Summary of
FDA Information:Approval Date: November 25, 1996
Freedom of
Information Summary
NADA 141-075
I. GENERAL INFORMATION:
NADA 141-075
Sponsor: Orphan Medical, Inc.
13911 Ridgedale Drive, Suite 475
Minnetonka, MN 55305
Generic Name: Fomepizole
Trade Name: Antizol-Vet™ (fomepizole) for
injection
Marketing Status: Rx (prescription)
II. INDICATIONS FOR USE
Antizol-Vet™ is indicated as an antidote for
ethylene glycol (antifreeze) poisoning in dogs who have ingested or
are suspected of
having ingested ethylene glycol.
III. DOSAGE
A. DOSAGE FORM Antizol-Vet™ (1.5 mL) is formulated as a sterile injectable liquid for
dilution with a 30 mL vial of
0.9% sodium chloride injection, USP. Both drugs are packaged together in an antidote kit.
B. ROUTE OF ADMINISTRATION Antizol-Vet™ is administered intravenously as soon as practical upon suspicion of
ethylene glycol poisoning.
C. RECOMMENDED DOSAGES: The recommended intravenous dosing schedule of
a 5% solution (50 mg/mL) of
Antizol-Vet™ for
treatment of
ethylene glycol poisoning in dogs is described below.
The drug will be administered following dilution in 0.9% sodium chloride injection, USP.
Initial dose: 20 mg/kg IV
Dose 2 (12 hours after initial dose): 15 mg/kg IV
Dose 3 (24 hours after initial dose): 15 mg/kg IV
Dose 4 (36 hours after initial dose): 5 mg/kg IV
If the animal has not recovered following this regimen and
there is a suspicion or
documentation of
remaining ethylene glycol in the
bloodstream of
the affected animal, the
practitioner should continue to dose the animal with 5 mg/kg every 12 hours until the ethylene glycol does not remain in the
bloodstream or
the animal has visibly recovered.
IV. EFFECTIVENESS
The currently recommended Antizol-Vet™ dosing regimen used to treat
dogs poisoned with ethylene glycol has been published in all editions of
Kirk's, Current Veterinary Therapy: Small Animal Practice since 1986 (ninth edition) and
is widely used in clinical practice.
A . Dose Confirmation
Antizol-Vet™ has been shown to be efficacious in treating ethylene glycol poisoning in two experimental laboratory studies and
in one clinical field trial.
The results of
these studies are summarized below.
1. Grauer GF, Thrall MA, Henre BA, Hjelle JJ., Comparison of
the effects of
ethanol and
4-methylpyrazole on the pharmacokinetics and
toxicity of
ethylene glycol in the
dog. Toxicology Letters 1987; 35:307-14.
Grauer, et al. (1987) studied the comparative efficacy of
ethanol and
fomepizole in the
treatment of
ethylene glycol toxicity in the
dog. Nine healthy, mixed-breed dogs of
both sexes, with an average weight of
21.8 kg, were
randomly assigned to one of
three groups (3 dogs/group); ethylene glycol alone (Group 1), ethylene glycol plus ethanol (Group 2), or
ethylene glycol plus fomepizole (Group 3). Each animal was
given an ethylene glycol dose of
10.6 g/kg (twice the lethal ethylene glycol dose) mixed with wet dog food. Group 1 animals received no antidotal therapy. Dogs in Group 2 were
treated with 1584 mg/kg ethanol (20% in water) IV at 3, 7, 14, and
24 hours after ingestion of
ethylene glycol. Dogs in Group 3 were
treated with fomepizole IV at doses of
20, 15, and
5 mg/kg at 3, 24, and
36 hours after ingestion of
ethylene glycol, respectively.
All of
the dogs exhibited progressive central nervous system depression, ataxia, and
polydipsia within 3 hours of
ethylene glycol ingestion.
The three dogs in Group 1 became progressively depressed, and
then moribund.
They were
euthanized at 12, 80 and
120 hours, respectively, after ethylene glycol ingestion. At necropsy, histopathology results revealed renal proximal tubular degeneration and
necrosis with intraluminal calcium oxalate crystal deposition in the
renal tissue of
all Group 1 animals. Tubular necrosis was
more severe in the
dogs euthanized at 80 and
120 hours. Treatment with either fomepizole or
ethanol yielded similar efficacy in terms of
preventing the metabolic acidosis and
renal tubular damage associated with ethylene glycol intoxication.
There was
a difference in the
safety of
the two products.
The dogs treated with fomepizole were
clinically normal within 24 hours.
The ethanol treated dogs, remained either recumbent or
severely ataxic for
36 hours and
were
depressed for
72 hours.
The central nervous system depression, along with the decreased water consumption, and
the ethylene glycol-induced diuresis caused severe dehydration and
complicated the management of
dogs treated with ethanol. When
these animals stopped drinking water, intravenous fluid therapy was
initiated at a rate of
5.0 ml/kg/hr. for
18 hours starting at 6 hours after ingestion to correct dehydration.
The amount of
ethylene glycol excreted unchanged in the
urine between 3 and
72 hours was
48%, 51%, and
71% in Groups 1, 2, and
3 respectively. Group 3 exhibited the greatest increase in ethylene glycol excreted unchanged in the
urine. Fomepizole was
a better antidote than ethanol because it was
less toxic and
it increased the amount of
ethylene glycol excreted unchanged in the
urine. No adverse experiences for
fomepizole were
reported by the authors.
2. Dial SM, Thrall MAH, Hamar DW, Efficacy of
4-methylpyrazole for
treatment of
ethylene glycol intoxication in dogs, Am J Vet Res 1994; 55(12):1762-1770.
Dial, et al. (1994) studied the effectiveness of
fomepizole in ethylene glycol poisoned dogs when
treatment was
delayed until 5 or
8 hours after ingestion. Eleven mature mixed breed dogs of
either sex with a mean body weight of
25.7 kg were
given ethylene glycol at a dose of
10.6 g/kg (twice the lethal dose).
A 95% ethylene glycol antifreeze solution was
mixed with canned dog food and
offered to each dog after food was
withheld for
24 hours. In two dogs, one from
each treatment group, 10.6 grams of
reagent grade ethylene glycol/kg was
administered in place of
the antifreeze solution. Animals were
assigned to two treatment groups: Group 1 (5) dogs were
treated with fomepizole at 5 hours after ethylene glycol ingestion while Group 2 (6) dogs were
treated with fomepizole 8 hours after ethylene glycol ingestion. Fomepizole was
administered intravenously in a polyethylene glycol-400 vehicle at a concentration of
50 mg/ml.
A loading dose of
20 mg/kg fomepizole was
given IV to each group of
dogs followed by fomepizole maintenance doses of
15, 10, and
5 mg/kg at 12, 24, and
36 hours after the loading dose.
All dogs became ataxic and
depressed by three hours after ethylene glycol ingestion. One dog (Group 2) vomited at five hours following ethylene glycol ingestion. By 12 hours, all dogs in Group 1 (5) and
4 of
6 dogs in Group 2 were
clinically normal.
The five dogs in Group 1 recovered without morphologic, biochemical, or
clinical evidence of
renal impairment. Two of
the six dogs in Group 2 developed acute renal failure. One of
the dogs in Group 2 remained isosthenuric for
two months but did not show any other signs of
renal impairment.
The remaining three dogs in Group 2 recovered without morphologic, biochemical, or
clinical evidence of
renal impairment.
The two animals that developed acute renal failure were
admitted to the intensive care unit of
the teaching hospital at 48 hours with azotemia and
peritoneal dialysis was
performed. By 96 hours post ingestion, anuria and
subsequent acute oliguric renal failure developed. One animal died during replacement of
an occluded catheter and
the other was
euthanized after eight weeks of
dialysis without improvement of
renal function.
The study
demonstrated that fomepizole administration is effective in preventing renal failure, even when
treatment is delayed as late as 5 to 8 hours after ethylene glycol ingestion, as long as unmetabolized ethylene glycol is present in serum and
the dog is not azotemic. No adverse experiences for
fomepizole were
reported by the authors.
3. Dial SM, Thrall MA, Hamar DW, 4-Methylpyrazole as treatment for
naturally acquired ethylene glycol intoxication in dogs, JAVMA 1989; 195(1):73-6.
Fomepizole was
successfully used as a clinical antidote in the
treatment of
ethylene glycol poisoned dogs in an open-label study
conducted by Dial, et al. (1989). Twenty-four dogs were
admitted to the Colorado State University Veterinary Teaching Hospital (CSVTH) from
1980 to 1985 and
evaluated for
placement into
the prospective study
. Of the 24 dogs, 15 had high serum and
urine ethylene glycol concentrations (greater than 50 mg/dl). Seven of
the 15 dogs were
azotemic upon admission and
were
excluded from
the trial. Eight dogs had high serum and
urine ethylene glycol concentrations without azotemia and
were
the basis of
this study
.
A diagnosis of
ethylene glycol poisoning was
made if serum and
urine ethylene glycol concentrations were
greater than 50 mg/dl. Fomepizole was
administered intravenously in a polyethylene glycol-400 vehicle at a concentration of
50 mg/mL at doses of
20 mg/kg upon presentation, 15 mg/kg, 17 hours later, and
5 mg/kg at 25 hours after presentation. In 2 of
the 8 dogs, an additional dose of
5 mg/kg was
administered at 36 hours after admission. Dogs were
monitored in the
intensive care unit during treatment.
By 24 hours, all dogs had clinical improvement (increased appetite, alleviation of
central nervous system and
gastrointestinal signs and
increased responsiveness). Duration of
hospitalization ranged from
3 to 7 days. Of the eight dogs, six were
released from
clinical care within three days of
admission, and
the remaining two were
released by day seven after admission. By 36 hours after admission, 7 of
8 dogs were
maintaining hydration by oral fluid intake and
fluid therapy was
discontinued. One animal remained polyuric and
the administration of
IV fluids was
maintained for
5 days. When
fluids were
discontinued, the
animal's hydration status was
maintained, but isosthenuria remained. Sixteen days after admission, this dog had regained the ability to concentrate urine, an indication of
return to normal tubular function. All four dogs that returned for
subsequent evaluation at one week after discharge had normal laboratory findings at that time.
This study
demonstrated that fomepizole is an effective antidote in treating dogs poisoned with ethylene glycol. No adverse experiences for
fomepizole were
reported by the authors.
B. Clinical Field Study
A retrospective open-label study
was conducted at Colorado State University Veterinary Teaching Hospital, Colorado State University, Fort Collins, Colorado, to assess the efficacy of
fomepizole as a treatment for
ethylene glycol poisoning in dogs.
The principal investigator was
Dr. Mary Anna Thrall. One-hundred five (54 males, 51 females) mixed breed and
purebred dogs, ranging from
3 months to 15 years of
age were
admitted to the CSVTH from
September 1983 through April 1995 for
treatment of
suspected or
confirmed ethylene glycol toxicity. Of 38 confirmed cases, 14 dogs were
confirmed by a commercial test kit, 10 by measurement of
ethylene glycol serum concentrations, and
the remaining by a combination of
history, suggestive clinical and
/or laboratory findings.
A commercial test kit is available for
measuring blood ethylene glycol concentrations greater than 50 mg/dl (EGT Test Kit, PRN Pharmacal, Inc., 5830 McAllister Ave., Pensacola, FL). Fomepizole was
administered intravenously in a polyethylene glycol-400 vehicle at a concentration of
50 mg/mL. Dogs were
treated with one of
the two following dosing regimens:
Dose Regimen 1
--------------------------------------------------------------------------------
Loading Dose 20 mg/kg IV
17 hours after initial dose 15 mg/kg IV
25 hours after initial dose 5 mg/kg IV
36 hours after initial dose 5 mg/kg IV
--------------------------------------------------------------------------------
Dose Regimen 2 (Antizol-Vet)
--------------------------------------------------------------------------------
Loading Dose 20 mg/kg IV
12 hours after initial dose 15 mg/kg IV
24 hours after initial dose 15 mg/kg IV
36 hours after initial dose 5 mg/kg IV
--------------------------------------------------------------------------------
Sixty-nine of
the dogs were
treated with dose regimen 1 and
five were
treated with dose regimen 2.
The remaining 31 dogs were
treated with slight variations of
these dosing regimens. Dogs were
monitored in the
intensive care unit during treatment. Fluid therapy and
other supportive treatment for
dehydration and
to promote fluid diuresis was
initiated as needed. Clinical laboratory data (chemistry profile, CBC, urinalysis, blood gases) were
collected. Eighty-four (80%) animals survived, 20 (19%) were
euthanized and
1 (1%) died (See diagram 1).
The dogs which
survived spent an average of
1.9 1.8 days in the
veterinary hospital. Of the 20 euthanized animals, 17 were
diagnosed azotemic at the
time of
admission, two were
azotemic at 18 hours post admission, and
one was
semicomatose and
anuric upon admission. Of the two diagnosed azotemic animals at 18 hours post admission, one animal was
administered the entire fomepizole dose regimen 1; however, this animal's condition progressed to acute renal failure, and
the owner opted for
euthanasia.
The other animal was
administered two doses of
fomepizole (regimen 1) before euthanasia.
The other animal that was
euthanized was
presented at admission in a semicomatose and
anuric state. It received a loading dose of
fomepizole (20 mg/kg) prior to its deterioration. Ethylene glycol poisoning was
confirmed in all of
the euthanized animals.
DIAGRAM 1
105 Dogs
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V
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V V
21 Azotemic (Confirmed) 84 Nonazotemic
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V V
19 Euthanized 67 Nonconfirmed*
1 Death 17 Confirmed
1 Survived
67 Nonconfirmed: 67 survived
17 Confirmed: 0 died, 16 survived, 1 euthanized
* Under actual conditions of
use in a veterinary practice ethylene glycol (EG)
poisoning may be diagnosed without using the commercial test kit or
measurement of
serum levels. While test kit results can be read in 30 minutes
the steps involved can be labor intensive. It is impractical to wait for
test
results (from a diagnostic laboratory) thereby delaying treatment for
this life
threatening emergency. History, clinical signs, etc. are practical ways of
diagnosing suspected EG poisoning. Clinical signs present upon admission included
ataxia, central nervous system depression, vomiting, disorientation, dehydration,
nystagmus, polyuria and
polydipsia. Sixty-three of
the 105 animals had no clinical
signs present. Of the 38 total confirmed cases, 32 had a combination of
these
clinical signs present. Abnormal clinical laboratory findings included increased
serum osmolality, metabolic acidosis, hyperglycemia, calcium oxalate crystalluria,
increased BUN and
creatinine.
One animal experienced an anaphylactic type reaction following the second dose of
fomepizole. Clinical signs included tachypnea, gagging, excessive salivation and
trembling. Dosing with fomepizole was
discontinued and
the dog survived.
Azotemia is a reliable indicator that significant renal dysfunction is present, and
in this study
, its presence had a significant impact on the outcome of
those cases (38) confirmed with ethylene glycol poisoning. Of the 21 animals confirmed with azotemia, only 1 (5%) survived. Dogs which
are azotemic usually have metabolized most of
the ingested ethylene glycol. Azotemia is also a reliable indicator that more toxic metabolites have been formed and
fomepizole is expected to be less effective as an antidote in these dogs. If an animal presents azotemic, prognosis is usually poor.
Conclusion: These results confirm that fomepizole is a safe and
effective antidote for
treating ethylene glycol poisoning in dogs. However, in order to prevent renal failure, it must be given before sufficient quantities of
ethylene glycol have been metabolized.
V. ANIMAL SAFETY
A. Overdosing Study
Dennis J. Naas, B.S.
WIL Research Laboratories, Inc.
1407 George Road
Ashland, Ohio 44805-9281
A Dose Range-Finding Toxicity Study with Intravenous 4-Methylpyrazole in Dogs
This study
, composed of
two phases, utilized ten outbred male Beagle dogs approximately six weeks of
age.
The objective of
the study
was to select doses for
the subacute toxicity study
based upon an evaluation of
the toxic effects of
the test article, fomepizole, when
administered IV (twice daily for
fourteen days). Dose levels of
150 and
75 (phase I) and
25 and
50 (phase II) mg/kg of
Antizol-Vet™ were
administered intravenously twice per day in 0.9% sodium chloride injection.
Antizol-Vet™ administered at 25 mg/kg resulted in decreased food consumption, body weight loss, and
breaths with sweet odors. At 50 mg/kg or
greater, Antizol-Vet™ administration resulted in adverse clinical signs (ataxia, hypoactivity, hypothermia, tremors and
/or prostration, injected sclera, ptosis, decreased defecation, and
protruding tongues), elevated clinical chemistries [ALP (231-400 U/L), ALT (422-6622 U/L), AST (335-5003 U/L), CPK (626-2215 U/L), BUN (61.8 MG/DL), total bilirubin (0.7 mg/dl), creatinine (1.6 mg/dl)] and
increased levels for
RBCs (8.67 mil/uL), hemoglobin (20 g/dl) and
hematocrit (61.7%).
B. Subacute Toxicity
Dennis J. Naas, B.S.
WIL Research Laboratories, Inc.
1407 George Road
Ashland, Ohio 44805-9281
An Intravenous Toxicity Study with 4-Methylpyrazole in Dogs
This study
was designed to evaluate the potential toxicity of
fomepizole when
administered intravenously to dogs two times a day for
fourteen days.
Thirty-two outbred beagle dogs were
used in this study
. Dogs were
all approximately 5 months in age and
weighed 6.9 - 9.0 kg for
the males, and
7.5 - 8.9 kg for
the females. Starting six days prior to initiation of
dosing, the
dogs were
acclimatized to jackets which
would contain an infusion pump.
Three days prior to the initiation of
the study
, an indwelling catheter was
surgically placed in the
jugular vein and
connected to the infusion pump.
Dogs were
randomly separated into
four groups of
4 males and
4 females each (8 dogs/group). Dosage levels of
10 (Group 2), 20 (Group 3), and
30 (Group 4) mg/kg fomepizole were
selected for
the study based on the results from
the overdosing toxicity study
.
A concurrent control group (Group 1) received only the vehicle, 0.9% sodium chloride. Control and
fomepizole formulations were
administered intravenously at a constant rate of
4 ml/kg/hour for
thirty minutes twice daily for
14 days. After the thirty minute infusion of
the control or
fomepizole, all animals received a continuous infusion of
0.9% sodium chloride at a rate of
0.4 ml/kg/hr until the next 30 minute infusion of
control or
fomepizole.
The animals were
observed twice daily for
mortality and
morbidity. Body weights were
recorded weekly during the pretest period, daily during the dosing period and
twice weekly during the recovery period. Individual food consumption was
recorded daily. Individual rectal temperatures were
recorded twice during the pretest period, and
weekly throughout the study
. Blood samples for
clinical pathologic evaluations were
collected from
each dog once prior to initiation of
dosing and
from all dogs on day 14 and
42 of
the study
. Urine for
urinalysis was
collected from
all dogs using metabolism cages once prior to initiation of
dosing and
on study
days 13 and
42. Ocular examinations were
conducted on all animals prior to the initiation of
dosing and
on study
days 12 and
40.
All animals survived the 14 day dosing period. After 14 days, the
cannulae and
associated equipment were
removed. Six animals from
each group (3/sex) were
selected for
necropsy after 14 days of
dosing.
The remaining study
animals (8) were
observed for
an additional 28 days post-dosing to evaluate recovery and
necropsies for
these animals were
conducted on day 42. Complete necropsies were
performed on all 32 dogs and
tissues were
preserved for
histological examination. Selected tissues were
examined microscopically from
all animals.
Hypoactivity was
observed in a single female animal in the
high-dose group and
was
considered treatment-related. Vomiting, diarrhea and
injected sclera were
seen in treated males and
females throughout the dosing period.
This finding was
also seen in the
vehicle control (group 1).
Food consumption was
not affected during the dosing period.
There were
no alterations in body weight or
body temperatures.
Mean bicarbonate values were
elevated and
mean potassium values were
decreased in the
30 mg/kg group at day 14, but returned to normal by day 42. Males and
females in Groups 3 (20 mg/kg) and
4 (30 mg/kg) exhibited increases in urine volume means and
associated decreases in the
urine specific gravity means when
compared to the control group values. An increase in urine volume is not necessarily an abnormal finding in this study
and may be associated with the continuous administration of
0.9% sodium chloride and
/or increased water consumption.
The ocular examinations revealed no abnormalities related to administration of
fomepizole.
At necropsy on day 14, two males and
two females in the
30 mg/kg group had pale livers and
one 30 mg/kg male had a swollen liver.
The mean liver weight for
the 30 mg/kg group males was
greater than all groups at day 14. No treatment effects were
seen on necropsy of
the remaining animals at day 42.
Intravenous infusion of
fomepizole to dogs for
14 days resulted in injected sclera, vomiting and
diarrhea in the
vehicle control and
the 10, 20, and
30 mg/kg groups.
A single occurrence of
hypoactivity and
an increase in the
mean liver weights was
observed in the
30 mg/kg group animals.
Pharmacokinetics Results from
this twice daily 14 day intravenous study
evaluating doses of
10, 20, and
30 mg/kg in dogs showed a dose proportional increase in plasma levels of
fomepizole after a single (first) dose. However, the
terminal elimination half life appears to increase (nonlinear kinetics) with dose following multiple administrations.
This nonlinearity was
particularly evident in the
30 mg/kg dose group and
appeared to occur in four of
the eight animals tested in the
20 mg/kg dose group. Accordingly, after the fourteen day dosing regimen in these animals, plasma fomepizole concentrations accumulated in a greater than dose proportional manner.
This apparent nonlinear plasma accumulation of
fomepizole is assumed to be a result of
a saturable elimination process. In contrast, linear pharmacokinetics and
an absence of
plasma fomepizole accumulation was
observed following the fourteen days of
dosing in the
10 mg/kg dose group.
Conclusion: The study
demonstrates that fomepizole is safe when
administered intravenously at doses up to 20 mg/kg.
VI. HUMAN FOOD SAFETY:
Data on human safety, pertaining to consumption of
drug residues in food, were
not required for
approval of this NADA.
The drug is to be labeled for
use in dogs, which
are non-food animals.
A user handler safety section is included on the label.
The label includes the following section: "Not for
use in humans. Keep out of
reach of
children. Irritant. Avoid ocular, dermal or
inhalation exposures. In case of
eye or
skin exposure, flush immediately with copious amounts of
water. Seek medical attention if irritation persists. Use product only in a well ventilated area. If accidental inhalation occurs, move to fresh air.
The material safety data sheet (MSDS) contains additional information regarding the safe use of
this product. For emergency medical assistance, to report adverse effects in users and
/or to obtain a copy of
the MSDS, call 1-888-867-7426 (888-8ORPHAN)."
VII. AGENCY CONCLUSIONS:
The data submitted in support of
this NADA comply with the requirements of
Section 512 of
the Act and
Section 514.111 of
the implementing regulations. It demonstrates that Antizol-Vet™ when
used under
labeled conditions of
use is safe and
effective.
The drug is restricted to use by or
on the order of
a licensed veterinarian because professional expertise is required to 1) diagnose ethylene glycol poisoning, 2) administer Antizol-Vet™ intravenously, and
3) recognize and
treat, if necessary adverse reactions to the drug.
Under Section 512(c)(2)(F)(i) of
the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 360b(c)(2)(F)(i), this approval qualifies for
FIVE years of
marketing exclusivity beginning on the date of
approval because no active ingredient (including any ester or
salt thereof) of
the drug has been previously approved in any other application filed under
section 512(b)(1) of
the Act.
VIII. LABELING (Attached)
1. Vial label
2. Diluent label
3. Carton label
4. Package Insert
Copies of
applicable labels may be obtained by writing to the:
Freedom of
Information Office
Center for
Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
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