Hydrocodone Bitartrate and Acetaminophen Drug Interactions

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Contents

Level Three: increased effect/toxicity

Acetaminophen: Caution because many combinations contain acetaminophen making it easy to overdose on acetaminophen.[1] The maximum daily dose is 4 grams per day.

Ethanol: Increases the risk of hepatic toxicity. This is especially true in patients who are regular users of alcohol. The toxicity to the liver can occur at doses of acetaminophen that are within the normal limits. The mechanism is via the induction of CYP2E1 which leads to an increased amount of the toxic metabolite of acetaminophen. Additionally, chronic use of alcohol can decrease the stores of glutathione.[2] [3]

Imatinib- Imatinub has a theoretical association of affecting the metabolism of acetaminophen leading to hepatotoxicity. One fatality was reported in a patient taking high doses of acetamiophen in conjunction with imatinuib for acute phase chronic myeloid leukemia. In vitro studies have noted interference with glucuronidation inhibition, thus affecting the detoxification of acetaminophen. Studies in humans have not been performed and no other cases have been published. [4][5]

Isoniazid- Isoniazid is a hepatic inducer of CYP2E1. This induction increases the risk of acetaminophen hepatotoxicity via increased production of acetaminophen’s toxic metabolite.[6] Whether the patient is a slow or fast acetylator plays a role in the deciding if they will suffer liver injury with this combination. In a study of 10 subjects who were slow acetylators, they received 7 days of isoniazid, and acetaminophen at some point during their treatment with isoniazid. It was found that isoniazid inhibited the formation clearance of hepatotoxin N-acetyl-p-benzoquinone imine and catechol oxidative metabolites of acetaminophen. Two days after stopping isoniazid, excretion of acetaminophen thioether, a marker for the hepatoxin, increased 56%.[7] A second study of healthy volunteers found that isoniazid inhibited the formation clearance of glutathione and catechol metabolites by 69.7% and 2.2%, respectively.[8]

Busulfan: When acetaminophen is used for 72 hours or less with busulfan, the clearance of busulfan decreases. The mechanism occurs because acetaminophen decreases glutathione levels. When Busulfan is given in high doses before acetaminophen is given, it decreases the levels of glutathione resulting in an increased likelihood of hepatotoxicity. [9]

Central Nervous System (CNS) Depressants: Narcotic analgesics such as buprenorphine, butorphanol, nalbuphine, or pentazocine may cause additive CNS depressive effects, such as drowsiness, respiratory depression, and hypotension. Antipsychotics, antianxiety, MAO inhibitors and tricyclic antidepressant agents can potentiate the effect of either agent and may necessitate a dose reduction in one or both agents.[9]

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Level Two: increased toxicity:

Diflunisal- When diflunisal is given with acetaminophen, there is an increased risk of hepatotoxicity because diflunisal increases the concentrations of acetaminophen.[10]

Lamotrigine- acetaminophen and lamotrigine are hepatotoxic, additive effects may be expected with co-administration. Additionally, the AUC of lamotrigine was decreased by 20% when coadministered with acetaminophen. The significance of this is unknown.[11]

Rifampin and rifabutin- rifampin and rifabutin both induce the cytochrome system leading to increased liver toxicity and decreased analgesic effects of acetaminophen. Rifampin increases the concentration of acetaminophen glucuronide and acetaminophen sulfate. (11-13)[12][13][14]

Salicylates- if acetaminophen is used for a long duration with salicylates, there is an increased risk of analgesic nephropathy, renal papillary necrosis, and ESRD. [15]

Tobacco- smoking induces CYP1A2, thus increasing the possibility of development of hepatotoxicity from acetaminophen.[16]

Warfarin- use with acetaminophen may increase the INR. This is especially a problem in higher doses and for long periods of use. The mechanism appears to be an interaction with the vitamin K-dependent clotting factors II, VII, IX, and X. [17]

Anticholinergics and antidiarrheal Agents: Concurrent use may lead to constipation, paralytic ileus, or additive depressant effects.[9][18]

Inhibitors of CYP2D6: Hydrocodone is metabolized by CYP2D6. Agents that inhibit CYP2D6 may result in an increase in the AUC of hydrocodone necessitating a dosage reduction to prevent toxicity. Examples of CYP2D6 inhibitors which may affect the serum levels of hydrocodone include: amiodarone, fluoxetine, paroxetine, thioridazine, quinidine, bupropion, chloroquine, haloperidol, fluoxetine, delavirdine, imatinib, ritonavir, terbinafine, propafenone, quinacrine, quinine.[9][19]


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Level Two: decreased effect:

Cholestyramine- Decreases the absorption of acetaminophen and its conjugates in the intestine. [20] To decrease the chance of drug interactions do not give acetaminophen for 1 hour before or 4-6 hours after cholestyramine.[21]

Lamotrigine- Acetaminophen and lamotrigine are hepatotoxic, additive effects may be expected with co-administration. Additionally, the AUC of lamotrigine was decreased by 20% when coadministered with acetaminophen. The significance of this is unknown.[22]

Rifampin and rifabutin- Rifampin and rifabutin both induce the cytochrome system leading to increased liver toxicity and decreased analgesic effects of acetaminophen. Rifampin increases the concentration of acetaminophen glucuronide and acetaminophen sulfate.[18][23][24]

Inducers of CYP450 isoenzymes: such as the barbiturates, phenobarbital and primidone may lead to an altered clinical response when administered concomitantly with hydrocodone/acetaminophen. The analgesic effect may be decreased requiring an increased dose of hydrocodone/acetaminophen to achieve the desired effect. Additionally there may be an increased risk of acetaminophen toxicity.[9]


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Level One: increased effect:

Carbamazepine, Oxcarbazepine, barbiturates and phenytoin or Fosphenytoin-increase the risk of hepatotoxicity because these drugs induce CYP2E1 and CYP1A2.[16]

St. John's wort- increased risk of hepatotoxicity because St. John’s wort induces CYP1A2 causing more NAPQI, the toxic metabolite of acetaminophen, to be formed.[25]


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References

  1. ↑ Jones A. Over-the-counter analgesics: a toxicology perspective. American journal of therapeutics. 2002 May-Jun;9(3):245-57.
  2. ↑ Yang F, Beard DA. Thermodynamically based profiling of drug metabolism and drug-drug metabolic interactions: a case study of acetaminophen and ethanol toxic interaction. Biophysical chemistry. 2006 Mar 20;120(2):121-34.
  3. ↑ Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991 Oct;20(10):1058-63.
  4. ↑ Systemic Therapy Update. BC Cancer Agency 2006;9(5). [cited 14 March 2007].Available from: http://www.bccancer.bc.ca/NR/rdonlyres/4478D9DB-662B-43C2-8839-6D3C374D3FAE/19815/UpdateMay2006final_28Apr06.pdf
  5. ↑ Imatinib mesylate. Am J Health Syst Pharm 2001;58(23):2241-2.
  6. ↑ Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis.Chest.1994 Feb;105(2):408-11.
  7. ↑ Zand R, Nelson SD, Slattery JT, Thummel KE, Kalhorn TF, Adams SP, et al. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clinical pharmacology and therapeutics. 1993 Aug;54(2):142-9.
  8. ↑ Epstein MM, Nelson SD, Slattery JT, Kalhorn TF, Wall RA, Wright JM. Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin Pharmacol. 1991 Feb;31(2):139-42.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Wishart DS et al., DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 1;34
  10. ↑ Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacology & therapeutics. 2005 Apr;106(1):97-132.
  11. ↑ Depot M, Powell JR, Messenheimer JA, Jr., Cloutier G, Dalton MJ. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clinical pharmacology and therapeutics. 1990 Oct;48(4):346-55.
  12. ↑ Stephenson I, Qualie M, Wiselka MJ. Hepatic failure and encephalopathy attributed to an interaction between acetaminophen and rifampicin. The American journal of gastroenterology. 2001 Apr;96(4):1310-1.
  13. ↑ Huang R, Okuno H, Takasu M, Takeda S, Kano H, Shiozaki Y, et al. Effects of rifampin on the glutathione depletion and cytochrome c reduction by acetaminophen reactive metabolites in an in vitro P450 enzyme system. Japanese journal of pharmacology. 2000 Jul;83(3):182-90.
  14. ↑ Dimova S, Stoytchev T. Influence of rifampicin on the toxicity and the analgesic effect of acetaminophen. European journal of drug metabolism and pharmacokinetics. 1994 Oct-Dec;19(4):311-7.
  15. ↑ Dipiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L, editors. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York; 2002.
  16. ↑ 16.0 16.1 Burton M, Shaw L, Schentag J, Evans W, editors. Applied Pharmacokinetics and Pharmacodynamics: Principles of therapeutic drug monitoring. 4th ed. Baltimore: Lippincott Williams and Wilkins; 2006.
  17. ↑ Mahe I, Bertrand N, Drouet L, Bal Dit Sollier C, Simoneau G, Mazoyer E, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica. 2006 Dec;91(12):1621-7.
  18. ↑ 18.0 18.1 Stephenson I, Qualie M, Wiselka MJ. Hepatic failure and encephalopathy attributed to an interaction between acetaminophen and rifampicin. The American journal of gastroenterology. 2001 Apr;96(4):1310-1.
  19. ↑ Hydrocodone and acetaminophen. 24 June 2000 cited 15 March 2007; Available from: http://www.fda.gov/cder/ogd/rld/16647s36.PDF
  20. ↑ Siegers CP, Moller-Hartmann W. Cholestyramine as an antidote against paracetamol-induced hepato- and nephrotoxicity in the rat. Toxicology letters. 1989 May;47(2):179-84.
  21. ↑ Par Pharmaceutical Inc. Questran® and Questran® Light (cholestyramine) package insert. Spring Valley, NY; 2002.
  22. ↑ Depot M, Powell JR, Messenheimer JA, Jr., Cloutier G, Dalton MJ. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clinical pharmacology and therapeutics. 1990 Oct;48(4):346-55.
  23. ↑ Huang R, Okuno H, Takasu M, Takeda S, Kano H, Shiozaki Y, et al. Effects of rifampin on the glutathione depletion and cytochrome c reduction by acetaminophen reactive metabolites in an in vitro P450 enzyme system. Japanese journal of pharmacology. 2000 Jul;83(3):182-90.
  24. ↑ Dimova S, Stoytchev T. Influence of rifampicin on the toxicity and the analgesic effect of acetaminophen. European journal of drug metabolism and pharmacokinetics. 1994 Oct-Dec;19(4):311-7.
  25. ↑ Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic & clinical pharmacology & toxicology. 2007 Jan;100(1):23-30.

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