Date of Approval JAN 2 4

FREEDOM OF INFORMATION SUMMARY

SUPPLEMENTAL NEW ANIMAL DRUG APPLICATION

NADA 110-048

VALBAZEN

Albendazole 1136 suspension Non-lactating goats

for the treatment of adult liver flukes (Fasciola hepatica) in nonlactating goats

Sponsored by

Pfizer Inc

Freedom of Information Summary NADA 110-048

TABLE OF CONTENTS

I GENERAL INFORMATION I

I1 EFFECTIVENESS 2

A Dosage Characterization 2 B Substantial Evidence 2

I11 TARGET ANIMAL SAFETY 4

A Toxicity Study 4

IV HUMAN FOOD SAFETY 6

A Toxicology 6 B Residue Chemistry 6 C Microbial Food Safety 7 D Analytical Method for Residues 7

V USER SAFETY 7

VI AGENCY CONCLUSIONS 8

A Marketing Status 8 B Exclusivity 8 C Supplemental Applications 8 D Patent Information 8

VII ATTACHMENTS 8

I GENERAL INFORMATION

A File Number

B Sponsor

C Proprietary Name

D Established Name

E Pharmacological Category

F Dosage Form

G Amount of Active Ingredient

H How Supplied

I How Dispensed

J Dosage

K Route of Administration

L SpeciesClass

M Indication

N Effect of Supplement

Freedom of Information Summary NADA 1 10-048

Page 1

NADA 1 10-048

Pfizer Inc 235 East 42d St New York NY 10017

Drug Labeler Code 000069

VALBAZEN

Albendazole

Antiparasitic

1 136 suspension

500 mLl169 fl oz 1 Ll338 fl oz and 5 Ll169 fl oz containers

OTC

4 mL1100 lb body weight (equivalent to 454 mg albendazolellb 10 mglkg)

Oral (drench)

Non-lactating goats

For the treatment of adult liver flukes in non-lactating goats

This supplement provides for the treatment of adult liver flukes (Fasciola hepatica) in non- lactating goats

Freedom of Information Summary NADA 1 10-048

Page 2

11 EFFECTIVENESS

Section 5 141 (d) of Title 21 of the Code of Federal Regulations (CFR) permits extrapolation of data from a major species to a minor species to satisfy the requirements of section 512 of the Federal Food Drug and Cosmetic Act with respect to the effectiveness of a new animal drug A combination of data from goats (a minor species) cattle (a closely related approved major species) and sheep (a minor species at the time of the albendazole approval with the exception of human food safety data collection requirements) were used to support the determination of effectiveness consistent with the Guidance for Industry FDA Approval of New Animal Drugs for Minor Uses and Minor Species (FDAICVM 211 199) As of July 26 1999 sheep were reclassified as a minor species for all data collection purposes (64 FR 4032 1)

A Dosage Characterization

The dose of 10 mg albendazolelkg body weight for goats was extrapolated from cattle and sheep

B Substantial Evidence

The following dose titration study serves as the required adequate and well- controlled dose confirmation study The concentration of the albendazole drench used in this study was 568 VALBAZEN (albendazole) is approved at concentrations of 455 (NADA 140-934) and 1 136 (NADA 1 10-048) The original sheep approval (59 FR 657 1 1 December 2 1 1994) was a 455 albendazole concentration However sheep were subsequently added to the label for the 1 136 cattle product (64 FR 1503 January 1 1 1999) The increased albendazole concentration was not expected to pose any specific risk hazard to sheep The actual amount of drug administered to sheep per unit body weight remained the same CVM concluded that the two formulations should perform in an identical manner when administered to sheep Accordingly the sponsors request for waiver of an in vivo study requirement was granted and no additional studies were required to support the approval of the 1 136 oral suspension of albendazole in sheep The same reasoning is applied to this goat supplement

Albendazole Study Against Fasciola hepatica in Goats Safety and Efficacy

1 Type of Study Dose titration study serving as a dose confirmation study

2 Investigator Dr William J Foreyt Department of Veterinary Microbiology and Pathology Washington State University Pullman Washington

Freedom of Information Summary NADA 1 10-048

Page 3 3 General Design

a Purpose of the study To determine the effectiveness of albendazole in the control of adult liver flukes (Fasciola hepatica) in goats and to determine an appropriate dosage

b Test animals Forty weaned male castrated male and female goats approximately 8 weeks of age were allocated for this study Goats were of several different breeds The goats were each inoculated per os with 250 Fasciola hepatica metacercariae in a gelatin capsule

c Dosage Form 568 suspension (drench)

d Route of Administration Oral with a dosing syringe

e Doses 5 mglkg 75 mglkg 10 mglkg or 15 mglkg body weight

f Treatment Groups The goats were randomly assigned to 5 dose groups (untreated control 5 75 10 and 15 mglkg body weight) The allocation into treatment groups was blocked based on weight Fourteen weeks after inoculation albendazole suspension was administered once per os to the treated groups at 5 mglkg 75 mgkg 10 mgkg or 15 mglkg body weight

g Controls The untreated control animals were given a water placebo at a volume equal to that given to the highest treatment group

h Test Duration 1 19 days from inoculation with metacercariae to necropsy

i Diagnosis Infection was confirmed by fecal sedimentation 14 weeks after inoculation and at necropsy The results were recorded as eggs of F hepatica per gram of feces

j Parameter The efficacy of albendazole relative to the control was calculated using the arithmetic means of the flukes recovered at necropsy The following formula was used

controlsEfficacy = Mean flukes - Mean flukes albendazole X 100

Mean fluke^^^^^^

k Results Refer to Table 1 below

Freedom of Information Summary NADA 1 10-048

Page 4

Table 1 Recovery of Adults of Fasciola hepatica at Necropsy and Efficacy at Different Dosages

Dosage (mgkg)

Goats with Flukes at necropsy

( inf examined)

Flukes recovered

mean (range) Efficacy

00 818 754 (43 to 117) --

All goats developed patent infections of F hepatica by 14 weeks post infection

Clinical observations No goats died during this trial and no adverse reactions associated with treatment were observed during the experiment

Necropsy findings All 40 of the study goats were euthanized and necropsied at study end (Day 119) Each animal was noted to have biliary hyperplasia and hepatic fibrosis on necropsy No other post mortem findings were noted

1 Conclusion

Based on this study and on data from the cattle and sheep approvals the recommended dose of albendazole in non-lactating goats of 10 mglkg body weight should be effective in the treatment of the adult liver fluke (Fasciola hepatica) The sponsor extrapolated the albendazole dose for goats of 10 mglkg from the cattle and sheep approvals In this study the 15 mg albendazolelkg dose shows better efficacy against Fasciola hepatica in goats than the 10 mglkg dose However in accordance with the Guidance for Industry FDA Approval of New Animal Drugs for Minor Uses and Minor Species (FDAICVM 211 199) the selection of 10 mglkg may be based on the following 1) the efficacy against adult flukes at 87 is similar to that in cattle and 2) there is no drug currently approved in goats which has efficacy against adult liver flukes

111 TARGET ANIMAL SAFETY

A Type of Study Toxicity Study

1 Title Target Animal Safety of VALBAZEN Oral Suspension (Albendazole) in Goats

2 Investigators Dr AL Craigmill Dr MA Payne and Dr SE Wetzlich University of California Department of Environmental Toxicology Davis California

Freedom of Information Summary NADA 1 10-048

Page 5 3 General Design

a Purpose of the study To provide data necessary to establish the safety of albendazole in goats

b Test Animals Twenty-six (22 female and 4 male) goats of various breeds and crosses 1 to 5 years of age weighing 40 to 71 kg

c Housing Goats were housed together in a single outdoor treatment pen

d Dosage Form VALBAZEN (albendazole) 1 136 suspension (drench)

e Route of Administration Oral with a dosing syringe

f Doses 10 mglkglday body weight (1 X the recommended dose of 10 mglkg) 30 mglkglday body weight (3X the recommended dose of 10 mglkg) and 50 mglkglday body weight (5X the recommended dose of 10 mgkg) administered 3 times 24 hours apart starting on Day 1

g Control Water was dosed at the volume of the 5X (50 mglkglday) group

h Test Duration 18 days

i Pertinent Parameters Measured Body weights were taken prior to dose initiation and daily during dosing to calculate treatment doses Daily observations of the study animals were done in the mornings at feeding from Day -2 to Day 1 1 and included assessment of general appearance appetite and feces Samples for hematology serum chemistry and urinalysis were collected on Day -7 Day 5 and Day 10 of the study

4 Results

The only abnormal finding noted during the daily clinical observations was 2 cases of diarrhea On the third day after the final treatment one of the does in the 5X group developed diarrhea which resolved in 48 hours On the seventh day after the final treatment a doe from the 1X group developed diarrhea The diarrhea in these animals may have been related to albendazole but it was mild and self- limiting

There were statistically significant decreases in phosphorus noted across all treatment groups (including controls) from pretreatment samples to post-treatment samples Similar but not statistically significant decreases in sodium chloride potassium total protein and hematocrit were found across all treatment groups There was a statistically significant difference between the 5X and control group for white blood cell count and total bilirubin on Day 7 post-treatment However the differences were considered to be clinically insignificant

Freedom of Information Summary NADA 1 10-048

Page 6 5 Conclusion

Oral administration of albendazole at the recommended dosage is safe in goats

IV HUMAN FOOD SAFETY

A Toxicology

CVM did not require toxicology studies for this supplemental approval The FOI Summary for the original approval of NADA 1 10-048 dated March 30 1989 contains a summary of all toxicology studies

B Residue Chemistry

1 Summary of Residue Chemistry Study

Tissue Residue Depletion Study in Goats Treated with Albendazole (1136 suspension) In accordance with 21 CFR part 58 this study was conducted in compliance with Good Laboratory Practices

Dr Arthur Craigmill Department of Environmental Toxicology University of California Davis California

Twenty-one commercial breed female goats (6 Lamancha and 15 Alpine) were allocated for this study The goats ranged in age from 1 to 8 years Twenty were treated with a single dose of 10 mg albendazolekg body One Alpine doe was used as an untreated control Treated goats were divided into five groups of four goats each The groups were slaughtered at 5 10 1520 and 25 days after treatment Samples of liver were taken from each animal after slaughter Tissue residues were determined using a modified version of the regulatory analytical method Results are shown Table 2

Table 2 Liver Concentrations of Albendazole (Mean kSD) on Days 5 through 25

Withdrawal period Residues (ppb) (days)

5 13850k2493 10 7870k1653 15 5069k1582 20 2948k217 2 5 2643k817

Freedom of Information Summary NADA 1 10-048

Page 7 Using a liver tolerance value of 250 ppb ( i e the sheep tolerance established following review of a full human food safety package for sheep) and a statistical tolerance limit algorithm the Agency concludes that non-lactating goats treated orally with up to 10 mg albendazole oral suspensionkg body weight will have tissue residues below tolerance if they are withheld from slaughter at least 7 days following drug administration

2 Target Tissue and Marker Residue Assignment

The target tissue and marker residue assigned for the supplemental approval for sheep under IVADA 1 10-048 dated December 2 1998 apply to this approval in goats Liver is assigned as the target tissue and the marker residue is albendazole 2-aminosulfone

3 Tolerance Assignments

The tolerance assigned for the supplemental approval for sheep under NADA 110-048 dated December 2 1998 applies to this approval in goats A tolerance of 250 ppb is assigned for residues of albendazole 2-aminosulfone in goat liver

4 Withdrawal Time

Based on the data provided in the residue depletion study titled Tissue Residue Depletion Study in Goats Treated with Albendazole (1 136 suspension) summarized above and using our statistical tolerance limit algorithm a preslaughter withdrawal time of 7 days is assigned for non-lactating goats treated with a single dose of 10 mg albendazole oral suspensionkg body weight

C Microbial Food Safety

CVM considered the impact of the use of 10 mgkg VALBAZEN (albendazole) oral suspension (1 136) in non-lactating goats on antimicrobial resistance development in bacteria of public health concern A microbial food safety assessment was not necessary at this time

D Analytical Method for Residues

The FOI Summary for the original approval of NADA 110-048 dated March 30 1989 contains the analytical method summaries for VALBAZEN in cattle The method is on file with the Center for Veterinary Medicine Food and Drug Administration 7500 Standish Place Rockville WID 20855

V USER SAFETY

The product labeling contains the following information regarding safety to humans handling administering or exposed to VALBAZEN

Freedom of Information Summary NADA 1 10-048

Page 8 For Use in Animals Only Not for human use Keep This and All Medication Out of Reach of Children

Studies to evaluate the safety of albendazole to users are discussed in the FOI Summary for NADA 1 10-048 approved March 30 1989

VI AGENCY CONCLUSIONS

The data submitted in support of this NADA satisfy the requirements of section 5 12 of the Federal Food Drug and Cosmetic Act and 2 1 CFR Part 5 14 The data demonstrate that VALBAZEN when used according to the label is safe and effective for the treatment of adult liver flukes (Fasciola hepatica) in non-lactating goats Additionally the data demonstrate that residues in food products derived from non-lactating goats treated with VALBAZEN will not represent a public health concern when the product is used according to the label

A Marketing Status

This product can be marketed over-the-counter (OTC) because the approved labeling contains adequate directions for use by laypersons and the conditions of use prescribed on the label are reasonably certain to be followed in practice

B Exclusivity

Under section 573(c) of the Federal Food Drug and Cosmetic Act (the Act) this approval qualifies for SEVEN years of exclusive marketing rights beginning on the date of approval because the new animal drug has been declared a designated new animal drug by FDA under section 573(a) of the Act

C Supplemental Applications

This supplemental NADA did not require a reevaluation of the safety or effectiveness data in the original IVADA (21 CFR 95 14106(b)(2))

D Patent Information

The sponsor did not submit any patent information with this application

VII ATTACHMENTS

Facsimile labeling

500 mL- container label and box carton 1 L- container label (front and back labels) 5 L- container label (front and back labels)

Valbazen (albendazole) Supplemental NADA

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