NADA 141-084 Sentinel™ Flavor Tablets® - supplemental approval (June 17, 1998)

Approval Date: June 17, 1998

I. GENERAL INFORMATION:

II. INDICATIONS FOR USE

SENTINEL Flavor Tabs are indicated for use in dogs and puppies four weeks of age and older and eleven pounds body weight or greater, for the prevention of heartworm disease caused by Dirofilaria immitis, for the prevention and control of flea populations, the control of adult Ancylostoma caninum (hookworm), and the removal and control of adult Toxocara canis, Toxascaris leonina (roundworm) and Trichuris vulpis (whipworm) infections.

III. DOSAGE FORM, ROUTE OF ADMINISTRATION AND RECOMMENDED DOSAGE

SENTINEL Flavor Tabs are given orally, once a month, at the recommended minimum dosage of 0.23 mg/lb (0.5 mg/kg) milbemycin and 4.55 mg/lb (10 mg/kg) lufenuron.

Recommended Dosage Schedule

Dogs over 100 lbs. are provided the appropriate combination of tablets.

IV. EFFECTIVENESS

The effectiveness of SENTINEL Flavor Tabs is based upon existing Novartis product approvals for milbemycin oxime (INTERCEPTORÒ Tablets, NADA 140-915) and lufenuron (PROGRAMÒ Tablets, NADA 141-035), the combination product (SENTINEL tablets NADA 141-084), and the following study comparing SENTINEL tablets and SENTINEL Flavor Tabs.

1) Hookworm Efficacy Study with Flavored Tablet

Purpose: SENTINEL tablets and SENTINEL Flavor Tabs were compared for efficacy against hookworms (Ancylostoma caninum).

Investigator:

Dwight Bowman, Ph.D.
Study Location:
CHK - R&D
Stanwood, Michigan

Type of Study: Natural infections of hookworms Ancylostoma caninum.

Animals: Thirty adult dogs (15 males, 15 females) were divided into three groups of ten dogs each.

Dosage Forms:

• Group 1: Placebo Tablets
• Group 2: SENTINEL (milbemycin oxime/lufenuron) tablets
• Group 3: SENTINEL Flavor Tabs (milbemycin oxime/lufenuron)

Route of Administration: Oral

Dose Tested:

Milbemycin Oxime 0.5 mg/kg

Lufenuron 10 mg/kg

Frequency of Treatment: One treatment.

Controls: Placebo control (group 1)

Duration of Study: The dogs were euthanized 9 days after treatment and worms were recovered, identified and counted.

Results: Efficacy was calculated by comparing the number of worms recovered from each of the two treatment groups versus control animals. The following table shows the mean (geometric) number of worms recovered and the percent efficacy for each group.

Using Wilcoxon Rank Sum Tests, the comparisons of Placebo versus SENTINEL FLAVOR TABS (p < .0001), Placebo versus SENTINEL (p < .0001), and SENTINEL FLAVOR TABS versus SENTINEL (p = .3681) indicated that both SENTINEL FLAVOR TABS and SENTINEL tablets were significantly different from Placebo tablets and were not different from one another. Both SENTINEL FLAVOR TABS and SENTINEL tablets were ³ 99.5% effective in eliminating hookworms from infected dogs when compared to Placebo tablets. There was no difference in effectiveness between SENTINEL FLAVOR TABS- and SENTINEL-treated dogs.

Conclusions: The flavored tablet formulation was equally efficacious as the non-flavored tablet formulation against Ancylostoma caninum infections.

Adverse Reactions: None reported.

2) Clinical Palatability/Acceptability Trial

Purpose: To assess the palatability/acceptability of SENTINEL Flavor Tabs in a clinical trial

Investigator/Study Locations:

Type of Study: Palatability/Acceptability

Animals: Two hundred twenty-five client-owned dogs were enrolled in the study, though only 223 were dosed. One dog was found to be heartworm positive and one dog was hit by a car and killed prior to dosing. Fifteen dogs were dosed with the drug and completed the study but were excluded from analysis for the following reasons: owner non-compliance (4) or use of concomitant drugs that could potentially affect appetite (11). A total of 208 dogs (109 F, 99 M) ranging in age from 2 months to 13 years and in weight from 2 to 100 pounds were included in the analysis of palatability/acceptability.

Dosage Forms:

SENTINEL Flavor Tabs (Milbemycin Oxime/Lufenuron)

Route of Administration: Oral

Dose Tested:

Milbemycin Oxime 0.5 mg/kg
Lufenuron 10 mg/kg

Frequency of Treatment: One dose

Controls: None

Duration of Study: Dogs were offered the tablets by hand and palatability/ acceptability was assessed within 3 minutes. If the dogs did not consume the tablets within this period, the owners were instructed to place the tablets in the food bowl and wait an additional 3 minutes. If this was unsuccessful, the tablets were placed in the dogs’ mouths followed by direct manually dosing, if necessary.

Results: Results are displayed in the following table.

Absolute and Cumulative responses provided by Owners.

Conclusions: SENTINEL Flavor Tabs are palatable to dogs.

Adverse Reactions: None reported.

V. ANIMAL SAFETY

The safety of SENTINEL Flavor Tabs is based upon existing Novartis product approvals for milbemycin oxime (INTERCEPTOR Tablets, NADA 140-915), lufenuron (PROGRAM Tablets, NADA 141-035), and the combination product (SENTINEL tablets NADA 141-084).

VI. Human Safety

Data on human safety, pertaining to consumption of drug residues in food, were not required for approval of this NADA. This drug is to be labeled for use in dogs which are non-food animals.

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. The data demonstrate that SENTINEL Flavor Tabs (milbemycin oxime/lufenuron), when used under labeled conditions of use are safe and effective.

The drug is restricted to use by or on the order of a licensed veterinarian because professional expertise is judged to be critical for the diagnosis of heartworms, whipworms and hookworms and for the safe use of the product.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for non food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug involved, or any studies of animal safety, required for the approval of the application and conducted or sponsored by the applicant. The three years of marketing exclusivity applies only to the new flavored formulation in three tablet sizes for which the supplemental application was approved.

Patent # 4,547,520 expires on June 14, 2004

VIII. Labeling

1. Package Inserts
   • Veterinarian's Insert
   • Client's Insert
2. Blister Cards (6 Tablets)
3. Unit Dose Carton (Flavor Tab and Swallow Tab)
4. Display Carton

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

Freedom of Information Office (HFI-35)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857