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NADA 140-921 PrednisTab™ - original approval

Approval Date: November 8, 1991

I. GENERAL INFORMATION:

NADA 140-921
Sponsor: VET-A-MIX, Inc.
604 West Thomas Avenue
Shenandoah, Iowa 51601-0130
Generic Name: Prednisolone, USP oral tablet 5.0 mg
Trade Name: PrednisTab™
Marketing Status:  

 

II. INDICATIONS FOR USE

PrednisTab(TM) is intended for use in dogs. The indications for PrednisTab(TM) are the same as those for other anti-inflammatory steroids and comprise the various collagen, dermal, allergic, ocular, otic, and musculoskeletal conditions known to be responsive to the anti-inflammatory corticosteroids. Representative of the conditions in which the use of steroid therapy and the benefits to be derived therefrom have had repeated confirmation in the veterinary literature are: (1) dermal conditions, such as nonspecific eczema, summer dermatitis, and burns; (2) allergic manifestations, such as acute urticaria, allergic dermatitis, drug and serum reactions, bronchial asthma, and pollen sensitivities; (3) ocular conditions, such as iritis, iridocyclitis, secondary glaucoma, uveitis, and chorioretinitis; (4) otic conditions, such as otitis externa; (5) musculoskeletal conditions, such as myositis, rheumatoid arthritis, osteoarthritis, and bursitis; (6) various chronic or recurrent diseases of unknown etiology such asulcerative colitis and nephrosis.

In acute adrenal insufficiency, prednisolone may be effective because of its ability to correct the defect in carbohydrate metabolism and relieve the impaired diuretic response to water, characteristic of primary or secondary adrenal insufficiency. However, because this agent lacks significant mineralocorticoid activity, hydrocortisone sodium succinate, hydrocortisone, or cortisone should be used when salt retention is indicated.

 

III. DOSAGE

A. DOSAGE FORM 5.0 mg compressed tablets
B. ROUTE OF ADMINISTRATION oral
C. RECOMMENDED DOSAGES:  
  The average total daily doses for dogs are as follows: 5 to 15 lb (2 to 7 kg) body weight----------2.5 mg
15 to 40 lb (7 to 18 kg) body weight---2.5 to 5 mg
40 to 80 lb (18 to 36 kg) body weight---5 to 10 mg
  NOTES VThe usual total daily dose of 2.5 mg per 10 pounds of body weight should be given in divided doses, 6 to 10 hours apart

 

IV. EFFECTIVENESS

a. Introduction

The biological and anti-inflammatory activity of methylprednisolone in dogs has been determined by the National Academy of Sciences/National Research Council (NAS/NRC) review to be effective and safe. The April 12, 1969 Federal Register publication reflects the Food and Drug Administration's concurrence with the findings of the NAS/NRC review.

Prednisolone and methylprednisolone are synthetic steroids, which chemically and pharmacologically are very similar, both being classified as corticosteroids. Authoritative standard texts, such as the United States Pharmacopeia Dispensing Information(USP DI)(Ref.1); Schleimer, Claman and Oronsky's Anti-Inflammatory Steroid Action, Basic and Clinical Aspects (Ref.2); and Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ref.4) were consulted. These references indicate that the biochemical mechanism of action of the two drugs is essentially the same.

The basic chemical structure of the glucocorticoids consists of 21 carbon atoms with a total of 4 rings: three 6-carbon rings designated A, B, and C, and a five- carbon ring, D.

Essential features of anti-inflammatory steroids consist of the following: 1) a 2-carbon chain at C-17; 2) methyl groups at C-18 and C-19; 3) a ketone oxygen at C-3; 4) an unsaturated bond between C-4 and C-5; 5) a hydroxyl group at C-11; and 6) a ketone oxygen at C-20. This is depicted by the structure of hydrocortisone (cortisol) in Figure 1.

Figure 1. Structure of Hydrocortisone

Figure 1. Structure of Hydrocortisone

Figure 2. Structure of Prednisolone

Figure 2. Structure of Prednisolone

Figure 3. Structure of Methylprednisolone

Figure 3. Structure of Methylprednisolone

The introduction of a double bond between C-1 and C-2 as shown in Figure 2 provides the structure for prednisolone, which has a fourfold enhancement of corticosteroid activity as compared to hydrocortisone. The addition of a methyl group at the 6alpha- position of prednisolone forms methylprednisolone as shown in Figure 3. Methylprednisolone is slightly more potent in glucocorticoid activity than prednisolone and has slightly less electrolyte regulating potency than prednisolone.

Available data (Refs.2, 3, 4) suggest a number of similarities in the metabolism of methylprednisolone and prednisolone. Both prednisolone and methylprednisolone undergo continuous enzyme-regulated interconversion by oxidation of the 11beta-hydroxyl group to the 11-keto group and its reduction back to the 11-hydroxy compound, i.e., reversible reactions to prednisolone and methylprednisolone, respectively. The interconversion reaction takes place primarily in the liver and to a lesser extent in the kidney. The reduced, (11beta-hydroxy) forms, prednisolone and methylprednisolone, are the active forms of these corticosteroids in the body.

Reduction of the C-4, 5 double bond in both compounds occurs at both hepatic and extrahepatic sites and yields a metabolite that is inactive. Subsequent reduction in both compounds of the 3-ketone to a 3-hydroxyl to form a tetrahydrocortisol occurs only in the liver. The reduced A-ring metabolites are enzymatically conjugated primarily in the liver and to some extent the kidney with sulfate or with glucuronic acid to form water-soluble sulfate esters or glucuronides, which are excreted in the kidney. Biliary or fecal excretion is not thought to be of quantitative importance.

The major metabolic enzyme involved in the transformation of prednisolone and methylprednisolone include the 11-beta- hydroxy-steroid dehydrogenase and 20-keto-steroid reductase. The metabolic fate of methylprednisolone and prednisolone may differ slightly and evidence for their interconversion by methylation or demethylation is lacking.

The duration of action of both prednisolone and methylprednisolone are such that their dosage regimes are similar.

The following pharmacokinetic data(Ref.5) (in humans) for methylprednisolone and prednisolone compare the two drugs:

(Eds. note: The following table consists of 7 columns.)

                  Availability   Urinary   Bound in
                     (oral)     Excretion   Plasma   Clearance   Vol. Dist.    Half-Life
  Corticosteroids     (%)          (%)        (%)   (mL/min kg)  (liters/kg)   (hours)

Methylprednisolone      83±13         4.9±2.3      78±3       6.2±0.9      1.2±0.2        2.3±0.5
   Prednisolone         82±13          26±9        90-95      8.7±1.6      1.5±0.2        2.2±0.5

The above data and the following data and discussion support the thesis that absence of the methyl group on prednisolone has little effect on the relative safety and efficacy of prednisolone in the dog. Methylprednisolone tablets in dogs were included in the NAS/NRC review while only prednisolone solution and suspension were reviewed. Accordingly, a bioequivalency study was conducted to demonstrate the comparative bioavailability of Vet-A-Mix's PrednisTab(TM) (prednisolone) tablets to the approved pioneer product, Upjohn's Medrol® (methylprednisolone) tablets, NADA #11-403, which was the product included in the NAS/NRC review.

b. Pivotal Studies

1) Bioequivalency study

2) The bioequivalency study was conducted by:
Joseph W. Denhart, DVM, at the College of Veterinary Medicine in the Toxicology section of the Veterinary Diagnostic Laboratory, Iowa State University, Ames, Iowa 50011 for Vet-A-Mix, Inc., Shenandoah, Iowa 51601. The sponsor certifies that the study was performed in compliance with Good Laboratory Practices (21 CFR, Part 58). It was audited by Patricia J. Varilek, an independent Quality Assurance Unit monitor, during critical phases, including dosing, testing and data processing, to certify compliance with GLPs. The dosing dates for Period I and Period II of the crossover study were July 28 and August 18, 1988, respectively. All dogs were additionally tested on July 25 (pre-trial) and August 25 (post-trial) for selected hematologic, serum biochemical and urine parameters.

3) General design of the investigation:

a) Purpose of the study
The crossover study was designed to demonstrate bioequivalency of PrednisTab(TM) (prednisolone 5 mg tablets) and Medrol® (methylprednisolone 1 mg tablets) in dogs.

b) Test animals
Nineteen healthy adult mixed-breed dogs (9 female and 10 male) obtained from Laboratory Animal Resources, Iowa State University were used.

c) Test drug
PrednisTab(TM) (prednisolone 5 mg tablets)

d) Type of control group
The pioneer product, Medrol® (methylprednisolone 1 mg tablets) was used as an active treatment control. Each animal was tested pre- and post-treatment for control values of test and selected clinical parameters.

e) Diagnosis
Normal animals were used.

f) Dosage form: oral tablets

g) Route of administration: single oral dose

h) Dosages used
A summary of dosing by test groups follows:

(Eds. note: The following table consists of 3 columns.)

               Group (Sequence) 1  Group (Sequence) 2

Period I     Drug:  (A) Medrol®          (B) PrednisTab(TM)
Dose (Dogs <40 lb)   0.27 mg/lb            0.34 mg/lb
Dose (Dogs >40 lb)   0.20 mg/lb            0.25 mg/lb

Period II    Drug:  (B) PrednisTab(TM)   (A) Medrol®
Dose (Dogs <40 lb)   0.34 mg/lb            0.27 mg/lb
Dose (Dogs >40 lb)   0.25 mg/lb            0.20 mg/lb

The basis for determining the relative 5:4 milligram dosage of PrednisTab(TM) versus Medrol® is documented under "Corroborative literary references." Haynes and Murad (Ref.4) show that the relative anti-inflammatory potency of Prednisolone to 6alpha-Methylprednisolone is 4 to 5. The relative sodium retaining potency is 0.8 to 0.5 and the equivalent dosage (mg) is 5 mg for prednisolone and 4 mg for 6alpha-methylprednisolone. Liddle (Ref.3), in comparing the relative effectiveness of 6alpha-methylated and non- methylated steroids on excretion of sodium and potassium in the adrenalectomized dog, show that the relative potency of prednisolone and methylprednisolone to be 3 to 2 respectively. Wilcke and Davis (Ref.6), Ferguson (Ref.8), and Mulnix (Ref.11) all reiterate that the relative anti- inflammatory potency of prednisolone to methylprednisolone is 4 to 5. Medleau (Ref.14) states "Four milligrams of methylprednisolone (Medrol® - Upjohn) is equivalent to 5 mg of prednisone or prednisolone." i) Test duration

The dogs were acclimated at least 14 days, followed by Period I in which each dog in a group of 9 or 10 dogs was administered a single oral dose of one of the two drugs. After a washout of 21 days the procedure was repeated in Period II with a reversal of the drug sequence. The dogs were fasted 24 hours before and 24 hours after administration of the drugs at each Period.

j) Pertinent parameters measured

Two biological responses were used to compare the bioactivity of the two drugs, 1) the suppression of circulating eosinophils; and 2) an increase in blood glucose values.

  1. Eosinophil counts

    Total circulating eosinophil counts were made at the following times in hours relative to dosing: -12, 0, +2, +4, +6, +8, +12, +18, +24, +36, +48, +72.

  2. Blood glucose

    Blood glucose values were determined at the following times in hours relative to dosing: -12, 0, +2, +4, +6, +8, +12, +18, +24.

  3. Additional Clinical parameters measured

    All dogs were additionally tested 3 days prior to Period I (Pre-trial) and 7 days after Period II (Post-trial) for several hematological and serum biochemical parameters plus urinalysis.

    1. Serum biochemistry (BUN, creatinine, alkaline phosphatase, SGPT and total bilirubin)
    2. Hematology [CBC (RBC, WBC, hemoglobin, packed cell volume) and differential blood count]
    3. Urinalysis (color, transparency, urobilinogen, blood or hemoglobin, bilirubin, ketones and protein)
  4. Results a) Eosinophil Counts

    The least square mean values for unadjusted eosinophil counts are listed in the following table at each time period for each drug.

    (Eds. note: The following table consists of 13 columns.)

                  -12     0    +2    +4     +6    +8   +12   +18    +24   +36   +48   +72
                   hr    hr    hr    hr     hr    hr    hr    hr     hr    hr    hr    hr
    Medrol®
       Drug A       48.9   54.2   45.2   13.7    3.5    1.0    1.5   22.1   35.0   35.8   41.9   45.3
    PrednisTab(TM)
       Drug B       51.2   53.2   41.5   13.6    3.1    1.0    2.5   24.5   37.9   31.9   41.1   39.9
    

    These values are unadjusted and need to be multiplied by 17.6 to obtain eosinophils/mm^3

    Graph of Least Square MEans Eosinophils

    The means, upper and lower 90% confidence intervals, and percentage of the reference drug for AUC, Tmin, and Cmin of eosinophils are listed in the following table.

    (Eds. note: The following table consists of 4 columns.)

                    AUC         Tmin     Cmin
                (mg/dl x hr)    (hr)    (mg/dl)
    Medrol®
       Drug A       2362.99         8.10       .52
    PrednisTab(TM)
       Drug B       2275.19         7.81       .67
    
    Lower 90% C.I.  -394.17        -1.26      -.41
    Upper 90% C.I.   218.57         0.69       .70
    L% of Drug A     -16.68       -15.60    -79.45
    U% of Drug A       9.25         8.47    134.77
    

b) Blood Glucose Concentration The least square mean values for glucose values are listed in the following table at each time period for each drug.

(Eds. note: The following table consists of 10 columns.)

               -12    0    +2    +4    +6    +8   +12   +18   +24
                hr   hr    hr    hr    hr    hr    hr    hr    hr
Medrol®
   Drug A        86.2  86.8   89.3   87.9  93.2   91.4   81.1   79.0  85.1
PrednisTab(TM)
   Drug B        85.6  86.9   89.8   89.2  94.4   91.8   81.6   81.3  84.5

These are fasted values at each time period.

Graph of Least Square Means - Plasma Glucose

The means, upper and lower 90% confidence intervals, and percentage of the reference drug for AUC, Tmax, and Cmax for glucose concentrations are listed in the following table.

(Eds. note: The following table consists of 4 columns.)

                     AUC         Tmax     Cmax
                 (mg/dl x hr)    (hr)    (mg/dl)

Medrol®
   Drug A             2036.74         5.99      94.82
PrednisTab(TM)
   Drug B             2058.57         6.52      96.62

  Lower 90% C.I.       -15.37        -1.34       -.50
  Upper 90% C.I.        59.03         2.41       4.10
  L% (of Drug A)        -0.75       -22.42       -.53
  U% (of Drug A)         2.90        40.23       4.33

c) Additional Clinical Parameters The mean values for the animals prior to testing and after testing with the normal reference values for the Clinical Pathology Laboratory, Iowa State University, Ames, Iowa are listed below.

(Eds. note: The following table consists of 4 columns.)

                              Normal
Parameters Measured           Values         Pre-trial    Post-trial
(1) Hematology
   Hemoglobin gm/dl                12-18              16.9         15.4
   Packed Cell Volume              37-55              49.1         45.7
   Red Blood Cells                  6-9                7.03         6.30
   White Blood Cells             6000-17000        10457.9      11021.1
     Banded Neutrophils             0-300              0.0         64.9
     Segmented Neutrophils       3000-11400         6358.4       6912.0
     Lymphocytes                 1000-4800          2944.2       2965.1
     Monocytes                    150-1350           518.6        361.3
     Eosinophils                  100-750            618.6        706.4
     Basophils                      0-30              18.1         11.5
        
(2) Serum Biochemistry
   Urea Nitrogen mg/dl             10-30              14.1         13.2
   Creatinine mg/dl               0.5-1.5              1.1          1.0
   Total Bilirubin                0.1-0.5              0.21         0.18
   Alanine Aminotransferase IU/l    0-75              45.3         38.1
   Alkaline Phosphatase IU/l        0-150             43.4         41.1

(3) Urinalysis
   Specific Gravity             1.015-1.045            1.033        1.028
   pH                               5-7                6.84         7.18

The following tests were also conducted on urine samples: color, transparency, urobilinogen, blood or hemoglobin, bilirubin, ketones, and protein. All of the clinical pathological parameters examined were within the range of normal accepted values prior to and after the dosing phase of the study.

5) Statistical analysis

a) Discussion of the statistical results

  1. Identification of statistical method(s).

    The Draft Bioequivalence Guidelines of CVM, Food and Drug Administration, April 1989, were used for statistical analysis utilizing the confidence interval approach.

    1. Eosinophil Counts

      The primary parameters statistically evaluated for eosinophils were area under the curve (AUC), minimum concentration (Cmin) and time to minimum concentration (Tmin).

    2. Blood Glucose Concentrations

      The primary parameters statistically evaluated for glucose concentration were area under the curve (AUC), maximum concentration (Cmax) and time to maximum concentration (Tmax).

  2. Statistical Results

    1. Eosinophil Counts

      The lower and upper 90% confidence interval percent of the reference drug for the mean minimum eosinophil count (Cmin) were outside the 20% guidelines. This reflects the number of zero values in the data pool that tended to cause a skewing effect which has invalidated a parametric analysis for Cmin. The lower and upper 90% confidence interval percent of the reference drug for both total area under the curve (AUC) and mean time to minimum eosinophil count (Tmin) are within the 20% guideline limit for acceptance of equal bioactivity. Therefore, Medrol® and PrednisTab(TM), when dosed at comparative doses, are bioequivalent when considering the anti-inflammatory action of depletion of circulating eosinophils.

    2. Blood Glucose Concentrations

      The upper and lower 90% confidence interval percent of the reference drug for the mean time to maximum plasma glucose concentration (Tmax) were outside the 20% guideline limits. The difference of approximately one- half hour between the two drugs to attain maximum plasma glucose concentration is too short a time to be biologically or therapeutically significant. The upper and lower 90% confidence interval percent of the reference drug for total area under the curve and maximum glucose concentration (Cmax) are well within the 20% guideline limit for acceptance of equal bioactivity. Therefore, Medrol® and PrednisTab(TM), when dosed at comparative doses, are bioequivalent when considering the glucocorticoid action of increased plasma glucose concentrations.

6) Conclusions
The biological and anti-inflammatory activity of methylprednisolone in dogs has been determined by the National Academy of Sciences/National Research Council (NAS/NRC) review to be effective and safe. The April 12, 1969 Federal Register publication reflects the Food and Drug Administration's concurrence with the findings of the NAS/NRC review.

The reference drug, methylprednisolone, with a 6-alpha methyl substitution on ring B of the molecule, is an analogue of the test drug, prednisolone.

The bioequivalency of the test drug, Vet-A-Mix's PrednisTab(TM), compared to the approved reference drug, Medrol®, was studied using two physiological endpoints, the anti-inflammatory action of the drugs as measured by depletion of circulating eosinophils and the glucocorticoid bioactivity as measured by increased plasma glucose concentration.

Statistical analyses of pharmacokinetic parameters using the confidence interval approach demonstrated bioequivalence of the two drugs. Bioequivalence was shown using the physiological endpoint of eosinophil counts as measured by area under the curve and mean time to minimum eosinophil count. Bioequivalence was shown using the physiological endpoint of increased plasma glucose concentration as measured by area under the curve and maximum glucose concentration.

In addition, the clinical parameters tested indicated that the dogs were essentially normal prior to dosing and that the drugs did not effect any toxicological changes after dosing.

7) Adverse Reactions

No adverse reactions that could be ascribed to treatments were noted in this study.

 

V. ANIMAL SAFETY

The biological and anti-inflammatory activity of methylprednisolone in dogs has been determined by the National Academy of Sciences/National Research Council (NAS/NRC) review to be effective and safe. The April 12, 1969 Federal Register publication reflects the Food and Drug Administration's concurrence with the findings of the NAS/NRC review.

The detailed narrative comparison of methylprednisolone and prednisolone should be referenced from pages 2 to 4. This information, bioequivalency data on pages 7 to 11 and additional clinical parameters measured pre and post- trial on page 10 support the thesis that absence of the 6alpha-methyl group on prednisolone has little effect on the relative safety of prednisolone in the dog. The conclusions of the bioequivalency study may be found on pages 11 and 12.

Corroborative literary references:

(1) USP DI. 1989. Adrenocorticoids/corticotropin (systemic- glucocorticoid effects). Pages 71-102 in Drug Information for the Health Care Professional, Volume 1A. 9th ed. The United States Pharmacopeial Convention, Rockville, Maryland.

(2) Szefler, S. J. 1989. General pharmacology of glucocorticoids. Pages 353-376 in R. P. Schleimer, H. N. Claman and A. L. Oronsky, eds. Anti-inflammatory Steroid Action: Basic and Clinical Aspects. Academic Press, Inc., San Diego, California.

The following table provides the relative potencies of prednisolone, methylprednisone, and other corticosteroids.

(Eds. note: The following table consists of 6 columns.)

Table 1. Relative Potencies of Corticosteroids

                   Glucocorticoid   Equivalent       Mineralocorticoid   Plasma        Biologic
                   Potency          Glucocorticoid   Potency             t1/2 (min)    t1/2 (hr)
                   dose (mg)

Short-acting
 Cortisol               1                   25                  1                   90              8-12
Intermediate-acting
 Prednisolone           4                    5                  0                  200             12-36
 Methylprednisolone     5                    4                  0                  200             12-36
 Triamcinolone          5                    4                  0                  200             12-36

Long-acting   
 Betamethasone         25                    0.60               0                  300             36-54
 Dexamethasone         30                    0.75               0                  300             36-54

Mineralocorticoid
Corticosterone          0.35                -----              15
Fludrocortisone        10                                     125

Modified from Axelrod, L. 1985. Glucocorticoids. Page 817 in W. N. Kelly, E. D. Harris, S. Ruddy, and C. B. Sledge, eds. Textbook of Rheumatology. Saunders, Philadelphia, Pennsylvania.

(3) Liddle, G. W. 1958. Studies of structure-function relationship of steroids. II. The 6alpha- methylcorticosteroids. Metab. Clin. Exp. 7:405-415. The excerpt from the following table compares the relative excretion of sodium and potassium in the adrenalectomized dog.

Table 1. Relative Effectiveness of 6alpha-Methylated and Non- Methylated Steroids on Excretion of Sodium and Potassium in the Adrenalectomized Dog, using DOC as a Standard.

(Eds. note: The following table consists of 3 columns.)

Table 1. Relative Effectiveness of 6alpha-Methylated and Non-Methylated Steroids on Excretion of Sodium and Potassium in the Adrenalectomized Dog, using DOC as a Standard

                                 95% Confidence
Steroid                Potency      Limit

Desoxycorticosterone       100
Hydrocortisone               4           (2-8)
Prednisolone                 3           (1-6)
6alpha-methyprednisolone     2           (1-3)

(4) Haynes, R. C., Jr. 1990. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. Pages 1431-1462 in A. G. Gilman et al, eds. The Pharmacological Basis of Therapeutics. 8th Ed., Pergamon Press, Elmsford, New York. The relative effectiveness of prednisolone and methylprednisolone was reviewed and it was determined that 6alpha- methylprednisolone has slightly greater anti- inflammatory potency and less electrolyte-regulating potency than prednisolone.
The excerpt from the following table compares the relative potencies and equivalent doses of the three closely related intermediate acting corticosteroids, prednisone, prednisolone, and methylprednisolone and two short acting corticosteroids, hydrocortisone and cortisone.

(Eds. note: The following table consists of 5 columns.)

Table 60-3. RELATIVE POTENCIES AND EQUIVALENT DOSES OF CORTICOSTEROIDS

                                    Relative                  Approximate
                    Relative Anti-   Sodium-    Duration of   Equivalent
Compound             Inflammatory   Retaining     Action*       Dose**
                       Potency       Potency                    (mg)

Cortisone
 (11-Dehydrocortisol)        0.8             0.8            S             25
Prednisone
 (Delta1-Cortisone)          4               0.8            I              5
Cortisol
 (Hydrocortisone)            1               1              S             20
Prednisolone
 (Delta1-Cortisol)           4               0.8            I              5
 6alpha-Methylprednisolone   5               0.5            I              4

S = short or 8 to 12 hour biological half-life.
* I = intermediate or 12- to 36-hour biological half-life.
** These dose relationships apply only to oral or intravenous administration; relative potencies may differ greatly when injected intramuscularly or into joint spaces.

(5) Benet L. Z. and R. L. Williams. 1990. Design and optimization of dosage regimens; pharmacokinetic data. Pages 1650-1735 in A. G. Gilman et al, eds. The Pharmacological Basis of Therapeutics. 8th Ed., Pergamon Press, Elmsford, New York. (6) Wilcke, J. R., and L. E. Davis. 1982. Review of glucocorticoid pharmacology. Vet. Clinics North Am. 12:3- 17.

A. Effects on Intermediary Metabolism

Administration of a glucocorticoid results in an increase in the concentration of glucose in the blood. An increase in gluconeogenesis, a decrease in synthesis of new protein, altered lipid metabolism, and an anti-insulin effect all contribute to this action.

B. Glucocorticoids as Drugs

...prednisone...lacks glucocorticoid activity until it is converted to prednisolone. If hepatic function is in doubt, the active drug prednisolone should be administered in preference to the prodrug prednisone.

Synthetic glucocorticoids have been produced to minimize undesirable mineralocorticoid effects and enhance glucocorticoid activity.

(Eds. note: The following table consists of 6 columns.)

Comparison of Corticosteroid Bases

                  Anti-inflam-  Mineralo-                        Substitutions
                    matory      corticoid   Dose*   Duration**    to
                   Potency      Potency     (mg)      (Hr)       Hydrocortisone

Intermediate-Acting
  Prednisone            3.5             +           5         12-36       11-ketol;1,2-delta bond
  Prednisolone          4.0             +           5         12-36       1,2-delta bond
  Methylprednisolone    5.0             0           4         12-36       6-alpha-methyl; 1,2-delta bond

* Daily replacement dose for 20 kg dog
** Length of hypothalamic-pituitary-adrenal suppression

C. Chronic Administration of Glucocorticoids The wide range of anti-inflammatory and metabolic effects of the glucocorticoids leads to their use in the treatment of a variety of diseases. The general indications for glucocorticoid therapy include ocular disease, hepatic disorders, malignant hematologic disease, solid tumors, intestinal disease, and most prominently immune-mediated and inflammatory-mediated disease.

The most successful approach to minimizing glucocorticoid side effects has been the application of alternate-day therapy.

D. Alternate-day Glucocorticoid Therapy

Any patient being placed on chronic (longer than 14 days) steroid therapy should be considered as a candidate for alternate-day therapy.

Glucocorticoids suitable for this method have a duration of action of 12 to 36 hours. Prednisolone, prednisone, and methylprednisolone are suitable for this method. ...the hypothalamic-pituitary-adrenal axis will be given a steroid-free rest which will allow the axis to maintain some degree of responsiveness to external stimuli.

E. Systemic Effects of Glucocorticoids

(Eds. note: The following table consists of 2 columns.)

Tissue, Organ or Function Effects

Central Nervous System         Euphoria and behavioral changes; maintenance of
                               alpha rhythm; lower seizure threshold
   
Autonomic Nervous System       Required for normal sensitivity of adrenergic
                               receptors
   
Gastrointestinal Tract         Decrease absorption of calcium and iron; facilitate
                               absorption of fat; increase secretion of acid,
                               pepsin, and trypsin; alter structure of mucin

Skeletal Muscle                Excess and deficiency cause weakness; excess causes
                               muscle atrophy

Skin                           Excess causes atrophy and thinning

Hematopoietic System           Involution of lymphoid tissue; decrease number of
                               peripheral lymphocytes, monocytes and eosinophils;
                               increase number of neutrophils, platelets, and
                               RBCs; decrease clotting time; decrease phagocyte
                               competence

Cardiovascular System          Positive inotropic effect; increase blood pressure
                               due to increased blood volume

Kidneys                        Increase reabsorption of water, sodium and
                               chloride; increase potassium and calcium excretion;
                               increase extracellular fluid volume

Bone                           Inhibit collagen synthesis by fibroblasts;
                               accelerate bone resorption; antagonize vitamin D

Cells                          Stabilize liposomal membranes; inhibit macrophage
                               response to migration inhibiting factor; block
                               sensitization of lymphocytes; block cellular
                               response to inflammatory mediators; inhibit
                               proliferation of fibroblasts
Reproductive Tract             Induce parturition during the latter part of
                               pregnancy in ruminants and horses; effect in dog
                               and cat unknown. Teratogenic during early pregnancy

(7) Coppoc, G. L. 1984. Relationship of the dosage form of a corticosteroid to its therapeutic efficacy. J. Am. Vet. Med. Assoc. 185:1098-1011. Corticosteroids can be safely and effectively used if the various factors influencing dose and duration of action are considered vis-a'-vis the biological response desired. Consideration of ester, vehicle, physical form, and route are not esoteric exercises, but are critical for rational clinical application of these drugs.

(8) Ferguson, D. C. 1985. Rational glucocorticoid therapy in small animals, Part 1. Mod. Vet. Pract. 66:101-105.

A. Though glucocorticoids are widely used in veterinary medicine, there is little objective information available on the efficacy and safety of these drugs in domestic animals. Rational use, therefore, largely depends on clinical experience and extrapolation of data from other species. Clinicians should consider anticipated duration of therapy, individual patient factors, the dose and preparation of glucocorticoid, and alternative modes of therapy that would limit potential side effects of glucocorticoids.

B. Glucocorticoids increase gluconeogenesis, decrease protein anabolism, suppress production of ACTH, TSH, GH and cortisol, inhibit inflammation, cause polyuria, polydipsia, immunosuppression, lymphopenia, eosinopenia, and have positive inotropic and chronotropic cardiac effects. They are only palliative and not curative, and may mask signs of underlying disease. Short-acting glucocorticoids should be used for long-term replacement or alternate-day therapy, while intermediate or long- acting glucocorticoids may be appropriate for initial immunosuppressive or anti-inflammatory therapy.

C. Characteristics of oral glucocorticoids used in small animals are listed in the following table.

(Eds. note: The following table consists of 5 columns.)

Characteristics of Oral Glucocorticoids Used in Small Animals

               Appropriate     Appropriate   Approximate Replace-    Comparative
              for Alternate-      for         ment Dose for a        Approximate
Drug               Day         Replacement       20-kg Dog(1)     Mineralocorticoid
                 Therapy        Therapy            (mg)               Activity

Short-Acting
 Hydrocortisone       No(2)            Yes                  20                      1
 Cortisone           Yes(3)            Yes                  25                      1
 Prednisolone        Yes               Yes                   5                      1
 Prednisone          Yes               Yes                   5                      0.2
 Methylprednisolone  Yes               Yes                   4                      0.1

Intermediate-Acting
 Triamcinolone        No                No                   4                      0

Long-Acting
 Flumethasone         No                No                   1.5                    0
 Dexamethasone        No                No                   0.75                   0
 Betamethasone        No                No                   0.60                   0

(1) Intermediate or long-acting glucocorticoids should not be used for replacement therapy.
(2) Duration of action too short for effective alternate-day therapy.
(3) Not commnly used in small animals for alternate-day therapy because of relatively high expense and short duration of action.

(9) MacDonald, J. M. 1987. The use of glucocorticoid therapy in small animal dermatology. Dermatology Reports6:8. A. The practice of dermatology would be extremely compromised without the use of glucocorticoids. Despite their necessity, glucocorticoids are the most overused and abused group of therapeutic agents. With rational use of these drugs, though, the plethora of side effects associated with their administration usually can be prevented. In dermatology, glucocorticoids are used for their anti-inflammatory (pruritic dermatoses such as atopy, flea allergy, scabies) or immunosuppressive (autoimmune dermatoses such as the pemphigus complex, lupus, pemphigoid, vasculitides) effects. Anticipated duration of therapy is a prime factor in drug selection and regimen of treatment. The specific disease being treated has a bearing on the dosage. Most glucocorticoids are administered systemically; there are fewer indications for topical therapy. Oral administration is preferred because it can be more closely regulated and it is the only safe method of long-term therapy.

B. If the anticipated duration of systemic therapy is less than three to four weeks (short term), the selection of glucocorticoids is not critical; however, if the disease requires long-term therapy (a period of more than three to four weeks), drug selection should be restricted to oral, short-acting drugs. Prednisolone, prednisone, or methylprednisolone is suitable for long-term oral administration.

C. Anti-inflammatory therapy includes induction and maintenance regimes. Induction therapy of an oral glucocorticoid is achieved through the administration of prednisone or prednisolone given SID or divided BID for five to seven days. The anti-inflammatory maintenance dosage may be administered every other morning.

D. Patients requiring maintenance therapy should be placed on an alternate-day regimen. Only short-acting oral glucocorticoids (prednisolone, prednisone, and methylprednisolone) should be used for this purpose. Alternate-day oral treatment with long- or intermediate- acting glucocorticoids such as triamcinolone, dexamethasone, or betamethasone defeats the purpose of alternate-day regimen, which is to provide the hypothalamic-pituitary-adrenal axis a steroid-free rest.

E. Glucocorticoids are an essential part of dermatologic therapy and are relied upon regularly for control of a variety of dermatoses. Side effects are minimized by the alternate-day administration of the smallest effective dose and the exclusion of dermatoses that are not steroid responsive.

(10) Ferguson, D. C. 1985. Rational glucocorticoid therapy in small animals, Part II. Mod. Vet. Pract. 66:175-179.

Such short-acting glucocorticoids as hydrocortisone, cortisone, prednisolone and prednisone should be used for replacement therapy or treatment of shock. Glucocorticoids may be used alone or with nonsteroidal drugs for immunosuppression. Nonsteroidal analgesics may be used to supplement the beneficial effects of glucocorticoids in palliative treatment of chronic arthritis or hip dysplasia. Alternate-day glucocorticoid use minimizes side effects and is safer in case of sudden cessation of therapy. Alternate-day therapy should be preceded by a period of daily use and should end with gradually reduced doses. Withdrawal of glucocorticoids should be gradual and prolonged to avoid complications. The ACTH stimulation test is used to assess adrenocortical function. Glucocorticoids should be supplemented in times of stress for animals with adrenocortical insufficiency.

(11) Mulnix, J. A. 1977. Corticosteroid therapy in the dog. Proc. Ann. Am. Anim. Hosp. Assoc.: 173-179.

A. Anti-inflammatory Potency and Approximate Replacement Dosages for Cortisol (Hydrocortisone) and its Analogues in the Dog.

(Eds. note: The following table consists of 4 columns.)

               Anti-inflammatory   Replacement    20 kg
Compound            Potency         Dose/Day      Dog

Short-Acting
 Hydrocortisone          1.0             1 mg/kg         20 mg
 Cortisone               0.8             1.25            25
 Prednisone              3.5             0.3              6
 Prednisolone            4               0.25             5

Intermediate-Acting
 Methylprednisolone      5               0.2              4
 Triamcinolone           5               0.2              4

Long-Acting
 Dexamethasone          30               0.03             0.6

B. Rational Use of Corticosteroids in the Dog

1. Reasons for Using Corticosteroids as Therapeutic Agents

a. Replacement therapy as in hypoadrenocorticism or following bilateral adrenalectomy

b. Treat wide variety of nonendocrine disorders - this is the most common reason for their use

2. Contraindications to the Indiscriminate Use of Glucocorticoids

a. Pregnancy

b. Topical steroids in presence of corneal ulcer

c. Deep fungal infections

d. Generalized bone disease (osteoporosis)

e. Diabetes mellitus

f. Evidence of chronic infection

3. General System Indications for the Glucocorticoids are as follows:

a. Ocular therapy

Glucocorticoids are a great help in the treatment of noninfectious inflammatory lesions of the eye. The complications that arise due to glucocorticoid use are many. Glaucoma is a steroid-induced condition that seems to be seen only in man and has a genetic link. Posterior subcapsular cataracts have been seen in animals (dogs and rabbits) on high dosages of systemic steroids for prolonged periods.

Steroids are contraindicated if there is any suspicion of a fungal or viral component to an ocular lesion. They will potentiate the problem which could lead to irreversible damage.

Both reversible pupillary dilation and ptosis have been reported with the use of glucocorticoids.

b. Hepatic disease

Steroids seem to have no beneficial use in treating hepatopathies except in the case of chronic active hepatitis in the dog.

c. Malignant hematologic diseases

The clinician is mainly concerned with lymphomas, lymphatic leukemia, and multiple myeloma. Glucocorticoids are used for two purposes in treating these disease conditions. First, they seem to directly destroy the neoplastic cells by inhibiting RNA, protein synthesis, and glucose utilization. Secondly, the steroids are useful in treating the secondary complications such as thrombocytopenia, hemolytic anemia and hypercalcemia.

d. Treatment of solid tumors

The glucocorticoids are used for secondary effects, i.e., hypercalcemia, hemolytic anemia, thrombocytopenia, and cerebral edema associated with metastatic or primary brain tumor.

e. Shock

There has been much controversy in the use of steroids in shock. The following is a brief summary of the effects of steroids in shock.

1) Cardiovascular effects

Steroids have not been proven to improve the cardiac output in any case of shock. Corticosteroids do not directly influence vascular responsiveness or function as adrenergic-blocking agents, nor are they direct vasodilators.

2) Membrane stability

Steroids are known to stabilize lysosomal membranes which contain acid hydrolases. Corticosteroids can prevent injury to capillary basement membrane and endothelium caused by endotoxin. There is evidence that corticosteroids help to restore the metabolism of underperfused tissue toward normal.

3) Metabolic effect

Corticosteroids may reverse some of the metabolic abnormalities associated with oxidative metabolism. In endotoxic shock there is definite benefit due to stabilization of the endothelium and detoxification of the endotoxin.

f. Intestinal disease

Glucocorticoids have been used in treating ulcerative colitis, regional enteritis and granulomatous colitis. The steroids reduce the inflammatory process along with restoring the integrity of the mucosal lining. The steroids are used for only a brief period of time to stabilize the condition.

g. Infectious diseases

Steroids should be used only as a last resort measure in those patients with serious infectious diseases. This measure is done more for the comfort of the patient than for treatment of the disease. Corticosteroids alter the host defense mechanism by: (1) suppression of acute and chronic inflammatory responses; (2) alteration of immunologic responsiveness; (3) impairment of the normal intracellular mechanism for disposal of ingested foreign material by phagocytic cells; (4) diminution of interferon synthesis; and (5) interference with healing of the injured tissue.

h. Allergic disease

The corticosteroids deplete histamine stores and delay resynthesis of histamine by degranulated mast cells. This reduces the hypersensitive and allergic reactions of patients. Steroids also have a direct suppressive action on pruritus. It must be remembered that steroids are only a symptomatic treatment.

i. Collagen vascular diseases

In this group of diseases are included systemic lupus erythematosus (SLE) and polymyositis. They have responded well to glucocorticoids and should be used in the treatment regimen.

(12) Muller, G. H., R. W. Kirk, and D. W. Scott. 1983. Small Animal Dermatology. 3rd ed. W. B. Saunders Company, Philadelphia, PA. Pages 166-174. Glucocorticoid Hormone in Dermatologic Therapy

A. The major indications for glucocorticoid therapy are hypersensitive dermatoses (flea allergy dermatitis, atopy, food hypersensitivity), acute moist dermatitis ("hot spot"), contact dermatitis (irritant or allergic), autoimmune dermatoses (pemphigus, pemphigoid, lupus erythematosus) and acral lick dermatitis.

B. Of the systemic routes, oral administration is preferred because (1) it can be more closely regulated (a daily dose is more precise than with a repository injection; the drug can be rapidly withdrawn if undesirable side effects occur), and (2) it is the only safe, therapeutic, physiologic way to administer glucocorticoids for more long-term therapy.

C. Factors that must be considered include the duration of therapy, the personality of the patient, the personality and reliability of the owner, the response of the patient to the drug, the response of the patient's disease to the drug, and other patient-disease considerations.

D. Dermatologically speaking, clinicians usually talk in terms of anti-inflammatory versus immunosuppressive doses, and induction versus maintenance doses of glucocorticoids.

E. Maintenance therapy with oral glucocorticoid is best accomplished with prednisolone, prednisone, or methylprednisolone on an alternate-day basis.

F. Rarely, anti-inflammatory alternate-day glucocorticoid therapy with the preferred prednisolone, prednisone, or methylprednisolone will not be successful. In these cases, the clinician has three therapeutic options (assuming that glucocorticoid therapy is all that can be done): 1) administer prednisolone, prednisone, methylprednisolone on a daily basis, informing the owner of the inevitability of iatrogenic hyperglucocorticoidism; 2) switch to a more potent oral glucocorticoid on an alternate-day basis; or 3) switch to injectable glucocorticoids. Although the more potent oral glucocorticoids are usually not satisfactory for alternate-day therapy (because of potency and duration of effect, they do not spare the hypothalamic-pituitary- adrenal axis).

G. Expected side effects with anti-inflammatory induction therapy include polydipsia, polyuria, and polyphagia. These are usually unavoidable, of little health significance, tolerated by most owners, and eliminated or greatly minimized when alternate-day maintenance therapy is achieved. Far less common, but much more alarming, are behavioral changes (depression, somnolence, viciousness), panting, and diarrhea (which may be bloody). These usually necessitate stopping therapy and often can be minimized or eliminated by switching to a different glucocorticoid.

H. Significant side effects with appropriate anti- inflammatory systemic glucocorticoid regimens are uncommon in dogs, occurring in less than 10 percent of the animals treated. However, with immunosuppressive regimens, the incidence and severity of glucocorticoid side effects escalate alarmingly, and less than 50 percent of the dogs so treated can be satisfactorily managed.

I. Evaluation of results during corticosteroid therapy is very important. The risks of appropriate systemic anti- inflammatory glucocorticoid therapy to an otherwise healthy dog are minimal. The risks of immunosuppressive doses are of greater concern, especially since the medication is usually prescribed for serious or life- threatening diseases.

(13) Jenkins, W. L. 1985. Pharmacologic control of inflammation. Pages 127-148 in L. E. Davis, ed. Handbook of Small Animal Therapeutics, W. B. Saunders Company, Philadelphia, PA.

Guidelines which should be followed when corticosteroids are administered include the following:

A. Use at correct dosage rate and frequency for a defined and appropriate indication.
B. A single large dose of a glucocorticoid is unlikely to be harmful.
C. Prolonged therapy, at doses above substitution level, may produce harmful effects.
D. Depression of the HHAA may occur and several months are required for recovery to take place.
E. For long-term therapy, early morning alternate-day administration minimizes detrimental effects on the HHAA (use short- or medium-acting corticosteroids).
F. Taper off doses gradually in chronic cases and administer adrenocorticotropic hormone (ACTH) to promote function of depressed adrenal cortex.
G. Recognize disadvantages of long-acting corticosteroids and depo-preparations--especially with regard to HHAA suppression.
H. Long-term therapy should be accompanied by dietary supplementation with high-quality protein, potassium, vitamin A, and vitamin D.
I. The risk/benefit ratio of the concurrent use of corticosteroids and antimicrobial agents should be appraised in each case. Bactericidal antibiotics are preferred.
J. Where acute inflammatory reactions may produce lifelong impairment of an organ's function, early effective doses of corticosteroids are vital.
K. Always recognize that corticosteroids may obscure clinical signs because of the euphoric effects produced, together with improved appetite, reduced fever, pain alleviation, and diminished inflammatory reaction.

Potential Side Effects and Precautions Associated with the Steroids

A. Acute adrenal insufficiency can occur from too rapid withdrawal.

B. Large repetitive doses or prolonged therapy with corticosteroids will result in iatrogenic hypercorticism:

  1. Fluid and electrolyte disturbances with sodium and water retention, potassium loss, and hypokalemic alkalosis.
  2. Hyperglycemia and glycosuria ("steroid diabetes"). Incipient diabetes mellitus may be precipitated.
  3. The catabolic effect of the corticosteroids results in a negative nitrogen balance and an increased urea synthesis.
  4. Abnormal fat deposition may occur.
  5. Polydipsia with polyuria and polyphagia.
  6. Osteoporosis as a result of calcium loss and an increased proneness to fractures.
  7. Decreased linear growth in growing animals.
  8. Myopathy, characterized by muscular weakness.
  9. Acute pancreatitis (rare).
  10. Susceptibility to infection may be increased and encapsulated lesions may break down. Normal wound healing may also be impaired.
  11. Suppression of normal immune mechanisms.
  12. Hypercoagulability of blood has been reported.
  13. Lymphocytopenia, eosinopenia, and neutrophilia.
  14. Temperament changes. An apparent increased feeling of well-being may mask a deterioration in the clinical condition.
  15. The corticosteroids have been incriminated in the exacerbation of seizures in epileptic patients.
  16. Peptic ulceration.
  17. Reversible hepatopathy has been described in dogs.
  18. Induction and inhibition of drug-metabolizing microsomal enzymes may alter the duration of an animal's response to other drugs.

Effects on laboratory findings may include:

A. Blood

  1. Neutrophilia, monocytosis, lymphopenia, eosinopenia
  2. Mild polycythemia (?)
  3. Hyperglycemia
  4. Blood urea nitrogen (BUN) and creatinine--normal to low
  5. Serum alkaline phosphatase (SAP) increased
  6. Alanine aminotransferase (AAT) and gamma - glutamyl transpeptidase (GGT) increased
  7. Lipemia and hypercholesterolemia
  8. Increased sulfobromophthalein (BSP) retention
  9. Elevated sodium, depressed potassium, elevated calcium (?)

B. Urine

  1. Dilute urine (S.G. < 2.007)
  2. Glycosuria
  3. Calciuria

(14) Medleau, L. 1990. Linking chronic steroid-responsive pruritus to allergies. Vet. Med. 85:259-271. The major differential diagnoses for dogs with pruritus that resolves with anti-inflammatory doses of steroids are atopy, food-allergic dermatitis, flea-allergic dermatitis, and allergic contact dermatitis. To complicate matters, dogs may have multiple allergies. Intradermal skin testing is used to rule out flea and inhalant allergies. Food allergies are ruled out by feeding the dog a trial hypoallergenic diet. And a diagnosis of allergic contact dermatitis is based on clinical signs, exclusion of other allergic causes, and, if possible, identification of the contact allergen.

(15) Chastain, C. G., and C. L. Graham. 1979. Adrenocortical suppression in dogs on daily and alternate-day prednisone administration. Am. J. Vet. Res. 40:936-941.

The purpose of this investigation was to evaluate functional and morphologic suppression of the adrenal cortex in dogs given daily physiological doses, daily pharmacological doses, and alternate-day doses of prednisone over a 4-week period.

Three groups of eight normal dogs each were orally given prednisone at doses of 0.22 mg/kg of body weight/day, 0.55 mg/kg/day, or 1.1 mg/kg on alternate mornings. Four dogs served as nontreated controls. Samples were obtained from members of each group to determine baseline serum cortisol and ACTH-stimulated cortisol values and histologic features in the lateral thoracic skin before prednisone administration, and after 1, 2, 3, and 4 weeks of administration. Some animals from each group were necropsied after 1, 2, 3, and 4 weeks of prednisone administration.

Each course of prednisone administration resulted in adrenocortical atrophy and hypofunction, but adrenocortical suppression was less severe and slower in onset in the group given prednisone on alternate days. Extra-adrenal effects observed were atrophy of the skin and focal, fatty change of the liver. These changes were most evident in dogs given daily pharmacologic doses of prednisone (0.55 mg/kg/day). Fewer extra-adrenal effects were observed in dogs given alternate-day therapy. There were no extra-adrenal lesions in the dogs given equivalent glucocorticoid replacement doses (0.22 mg/kg/day).

(16) Spencer, K. B., F. N. Thompson, M. D. Lorenz. 1980. Adrenal gland function in dogs given methylprednisolone. Am. J. Vet. Res. 41:1503-1506.

Serum cortisol (hydrocortisone) was measured by radioimmunoassay in dogs given methylprednisolone (MP) orally or methylprednisolone acetate (MPA) IM. The MP was given on a daily and on an alternate-day basis to different treatment groups and the MPA was administered weekly. Samples of blood were obtained twice a week over a 9-week treatment period for serum cortisol determination, and the adrenal gland response to ACTH was assessed on post-treatment days 1, 3, 5, and 7. Administration of MP on an alternate or daily basis caused a slight but significant (P < 0.05) depression in mean resting cortisol values over time. The MPA administration caused a severe depression of resting serum cortisol values. In response to ACTH, cortisol values invariably increased sharply in non-treated control dogs and in those dogs given MP on an alternate- day basis. Dogs given MP daily had a depressed response to ACTH. The MPA treatment resulted in adrenal cortices that were unresponsive to ACTH. Dogs given MPA, but not challenge exposed with ACTH, had markedly lowered cortisol values for at least 2 weeks after cessation of treatment. Consequently, a difference between daily- and alternate-day MP administration was detected after ACTH challenge exposure; MPA administration inhibited adrenal cortisol secretion for at least the duration of the experiment.

(17) Papich, M. G. and L. E. Davis. 1989. Glucocorticoid Therapy. Pages 54-62 in R. W. Kirk, ed. Current Veterinary Therapy X. W. B. Saunders Company, Philadelphia, PA.

A. Prednisolone suppresses the hypothalamic-pituitary- adrenal (HPA) axis for 24 to 36 hours. Administration of glucocorticoids to dogs for 1 to 2 weeks is unlikely to have a prolonged effect on the adrenal cortex. However, following prolonged administration, adrenal cortical atrophy is possible.

B. Recovery of adrenal function occurs relatively quickly in dogs after chronic steroid administration.

C. Although adrenocortical insufficiency following long- term glucocorticoid therapy has been demonstrated in dogs, via ACTH stimulation test results, clinical signs of iatrogenic hypoadrenocorticism have been uncommon.

D. Potential Adverse Effects of Glucocorticoids

  • Central Nervous System
  • Polyphagia
  • Euphoria
  • Musculoskeletal System
  • Osteoporosis
  • Myopathy
  • Fibroblast inhibition
  • Decreased intestinal calcium absorption
  • Gastrointestinal System
  • GI ulceration
  • Pancreatitis
  • Colonic perforation
  • Fluid Balance
  • Sodium and fluid retention
  • Polyuria and polydipsia
  • Metabolic
  • Hyperlipidemia
  • Lipolysis
  • Protein catabolism
  • Fatty infiltration of liver
  • Steroid hepatopathy
  • Endocrine
  • HPA-axis suppression
  • Diabetogenic
  • Decreased thyroid synthesis
  • Increased parathyroid hormone Host Defenses
  • Decreased bacterial killing
  • Increased risk of septicemia
  • Recurrent septic cystitis

(18) Nelson, R. W. 1987. Glucocorticoid therapy. Pages 218-228 in E. C. Feldman, ed. Handbook of Canine and Feline Endocrinology and Reproduction. W. B. Saunders Company, Philadelphia, PA. A. The oral route for glucocorticoid therapy is preferred in most systemic illnesses. Oral dose forms are usually tablets containing the free steroid alcohol. Oral absorption is usually quite rapid, and plasma half-lives are relatively brief. Unlike many other drugs, however, the duration of glucocorticoid biologic action (as measured by suppression of the hypothalamus and/or pituitary) does not directly parallel the plasma half- life but persists for some time after plasma levels decline. This apparent discrepancy is understood by reiterating that glucocorticoids act by enhancing transcription of both messenger RNA and ribosomal RNA in individual cells, thus creating a wide array of results as well as different durations of action.

B. Prednisolone and methylprednisolone are considered intermediate (12-36 hours) in duration of action.

C. Glucocorticoids inhibit inflammation whether the inciting agent is radiant, mechanical, chemical, infectious, or immune-mediated. Such therapy is palliative in that the underlying cause of a disorder may remain but its clinical manifestations are suppressed. This ability to suppress inflammation, regardless of its cause, has made glucocorticoids valuable therapeutic agents. However, these encompassing properties also make glucocorticoid therapy dangerous because these agents are potent at masking the clinical expression of a disease process. The inflammation that allows the clinician to evaluate a chosen course of therapy can be completely suppressed, allowing a disease to continue or worsen but not be identified. As with any therapy, the benefits of glucocorticoid medication must be weighed against the risks of their use.

(19) Knecht, C. D., B. Henderson, R. C. Richardson. 1978.
Central nervous system depression associated with
glucocorticoid ingestion in a dog. JAVMA. 173:91-92.

Signs of a central nervous system disorder were observed following 2 instances of accidental ingestion of glucocorticoid, one time being 250 mg of prednisolone in tablets, in a young female Doberman Pinscher. The signs included transient aggressive and paranoid behavior, amaurosis, disorientation, ataxia with circling backward and depression. Vomiting, weight loss, and abnormal drinking behavior persisted for several weeks following recovery from the acute illness.

(20) Nara, P. L., S. Krakowka, T. E. Powers. 1979. Effects of prednisolone on the development of immune responses to canine distemper virus in beagle pups. Am. J. Vet. Res. 40:1742-1747.

Effects of oral prednisolone (OP) on the development of immune responses of Beagle pups to canine distemper virus (CDV) were studied. Dogs were treated with OP for 21 days, twice a day for the first 7 days, once a day for the next 7 days, and on alternate days for the last 7 days. Dogs given dosages of OP (1 mg/kg and 10 mg/kg) showed a normal in vivo immunogenic response after CDV vaccination and survived a virulent CDV challenge exposure, whereas nontreated, non-vaccinated dogs became ill or died after challenge exposure. The most marked effect of corticosteroid treatment on the immune system was the graded phytoimmunosuppressive effect upon the lymphocyte blast transformation test.

 

VI. HUMAN SAFETY:

a. 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 oral use in dogs, which are non-food animals.

b. Safety Relative to Possession, Handling and Administration

The labeling contains adequate caution/warning statements.

 

VII. AGENCY CONCLUSIONS:

This is a "pipeline DESI" product. This application was filed November 3, 1988 under the Drug Efficacy Study Implementation (DESI) policy for New Animal Drug Applications (NADA), prior to November 16, 1988 enactment of the Generic Animal Drug and Patent Term Restoration Act (GADPTRA) (refer to the fourth policy letter for GADPTRA, November 2, 1989). The NADA, filed under DESI policy, is based on a demonstration of bioequivalence of an approved pre-1962 pioneer product and an "identical, like or related" "me-too" product.

This NADA is for PrednisTab(TM) (prednisolone) tablets, an oral anti-inflammatory drug for use in dogs. The pre-1962 pioneer product is Medrol® (methylprednisolone) tablets, NADA #11-403, sponsored by the Upjohn Co. The National Academy of Sciences/National Research Council (NAS/NRC) DESI Review determined methylprednisolone tablets to be effective and safe as an oral anti-inflammatory agent for dogs. The April 12, 1969 Federal Register publication reflects the Food and Drug Administration's concurrence with the findings of the NAS/NRC review.

A bioequivalency study comparing the anti-inflammatory activity of the two steroids was completed prior to November 16, 1988 enactment of GADPTRA. Based on the established potency rating of 1 for hydrocortisone, the relative anti-inflammatory potencies of prednisolone and methylprednisolone are 4:5, respectively (A. G. Gilman et al, eds. The Pharmacological Basis of Therapeutics, 8th ed., 1990, p. 1447). The above referenced study conducted by Vet-A-Mix confirmed the relative potencies and established the bioequivalence of prednisolone/methylprednisolone at a dosage ratio of 5:4, respectively.

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and Section 514.111 of the regulations. It demonstrates that PrednisTab (prednisolone), when used under the labeled conditions of use, is safe and effective.

The approval of this NADA is based on the demonstration of bioequivalency with a pre-1962 NAS/NRC (DESI) reviewed product; therefore, the product does not qualify for marketing exclusivity.

The drug is restricted to use by or on the order of a licensed veterinarian because a knowledge of veterinary medicine is needed for the accurate diagnosis of conditions for which the drug is intended and for determination of appropriate dose, monitoring of treatment, and detection of possible adverse reactions.

 

VIII. LABELING (Attached)

  1. PrednisTab(TM) 5mg 1000 tablet package label
  2. PrednisTab(TM) package insert

Copies of these labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855