Sentinel Flavor Tabs

Novartis Animal Health US, Inc.

Sentinel Flavor Tabs

FULL PRESCRIBING INFORMATION

SENTINEL ^® ( milbemycin   oxime • lufenuron ) Flavor Tabs ^®

The palatable once-a-month prescription tablet that prevents heartworm disease and flea populations in dogs and puppies. SENTINEL® (milbemycin oxime/lufenuron) Flavor Tabs® also control flea populations and adult hookworms, and remove and control adult roundworm and whipworm infections in dogs and puppies.

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Not for human use. Keep this and all drugs out of the reach of children.

SENTINEL Flavor Tabs are available in four tablet sizes in color-coded packages for oral administration to dogs and puppies according to their weight. (See Dosage Section). Each tablet is formulated to provide a minimum of 0.23 mg/pound (0.5 mg/kg) of milbemycin oxime and 4.55 mg/pound (10 mg/kg) body weight of lufenuron.

Milbemycin oxime consists of the oxime derivatives of 5-didehydromilbemycins in the ratio of approximately 80% A₄ (C₃₂H₄₅NO₇, MW 555.71) and 20% A₃ (C₃₁H₄₃NO₇, MW 541.68). Milbemycin oxime is classified as a macrocyclic anthelmintic.

Lufenuron is a benozylphenylurea derivative with the following chemical composition: N-[2,5-dichloro-4-(1,1,2,3,3,3, - hexafluoropropoxy)-phenylaminocarbonyl]-2,6- difluorobenzamide (C₁₇H₈Cl₂F₈N₂O₃, MW 511.15). Benzozylphenylurea compounds, including lufenuron, are classified as insect development inhibitors (IDIs).

Milbemycin oxime, one active ingredient in SENTINEL Flavor Tabs, is a macrocyclic anthelmintic which is believed to act by interfering with invertebrate neurotransmission. Milbemycin oxime eliminates the tissue stage of heartworm larvae and the adult stage of hookworm (Ancylostoma caninum), roundworm (Toxocara canis  and Toxascaris   leonin a) and whipworm (Trichuris vulpis) infestations when administered orally according to the recommended dosage schedule.

Lufenuron, the other active ingredient in SENTINEL Flavor Tabs, is an insect development inhibitor which breaks the flea life cycle by inhibiting egg development. Lufenuron’s mode of action is interference with chitin synthesis, polymerization and deposition. Lufenuron has no effect on the adult flea. After biting a lufenuron-treated dog, the female flea ingests a blood meal containing lufenuron which is subsequently deposited in her eggs. Lufenuron prevents most flea eggs from hatching or maturing into adults and thus prevents and controls flea populations by breaking the life cycle. (See Efficacy).

SENTINEL Flavor Tabs are indicated for use in dogs and puppies, four weeks of age and older, and two pounds body weight or greater. SENTINEL Flavor Tabs are also indicated 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 and Toxocara leonina (roundworm) and Trichuris vulpis (whipworm) infections.

Lufenuron controls flea populations by preventing the development of flea eggs and does not kill adult fleas. Concurrent use of an adulticide product may be necessary for adequate control of adult fleas.

SENTINEL Flavor Tabs may be used concurrently with CAPSTAR® (nitenpyram) Tablets to provide a Flea Management System that kills adult fleas and prevents flea eggs from hatching. Please see the Supplemental Veterinary Package Insert provided with this product for information about concurrent use of the two products,

Without concurrent use of an adulticide, adequate flea control may not be achieved in do g s that have repeated exposure to flea infested animals or environments.

Do not use in puppies less than four weeks of age and less than two pounds of body weight. Prior to administration of SENTINEL Flavor Tabs, dogs should be tested for existing heartworm infections. Infected dogs should be treated to remove adult heartworms and microfilariae prior to initiating treatment with SENTINEL Flavor Tabs. Mild, transient hypersensitivity reactions manifested as labored respiration, vomiting, salivation and lethargy have been noted in some treated dogs carrying a high number of circulating microfilariae. These reactions are presumably caused by release of protein from dead or dying microfilariae.

SENTINEL Flavor Tabs immediately break the flea life cycle by inhibiting egg development. However, preexisting flea populations may continue to develop and emerge after treatment with SENTINEL Flavor Tabs has begun. Based on results of clinical studies, this emergence generally occurs during the first 30-60 days. Therefore, noticeable control may not be observed until several weeks after dosing when a preexisting infestation is present. Cooler geographic areas may have longer lag periods due to a prolonged flea life cycle. The concurrent use of an approved adulticide, like CAPSTAR may be employed depending on the severity of the infestation.

If a SENTINEL Flavor Tabs-treated dog comes in contact with a flea-infested environment, adult fleas may infest the treated animal. These adult fleas are unable to produce viable offspring. The temporary use of an adulticide product may be necessary to kill these adult fleas.

Milbemycin oxime provided complete protection against heartworm infection in both controlled laboratory and clinical trials.

In laboratory studies, a single dose of milbemycin oxime at 0.5 mg/kg was effective in removing roundworm, hookworm and whipworm. In well-controlled clinical trials, milbemycin oxime was also effective in removing roundworms and whipworms and in controlling hookworms.

Lufenuron provided 99% control of flea egg development for 32 days following a single dose of lufenuron at 10 mg/kg in studies using experimental flea infestations. In well-controlled clinical trials, when treatment with lufenuron tablets was initiated prior to the flea season, mean flea counts were lower in lufenuron-treated dogs versus placebo-treated dogs. After 6 monthly treatments, the mean number of fleas on lufenuron-treated dogs was approximately 4 compared to 230 on placebo-treated dogs.

When treatment was initiated during the flea season, lufenuron tablets were effective in controlling flea infestations on dogs that completed the study. The mean flea count per lufenuron-treated dog was approximately 74 prior to treatment but had decreased to 4 after six monthly doses of lufenuron. A topical adulticide was used in the first eight weeks of the study to kill the pre-existing adult fleas.

Milbemycin oxime has been tested safely in over 75 different breeds of dogs, including collies, pregnant females, breeding males and females, and puppies over two weeks of age. In well-controlled clinical field studies 786 dogs completed treatment with milbemycin oxime. Milbemycin oxime was used safely in animals receiving frequently used veterinary products such as vaccines, anthelmintics, antibiotics, steroids, flea collars, shampoos, and dips.

Two studies in heartworm-infected dogs were conducted which demonstrated mild, transient hypersensitivity reactions in treated dogs with high microfilaremia counts (see Precautions for reactions observed). Safety studies in pregnant dogs demonstrated that high doses (1.5 mg/kg = 3X) of milbemycin oxime given in an exaggerated dosing regimen (daily from mating through weaning), resulted in measurable concentrations of the drug in milk. Puppies nursing these females which received exaggerated dosing regimens demonstrated milbemycin-related effects. These effects were directly attributable to the exaggerated experimental dosing regime. The product is normally intended for once-a-month administration only. Subsequent studies included using 3X daily from mating to one week before weaning and demonstrated no effects on the pregnant females or their litters. A second study where pregnant females were dosed once at 3X the monthly use rate either before, on the day of or shortly after whelping resulted in no effects on the puppies.

Some nursing puppies, at 2, 4, and 6 weeks of age, given greatly exaggerated oral doses of milbemycin oxime (9.6 mg/kg = 19X) exhibited signs typified by tremors, vocalization and ataxia. These effects were all transient and puppies returned to normal within 24 to 48 hours. No effects were observed in puppies given the recommended dose of milbemycin oxime (0.5 mg/kg). This product has not been tested in dogs less than 2.2 pounds in body weight.

A rising-dose safety study conducted in rough-coated collies manifested a clinical reaction consisting of ataxia, pyrexia and periodic recumbency in one of fourteen dogs treated with milbemycin oxime at 12.5 mg/kg (25X monthly use rate). Prior to receiving the 12.5 mg/kg dose (25X monthly use rate) on day 56 of the study, all animals had undergone an exaggerated dosing regimen consisting of 2.5 mg/kg milbemycin oxime (5X monthly use rate) on day 0, followed by 5.0 mg/kg (10X monthly use rate) on day 14 and 10.0 mg/kg (20X monthly use rate) on day 32. No adverse reactions were observed in any of the collies treated with this regimen up through the 10.0 mg/kg (20X monthly use rate) dose.

Lufenuron tablets have been used and tested safely in over forty breeds of dogs, including pregnant females, breeding males and puppies over six weeks of age. In well-controlled clinical trials, 151 dogs completed treatment with lufenuron tablets. Lufenuron tablets were used safely in animals receiving frequently used veterinary products such as vaccines, anthelmintics, antibiotics and steroids. In a ten-month study, doses up to 10X the recommended dose rate of 10 mg/kg caused no overt toxicity. A single dose of 200 mg/kg (20X the recommended dose rate) had no marked effect on adult dogs, but caused decreased activity and appetite in eight week old puppies. Mean body weights of male and female puppies were higher in treated versus control group at the end of the study. In specifically designed target animal safety studies, lufenuron tablets were tested with concurrent administration of flea adulticides containing carbaryl, permethrin, chlorpyriphos and cythioate. No toxicity resulted from these combinations. Lufenuron tablets did not cause cholinesterase inhibition nor did they enhance cholinesterase inhibition caused by exposure to organophosphates.

Four reproductive safety studies were conducted in breeding dogs with lufenuron tablets: two laboratory and two well-controlled clinical studies. In one of the laboratory studies, where lufenuron was administered to beagle dogs at doses equivalent to 90X (3X daily) the monthly recommended dose of 10 mg/kg, the ratio of gravid females to females mated was 8/8 or 100% in the control group and 6/9 or 67% in the lufenuron-treated group. The mean number of pups per litter was two animals higher in the treated versus control groups and the mean birth weights of pups from treated bitches in this study was lower than control groups.

These pups grew at a similar rate to control pups. There was a higher incidence of four clinical signs in the lufenuron-treated versus control group: nasal discharge, pulmonary congestion, diarrhea/dehydration and sluggishness. The incidence of these signs was transient and decreasing by the end of lactation. Results from three additional reproductive safety studies, one laboratory and two clinical field studies evaluating eleven breeds of dogs, did not demonstrated any adverse finding for the reproductive parameters measured including fertility, pup birth weights and pup clinical signs after administration of lufenuron up to 5X the recommended monthly use rate.

Data from analysis of milk from lactating animals treated with lufenuron tablets at 2X and 6X the recommended monthly use rate demonstrates that lufenuron concentrates in the milk of these dogs. The average milk: blood concentration ratio was approximately 60 (i.e., 60X higher drug concentrations in the milk compared to drug levels in the blood of treated bitches). Nursing puppies averaged 8-9 times higher blood concentrations of lufenuron compared to their dams.

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

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

*Please see separate insert in this package for concurrent dosing of SENTINEL Flavor Tabs and CAPSTAR Tablets

SENTINEL Flavor Tabs are palatable and most dogs will consume the tablet when offered by the owner. As an alternative to direct dosing, the tablets can be hidden in food. Be certain the dog consumes the entire tablet or tablets. Administer SENTINEL Flavor Tabs to dogs, immediately after or in conjunction with a normal meal. Food is essential for adequate absorption of lufenuron. Watch the dog closely following administration to be sure the entire dose has been consumed. If it is not entirely consumed, redose with the full recommended dose as soon as possible.

SENTINEL Flavor Tabs must be administered monthly, preferably on the same date each month. Treatment with SENTINEL Flavor Tabs may begin at any time of year. In geographic areas where mosquitoes and fleas are seasonal, the treatment schedule should begin one month prior to the expected onset and should continue until the end of “mosquito and flea season.” In areas with year-round infestations, treatment should continue through the entire year without interruption.

If a dose is missed and a 30-day interval between dosing is exceeded, administer SENTINEL Flavor Tabs immediately and resume the monthly dosing schedule. If SENTINEL Flavor Tabs replace daily diethylcarbamazine (DEC) for heartworm prevention, the first dose must be given within 30 days after the last dose of DEC.

The following adverse reactions have been reported in dogs after giving milbemycin oxime or lufenuron: vomiting, depression/lethargy, pruitus, urticaria, diarrhea, anorexia, skin congestion, ataxia, convulsions, hypersalivation and weakness.

SENTINEL Flavor Tabs are available in four tablet sizes, (see Dosage Section), formulated according to the weight of the dog. Each tablet size is available in color-coded packages of 6 or 12 tablets each, which are packaged 10 per display carton.

Store in a dry place at controlled room temperature, between 59º and 77ºF (15-25ºC).

Questions? Comments? Please Call 1-800-332-2761

Visit our website at www.petwellness.com

Manufactured for:      
Novartis Animal Health US, Inc.
Greensboro, NC 27408

NADA #141-084, Approved by FDA
©2013 Novarits Animal Health US, Inc.
SENTINEL, Flavor Tabs and CAPSTAR are registered trademarks of Novartis AG.

NAH/SEN-FT/VIPI/6-A
05/13

FLEA MANAGEMENT SYSTEM

Supplemental Veterinary Package Insert
This insert describes the concurrent use of SENTINEL® (milbemycin oxime/lufenuron) Flavor Tabs® and CAPSTAR® (nitenpyram) Tablets for the management of fleas on dogs and puppies. Please read the insert contained in each package for complete information of the individual products prior to dispensing or dosing. The effects of SENTINEL Flavor Tabs on heartworm disease and internal parasites are not described in this supplement.

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Not for human use. Keep this and all drugs out of the reach of children.

In dogs and puppies, the concurrent use of SENTINEL Flavor Tabs and CAPSTAR Tablets is indicated to kill adult fleas and prevent eggs from hatching. The effects of SENTINEL Flavor Tabs, which prevent and control flea populations, and CAPSTAR Tablets, which treat flea infestations, are combined to provide a FLEA MANAGEMENT SYSTEM.

Give SENTINEL Flavor Tabs once per month to prevent and control flea populations. SENTINEL Flavor Tabs contain lufenuron. Lufenuron controls flea populations by preventing the development of flea eggs and does not kill adult fleas. If a dog currently has a flea infestation, more rapid relief can be accomplished by adding CAPSTAR to the treatment as follows.

If your pet currently has a flea infestation, add CAPSTAR Tablets to kill adult fleas. CAPSTAR Tablets contain nitenpyram and are effective for treatment of flea infestations. Nitenpyram starts killing adult fleas within 30 minutes of administration.

• Administer CAPSTAR Tablets once per week until adult fleas are no longer observed.
  
• For a severe flea infestation, administer CAPSTAR Tablets twice per week until adult fleas are no longer observed.
  
• Additional CAPSTAR Tablets may be administered as needed to kill the occasional adult flea picked up from infested environments.
  
• It is important to treat all cats and dogs in the household. All cats should be treated with approved products like lufenuron in combination with nitenpyram as needed. Fleas can reproduce on untreated pets and allow infestations to persist.

The combination of SENTINEL Flavor Tabs and CAPSTAR Tablets should be administered according to the following schedule. Weigh your dog prior to administration to ensure proper dosage. Do not administer to dogs under 2 pounds or less than 4 weeks of age .

TO ENSURE ADEQUATE ABSORPTION, ALWAYS ADMINISTER SENTINEL FLAVOR TABS TO DOGS IMMEDIATELY OR IN CONJUNCTION WITH A NORMAL MEAL
(See package insert for SENTINEL Flavor Tabs for details).

*If adult fleas are seen

**Dogs over 100 lbs. are provided the appropriate combination of SENTINEL Flavor Tabs.

The safety of the concurrent use of SENTINEL Flavor Tabs and CAPSTAR Tablets in pregnant or nursing dogs or in puppies less than 11 weeks of age has not been demonstrated.

The following adverse reactions have been reported in dogs after giving SENTINEL Flavor Tabs: vomiting, depression/lethargy, pruritus, urticaria, diarrhea, anorexia, skin congestion, ataxia, convulsions, hypersalivation and weakness.

The following adverse reactions have been reported in dogs after giving CAPSTAR: lethargy/depression, vomiting, itching, decreased appetite, diarrhea, hyperactivity, incoordination, trembling, seizures, panting, allergic reactions including hives, vocalization, salivation, fever, and nervousness.

The frequency of serious signs, including neurologic signs and death, was greater in animals under 2 pounds of body weight, less than 8 weeks of age, and/or reported to be in poor body condition. In some instances, birth defects and feta l /neonatal loss were reported after treatment of pregnant and/or lactating animals.

To report suspected adverse drug events and/or for a complete listing of adverse reactions for milbemycin oxime, lufenuron and nitenpyram reported to the FDA CVM please refer to the insert contained within the CAPSTAR package for contact information.

Please refer to the labeling for SENTINEL Flavor Tabs and CAPSTAR Tablets for information about the effectiveness of each product. Studies testing the concurrent use of the two products demonstrated that each product remains effective for its labeled indication when both are administered concurrently. In a simulated home environment, the administration of SENTINEL Flavor Tabs monthly and CAPSTAR either once or twice weekly demonstrated a greater and more rapid reduction of established flea infestations than SENTINEL Flavor Tabs alone.

The combination of nitenpyram, milbemycin oxime and lufenuron has been tested in a 90 day laboratory study. Administration of 5X the recommended use rate of CAPSTAR Tablets for 90 consecutive days, concurrently with administration of 5X the recommended use rate of SENTINEL Flavor Tabs every 2 weeks for 7 treatments was well tolerated.

In addition to the common nuisance irritations associated with infestations, fleas can be responsible for skin conditions in the dog such as flea allergy dermatitis. Fleas also transmit other parasites, including tapeworms. The control of flea infestations reduces the problems associated with these parasites.

SENTINEL Flavor Tabs break the flea life cycle by inhibiting egg development. CAPSTAR Tablets rapidly kill adult fleas on the dog. The concurrent use of these two products provides an effective flea management system.

The following diagram illustrates the flea’s life cycle and where the combination of SENTINEL Flavor Tabs and CAPSTAR Tablets work:

A single female flea may produce up to 2,000 eggs over her lifetime. Eggs hatch and can develop into adults within only three weeks. Adult female fleas feed by ingesting blood from the pet and subsequently lay eggs, which drop off the pet’s coat. Within days, larvae hatch from the eggs and live undetected in the pet’s surroundings, such as the carpet and bedding. Flea larvae spin a cocoon, and when appropriately stimulated, a young adult flea emerges and jumps onto the pet to continue the life cycle.

After reading this insert, if you have any questions about the concurrent use of SENTINEL Flavor Tabs and CAPSTAR Tablets for your patients, please call Novartis Animal Health US, Inc. Veterinary Product Support at 1 (800)-332-2761.

Store SENTINEL Flavor Tabs and CAPSTAR Tablets as described on the individual product inserts.

Questions? Comments? 
Please Call 1-800-332-2761

For technical assistance or to report an adverse event please call 1-800-637-0281

Visit our website at www.petwellness.com

Manufactured for:      
Novartis Animal Health US, Inc.
Greensboro, NC 27408

NADA 141-204, Approved by FDA.

©2013 Novartis Animal Health US, Inc.

SENTINEL, Flavor Tabs and CAPSTAR are registered trademarks of Novartis AG.

NAH/SEN-FMS/VIPI/4-A
05/13
PCR-750-06980

Package Label - 2.3 mg milbemycin   oxime / 46 mg lufenuron
Recommended for dogs and puppies 2-10 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal

Package Label - 2.3 mg milbemycin   oxime / 46 mg lufenuron
Recommended for dogs and puppies 2-10 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
12 PACK Give with a meal

Package Label - 2.3 mg milbemycin   oxime / 46 mg lufenuron
Recommended for dogs and puppies 2-10 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal
Made in France

Sentinel 2.3mg/46mg Flavor Tabs
NAH Item# 611273/ NCH Item #70800
EACH TABLET CONTAINS: milbemycin   oxime 2.3 mg/ lufenuron 46mg
Store at room temperature between 59 ^◦ and 77 ^◦ F (15 ^◦ - 25 ^◦ C).

Package Label - 5.75 mg milbemycin   oxime / 115 mg lufenuron
Recommended for dogs and puppies 11-25 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal

Package Label - 5.75 mg milbemycin   oxime / 115 mg lufenuron
Recommended for dogs and puppies 11-25 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
12 PACK Give with a meal

Package Label - 5.75 mg milbemycin   oxime / 115 mg lufenuron
Recommended for dogs and puppies 11-25 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
12 PACK Give with a meal
Made in France

Sentinel Flavor Tabs
5.75mg/115mg
( milbemycin   oxime + lufenuron )
PROD. NO. 613788
CAS-NO 122674-17-3 (milbemycin oxime)
CAS-NO 103055-07-8 (lufenuron)

Package Label – 11.5 mg milbemycin   oxime / 230 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal

Package Label – 11.5 mg milbemycin   oxime / 230 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
12 PACK Give with a meal

Package Label – 11.5 mg milbemycin   oxime / 230 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal
Made in France

Sentinel Flavor Tabs
11.5mg/230mg
( milbemycin   oxime + lufenuron )
PROD. NO. 613788
CAS-NO 122674-17-3 (milbemycin oxime)
CAS-NO 103055-07-8 (lufenuron)

Package Label – 23 mg milbemycin   oxime / 460 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal

Package Label – 23 mg milbemycin   oxime / 460 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
12 PACK Give with a meal

Package Label – 23 mg milbemycin   oxime / 460 mg lufenuron
Recommended for dogs and puppies 26-50 lbs.
NOVARTIS ANIMAL HEALTH
Sentinel^®flavor tabs^® (milbemycin oxime + lufenuron)
Once-a-month flavored tablets
6 PACK Give with a meal
Made in France

Sentinel Flavor Tabs
23.0mg/460mg
( milbemycin   oxime + lufenuron )
PROD. NO. 613788
CAS-NO 122674-17-3 (milbemycin oxime)
CAS-NO 103055-07-8 (lufenuron)