RT Book, Section
A1 Kearney, Thomas E.
A2 Olson, Kent R.
A2 Anderson, Ilene B.
A2 Benowitz, Neal L.
A2 Blanc, Paul D.
A2 Clark, Richard F.
A2 Kearney, Thomas E.
A2 Kim-Katz, Susan Y.
A2 Wu, Alan H. B.
SR Print(0)
ID 1174607441
T1 FOMEPIZOLE (4-METHYLPYRAZOLE, 4-MP)
T2 Poisoning & Drug Overdose, 7e
YR 2018
FD 2018
PB McGraw-Hill Education
PP New York, NY
SN 9780071839792
LK accessmedicine.mhmedical.com/content.aspx?aid=1174607441
RD 2024/04/16
AB PharmacologyFomepizole  (4-methylpyrazole)  is  a  potent  competitive  inhibitor  of  alcohol  dehydrogenase,  the  first  enzyme  in  the  metabolism  of  ethanol  and  other  alcohols.  Fomepizole  can  prevent  the  formation  of  toxic  metabolites  after  methanol  or  ethylene  glycol  ingestion.  Furthermore,  early  treatment  with  fomepizole  for  ethylene  glycol  or  methanol  poisoning  (before  the  appearance  of  a  significant  acidosis)  may  obviate  the  need  for  dialysis.  Since  the  introduction  of  fomepizole,  most  patients  with  ethylene  glycol  or  methanol  poisoning  probably  will  be  treated  with  this  drug  instead  of  ethanol,  particularly  in  cases  involving  small  children,  patients  taking  disulfiram,  patients  with  altered  consciousness  and  ingestion  of  multiple  substances,  patients  with  pancreatitis  or  active  liver  disease,  and  hospitals  lacking  laboratory  support  to  perform  rapid  ethanol  levels  (for  monitoring  treatment).  Economic  models  have  suggested  that  fomepizole  may  be  more  cost-effective  than  ethanol  despite  the  high  acquisition  cost  of  fomepizole.Fomepizole  is  eliminated  mainly  via  zero-order  kinetics,  but  cytochrome  P-450  metabolism  can  undergo  autoinduction  within  2–3  days.  The  drug  is  dialyzable.  It  is  well  absorbed  and  has  been  used  successfully  with  PO  administration  but  is  not  approved  for  this  route  in  the  United  States.Indications  are  suspected  or  confirmed  methanol  (methyl  alcohol)  or  ethylene  glycol  poisoning  with  one  or  more  of  the  following:A  reliable  history  of  ingestion  of  a  toxic  dose  but  no  available  blood  concentration  measurements  (when  used  empirically,  allows  a  12-hour  "window"  after  one  dose  to  assess  the  patient);Metabolic  acidosis  and  an  unexplained  elevated  osmol  gap;  orSerum  methanol  or  ethylene  glycol  concentration  of  20  mg/dL  or  higher.Other  substances  that  are  metabolized  by  alcohol  dehydrogenase  to  toxic  metabolites  include  propylene  glycol,  diethylene  glycol,  triethylene  glycol,  glycol  ethers  (eg,  ethylene  glycol  ethyl  ether,  ethylene  glycol  butyl  ether),  and  1,4-butanediol.  The  criteria  for  fomepizole  therapy  and  evidence  for  improved  outcomes  are  lacking  for  all  these  substances.  However,  case  reports  of  poisonings  from  some  of  these  other  glycols  (eg,  propylene  glycol,  diethylene  glycol)  have  suggested  benefit  when  fomepizole  therapy  is  coupled  with  dialysis  to  remove  the  potentially  toxic  parent  compound  and  concomitantly  prevent  the  formation  of  toxic  metabolites.Disulfiram  reaction  (or  risk  for):  to  halt  progression  or  the  production  of  acetaldehyde,  assuming  that  ethanol  is  still  present  (based  on  case  reports).Contraindications.  History  of  allergy  to  the  drug  or  to  other  pyrazoles.Adverse  effectsVenous  irritation  and  phlebosclerosis  after  intravenous  injection  of  the  undiluted  product.Headache,  nausea,  and  dizziness  are  the  most  commonly  reported  side  effects.  Less  common  effects  are  vomiting,  tachycardia,  hypotension,  feeling  of  inebriation,  rash,  fever,  and  eosinophilia.Transient  non-dose-dependent  elevation  of  hepatic  transaminases  has  been  reported  after  multiple  doses.Although  safety  and  effectiveness  in  children  have  not  been  established  by  the  manufacturer,  fomepizole  has  been  used  successfully  and  reported  for  pediatric  poisonings  (in  children  as  young  as  8  months).Use  in  pregnancy.  FDA  Category  C  (indeterminate).  Has  been  used  in  pregnant  patients  without  immediate  adverse  effects  on  the  mother  or  the  fetus  (Introduction).Drug  or  laboratory  interactionsDrugs  or  chemicals  metabolized  by  alcohol  dehydrogenase  (eg,  chloral  hydrate,  ethanol,  isopropyl  alcohol)  will  also  have  impaired  elimination.  Fomepizole  inhibits  the  metabolism  of  ethanol,  and  vice  versa.Drugs  or  chemicals  metabolized  by  cytochrome  P-450  enzymes  may  compete  with  ...