Acute Porphyria Drugs

Acute Porphyria Drug Database

N06AB08 - Fluvoxamine
Propably not porphyrinogenic
PNP
Important Information
Risk for gastrointestinal adverse events in the form of abdominal pain, obstipation, diarrhoea, nausea and vomiting motivates vigilance against insufficient intake of food, especially of carbohydrate.
Side effects
Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are abdominal pain, constipation, diarrhoea, nausea and vomiting. Other common side effects are anorexia, insomnia, somnolence, tremor, headache and tachycardia.
Rationale
Fluvoxamine is a strong inhibitor of CYP1A2 and a moderate/weak inhibitor of CYP2C9 and CYP3A4. In vitro data indicates that it is a reversible inhibitor of CYP3A4, CYP2C9 and CYP1A2.
Therapeutic characteristics
Fluvoxamine is a selective serotonin reuptake inhibitor and an antidepressant. It is indicated for the treatment of depression and obsessive compulsive disorders.
Metabolism and pharmakokinetics
CYP2D6 and CYP1A2 is the main enzyme metabolising fluvoxamine in vitro (SPC and Spina 2008). Elimination half-life is 17-22 hours. Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19 and a moderate/weak inhibitor of CYP2C8, CYP2C9 and CYP3A4 (FDA, Isoherranen 2009, Pelkonen 2008, SPC and Spina 2008). It is listed as a competitive inhibitor of CYP2B6, CYP2C9, CYP2C19 and CYP2D6 in vitro (Pelkonen 2008). Fluvoxamine is listed as a mechanism-based inhibitor of CYP3A4 in vitro (Zhou 2009). However, IC50 and IC50-shift experiments indicate that fluvoxamine is a reversible inhibitor of CYP3A4 and CYP2C9 (Berry 2008). It is also listed as a reversible inhibitor of CYP1A2 in vitro (Polasek 2008).
Published experience
Fluvoxamine is listed as safe for use in acute porphyria (Moore 1997).
IPNet drug reports
Uneventful use reported in 2 patients with acute porphyria.

References

  1. Scientific articles
  2. Spina E, Santoro V, D´Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008 Jul;30(7):1206-27. PMID 18691982. #4695
  3. Berry LM, Zhao Z. An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes. Drug Metab Lett. 2008 Jan;2(1):51-9. PMID 19356071. #1684
  4. Hisaka A, Ohno Y, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther. 2010 Feb;125(2):230-48. #1138
  5. Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
  6. Jones DR, Ekins S, Li L, Hall SD. Computational approaches that predict metabolic intermediate complex formation with CYP3A4 (+b5). Drug Metab Dispos. 2007 Sep;35(9):1466-75. PMID 17537872. #4694
  7. Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
  8. Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
  9. Polasek TM, Miners JO. Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants. Br J Clin Pharmacol. 2008 Jan;65(1):87-97. PMID 17662092. #2709
  10. Zhou ZW, Zhou SF. Application of mechanism-based CYP inhibition for predicting drug-drug interactions. Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):579-605. PMID 19466877. #1451
  11. Government bodies
  12. U.S Food and Drug Administration (FDA). #1450
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