NADA 141-107 BAPTEN® For Injection - original approval

Approval Date: June 10, 1998

I. GENERAL INFORMATION:

NADA	141-107
Sponsor:	Alaco, Inc. 1500 N. Wilmot Road Suite 290-C Tucson, Arizona 85712
Generic Name:	b -aminopropionitrile fumarate
Trade Name:	BAPTEN® For Injection
Marketing Status:	Prescription

 

II. INDICATIONS FOR USE:

BAPTEN is indicated for the treatment of tendinitis of the superficial digital flexor tendon (SDFT) in the adult horse where there is sonographic evidence of fiber tearing.

 

III. PRODUCT INFORMATION:

A. Background:

Superficial digital flexor tendinitis is a severe debilitating injury which is common in performance horses. In the following studies, tendon remodeling following BAPTEN treatment was evaluated using diagnostic ultrasound (DUS), primarily by the measurement of tendon cross-sectional area (CSA). The percent change in CSA for the total tendon, the total injured zone, and the maximum injured zone were evaluated over a four month period. Other parameters evaluated by DUS included echogenicity of the lesion, and parallelism of newly formed collagen fiber bundles. Following BAPTEN injections, a low level exercise program was initiated during the four month studies. Increases in exercise were scheduled to occur only after improvement in ultrasound parameters. The studies conducted support the treatment of equine tendon injuries with BAPTEN to enhance scar collagen remodeling as evaluated by DUS.

During tendon healing, an early increase in tensile strength occurs as a result of random collagen deposition (as layed down by migrating fibroblasts)¹. During tendon repair, maximal crosslinking of collagen occurs from approximately day 10 to day 35². BAPTEN inhibits covalent crosslinking of collagen by irreversibly blocking the enzyme lysyl oxidase^3,4. Collagen synthesis proceeds at the same rate; however, tensile strength is weak since early random crosslinking does not occur^5,6. A closely regulated low impact exercise program facilitates longitudinal collagen fiber alignment (remodelling)¹. Once the effects of BAPTEN dissipate, active enzyme is once again able to crosslink collagen. The collagen fibers are then more longitudinally aligned for better tensile strength. Although the healing process is not shortened by the use of BAPTEN, the healed tendon should be stronger due to remodelling.

Due to its inhibition of collagen crosslinking and healing, tendon lesions could worsen if exercise recommendations are exceeded or lesion status is not monitored by DUS. The duration of the effects of BAPTEN on collagen crosslinking in the horse has not been determined. However, normal tendon healing was ultrasonographically demonstrated in the 4 month long efficacy studies described in this FOI Summary.

B. Dosage Form:

BAPTEN is available as a sterile lyophilized powder. Each vial contains 7 mg of b -aminopropionitrile fumarate which is to be reconstituted with the accompanying 10mL vial of sterile physiologic saline, USP, to a final concentration of 0.7 mg/mL.

C. Route of Administration:

BAPTEN is injected directly into the tendon lesion area.

D. Recommended Dosage:

Following lesion evaluation using diagnostic ultrasound (DUS), injection of BAPTEN should begin approximately 30 days after the initial injury.

Each reconstituted vial contains 7 mg of BAPTEN in a volume of 10 mL. One vial should be injected intralesionally every other day for a series of 5 injections. As much of the total volume of solution should be injected as possible, but this may vary with the size of the lesion.

BAPTEN is administered at 0.2 mL per site into multiple sites at 1.5 cm intervals beginning 1.5 cm distal to the lesion and continuing 1.5 cm proximal to the lesion. Injections are placed medially, laterally and on the palmar surface of the tendon at each 1.5 cm level, directly into the tendon to a maximum of 10 mL (50 injections).

The contents of each reconstituted vial must be used immediately or discarded.

 

IV. EFFECTIVENESS:

Dose Determination, Dose Confirmation, and Clinical Field Trial Studies were conducted. Based on the results of the controlled, blinded Dose Determination and Dose Confirmation Studies, efficacy was best demonstrated in the 7 mg treatment group. The uncontrolled, unblinded clinical use study evaluated the use of BAPTEN in the hands of twelve investigators in the United States and the United Kingdom. All studies were conducted over a four month period.

Diagnostic ultrasound (DUS): Tendon lesions and lesion healing were evaluated using DUS. The palmar surface of the equine foreleg behind the metacarpal bone is evenly divided into seven sections (1A, 1B, 2A, 2B, 3A, 3B, 3C) beginning at the base of the accessory carpal bone and proceeding distally at approximately 4 cm intervals. Each level was evaluated for the following parameters:

Cross-sectional area (CSA):

Ultrasound efficacy parameters include the whole tendon cross-sectional area (CSA), the total injured area CSA, and the maximum injury zone CSA. The average percent change for each parameter is computed by first calculating the average at week 0 and the average at week 16. These averages are then used to obtain the percent change.

Echogenicity was scored as follows:
0 = isoechogenic
1 = mostly isoechogenic (>50%)
2 = mixed echogenicity
3 = mostly anechoic

Hypoechogenic fiber bundles (as evaluated with DUS) represent compromised fiber paths. Persistent hypoechoic fiber bundles over the time of rehabilitation represent weak collagen repair. Ultrasonographic resolution of hypoechogenic fiber bundles as demonstrated in this study is related to the return of more normal tendon collagen; this in turn is related to tendon strength.

Fiber alignment, the subjective visual estimate of parallelism of fiber bundles, was examined in the sagittal plane for all three parameters (total tendon, injury zone, maximum injury level) and scored as follows:
0 = 76-100% parallel fiber bundles
1 = 51-75% parallel fiber bundles
2 = 26-50% parallel fiber bundles
3 = 0-25% parallel fiber bundles

Normal fiber alignment is the ultrasonographic indicator that the tendon has regained adequate functional strength to withstand initiation of athletic exercise. Since the SDF tendon is loaded almost exclusively in tension, parallel fiber alignment along the tension axis provides the greatest load-bearing capacity.

A. DOSE DETERMINATION STUDY:

Study Title: "Dose Ranging Study For the Efficacy of b -Aminoproprionitrile Fumarate (BAPTEN) in the Treatment of Tendon Injuries in the Horse"

Investigators:

1. J. Wade Byrd, DVM
   Equine Medical Center
   10542 Walker St.
   Cypress, CA 90630
2. Ronald Genovese, DVM
   Randall Veterinary Hospital, Inc.
   20600 Miles Parkway
   Warrensville Heights, OH 44128
3. Virginia Reef, DVM
   University of Pennsylvania
   School of Veterinary Medicine
   New Bolton Center
   382 West Street Road
   Kennett Square, PA 19348-1692

Thirty-nine horses completed the sixteen week observation period and followed the protocol.

With the use of a random numbers table, client-owned performance horses aged 2 to 14 years of both sexes from three breeds (Thoroughbred, Standardbred and Arabian), were allocated to 4 groups: placebo, 3.5 mg, 7 mg and 8 mg BAPTEN. Inclusion criteria required that horses be in good health and have a single superficial digital flexor tendon (SDFT) injured foreleg with the remaining legs being clinically sound. All degrees of injury were allowed into the study.

Treatment was begun approximately 10 days after injury to allow time for collagen production to begin. Clinical evaluations and ultrasound evaluation (in two planes) were performed prior to treatment, at the time of treatment, and 8, 12, and 16 weeks after treatment.Immediately following the series of five BAPTEN treatments given every other day, horses began a graded exercise protocol for tendon rehabilitation. Emphasis was directed at not increasing the horses’ exercise (i.e. tendon loading) except in the face of sonographic lesion improvement (for example, decreased cross-sectional area, increased or stable parallel fiber score and decreased areas of echogenicity.

Success was determined by decrease in tendon cross-sectional area (main parameter) and improvement in fiber score/echogenicity as determined by ultrasound grading. The effects of the horses’ clinical responses to the injections as well as lameness grading during sequential evaluations (weeks 0, 8, 12 and 16) were also recorded. Tendon cross-sectional area (CSA) was measured directly (total tendon, total injured area, and maximum injured zone area). Echogenicity and fiber alignment were graded together. Adverse reactions to tendon injections were scored for 36 of 39 horses as none (0), mild (1), moderate (2) or severe (3).

RESULTS:

EFFICACY:

The following table shows the mean percent decrease in total tendon area and the percent improvement for fiber score for each dose group from week 0 to week 16.

Percent Change from Week 0 And Week 16

Dose (mg)	Number	%Decrease in Total Tendon CSA	%Improvement in Fiber Score
0	9	9.7	30.4
3.5	11	1.8	26.3
7.0	10	13.0	47.3
8.0	9	24.1	45.0

Total injury area CSA was analyzed using analysis of covariance with week 0 as the covariate and week 16 as the dependent variable. The following table shows the least square adjusted means at week 16 for the total injury zone CSA:

Dose (mg)	Placebo	3.5	7.0	8.0
Least square Adjusted Means	11.66	10.24	8.50	9.49

The 3.5 mg dose was not significantly different from the placebo (p=.13); the 7 and 8 mg doses were significantly different from the placebo (p=.00 and p=.03, respectively); the 7 mg dose was significantly different from the 3.5 mg dose (p=.06); the 8 mg dose was not significantly different from the 3.5 mg dose (p=.41) but it was numerically less than the 3.5 mg dose.

The study demonstrated that 7 mg of Beta-aminopropionitrile fumarate was the lowest dose that resulted in a decrease in CSA, as well as an improvement in the fiber score. On an individual basis, there were some failures in the higher groups and some successes in the lower groups.

ADVERSE REACTIONS:

The following table shows the mean scores for the series of 5 injections:

Adverse Reactions To Injection Treatment

Dose (mg)	Number	cc Injected	Swelling	Heat	Pain	Lameness
0	6*	9.4	2.1	0.6	0.4	0.3
3.5	11	9.0	1.4	0.9	0.6	0.4
7	10	8.9	1.4	0.7	0.3	0.2
8	9	9.4	1.6	0.5	0.4	0.4

*data not available on three placebo horses

Severe, moderate, and mild reactions occurred throughout all groups. There was no clinical difference among the groups regarding reactions in tendons that received BAPTEN or placebo injections.

B. DOSE CONFIRMATION STUDY

A dose confirmation study was planned using the 7 mg dose. Inclusion and exclusion criteria were more restrictive than in the dose determination study. Horses with a history of a previous episode of SDF tendinitis (rebows) were excluded. Also, the administration of BAPTEN was delayed until 2 to 4 weeks post injury in the remaining pivotal studies and in the label recommendations, to allow time for dissipation of the hematoma and associated edema that followed the initial traumatic injury. Also, antiinflammatory medication was allowed until 2 weeks before the initiation of the series of BAPTEN injections.

In the dose confirmation study, a total of 37 animals (27 treated and 10 placebo) were evaluated at two geographical sites. The purpose of the studies was to confirm the 7 mg BAPTEN dose for the intralesional treatment of injuries to the SDFT, compared to the use of a placebo.

Study Title: "Dose Confirmation Study for the Efficacy of Beta-aminopropionitrile

Fumarate (BAPTEN) in the Treatment of Tendon Injuries in the Horse"

Investigators:

1. Ronald Genovese, DVM
   Randall Veterinary Hospital, Inc.
   20600 Miles Parkway
   Warrensville Heights, OH 44128
2. Virginia Reef, DVM
   University of Pennsylvania
   School of Veterinary Medicine
   New Bolton Center
   382 West Street Road
   Kennett Square, PA 19348-1692

RESULTS:

EFFICACY:

The following table shows the percent change in total tendon CSA between week 0 and week 16:

DOSE CONFIRMATION STUDY		CSA			Fiber Alignment			Echogenicity
dose	tendon number	% change tendon	% change total injury zone	% change max injury zone	% change tendon	% change total injury zone	% change max injury zone	% change tendon	% change total injury zone	% change max injury zone
0 mg	10	-1.06	-1.56	7.58	42.11	42.86	51.72	52.63	54.55	53.85
7 mg	27	20.40	21.43	27.23	70.00	69.57	65.52	60.00	63.64	66.67

Total tendon CSA percent change and fiber tendon percent change were analyzed using analysis of variance. The percent change for each horse was calculated as follows:

week 0 - week 16 X 100
week 0

The 7 mg dose of Bapten enhanced tendon healing and scar remodeling by significantly reducing tendon cross sectional area (total tendon percent change, p<.0001) and improving tendon fiber score (fiber tendon percent change, p=.01) when compared to the placebo.

ADVERSE REACTIONS:

There were five injection times and clinical signs of swelling, heat, pain, and lameness were observed at each injection time. The following table shows the mean scores for the series of 5 injections:

Adverse Reactions To Injection Treatment

Dose (mg)	Number	Swelling	Heat	Pain	Lameness
0	10	1.3	0.7	0.7	0.9
7	27	1.4	0.7	0.4	0.5

Reaction scores: 0=none, 1=mild, 2=moderate, 3=severe

There were no clinical differences between placebo and drug treatment group for the reactions to injections. Only one animal had to interrupt the injection schedule for one week due to swelling and heat. This horse had persistent peritendinous thickening over the following months; however, the tendon itself continued to heal as expected and the exercise program progressed on schedule.

C. CLINICAL FIELD TRIAL:

One hundred eleven (111) thoroughbred, standardbred and mixed breed horses, ages 2-14 years, with 109 single and 2 double forelimb superficial digital flexor tendon (SDFT) injuries were treated in this study at twelve test sites (10 USA, 2 England).

Horses were initially treated with anti-inflammatory medications, rest, ice packs, and/or leg wraps until 2 weeks prior to intralesional injections. Injections were begun at baseline (approximately 30 days post injury) and given every other day for 5 treatments. Tendons were evaluated by DUS at time 0, 8, 12, and approximately 16 weeks (15 to 18 weeks).

One hundred ten horses (112 tendons) concluded the injection series and were evaluated for injection reactions and safety considerations associated with BAPTEN treatments. Seventy-seven horses (79 tendons) completed the 4 month observation period with full data for safety and efficacy evaluation. One inadequately sedated horse received a single injection, resulting in a broken needle within the tendon that required surgical removal.

Study Title: "Field Trial Study for the Efficacy of Beta-aminopropionitrile Fumarate in the Treatment of Tendon Injuries of the Horse"

Investigators:

1. Ernest Benner,DVM
   Valley Veterinarian Service
   515 E. 5th Avenue
   Ranson, W. Virginia 25438
2. J. Wade Byrd, DVM
   Equine Medical Center
   10542 Walker Street
   Cypress, CA 90630
3. M. Keith Chaffin, DVM
   Department of Large Animal
   Medicine & Surgery College of
   Veterinary Medicine
   Texas A&M University
   University Drive
   College Station, TX 77843-4475
4. Sue Dyson MA, VetMB,PhD, DEO, FRCVS
   Equine Clinical Unit
   Animal Health Trust
   Snailwell Road Newmarket
   Suffolk CB8 7DW
   England
5. Carol Gillis
   UC Davis
   School of Veterinary Medicine
   Large Animal Clinic
   Davis, CA 95616
6. James Gilman, DVM
   Gilman & Johnson
   867 Wembley Court
   Elgin, IL 60120-5126
7. Celia M. Marr BVMS, MVM, PhD,
   MRCVS
   Dept. of Farm Animal and Equine
   Medicine and Surgery
   Equine Referral Hospital
   The Royal Veterinary College
   University of London
   Hawkshead Lane, North Mymms
   Hatfield
   Herts AL9 7TA
   England
8. Paul D. McClellan, DVM
   Equine Medicine & Diagnostic
   Ultrasound
   6525 Calle del Nido
   Rancho Sante Fe, CA 92067
9. Frank Nickels, DVM
   Michigan State University
   Large Animal Clinic
   E. Lansing, MI 48824-1314
10. Johanna Reimer, DVM
    Rood & Riddle
    2150 Georgetown Rd.
    Lexington, KY 40511
11. Alan Ruggles, DVM
    Ohio State University
    School of Veterinary Medicine
    601 Vernon L. Tharp St.
    Columbus, OH 43210
12. Nathaniel A. White II, DVM
    Marion DuPont Scott Equine
    17690 Old Waterford Rd.
    Leesburg, VA. 22075

RESULTS:

EFFICACY:

The following table summarizes the average percent change values between week 0 and week 16 for CSA, fiber alignment, and echogenicity in the total tendon, the total injured area, and the maximum injury zone. The table compares the results from the clinical trial with the results from the controlled dose confirmation study.

		CSA				Fiber alignment				Echogenicity
dose	tendon number	% change tendon	% change total injury zone	% change max injury zone	% change tendon		% change total injury zone	% change max injury zone	% change tendon		% change total injury zone	% change max injury zone
DOSE CONFIRMATION STUDY
0 mg	10	-1.06	-1.56	7.58	42.11		42.86	51.72	52.63		54.55	53.85
7 mg	27	20.40	21.43	27.23	70.00		69.57	65.52	60.00		63.64	66.67
CLINICAL FIELD TRIAL
7 mg	79	6.75	6.74	8.55	62.50		66.67	65.38	66.67		75.00	68.18

Overall, during the 4 month clinical trial evaluation period, the total tendon mean cross-sectional area (CSA) as determined by DUS decreased by 6.75%. The mean total injury zone CSA decreased in size by 6.74% and the maximum injury level mean CSA decreased by 8.55%. In the dose confirmation study, the total tendon area decreased by 20.40%, the total injury zone by 21.43%, and the maximum injury level by 27.23%.

Twenty-seven of the 79 severely injured tendons (34%) had increases in their total tendon cross-sectional area at 16 weeks compared to week 0. Nineteen of these violated the protocol exercise recommendations by increasing tendon loading without a concomitant decrease in total tendon cross-sectional area compared to week 0.

Fiber alignment and echogenicity consistently improved in nearly all horses compared to baseline.

SAFETY:

Clinical signs of swelling, heat, pain, and lameness were observed at each of 5 injection times. Fifty-seven of the 112 tendons (50.9%) showed moderate or severe swelling during at least one of the injection times. Twenty-seven of the 112 tendons (24.1%) showed moderate or severe heat during at least one of the injection times. Ninety-three (83.0%) of the injected tendons had mean swelling scores in the mild or less range. Mean heat scores of mild or less were seen in 102 (91.1%) of the tendons.

INJECTION SAFETY ASSESSMENT:

The mean side effect scores* for all horses for the complete series of 5 BAPTEN treatments are shown in the following table:

Number of tendons	Swelling	Heat	Pain	Lameness
112	1.2	0.7	0.5	0.5

*Scoring for injection reactions: 0=none, 1=mild, 2=moderate, 3=severe

Severe pain and swelling delayed the third injection in one horse for two days. The horse then completed the series of injections.

Most adverse reactions during the study were transient and associated with BAPTEN injections. However, one horse exhibited swelling and heat similar to many horses during the injection period. This horse continued to have problems with swelling during the post injection period and became lame 3 weeks after the last injection. The tendon showed an increase in CSA, as well as subcutaneous fluid and peritendinous inflammation. The lameness persisted for the entire 4 month evaluation period. The core lesion showed signs of healing, but recurred during the 5th month post-treatment (investigator follow-up report on adverse reaction).

Another horse violated the exercise protocol and developed chronic diffuse tendinitis after being turned out. Many other horses showed increases in CSA after violations of the protocol exercise regimen.

No infections were noted; veterinarians used aseptic skin preparation prior to BAPTEN injections.

CONCLUSIONS:

The effectiveness of BAPTEN is reflected in the change in the cross-sectional area and fiber score for the total tendon, total injury zone, and maximum injury zone. Best results are obtained when conservative tendon loading (exercise) is employed, and changes in exercise level are based on the results of intermittent DUS monitoring.

These studies demonstrate that BAPTEN frequently causes inflammatory side effects that are controllable. The necessity for adequate control of the horse during the tendon injections and the importance of adhering to a carefully monitored (DUS) exercise program were also demonstrated.

 

V. ANIMAL SAFETY

A. ACUTE TOXICITY

An acute toxicity study was conducted to identify systemic toxic effects and affected organ systems after 5 treatments (1X duration) of BAPTEN at 10X (70 mg) the intended single dose concentration for field use.

Due to the technical difficulty associated with the injection of significant volumes of test article into the intact equine tendon, BAPTEN was administered subcutaneously at the base of the neck. Doses were administered on alternate sides of the neck in a different area for each injection.

Study No. C9505

Study Title: "Acute Toxicity Study of Beta-Aminoproprionitrile Fumarate (BAPTEN) in the Horse"

Investigator:

Martha A. Ferris, DVM, MS
Colorado Animal Research Enterprises, Inc. (CARE)
Fort Collins, CO 80524

Study dates: October 18, 1995-November 23, 1995

The study was conducted in accordance with the FDA Good Laboratory Practice Regulations.

Four mixed breed horses (two geldings and two mares), 2-8 years of age and weighing from 979 to 1173 pounds, were dosed every other day over 9 days for 5 treatments at 10X the label dose.

Clinical observations, physical exams, and body weight measurements were monitored. Blood, fecal and urine samples were collected and analyzed pre and post treatment.

The following table lists measured parameters and times for sampling:

Study Schedule (days)
Test	-14	-7	-5	1	3	5	7	9	10
body condition score				X					X
body weight	X	X		X					X
physical examination	X			X		X			X
hematology		X	X	X		X			X
urinalysis		X	X	X		X			X
fecal analysis		X	X	X		X			X
serum chemistry		X	X	X		X			X
coagulation tests		X	X	X		X			X
injection				X	X	X	X	X
termination*									X

* Complete necropsies were conducted on 2 of the 4 horses and gross and microscopic pathology performed.

RESULTS:

No clinical abnormalities were attributable to BAPTEN. No statistically significant hematology or serum chemistry abnormalities related to drug toxicity were observed. Urinalyses results remained normal during both pre and post treatment periods with no statistically significant changes from baseline values.

Histopathology examination revealed only one test article related finding, which was subacute inflammation observed at the last BAPTEN injection site of one horse.

CONCLUSION:

There were no signs of systemic toxicity following subcutaneous administration of 10X the recommended dosage of BAPTEN.

B. CHRONIC TOXICITY

A Target Animal Safety Study was conducted to evaluate injectable BAPTEN when administered subcutaneously at 0X, 1X, 3X, and 5X the intended dose of 7 mg for 3X the labeled duration (15 treatments every other day over a 29 day period).

Study No. C-9504

Study Title: "Chronic Toxicity Study for Beta-Aminopropionitrile Fumarate (BAPTEN) in the Horse"

Investigator:
Martha A. Ferris, DVM, MS
Colorado Animal Research Enterprises, Inc. (CARE)
Fort Collins, CO 80524

Study dates: October 18, 1995-December 13, 1995 (days -14 through 31)

The study was conducted in compliance with FDA Good Laboratory Practice Regulations.

Twenty-four mixed breed horses (11 geldings and 13 mares), 2-11 years of age, and weighing 825 to 1221 pounds, were randomly assigned to treatment groups:

Group	Dose	Test Article	Conc.	Volume	Total mg	Route	No. Horses	Regime
A	0X	vehicle	0 mg/mL	10 mL	0	SC	6	eod X 15 tx*
B	1X	BAPTEN	0.7	10	7	SC	6	eod X 15 tx
C	3X	BAPTEN	1.06	19.8	21	SC	6	eod X 15 tx
D	5X	BAPTEN	1.75	20	35	SC	6	eod X 15 tx

*every other day for 15 treatments

Clinical observations were conducted twice daily from day -14 through day 30. The following study schedule illustrates the parameters that were measured and when samples were taken:

Study Schedule
Test	-14		-7	-5	1	11	21	31
body condition score					X			X
body weight	X		X		X	X	X	X
physical examination	X				X	X	X	X
hematology			X	X	X	X	X	X
urinalysis			X	X	X		X
fecal analysis			X	X	X	X	X	X
serum chemistry			X	X	X	X	X	X
coagulation tests			X	X	X	X	X	X
injection					X	X	X	X
termination								X*

*12 predesignated horses (3 per group) were euthanized and necropsied

RESULTS:

No hematology or clinical chemistry findings suggestive of drug related toxicity were observed. Urinalysis results were normal and fecal occult or gross blood analyses were negative for all horses from all four treatment groups during the pre- and post-treatment periods.

The only clinical sign which may have been drug related was loose fecal consistency which occurred in one horse from each of the three treated groups. However, this sign was also observed during the pre-treatment period in 2 horses and in one horse in the placebo group during the treatment period.

The gross and microscopic histopathological examinations revealed a single occurrence of perarteritis of the cranial mesenteric artery, mesenteric lymph node congestion, and thymus congestion. These findings were not determined to be related to BAPTEN administration. Subacute inflammation was observed at the last injection site in several horses from both the placebo and treated groups.

CONCLUSIONS:

The multiple dose toxicity study results demonstrate that subcutaneous BAPTEN given at 1X, 3X, or 5X the proposed therapeutic dose every other day for 15 treatments did not result in systemic toxicity that was directly attributable to the test article.

Any other clinically significant signs found during the treatment period were attributable to causes other than the test article.

The only finding attributable to the placebo or test article was the inflammation of the subcutaneous injection site in 3 of the 12 euthanized horses.

 

VI. HUMAN SAFETY

A. Human Food Safety

Data on human safety, pertaining to the consumption of drug residues in food were not required for the approval of this New Animal Drug Application. The drug is approved for use only in horses that are not intended for food and is labeled: "Not to be used in horses intended for food."

B. Safety Related to Possession, Handling and Administration.

Labeling contains adequate warnings against accidental self-administration and exposure to drug. An "800" number is provided by the sponsor for the provision of Material Safety Data Sheets (MSDS).

 

VII. AGENCY CONCLUSIONS

The data in support of this NADA comply with the requirements of Section 512 of the Act and Section 514 of the implementing regulations, and demonstrate that Baptenâ when used under labeled conditions of use, is safe and effective.

Under Section 512(c)(2)(F)(i) of the Federal Food, Drug, and Cosmetic Act, this approval qualifies for FIVE years of marketing exclusivity beginning on the date of approval because no active ingredient of the drug (including any ester or salt of the active ingredient) has been approved in any other application.

The drug is restricted to use by or on the order of a licensed veterinarian because professional expertise is required to diagnose and treat tendinitis in horses.

 

VIII. REFERENCES

1. McCullagh, KG, BVSc, PhD, MRCVS, et.al. Tendon injuries and their treatment in the horse. Veterinary Record. 105: 54-57 (1979).
2. Williams, IF. Studies on the pathogenesis of equine tendinitis following collagenase injury. Research in Veterinary Science. 36: 326-338 (1984).
3. Page, RC, et.al. Molecular disease of connective and vascular tissues. II. Amino-oxidase inihibition by the lathyrogen, beta-aminopropionitrile. Biochemistry. 6: 1142 (1967).
4. Bornstein, P. The crosslinking of collagen and elastin and its inhibition in osteolathyrism. Am J Med. 49: 429 (1970).
5. Levene, CI. Possibilities for the therapeutic control of fibrosis. British Journal of Dermatology. 112: 363-371 (1985).
6. Levene, CI, et.al. Alteration in the state of molecular aggregation of collagen induced in chick embryos by b -aminopropionitrile (lathyrus factor). Journal of Experimental Medicine. 110: 171 (1959).

 

IX. LABELING

1. Package Insert
2. Carton Label
3. Bapten Vial Label
4. Diluent Vial Label

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