Antidotes and Alcohols: Has Fomepizole Made Ethanol an Obsolete Therapy?
University of Colorado Health Sciences Center
January 1998; 1(1): 2
There is presently an intense debate being carried on via ACMTNet regarding the subject of this editorial. I will attempt to summarize the issues germane to this evolving dialogue. In November of 1997, the Federal Food and Drug Administration (FDA) gave approval for the use of 4-methylpyrazole as an antidote for ethylene glycol (EG) poisoning. Now that this substance has the status of a pharmaceutical, it is appropriate to use it's generic name, fomepizole. The approval of fomepizole has stimulated a lively discussion of the comparative benefits of this agent with our only prior alternative, ethanol. I will attempt to review the pros and cons for both of these agents in the treatment of EG and methanol poisoning.
It has been known for nearly thirty years that both pyrazole and its 4-methyl derivative inhibited alcohol dehydrogenase (ADH) in both animals and humans. (1-3) However, fomepizole appeared to be the more promising agent because it lacked the hepatotoxicity of pyrazole (4-8) and was a more potent inhibitor of ADH. (1,9)
Twenty five years ago, it was shown that administration of fomepizole to man inhibits ethanol metabolism without significant adverse effects.(7) Fomepizole's potential as an antidote for toxic alcohol poisoning became quickly apparent, and in 1974 Mundy et al demonstrated that 4MP could protect against EG poisoning in animals. (10) Clay and Murphy subsequently showed that fomepizole can prevent metabolic acidosis and glycolate formation in EG poisoned dogs and monkeys. If fomepizole was given after the EG, once a metabolic acidosis was established, then treatment with this agent caused a resolution of the metabolic acidosis and a fall in glycolate levels. (11) Glycolic acid is the major circulating metabolite of ethylene glycol, and is responsible for the metabolic acidosis. (11,13) The antidotal effect of fomepizole in animal models of EG poisoning has been repeatedly demonstrated. (10, 11, 14-16)
Simultaneous with the development of fomepizole as an antidote in animal models of EG poisoning was the development of its use in methanol toxicity. In 1975, McMartin et al showed that the metabolic acidosis induced by methanol was due to format accumulation, a process which was prevented by the administration of fomepizole. Furthermore, methanol-induced metabolic acidosis tended to reverse after fomepizole administration. (17)
Simultaneously, Pietruszko (18) demonstrated in vitro that fomepizole inhibits methanol metabolism by human liver ADH with a micromolar Ki indicating that fomepizole is a potent inhibitor of methanol metabolism.
The first clinical use of fomepizole was in 1981 when Lindros et al used this agent to inhibit ethanol metabolism in the treatment of a disulfiram reaction. (19) Subsequently, volunteer studies showed that fomepizole was safe when administered to humans.(20-22) Thus the stage was set for clinical trials with this agent as a potential antidote.
Between 1986 and 1996, there were 5 case reports describing 9 cases of EG poisoning treated with fomepizole. (23-27) A tantalizing aspect of these reports is that three of the nine patients developed renal injury. All three of these patients had abnormal serum creatinines at the time fomepizole therapy was started. The remaining six patients had normal serum creatinines at the time of initiation of therapy. None of these six developed renal injury. This observation suggested that fomepizole may be nephroprotective in EG poisoning. In 1995, the Methylpyrazole for Toxic Alcohols (META) study group was constituted. The investigators making up the META Study Group are given in Table 1. Since November 1995, a total of 30 patients with EG or methanol poisoning have been enrolled in the META Study. This was a highly protocol driven study in which patients meeting precise inclusion criteria were enrolled using a specific dosing and dialysis protocol, schedule for obtaining samples for serum and urinary metabolites of EG and methanol, and samples for fomepizole pharmacokinetics.
Table 1: META Study Group
| Cynthia Aaron
|| Daniel Douglas
|| Ken Kulig
| Jawaid Achtar
|| Marsha Ford
|| Charles McKay
| Randall Berlin
|| Candace Graudins
|| Ken McMartin
| Gregory Bogdan
|| Christine Hantsch
|| Scott Phillips
| Jeffrey Brent
|| Selia Hartigan
|| Donna Seger
| Keith K. Burkhart
|| Keenan Heard
|| Christian Tomaszewski
| Michael Burns
|| Judd Hollander
|| Kevin Wallace
| Steven Curry
|| William Kerns
|| Paul Wax
| Richard Dart
|| Mark Kirk
|| Suzanne White
| Ward Donovan
|| Lada Kokan
In the summer of 1997, Orphan Medical, Inc. submitted a new drug application for fomepizole to the Food and Drug Administration. This application's clinical component consisted primarily of the data from the META study, supplemented by a compilation of cases treated by Dr. Frederick Baud in Paris. In December, approval was granted.
Ethanol has been used as an antidote for EG and methanol poisoning since 1946. (28) Thus we have a long history of experience with this agent. Those of us who have used it frequently have developed a facility with this tricky antidote. Ethanol's major advantages are that it is inexpensive and, in the absence of a pharmaceutically prepared preparation,can even be administered orally in selected patients. The latter can be done with commercial alcoholic beverages. A comparison of the advantages and disadvantages of ethanol as an antidote is given in Table 2.
Table 2: Ethanol Treatment of Ethylene
Glycol or Methanol Poisoning -
Pros and Cons
- Long history of use
- Available in many forms, including oral spirits
- Non-FDA approved
- Parenteral forms often not available
- Requires frequent checks of levels
- Unpredictable kinetics
- Requires infusion pump
- Oral treatment unreliable
- Causes intoxication
- Causes depressed mental status
- Often unpleasant for patient
- Requires an intensive care unit.
- Degree to which it inhibits metabolism has not been
- May cause hepatotoxicity
- Errors in its use common
- General reluctance to use presumptively in metabolic
acidosis of unknown etiology
- May cause hypoglycemia
Ethanol is not approved as an antidote for EG or methanol poisoning. Although
commercial 10% ethanol solutions are manufactured, they are frequently not available. Thus
hospitals must often resort to a 5% solution, or to compounding from absolute ethanol.
Using the more dilute solution requires large volumes to be administered, which is
potentially a serious problem for both pediatric patients and those with cardiac or renal
insufficiency. Compounding an ethanol solution de novo can cause delays in treatment. As
all of us who have experience with this antidote know, ethanol is difficult to use. Most
of the information regarding the difficulty of the use of ethanol derives from case
reports, other kinds of anecdotes, and personal experience. Although there is an
accumulated tribal wisdom of clinical toxicologists that ethanol is difficult to use, this
has never been systemically demonstrated.
In order to use ethanol effectively, one has to be cognizant of its unpredictable
kinetics, and therefore frequent levels must be obtained. I personally obtain these levels
every one to two hours unless I am sure that these have been stable for a long period of
time. The latter, however, is an unusual circumstance. Because any unplanned alterations
in the infusion rate can have major consequences by virtue of either causing ethanol
levels to become subtherapeutic or causing them to rise to unwanted high concentrations,
it is necessary to closely watch the infusion and have it administered through an infusion
pump. Patients who are maintained on an ethanol infusion may develop alterations in mental
status, initially being intoxicated, subsequent to which their mental status may
deteriorate, thus increasing the risk of aspiration. Patients treated with ethanol must be
in an intensive care unit and may require intubation. Although we know that ethanol has
the ability to competitively inhibit the metabolism of EG and methanol, the degree to
which it inhibits the formation of metabolites in poisoned patients has not been well
studied. The therapeutic efficacy of ethanol remains unvalidated. Patients who are treated
with ethanol are at risk for developing hypo-glycemia, a problem which is particularly
prevalent in both pediatric and malnourished populations. Because ethanol treatment may
last for several days, patients need to be monitored for the development of elevated liver
enzymes. Given the challenges associated with the therapeutic use of ethanol, there are
legitimate questions regarding its reliability in the hands of those less experienced in
it's use than amedical toxicologist.
In the META trial, patients were allowed to be entered into the trial if they were
transferred from another hospital after being loaded with ethanol. It was our experience
that most of these patients were inappropriately treated with ethanol, resulting in
subtherapeutic levels. The majority of patients diagnosed with EG or methanol poisoning
have metabolic acidosis as their initial presentation. Frequently there is a time delay
between the time that these diagnoses are considered and the time that they are verified
by a serum level. In the interim, presumptive therapeutic maneuvers could be taken.
However, because of the problems related to the use of ethanol, patients are frequently
not treated in a presumptive manner. Therapy may thus be delayed until as a definitive
diagnosis is made. Because of the difficulties in obtaining EG and methanol levels, this
delay can be substantial. Lastly, although one can use oral loading of ethanol emergently,
this route of administration is associated with unpredictable concentrations initially,
and even greater difficulty in maintaining target levels.
Fomepizole is an alternative to ethanol therapy without the disadvantages of the
latter. Although approved for the treatment of EG poisoning, like ethanol it is not FDA
approved for the treatment of methanol intoxication. It is anticipated that an application
for this indication will be filed shortly, largely based on the methanol arm of the META
trial. The cost of fomepizole makes it considerably more expensive to purchase than
ethanol. As reviewed above, there is a long history of clinical experience with ethanol
that we do not yet have with fomepizole, although the latter has been more systematically
studied in intoxicated patients. A comparison of the pros and cons associated with
fomepizole therapy is given in Table 3.
Table 3: Fomepizole Treatment of Ethylene
Glycol or Methanol Poisoning - Pros and Cons
- FDA approved for ethylene glycol poisoning
- Reliable pharmacokinetics
- No need to check levels
- No need to use infusion pump
- Dosing regimen standardized and validated
- Documented inhibition of toxic metabolite production in patients
- Documented nephroprotection in ethylene glycol poisoned patients
- Documented visual protection in methanol treated patients
- No effect on mental status
- Do not need intensive care unit treatment in uncomplicated patients
- Does not cause hypoglycemia
- Few adverse effects
- Better studied in poisoned patients than ethanol
- Not FDA approved for methanol poisoning
- Less clinical experience than with ethanol
Fomepizole is presently the only FDA approved antidote for the treatment of EG
poisoning. Unlike ethanol, fomepizole has been demonstrated to have very reliable
pharmacokinetics. (22, 29) Patients treated with the dosing regimen that was used in the
META study were shown to reliably have plasma fomepizole levels above the presumed 10
micromolar target. This concentration was chosen based on animal studies.(17, 30) Most
patients had plasma levels considerably above that target. However, there was some
variation in the levels attained, perhaps indicating a metabolic polymorphism, which
caused some patients to have levels relatively close to the 10 micromolar target. Lower
doses are therefore not recommended. Because of the reliable attainment of therapeutic
plasma levels in the META trial, it is unnecessary to measure fomepizole levels during
therapy, or adjust the dosage in ways other than the standard dosing protocol. The
therapeutic efficacy of the dosing protocol has been validated by both the
nephroprotective effect and the inhibition of metabolite formation. Because the drug is
administered by an intermittent bolus regimen, there is no need to use an infusion pump
and the difficulties in attaining a therapeutic levels seen with ethanol should not occur,
even in inexperienced hands.
Unlike ethanol, the inhibition of the formation of metabolites of ethylene glycol or
methanol in poisoned patients treated with fomepizole has been demonstrated. (31, 32)
Similarly, there are no adverse effects on the mental status of patients treated with
fomepizole. Thus, patients treated with this fomepizole may be placed in non intensive
care settings unless other aspects of their poisonings require a higher level of
Hypoglycemia is not seen with fomepizole therapy and adverse effects of any kind appear
to be both rare and minor. In patients who have EG poisoning, treatment with fomepizole
has been shown to inhibit metabolite formation and protect against renal injury. (31) In
patients with methanol poisoning, treatment with fomepizole has been shown to inhibit
formic acid production and protect against visual injury.(32, 33) Similar validation with
ethanol does not exist. As described above, many patients with methanol or EG poisoning
present with metabolic acidosis. Because of the benign nature of treatment with
fomepizole, there should be little concern about potential adverse effects
associated with its early use in patients whose metabolic acidosis is still under
investigation. Because of the lack of requirement for frequent checking of ethanol levels,
probable decreased morbidity, and the possibility of treatment outside of intensive care
unit settings, it is likely that some of the additional cost associated with the use of
fomepizole will be offset. It is even conceivable that patients with low levels of EG or
methanol poisoning, for example levels in the 20-30mg/dL range, in the absence of
metabolic acidosis, could be treated as outpatients.
Dr. Brent has received research support from Orphan Medical, Inc. for the META study.
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January 1998; 1(1): 2
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