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Guidance for Industry 
 
 
ANESTHETICS FOR COMPANION ANIMALS 
 
 
 
 
Comments and suggestions regarding this guidance should be sent to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, 
Rockville, MD  20852.  Comments can be submitted electronically on the Internet at 
http://www.regulations.gov.  All written comments should be identified with the Docket No. 
FDA-2008-D-0623.  
 
For questions regarding this document, contact Germaine Connolly, Center for Veterinary 
Medicine, (HFV-116), Food and Drug Administration, 7500 Standish Place, Rockville, MD 
20855, (240) 276-8331, e-mail:  germaine.connolly@fda.hhs.gov.  
 
Additional copies of this guidance document can be requested from the Communications Staff 
(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD  20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm.   
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
March 25, 2010  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
III.  TARGET ANIMAL SAFETY.........................................................................................2 
A.  Exaggerated Dose/Duration Safety Studies.................................................................................2 
B.  Compatibility Studies....................................................................................................................3 
1.  Study Design...................................................................................................................................4 
2. Evaluation of dose sparing effects...................................................................................................5 
3. Choice of anesthesiology drugs for compatibility study..................................................................5 
4. Anesthesiology drug doses in compatibility studies.........................................................................6 
5.  Specific Safety Issues.......................................................................................................................6 
IV.   EFFECTIVENESS...........................................................................................................7 
A.  Dosage Characterization...............................................................................................................7 
B.  Field Effectiveness Study...............................................................................................................8 
1. Evaluation of Subpopulations..........................................................................................................8 
2. Treatment Groups............................................................................................................................8 
3. Evaluation of Anesthetic Dose Sparing Effects................................................................................9 
V.  RECOMMENDED VARIABLES FOR SAFETY AND EFFECTIVENESS 
STUDIES.......................................................................................................................................9 
VI.   ADVERSE REACTIONS...............................................................................................11 
A.  Adverse Reactions During Safety And Effectiveness Studies..................................................11 
B.  Adverse Reaction Reports From Other Countries In The Target Species.............................12 
C.  Adverse Reaction Reports From Humans.................................................................................13 
VII.  OTHER CONSIDERATIONS.......................................................................................13 
A.  Data Presentation in the Final Study Report (FSR).................................................................13 
B.  Anesthetic Labeling.....................................................................................................................14 
1. Dosage and Administration Section...............................................................................................14 
2.  Target Animal Safety Section.........................................................................................................15 
3.  Contraindications, Warnings, and Precautions, Sections.............................................................15 
C.  Assessment for Human Abuse Potential....................................................................................16 
GLOSSARY.................................................................................................................................18 
 
  Contains Nonbinding Recommendations 
 
 
Guidance for Industry 
1
Anesthetics for Companion Animals  
 
 
 
 
This guidance represents the agencys current thinking on the topic.  It does not create or confer any 
rights for or on any person and does not operate to bind FDA or the public.  You can use an alternative 
approach if the approach satisfies the requirements of the applicable statutes and regulations.  If you want 
to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.  If 
you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
 
 
I.  INTRODUCTION 
 
This guidance document makes recommendations to assist developers of general anesthetic 
drugs (injectable or inhalational) for use in companion animals (dogs, cats, and horses).  The 
guidance discusses the contents of the target animal safety, effectiveness, and labeling technical 
sections of a new animal drug application (NADA) for general anesthetics.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidances means that 
something is suggested or recommended, but not required. 
 
II.  BACKGROUND 
 
This guidance makes recommendations for the development of anesthetic new animal drug 
products for companion animals.  The guidance specifically describes what should be considered 
while planning and executing safety and field studies for the proposed anesthetic.  The following 
sections also include recommendations on how to analyze and package the collected data for 
submission to the Center for Veterinary Medicine (CVM).  
You may follow the guidance document or may choose alternate procedures.  It is recommended 
that you discuss your proposed study plans with CVM, especially if you choose to use alternate 
procedures.  We would like to emphasize the importance of scheduling a presubmission 
conference with the appropriate division of CVM as you begin to make your investigational 
                                                 
 
1 This guidance was prepared by the Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for 
Non-Food Animals in the Center for Veterinary Medicine at the Food and Drug Administration.   
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  Contains Nonbinding Recommendations 
 
plans to ensure that you are completely informed on the requirements contained in the statute 
and regulations.  
 
III.  TARGET ANIMAL SAFETY     
 
When developing a product for use in companion animals, it is critical to determine that the 
product can be used safely in the target animal (21 U.S.C.  360b(d)(1)(B); 21 CFR 
 514.1(b)(8)).  Safety studies conducted in the laboratory should be carried out in compliance 
with FDA's good laboratory practices regulations (21 CFR Part 58) and should follow the 
principles outlined in CVMs Guidance for Industry #185 - Target Animal Safety for Veterinary 
Pharmaceutical Products, VICH GL43.  The type of general anesthetic being studied (for 
example, injectable, inhalational) will help determine what approach should be used to design 
and evaluate the safety studies.  We recommend that sponsors discuss safety study designs with 
us and submit protocols for our review before initiating the studies.   
 
In the following sections, we discuss exaggerated dose/duration studies (evaluating the safety of 
the anesthetic alone) and compatibility studies (evaluating safety of the anesthetic in the 
presence of preanesthetics).  
 
A.  Exaggerated Dose/Duration Safety Studies 
 
The exaggerated dose/duration safety study evaluates the anesthetic alone in healthy animals.  
The purpose of this study is to identify adverse reactions and determine a safe upper limit for the 
anesthetics recommended dose orduration.  In some cases, an exaggerated dose study may be 
inappropriate, because the use of exaggerated anesthetic doses could result in signs of such 
severity that little useful information is obtained.  Excessive anesthetic doses may be fatal.  
However, death should not be an outcome of anesthetic safety studies.  The margin of safety 
should be defined by clinical observations following toxic, but non-lethal doses.  If anesthetic 
potency is such that the administration of exaggerated doses in the study results in severe clinical 
signs, you may consider appropriate alternatives such as increasing the number of anesthetic 
episodes (total excessive dose over time) or exaggerating the duration of anesthesia.   
  
We recommend that you identify the appropriate doses for use in the exaggerated dose/duration 
safety study by first evaluating a limited number of healthy animals that receive progressively 
increasing anesthetic doses (these may be pilot studies).  Incremental increases in anesthetic dose 
are administered until a serious adverse reaction occurs.  Examples of serious adverse reactions 
include apnea >120 seconds, HR <50 beats per minute, BP <60 mm Hg, potentially life-
threatening ECG rhythms, potentially life-threatening clinical signs, or excessively prolonged 
recovery times.  If you use the same group of animals for successive increases in anesthetic dose, 
anesthetic episodes should be separated by an adequate washout period to prevent carry-over 
effects.  Once the appropriate exaggerated dose levels are identified, you should proceed to the 
exaggerated dose/duration safety study.  
 
The following study designs are general examples.  For exaggerated dose/duration safety studies, 
animals should be randomly assigned to treatment groups.  We encourage you to consult with us 
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  Contains Nonbinding Recommendations 
 
during product development to determine the most appropriate study design for a particular 
product.   
 
Injectable Anesthetics:  To evaluate the induction dose, the following examples 
may be appropriate: 
 
  Exaggerated dose:  Treatment groups compare higher multiples of the 
induction dose to the recommended induction dose and to a control 
(traditional design). 
 
  Exaggerated frequency of induction:  Animals are anesthetized every other 
day for a period of days/weeks; the total anesthetic induction dose over 
time is measured. 
     
If the injectable anesthetic is indicated for maintenance anesthesia, the study 
design should also reflect this, as in the following examples:  
 
  Exaggerated number of maintenance injections:  For anesthesia 
maintained by repeated bolus injections, the study evaluates the number of 
maintenance doses intended for the label as well as multiples of the 
proposed number of maintenance boluses (traditional study design).   
 
  Exaggerated duration of maintenance by continuous rate infusion (CRI):  
 For anesthesia maintained by continuous rate infusion, the study evaluates 
 the intended duration and exaggerated durations of administration. 
 
Inhalational Anesthetics  
  Exaggerated dose:  Treatment groups compare higher multiples of the 
vaporizer settings to the recommended settings and to a control 
(traditional study design). 
  Exaggerated frequency:  Animals are anesthetized every other day for a 
typical surgical duration over a period of days/weeks; the total anesthetic 
dose over time is evaluated. 
  Exaggerated duration:  Anesthesia is maintained for a typical surgical 
duration as well as multiples of this duration.  
 
B.  Compatibility Studies 
 
Compatibility studies are controlled studies in which the proposed general anesthetic is 
evaluated prospectively in conjunction with other drugs commonly used as part of an anesthetic 
regimen.  These generally include preanesthetics, other induction or maintenance anesthetics, 
and anticholinergic medications.  The choice of appropriate drugs for compatibility studies 
should be determined by the current standard of veterinary anesthesiology.   
 
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  Contains Nonbinding Recommendations 
 
Before anesthesia, for most clinical procedures, one or more preanesthetic drugs are 
administered to calm, sedate, provide analgesia and/or provide muscle relaxation.  Preanesthetic 
drugs can also decrease the amount of induction and/or maintenance anesthetic required, 
decrease salivation and airway secretions, and suppress vomiting and regurgitation.   
 
Because the probability of a drug interaction increases with the number of drugs that a patient 
receives, the potential exists for undesirable drug interactions between the proposed anesthetic 
and other concurrently administered drugs.  Compatibility studies identify safety issues 
associated with these interactions.  Examples of potential preanesthetic/anesthetic effects that 
can be measured during compatibility studies include anesthetic dose sparing, changes in the 
quality of induction and recovery, as well as toxicity. You do not need to show that the 
concurrent use of the preanesthetic with the anesthetic provides additional benefits (synergism). 
 
We encourage you to evaluate compatibility with a representative from each class of commonly 
used preanesthetics and anesthetics that could appropriately be used with the proposed anesthetic 
drug.  Commonly used preanesthetic drug classes include phenothiazine tranquilizers, alpha -
2
agonists, opioids, benzodiazepines, and anticholinergics.  NSAIDS (nonsteroidal 
antiinflammatory drugs) are not referred to as preanesthetics within the scope of this guidance.  
Commonly used anesthetics include barbiturates, dissociatives, propofol, and inhalational agents. 
 
We make the following recommendations with respect to anesthetic compatibility studies: 
 
1.   Study Design 
 
We recommend that compatibility studies be conducted in the laboratory (instead 
of evaluation in field studies) because the controlled conditions minimize 
variability.  Compatibility studies performed in a laboratory have the following 
benefits:  
 
  Fewer animals are needed to provide usable results. 
 
  Randomization of homogeneous animals to treatment groups is facilitated. 
 
  More study designs are available (for example, crossover designs have the 
      ability to use animals more than once, following suitably 
documented       washout periods). 
 
     Use of an anesthetic-only group for baseline measurements may be more  
      acceptable. 
 
     Well-controlled study conditions are easier to achieve.  
     Use of concomitant medications that are not part of the anesthetic regime  
      can be avoided. 
 
  4
 
  Contains Nonbinding Recommendations 
 
     Arterial systolic, diastolic, and mean blood pressure can be more easily  
      and appropriately monitored. 
 
     Invasive instrumentation/procedures can be used to provide more 
complete       data, should they be needed. 
 
     Anesthetic assessment procedures (for example, nonsurgical noxious  
      stimulation) can be repeated at predetermined intervals. 
 
     Investigator variability is more easily controlled. 
 
     Consistent evaluation of adverse reactions (onset, duration, treatment,  
      resolution) is easier to achieve. 
 
     Complete necropsies can be performed on animals that die during the  
      study. 
 
    Adequate staffing can be assured for the evaluation of physiological 
  variables. 
 
Treatment groups can include more than one preanesthetic agent.  A treatment 
group that evaluates the effects of the anesthetic alone provides baseline 
information.  Appropriate clinical, physiologic, and anesthetic variables (see 
section V) should be compared among treatment groups to provide animal safety 
information.  In addition to drug interactions, effects of special interest include 
anesthetic dose sparing, and changes in the quality of induction and recovery.  
 
2.  Evaluation of dose sparing effects 
 
When a preanesthetic drug (for example, a sedative) exerts its effect concurrently 
with the general anesthetic, it may be appropriate to reduce the general anesthetic 
dose to maintain safe anesthetic conditions during induction, maintenance, and 
recovery.  This anesthetic dose sparing results in balanced anesthesia, avoids 
anesthetic overdosage, and provides valuable safety information for labeling.  
Actual dose administered, induction time, duration of anesthesia, time to sternal 
recumbency, and time to standing recovery are useful measures of this effect.  A 
treatment group evaluating the effects of the anesthetic alone provides 
comparative information.  In the presence of a dose sparing preanesthetic, the 
desired levels of physiological variables are achieved at a reduced anesthetic 
dose.  The appropriate reduced anesthetic dose is also reflected by satisfactory 
anesthetic scores for induction, maintenance, and recovery.   
 
3.  Choice of anesthesiology drugs for compatibility study 
 
  5
 
  Contains Nonbinding Recommendations 
 
Our preference is that the preanesthetics and other anesthetics chosen for the 
compatibility study are already approved with the appropriate indication in the 
target species.  Each preanesthetic or additional anesthetic should be used 
according to its labeled indication (for example, prevent bradycardia, induce 
anesthesia).  In some cases, a drug (usually preanesthetic), provides the desired 
effect but its approved labeling does not contain the appropriate indication.  If  
the drug is commonly used by veterinarians and can be shown to reflect the 
standard of care in companion animals, then, for safety reasons, it should be 
evaluated in the presence of the proposed anesthetic.  However, its extralabel use 
must meet the relevant requirements of 21 CFR Part 530.  We also recommend 
that you explain the necessity for the drug's use based on a cogent, scientific 
rationale and document its common use in the field (as veterinary standard of 
care).   
 
4.  Anesthesiology drug doses in compatibility studies 
 
The preanesthetic or additional anesthetic should be used at the approved labeled 
dose or current, scientifically valid, and documented clinical field dose.  Some 
preanesthetics or other anesthetics are labeled for stand alone use (for example, 
for sedation).  When used with the proposed anesthetic, the same drug could 
require an adjustment to its stand alone dose.  A rationale for an adjusted dose 
could include information from preliminary studies, literature, formularies, or 
textbooks.  We recommend that you discuss all preanesthetic or additional 
anesthetic doses with us before conducting the compatibility study.   
 
It is important that preanesthetic effects are present before the induction of 
anesthesia so that balanced anesthesia is achieved.  However, to prevent the 
introduction of variability into study results, we recommend standardizing the 
interval (within a time range) between the administration of preanesthetic and 
induction anesthetic.  
 
5.   Specific Safety Issues 
 
The main safety studies may not evaluate all safety issues that should be 
addressed before marketing approval.  Some examples of issues often not 
evaluated in safety studies include: 
 
  Arrhythmogenicity of volatile inhalational anesthetics 
 
  Risks associated with specific population subgroups 
 
  Particular safety issues specific to a class of anesthetics 
 
  Particular safety issues specific to the proposed anesthetic itself   
 
  6
 
  Contains Nonbinding Recommendations 
 
When applicable, you  should address these types of safety issues (for example, 
through the use of exclusionary labeling comments, literature reviews, and/or 
additional studies). 
 
IV.   EFFECTIVENESS   
 
The regulations at 21 CFR 514.117(b) describe the characteristics that are generally recognized 
as the essentials of adequate and well-controlled studies intended to demonstrate effectiveness 
and support the approval of a new anesthetic product or a new use of an approved anesthetic 
product.  You should refer to these regulations when designing effectiveness studies. 
 
In the following paragraphs, we discuss and make recommendations on key issues related to 
anesthetic effectiveness studies.  We do not usually recommend placebo or active controls in 
effectiveness studies for anesthetic drugs.  Each animal is either anesthetized or not anesthetized, 
as determined by the ability to intubate, by reflex responses, purposeful movements, and other 
clinical observations. 
   
A.  Dosage Characterization 
 
Dosage characterization includes information on the dose or dose range, the dosing frequency, 
and the dosing duration.  For inhalational anesthetics, minimal alveolar concentration (MAC) 
determination is considered part of dosage information and you should characterize it.   
You need not provide dosage characterization as part of substantial evidence of effectiveness. 
You should, however, submit sufficient information to characterize the critical aspects of the 
dose response relationship.  You may derive dosage characterization from dose titration studies, 
pilot studies, foreign studies, scientific literature, and assessments based on the modeling of 
pharmacokinetic and pharmacodynamic data. 
 
The anesthetic maintenance dose (if appropriate for that anesthetic) should be characterized.  
Maintenance doses are administered by inhalation, by repeat bolus injections, or by continuous 
rate infusion (CRI).  We encourage you to consider the following questions when designing 
studies to evaluate maintenance anesthesia using repeat bolus injections or CRI.  
 
  How many times may the boluses be repeated or how long will CRI last? 
 
  What is the rate of administration for a maintenance bolus or CRI? 
 
  What types of procedures are indicated during maintenance of anesthesia using 
  bolus injections or CRI? 
 
  How frequently do boluses need to be repeated, or how are variations in the CRI 
  rate determined? 
 
  How are heart rate, blood pressure, respiratory rate, and other physiological 
  variables affected when you give a maintenance bolus or change the rate of CRI? 
  7
 
  Contains Nonbinding Recommendations 
 
 
  Does the number of boluses, or the duration of CRI, affect recovery times?  Is 
  there any evidence of anesthetic accumulation (delayed recovery)? 
 
B.  Field Effectiveness Study 
 
The purpose of a field study is to evaluate whether the proposed anesthetic is safe and effective 
for the target animal under the actual conditions of use according to its proposed indications.  
The field study confirms the dosage and provides additional information to that obtained from 
the compatibility study in the intended patient population.   
 
Field studies, whether conducted in the United States or in other countries, should use the same 
drugs and standard of veterinary practice as in the United States, according to an acceptable 
protocol.  All study data and reports must be submitted in English (21 CFR 514.110(b)(1)).  We 
recommend reporting data in units commonly used in the United States.  We also recommend 
that procedures conducted under anesthesia are similar to those commonly performed in the 
United States.   
 
1.  Evaluation of Subpopulations
 
 
The field study provides safety and effectiveness information in the target animal and 
may also include some data generated in specific subpopulations (for example, juveniles, 
geriatric animals, sighthounds, and animals with compromised cardiovascular, renal, or 
hepatic function).  If the field study does not provide substantial evidence of 
effectiveness to adequately assess the effects of the anesthetic within a significant 
subpopulation (usually because there are inadequate numbers of cases within the 
subpopulation), we may require product labeling to exclude certain subpopulations (for 
example, ...the use of the anesthetic has not been evaluated in foals, pregnant animals, 
puppies, or geriatrics.)   
 
2.  Treatment Groups 
 
We encourage the inclusion of a representative of each class of preanesthetic (for 
example, opioid, alpha -agonist, phenothiazine tranquilizer, benzodiazepine) in treatment 
2
groups.  You may include more than one preanesthetic in a treatment group.  When 
clinically acceptable, we encourage you to evaluate the anesthetic alone (in the absence 
of preanesthesia) to provide baseline information.  
 
Depending on the indication, it may be necessary to evaluate an anesthetic in the 
presence of other anesthetics.  If the proposed anesthetic requires evaluation with other 
induction agents, treatment groups should include an appropriate representative of each 
class of induction agent commonly used in the target species (for example, barbiturates, 
dissociatives, propofol).   
 
To decrease variability and assist the formation of conclusions relative to anesthetic 
safety and effectiveness, we recommend that predetermined anesthetic regimens be 
  8
 
  Contains Nonbinding Recommendations 
 
defined in the protocol and that they reflect the standard of veterinary practice.  The 
veterinarian (clinical investigator) then selects the appropriate anesthetic regimen that 
best meets each patients needs within the limits of the protocol.  In anesthetic field 
effectiveness studies, animals are usually assigned to treatment group by the clinician 
based on the nature of the clinical procedure rather than by randomization.  The goal is 
not to compare treatment groups, but to evaluate the safety and effectiveness of the 
anesthetic in the presence of drugs contained in various regimens.  The number of sites 
and procedures can be limited to decrease study variability and increase case numbers so 
that there are comparable groups of animals.  During protocol review, we strongly 
recommend that you discuss the field study design so that each anesthetic regimen is 
represented by adequate numbers of cases within each group and at each location.   
 
The decision to use an anticholinergic within each treatment group rests with the clinical 
investigator.  When anticholinergics are used, we recommend that you clearly delineate 
the dose and timing of administration on the case report forms.  You should compare 
cases treated with anticholinergics with those that do not receive anticholinergics within 
and across treatment groups. 
 
3.  Evaluation of Anesthetic Dose Sparing Effects 
 
Dose sparing effects derived from laboratory compatibility studies should be confirmed 
in the field study.  Actual dose administered, induction time, duration of anesthesia, time 
to sternal recumbency, and time to standing recovery are useful measures of this effect.  
Physiological measurements should be acceptable during anesthesia and the desired 
procedure should be satisfactorily accomplished.  If clinically appropriate, a treatment 
group evaluating the effects of the anesthetic alone provides comparative information for 
these variables.   
 
V.  RECOMMENDED VARIABLES FOR SAFETY AND EFFECTIVENESS 
STUDIES   
 
  Variables that are not specifically related to anesthetic evaluation, may not be represented 
in this section of the guidance (for example, signalment, physical examinations, clinical 
pathology, necropsy, pharmacokinetic).  Physical examination results should be recorded 
on forms according to organ systems.  Injection sites, whether intravenous, 
subcutaneous, or intramuscular, should be grossly and histologically evaluated in safety 
studies, and clinically evaluated in field studies.  The following anesthetic related 
variables should be measured in anesthetic safety and effectiveness studies; however, the 
inclusion of study variables may vary between field and laboratory settings.   
 
 
 
 
A.     Clinical Variables 
           ability to intubate 
  purposeful movements 
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  Contains Nonbinding Recommendations 
 
  response to noxious stimuli at predesignated intervals 
            (for example, surgical stimulation, hot or cold thermal 
              stimuli, tail clamp) 
  muscle relaxation 
 
 
 
B.     Physiologic    
        systolic, diastolic, and mean arterial blood pressure  
Variables 
  blood gas analysis (partial pressure of oxygen, partial     
     pressure of carbon dioxide, total carbon dioxide, pH,       
     bicarbonate concentration)  
  K+, Ca++, other electrolytes 
  end tidal CO  
2
  pulse rate (PR) 
  respiratory rate (RR) 
  mucous membrane color (mm) 
  body temperature (T) 
  percent oxygen hemoglobin saturation (O sat) 
2 
  cardiac rhythm measured by electrocardiogram (ECG) 
 
 
 
C.     Anesthetic                   induction time (beginning of anesthetic administration to    
         Variables       intubation) 
 
  duration of anesthesia (time from intubation to extubation) 
 
  recovery: 
                      -extubation to initial purposeful movement 
                      -extubation to sternal recumbency 
                      -extubation to standing recovery 
 
          anesthetic performance: 
                      -quality of anesthetic induction 
                      -quality of anesthetic maintenance  
                      -quality of anesthetic recovery 
 
  for inhalational anesthetics: 
           -vaporizer concentration and oxygen flow rates 
during induction and maintenance 
                      -total volume per anesthetic episode (mL) 
            -occurrence, number, and reasons for changes in        
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  Contains Nonbinding Recommendations 
 
                       vaporizer settings 
           -spontaneous breathing of room air or oxygen  
                        enriched mixture positive pressure ventilation 
                       
  for injectable anesthetics: 
        -dose of anesthetic for induction (mg, mL, mg/kg)  
        -dose of anesthetic for maintenance (mg, mL, mg/kg) 
        -duration of anesthesia per injection (min) 
        -duration of bolus dose administration (seconds) 
        -number of bolus injections used for maintenance  
        -maintenance using continuous infusion (mg, mL,       
         mg/kg/min and mL/kg/minute) 
 
  administration of supplemental oxygen (duration, reason,   
       frequency, stage of anesthesia) 
 
 
 
VI.   ADVERSE REACTIONS  
 
A.  Adverse Reactions During Safety And Effectiveness Studies 
 
You must promptly investigate and report to FDA any findings associated with the use of the 
new animal drug that may suggest significant hazards pertinent to the safety of the new animal 
drug (see 21 CFR 511.1(b)(8)(ii)).  For all studies that you conduct, you should provide 
information on adverse reactions in the final study report. You should provide detailed 
descriptions of adverse reactions, including the following: 
 
  Description of the adverse reaction 
 
  Anesthetic phase when the reaction was observed (induction, maintenance, 
recovery)  
 
  Duration  
      
  Treatment, if given 
 
  Outcome  
 
  Relationship to administration of the proposed anesthetic 
 
  Likelihood of a drug interaction with the proposed anesthetic 
 
  Type, quantity, and duration of concomitant medications/therapies 
 
  Clinical pathology 
 
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  Contains Nonbinding Recommendations 
 
  Necropsy results (as appropriate) 
 
  Other  
 
We recommend that you organize descriptions of adverse reactions by body system: 
 
Examples of organ systems 
Cardiovascular  Neurologic  Integumentary/Dermatologic  
Respiratory  Renal  Other 
Hepatic  Gastrointestinal 
 
We strongly recommend that you look for associations between adverse reactions and the results 
from clinical, physiological, and anesthetic variables in the final study report.  
 
Terms such as side effects, expected adverse events, or problems beyond usual clinical 
experience are confusing and inappropriate for evaluation of an anesthetic.  It is helpful to 
define some of the adverse reactions of greatest concern in advance using specific parameters.  
The following definitions are given as examples that may change according to the species, drug, 
and type of study:  
 
     apnea of > 120 seconds 
     heart rate of < 50 beats per minute 
     mean indirect arterial blood pressure of < 60 mm Hg 
     potentially lethal ECG rhythm or adverse clinical signs during anesthesia 
     mean oxygen saturation of <80% (any duration) or <90% for > 3 minutes 
     death 
 
B.  Adverse Reaction Reports From Other Countries In The Target Species 
 
For anesthetic agents, we are interested in adverse reaction reports for anesthetics already 
approved and marketed in countries other than the United States.  The regulations require the 
submission of this information (21 CFR 514.1(b)(8)(iv)).  Information on the number of doses 
sold (by year, by country, etc.) should be provided to give context to the number of adverse 
reaction reports.  We recommend tabulating all information so that results may be easily 
compared.     
 
Tabulated information should include dose delivered (label dose or overdose), concurrent 
medications, and outcome (death, recovery).  Deaths should be classified as anesthetic-related or 
deaths with an undetermined causal relationship to the anesthetic.  You should include individual 
case reports (if available) for animals that died and for those showing severe or unusual adverse 
reactions, with a summary of clinical pathology and/or necropsy results.   
 
We recommend tabulating adverse reactions by organ system.  We also recommend that you 
break down the adverse reactions into subcategories based on clinical signs.  For example, you 
could divide large numbers of cases having adverse respiratory signs into subcategories, such as 
apnea, respiratory acidosis, and inadequate oxygen saturation.   
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C.  Adverse Reaction Reports From Humans  
 
If an anesthetic is already approved for use in humans (in the United States or elsewhere), we 
recommend that you submit the most recently approved package insert for the human product, 
accompanied by an update on safety issues associated with the use of the approved human 
anesthetic (reports of human adverse events since approval). 
 
VII.  OTHER CONSIDERATIONS 
 
The following sections discuss key issues related to the design, performance, and evaluation of 
safety and effectiveness studies, with comments on the submission of data to CVM in study 
reports for approval of anesthetics for companion animals.   
 
A.  Data Presentation in the Final Study Report (FSR) 
 
The preparation of a final study report is a required component of an adequate and well-
controlled study.  The required characteristics of an adequate and well-controlled study 
are described in 21 CFR  514.117(b).  The final study report should be a comprehensive, 
stand-alone document.  It must provide a clear explanation of the study objectives, 
experimental materials and methods, and a presentation and critical scientific evaluation 
of the results.  The final study report should be written when collection of all raw data for 
that study is complete.  CVMs Guidance For Industry #104 provides recommendations 
for the content of the final study report in detail.   
 
All data collected during a study should be summarized and analyzed.  A description of 
how the results for each protocol-defined variable support effectiveness or safety should 
be included.  We recommend that you analyze certain variables (for example, clinical 
pathology) for statistically significant differences between treatment groups.  This 
analysis is not unique to anesthetics (see CVM Guidance For Industry #33).  Results 
should be presented using text, with tables and graphs.   
 
We recommend that you present data in tables containing individual animal results and in 
summary tables for each variable (descriptive statistics).  Summary tables should include 
means, ranges, and standard deviations for each variable.  Additionally, it is useful to 
stratify summary tables simultaneously according to treatment group and sex.  Tables can 
be further stratified by dose for intramuscular anesthetics or anesthetic bolus injections. 
An identification key should accompany the report to define any abbreviations used in 
data tables.  You can use graphs to present data, along with the tables from which they 
are derived.   
 
We recommend that you thoroughly discuss the information in the data tables in the final 
study report.  For each individual animal, you should explain the interrelationship of 
clinical signs, physiological data, anesthetic variables, subjective quality assessments, 
adverse reactions, etc.  In a similar manner, you should discuss the information in the 
summary tables and evaluate relationships between all variables among treatment groups 
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  Contains Nonbinding Recommendations 
 
and important population subgroups ( breed, gender, age, health status, etc.). In addition, 
you should discuss the association of treatment, time, procedure, dose, or other 
conditions with the occurrence of adverse reactions.  
 
Presentation of descriptive statistics will help determine anesthesia times (for example,  
time to induction, length of recovery with and without preanesthetic administration) for 
inclusion in labeling.  Anesthesia time intervals should be presented for the anesthetic 
when used alone (if appropriate), used concurrently with preanesthetics, and used with 
other induction and maintenance anesthetics.  Dose information based on descriptive 
statistics should describe dose sparing effects among treatment groups and important 
population subgroups.   
 
The final study report should contain the conclusions drawn from the analysis of the data. 
A description of all circumstances that may have affected the quality or integrity of the 
data should be included.  New or unexpected findings and their impact on the study 
outcome should be identified.  Adverse events and their potential impact, and any results 
that are inconsistent with the overall study conclusions, should also be discussed in 
detail. 
 
B.  Anesthetic Labeling  
  
The package insert should include certain labeling information unique to anesthetics.  In 
this section of the guidance, we discuss several examples and provide some proposed 
wording. 
 
1.  Dosage and Administration Section 
 
The Dosage and Administration section should include safety recommendations related 
to anesthetic dose sparing effects.  Examples of labeling statements regarding dose 
sparing follow: 
  When used with [opioid, alpha -agonist, etc.] premedication, the 
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anesthetic dose should be decreased by approximately x amount. 
  The dose of anesthetic is not affected by anticholinergic 
premedication. 
  Anesthetic induction dosages administered with premedication 
ranged from ..to.. 
  Anesthetic induction dosages administered without premedication 
ranged from ..to.. 
 
Safety recommendations on the use of the proposed anesthetic in the presence of typical 
preanesthetics should refer to preanesthetic drug classes, rather than specific 
preanesthetic drugs. 
 
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  Contains Nonbinding Recommendations 
 
You should include a statement (if supported by your data), such as the following, in the 
Dosage and Administration section of the label: 
 
Premedication:  No specific premedication is either indicated or 
contraindicated with [the proposed anesthetic].  The necessity for, 
choice of, as well as any necessary reduction of dose for the 
premedicant, is left to the discretion of the veterinarian.   
 
This statement should be followed with current references for the selected doses (for 
example, a textbook or formulary). 
 
2.   Target Animal Safety Section 
 
The Target Animal Safety section of the package insert should discuss drug interactions 
providing information on the safe use of the proposed anesthetic with at least one 
representative from each preanesthetic and anesthetic drug class.  The following are 
examples of typical labeling statements regarding drug interactions: 
 
If the proposed anesthetic is inhalational, a statement should describe its safety with 
injectable anesthetics.   
 
[Proposed inhalational anesthetic] is compatible with 
[barbiturates, propofol, dissociatives anesthetics, and/or other 
commonly used injectable anesthetics.] 
 
If the proposed anesthetic is injectable, a statement should describe its safety with other 
inhalational anesthetics.   
 
[Proposed injectable anesthetic] is compatible with commonly 
used halogenated volatile inhalational anesthetics. 
 
For all proposed anesthetics, the following statement can be used to describe its safety 
with classes of preanesthetics: 
 
[Proposed anesthetic] is compatible with benzodiazepines, opioids, alpha -
2
agonists, and phenothiazines as commonly used preanesthetics in surgical 
practice. 
 
3.   Contraindications, Warnings, and Precautions, Sections  
 
The Contraindications, Warnings, and Precautions sections of the package insert should 
also provide statements about anesthetic safety when used alone or in the presence of 
premedicants.  These statements should be based on preapproval study data, human or 
veterinary package inserts for similar products, scientific literature, and/or other sources. 
  
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  Contains Nonbinding Recommendations 
 
The Warnings section should contain information on human user safety when there is 
evidence of an association of a serious hazard with a drug.  Warning statements should 
also refer to human use or accidental exposure.  Various examples of labeling statements 
regarding human user safety follow:   
 
  For inhalational anesthetics:   
Operating rooms and animal recovery areas should be provided with 
adequate ventilation to prevent the accumulation of anesthetic vapors.  
Symptoms of human overexposure (inhalation) to vapors include 
respiratory depression, hypotension, bradycardia, shivering, nausea, and 
headache.  If these symptoms occur, remove the individual from the source 
of exposure and seek medical attention. 
The National Institute for Occupational Safety and Health (NIOSH) 
recommends an 8 hour time-weighted average limit of 2 ppm for 
halogenated anesthetic agents in general. 
 
  For injectable anesthetics: 
[The proposed anesthetic] should be managed to prevent the risk of diversion, 
through such measures as restriction of access and the use of drug 
accountability procedures appropriate to the clinical setting. 
Exercise caution to avoid accidental self-injection. Overdose is likely to cause 
cardiorespiratory depression (such as hypotension, bradycardia, and/or 
apnea).  Remove the individual from the source of exposure and seek medical 
attention.   
Rare cases of self-administration have been reported, including fatalities in 
humans. 
 
C.  Assessment for Human Abuse Potential  
 
The Controlled Substances Act (CSA), Title II of the Comprehensive Drug Abuse Prevention 
and Control Act of 1970, requires that the Secretary of the Department of Health and Human 
Services (HHS) make a recommendation for scheduling to the Drug Enforcement Administration 
(DEA) for any drug that has abuse potential  (21 U.S.C.  811 and 812).  The FDAs Controlled 
Substance Staff (CSS) performs the scientific evaluation of the abuse potential of a drug. 
 
Early in the drug development process, you should contact the CSS in FDAs Center for Drug 
Evaluation and Research.  The CSS will help you identify what information should be included 
in the abuse liability assessment package.  The CSS evaluates whether the drug needs to be 
scheduled under the CSA and/or have other warnings relative to human abuse and dependence 
placed in its labeling.  If necessary, the CSS makes a drug scheduling recommendation to the 
Drug Enforcement Administration (DEA).  Examples of information that should be submitted in 
the abuse liability assessment package include: 
   A description of the drugs chemical structure and class, formulation, 
pharmacology, biochemical profile, chemistry, pharmacokinetics, and adverse 
reactions 
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  Contains Nonbinding Recommendations 
 
   A summary of available safety and effectiveness data, including information on 
overdosage 
   Data on actual use, abuse, and misuse, including fatalities, hospital emergency 
reports, and suicides/suicide attempts 
  A sponsor-proposed schedule for the drug 
 
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  Contains Nonbinding Recommendations 
 
GLOSSARY 
 
The following definitions are presented for use with this guidance document. 
 
Anesthetic Regimen:  A selection of premedicants (analgesics, sedatives, tranquilizers, 
anticholinergics) used with a general anesthetic to achieve balanced anesthesia.   
 
Balanced Anesthesia:  An anesthetic experience of maximal safety and effectiveness achieved 
by adjusting the presence and the amounts of various preanesthetics with induction and 
maintenance general anesthetics.  
 
Compatibility Study:  The compatibility study defines safety issues including anesthetic dose 
sparing effects in a controlled study in which the proposed general anesthetic is evaluated 
prospectively in conjunction with preanesthetics identified by the current standard of veterinary 
anesthesiology.   
 
Continuous Rate Infusion (CRI):  CRI is continuous injection of the dose of a drug directly 
into a vein over time, usually to maintain anesthesia, using some method of infusion.  The dose 
is usually expressed in terms of mass and time (for example, mg/min or g/hr), or mass per unit of 
body weight per unit of time (for example, mcg/kg/min).   
 
Dose Sparing Effects:  The reduction of anesthetic dosage that may occur when a preanesthetic 
drug (for example, a sedative) exerts its effect concurrently with that of the general anesthetic.  
The reduced anesthetic dose is used to maintain safe anesthetic conditions during induction, 
maintenance, and recovery.  
 
Minimal Alveolar Concentration (MAC):  A standard of comparison for potency of general 
anesthetics.  The alveolar concentration of an inhalational anesthetic at which 50 percent of 
healthy patients fail to respond to surgical stimuli (for example, an incision) is 1 MAC.  
Multiples of MAC are used as a guide for surgical levels of anesthesia, which are typically 1.3 to 
1.5 times the MAC value. 
 
Preanesthetics (premedicants):  Drugs administered before anesthesia to prepare the patient for 
anesthesia and contribute to balanced induction, maintenance, and/or recovery.  Preanesthetics 
may calm, sedate, provide analgesia, cause muscle relaxation, decrease anesthetic requirements, 
decrease salivation, decrease airway secretions, and/or suppress vomiting and regurgitation.  
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