interactions with macrolide antibiotics." J Antimicrob Chemother 15 (1985): 659-64
  14. Ludden TM "Pharmacokinetic interactions of the macrolide antibiotics." Clin Pharmacokinet 10 (1985): 63-79
  15. Reisz G, Pingleton SK, Melethil S, Ryan PB "The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis." Am Rev Respir Dis 127 (1983): 581-4
  16. Jonkman JH, Upton RA "Pharmacokinetic drug interactions with theophylline." Clin Pharmacokinet 9 (1984): 309-34
  17. Pfeifer HJ, Greenblatt DJ, Friedman P "Effects of three antibiotics on theophylline kinetics." Clin Pharmacol Ther 26 (1979): 36-40
  18. Wiggins J, Arbab O, Ayres JG, Skinner C "Elevated serum theophylline concentration following cessation of erythromycin treatment." Eur J Respir Dis 68 (1986): 298-300
  19. Rockwood RP, Embardo LS "Theophylline, ciprofloxacin, erythromycin: a potentially harmful regimen." Ann Pharmacother 27 (1993): 651-2
  20. Kozak PP, Cummins LH, Gillman SH "Administration of erythromycin to patients on theophylline." J Allergy Clin Immunol 60 (1977): 149-51
  21. Parish RA, Haulman NJ, Burns RM "Interaction of theophylline with erythromycin base in a patient with seizure activity." Pediatrics 72 (1983): 828-30
  22. Tenenbein M "Theophylline toxicity due to drug interaction." J Emerg Med 7 (1989): 249-51
  23. Bachmann K, Nunlee M, Martin M, et al. "Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin." J Clin Pharmacol 30 (1990): 1001-5
  24. Bachmann K, Jauregui L, Sides G, Sullivan TJ "Steady-state pharmacokinetics of theophylline in COPD patients treated with dirithromycin." J Clin Pharmacol 33 (1993): 861-5
  25. Amsden GW "Macrolides versus azalides: a drug interaction update." Ann Pharmacother 29 (1995): 906-17
  26. Amsden GW "Erythromycin, clarithromycin, and azithromycin: are the differences real?" Clin Ther 18 (1996): 56-72
  27. Gillum JG, Israel DS, Scott RB, Climo MW, Polk RE "Effect of combination therapy with ciprofloxacin and clarithromycin on theophylline pharmacokinetics in healthy volunteers." Antimicrob Agents Chemother 40 (1996): 1715-6
  28. Pollak PT, Slayter KL "Reduced serum theophylline concentrations after discontinuation of azithromycin: evidence for an unusual interaction." Pharmacotherapy 17 (1997): 827-9
  29. Nahata M "Drug interactions with azithromycin and the macrolides: an overview." J Antimicrob Chemother 37 Suppl C (1996): 133-42
  30. von Rosenstiel NA, Adam D "Macrolide antibacterials. Drug interactions of clinical significance." Drug Saf 13 (1995): 105-22
  31. Principi N, Esposito S "Comparative tolerability of erythromycin and newer macrolide antibacterials in paediatric: Patients." Drug Safety 20 (1999): 25-41
  32. Kamada AK, Hill MR, Brenner AM, Szefler SJ "Effect of low-dose troleandomycin on theophylline clearance: implications for therapeutic drug monitoring." Pharmacotherapy 12 (1992): 98-102
View all 32 references

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Minor

theophylline ePHEDrine

Applies to: Primatene Dual Action (ephedrine / guaifenesin / theophylline) and Primatene Dual Action (ephedrine / guaifenesin / theophylline)

Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

References

  1. Weinberger M, Bronsky E, Bensch GW, Bock GN, Yecies JJ "Interaction of ephedrine and theophylline." Clin Pharmacol Ther 17 (1975): 585-92
  2. Sims JA, doPico GA, Reed CE "Bronchodilating effect of oral theophylline-ephedrine combination." J Allergy Clin Immunol 62 (1978): 15-21
  3. Tinkelman DG, Avner SE "Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects." JAMA 237 (1977): 553-7
  4. Weinberger MM, Brousky EA "Evaluation of oral bronchodilator therapy in asthmatic children: bronchodilators in asthmatic children." J Pediatr 84 (1974): 421-7
  5. Badiei B, Faciane J, Sly M "Effect of throphylline, ephedrine and theri combination upon exercise-induced airway obstruction." Ann Allergy 35 (1975): 32-6
View all 5 references

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Drug and food interactions

Moderate

theophylline food

Applies to: Primatene Dual Action (ephedrine / guaifenesin / theophylline)

GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

ADJUST DOSING INTERVAL: Administration of theophylline with continuous enteral nutrition may reduce the serum levels or the rate of absorption of theophylline. The mechanism has not been reported. In one case, theophylline levels decreased by 53% in a patient receiving continuous nasogastric tube feedings and occurred with both theophylline tablet and liquid formulations, but not with intravenous aminophylline.

MANAGEMENT: When administered to patients receiving continuous enteral nutrition , some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 1 hour after the dose of theophylline is given; rapid-release formulations are preferable, and theophylline levels should be monitored.

References

  1. Jonkman JH, Sollie FA, Sauter R, Steinijans VW "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther 49 (1991): 248-55
  2. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol 44 (1993): 295-8
  3. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm 66 (2009): 1438-67

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Moderate

theophylline food

Applies to: Primatene Dual Action (ephedrine / guaifenesin / theophylline)

GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

References

  1. Jonkman JH, Sollie FA, Sauter R, Steinijans VW "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther 49 (1991): 248-55
  2. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol 44 (1993): 295-8

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Moderate

ePHEDrine food

Applies to: Primatene Dual Action (ephedrine / guaifenesin / theophylline)

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

References

  1. Rosenblatt JE, Lake CR, van Kammen DP, Ziegler MG, Bunney WE Jr "Interactions of amphetamine, pimozide, and lithium on plasma norepineophrine and dopamine-beta-hydroxylase in schizophrenic patients." Psychiatry Res 1 (1979): 45-52
  2. Cavanaugh JH, Griffith JD, Oates JA "Effect of amphetamine on the pressor response to tyramine: formation of p-hydroxynorephedrine from amphetamine in man." Clin Pharmacol Ther 11 (1970): 656
  3. "Product Information. Adderall (amphetamine-dextroamphetamine)." Shire Richwood Pharmaceutical Company Inc PROD (2001):
  4. "Product Information. Tenuate (diethylpropion)." Aventis Pharmaceuticals PROD (2001):
  5. "Product Information. Sanorex (mazindol)." Novartis Pharmaceuticals PROD (2001):
  6. "Product Information. Focalin (dexmethylphenidate)." Mikart Inc (2001):
  7. "Product Information. Strattera (atomoxetine)." Lilly, Eli and Company (2002):
View all 7 references

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

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