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Drug Interactions between amitriptyline and amprenavir

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

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Interactions between your drugs

Moderate

amitriptyline amprenavir

Applies to: amitriptyline and amprenavir

MONITOR: Product labeling for certain protease inhibitors (PIs) such as amprenavir and atazanavir states that serious and/or life-threatening drug interactions may occur with tricyclic antidepressants (TCAs), presumably due to PI inhibition of TCA metabolism via CYP450 3A4. High plasma levels of TCAs could conceivably lead to serious adverse reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. However, the clinical significance of such an interaction is unknown, as it has not been studied and there are no case reports of it published in the medical literature. Moreover, many TCAs are thought to be substrates of multiple CYP450 isoenzymes, thus the effects of CYP450 3A4 inhibition alone are unknown. Some TCAs such as desipramine, doxepin, and nortriptyline are also thought to be primarily metabolized by CYP450 2D6, which is not known to be inhibited by most PIs (except ritonavir) to any significant extent.

MANAGEMENT: Until further information is available, caution is advised if protease inhibitors must be used with certain TCAs. Pharmacologic response and plasma TCA levels should be monitored more closely whenever a PI is added to or withdrawn from therapy, and the TCA dosage adjusted as necessary.

References

  1. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Duan SX, Harmatz JS, Shader RI "Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo." J Pharmacol Exp Ther 268 (1994): 1278-83
  2. Vonmoltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI "Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants." J Clin Psychopharmacol 15 (1995): 125-31
  3. Nielsen KK, Flinois JP, Beaune P, Brosen K "The biotransformation of clomipramine in vitro, identification of the cytochrome p450s responsible for the separate metabolic pathways." J Pharmacol Exp Ther 277 (1996): 1659-64
  4. Ghahramani P, Ellis SW, Lennard MS, Ramsay LE, Tucker GT "Cytochromes p450 mediating the n-demethylation of amitriptyline." Br J Clin Pharmacol 43 (1997): 137-44
  5. "Product Information. Agenerase (amprenavir)." Glaxo Wellcome PROD (2001):
  6. Venkatakrishnan K, Schmider J, Harmatz JS, et al. "Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies." J Clin Pharmacol 41 (2001): 1043-54
  7. Shimoda K, Someya T, Yokono A, et al. "The Impact of CYP2C19 and CYP2D6 Genotypes on Metabolism of Amitriptyline in Japanese Psychiatric Patients." J Clin Psychopharmacol 22 (2002): 371-378
  8. Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, Gelbon HV "Eight inhibitory monoclonal antibodies define the role of individual P-450S in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism." Drug Metab Dispos 27 (1999): 102-9
  9. Tacke U, Leinonen E, Lillsunde P, et al. "Debrisoquine hydroxylation phenotypes of patients with high versus low to normal serum antidepressant concentrations." J Clin Psychopharmacol 12 (1992): 262-7
  10. Eap CB, Bender S, Gastpar M, et al. "Steady state plasma levels of the enantiomers of trimipramine and its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients." Ther Drug Monit 22 (2000): 209-14
  11. "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb (2003):
  12. Kirchheiner J, Muller G, Meineke I, Wernecke KD, Roots I, Brockmoller J "Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics." J Clin Psychopharmacol 23 (2003): 459-66
  13. "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline (2003):
  14. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C "The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19." Pharm Res 19 (2002): 1034-7
  15. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J "Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers." Pharmacogenetics 12 (2002): 571-80
  16. Haritos VS, Ghabrial H, Ahokas JT, Ching MS "Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin." Pharmacogenetics 10 (2000): 591-603
  17. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI "Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4." J Clin Pharmacol 38 (1998): 112-21
View all 17 references

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Drug and food interactions

Moderate

amprenavir food

Applies to: amprenavir

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.

References

  1. "Product Information. Agenerase (amprenavir)." Glaxo Wellcome PROD (2001):
  2. Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM "Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice." Antimicrob Agents Chemother 46 (2002): 1589-1590

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Moderate

amitriptyline food

Applies to: amitriptyline

GENERALLY AVOID: Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills. Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

MANAGEMENT: Patients should be advised to avoid alcohol during TCA therapy. Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy. Dosage adjustments may be required.

References

  1. Dorian P, Sellers EM, Reed KL, et al. "Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction." Eur J Clin Pharmacol 25 (1983): 325-31
  2. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7
  3. Sandoz M, Vandel S, Vandel B, Bonin B, Allers G, Volmat R "Biotransformation of amitriptyline in alcoholic depressive patients." Eur J Clin Pharmacol 24 (1983): 615-21
  4. Ciraulo DA, Barnhill JG, Jaffe JH "Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers." Clin Pharmacol Ther 43 (1988): 509-18
  5. Seppala T, Linnoila M, Elonen E, Mattila MJ, Makl M "Effect of tricyclic antidepressants and alcohol on psychomotor skills related to driving." Clin Pharmacol Ther 17 (1975): 515-22
  6. Ciraulo DA, Barnhill JG, Jaffe JH, Ciraulo AM, Tarmey MF "Intravenous pharmacokinetics of 2-hydroxyimipramine in alcoholics and normal controls." J Stud Alcohol 51 (1990): 366-72
  7. Ciraulo DA, Alderson LM, Chapron DJ, Jaffe JH, Subbarao B, Kramer PA "Imipramine disposition in alcoholics." J Clin Psychopharmacol 2 (1982): 2-7
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.

Further information

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

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