ATOPICA (cyclosporine capsules, USP) MODIFIED 

ATOPICA (cyclosporine capsules, USP) MODIFIED is indicated for the control of atopic

dermatitis in dogs.

Caution:

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

Keep this and all drugs out of reach of children.

Description:

ATOPICA (cyclosporine capsules, USP) MODIFIED is an oral form of cyclosporine that

immediately forms a microemulsion in an aqueous environment. Cyclosporine, the active

ingredient in ATOPICA, is a cyclic polypeptide, immune modulating agent consisting of 11

amino acids. It is produced as a metabolite by the fungal species Beauveria nivea.

Chemically, cyclosporine A is designated [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl-N-methyl-

L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N, 4-dimethyl-L-2amino-

6-octenoyl-L- α -amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-

L-leucyl). The structural formula is:

ATOPICA capsules contain cyclosporine formulated together with inactive ingredients.

ATOPICA is available in 10, 25, 50, and 100 mg capsule strengths in color-coded packaging

for oral administration to dogs.

Indications:

ATOPICA is indicated for the control of atopic dermatitis in dogs weighing at least 4 lbs

body weight.

Dosage and Administration:

The initial daily dose of ATOPICA is 5 mg/kg/day (3.3-6.7 mg/kg/day) as a single daily

dose for 30 days. Following this initial daily treatment period, the dose of ATOPICA

may be tapered by decreasing the frequency of dosing to every other day or two

times a week, until a minimum frequency is reached which will maintain the desired

therapeutic effect. ATOPICA should be given at least one hour before or two hours

after a meal. If a dose is missed, the next dose should be administered (without doubling)

as soon as possible, but dosing should be no more frequent than once daily.

Dose Administration

Contraindications:

ATOPICA is contraindicated for use in dogs with a history of neoplasia.

WARNINGS:

ATOPICA (cyclosporine) is a potent systemic immunosuppressant that may increase the

susceptibility to infection and the development of neoplasia.

Precautions:

Gastrointestinal problems and gingival hyperplasia may occur at the initial recommended

dose (See Animal Safety).

ATOPICA should be used with caution with drugs that affect the P-450 enzyme system.

Simultaneous administration of ATOPICA with drugs that suppress the P-450 enzyme

system, such as ketoconazole, may lead to increased plasma levels of cyclosporine.

The safety and effectiveness of ATOPICA has not been established in dogs less than 6

months of age or less than 4 lbs body weight. ATOPICA is not for use in breeding

dogs, pregnant or lactating bitches.

Since the effect of cyclosporine use on dogs with compromised renal function has not

been studied, ATOPICA should be used with caution in dogs with renal insufficiency.

There have been reports of convulsions in human adult and pediatric patients receiving

cyclosporine, particularly in combination with high dose methylprednisolone (See

Animal Safety).

Killed vaccines are recommended for dogs receiving ATOPICA because the impact of

cyclosporine on the immune response to modified live vaccines is unknown (See

Animal Safety).

As with any immunomodulation regimen, exacerbation of sub-clinical neoplastic conditions

may occur.

Effectiveness Field Study:

A multisite, placebo controlled, double masked, field study was conducted in the

United States and Canada using 16 investigators. Two hundred sixty five (265) dogs

aged 1-10 years, weighing 4-121 lbs received either ATOPICA capsules at 5 mg/kg/day

or placebo capsules. After 30 days, placebo dogs were switched to ATOPICA capsules.

Dogs were treated with ATOPICA capsules for a total of 4 months. No additional therapy

with antihistamines, corticosteroids or medicated shampoos was permitted.

Evaluations for pruritus and for skin lesions to derive a Canine Atopic Dermatitis Extent

and Severity Index (CADESI) score occurred at enrollment and at monthly intervals. One

hundred ninety-two (192) dogs were included in the statistical analysis of effectiveness.

At the end of the 30 day placebo controlled period, CADESI scores of dogs treated with

ATOPICA capsules improved by 45% from enrollment, while CADESI scores of dogs

treated with placebo worsened by 9%. Seventy-four (74)% of ATOPICA treated dogs

showed improvement in their pruritus scores over the first 30 day period, while only

24% of the placebo treated dogs showed an improvement. Owner and Veterinary

Global Assessment in response to treatment also demonstrated statistically significant

(p<0.0001) improvement. After 4 weeks of therapy, Owner and Veterinary Global

Assessments showed approximately twice as much improvement in the ATOPICA treated

dogs as compared to placebo treated dogs.

Improvements in pruritus accompanied by 50% or 75% improvements in CADESI

scores resulted in dose reductions to every other day or twice weekly respectively. Not

all dogs were able to decrease to twice weekly dosing. Some animals required upward

or downward dosage adjustments during the study. Such adjustments should be

expected during therapy of this disease. Dogs unable to decrease from once daily dosing

after 60 days were considered dose reduction failures for the purposes of the study.

The results of dose assignments, based on the study criteria, for each 4-week dosing

period, are shown in the graph below.

Analysis of blood levels of cyclosporine drawn during the study demonstrated no

correlation between blood cyclosporine levels and CADESI scores or pruritus; therefore

monitoring blood cyclosporine levels is not an appropriate predictor of effectiveness.

Adverse Reactions:

A total of 265 dogs were included in the field study safety analysis. One hundred and

eleven (111) dogs were treated with placebo for the first 30 days. For the remainder of

the study, all dogs received ATOPICA capsules.

Fourteen dogs withdrew from the study due to adverse reactions. Four dogs withdrew

from the study after vomiting. One dog each withdrew from the study after diarrhea;

vomiting, diarrhea and pruritus; vomiting, depression and lethargy; lethargy, anorexia

and hepatitis; gingival hyperplasia, lethargy, polyuria/polydipsia and soft stool; seizure;

sebaceous cyst; pruritus; erythema; or otitis externa.

Vomiting and diarrhea were the most common adverse reactions occurring during the

study. In most cases, signs spontaneously resolved with continued dosing. In other

cases, temporary dose modifications (brief interruption in dosing, divided dosing, or

administration with a small amount of food) were employed to resolve signs.

Persistent otitis externa, urinary tract infections, anorexia, gingival hyperplasia,

lymphadenopathy and lethargy were the next most frequent adverse events observed.

Gingival hyperplasia regressed with dose tapering. Owners of four dogs reported

seizures while dogs were receiving ATOPICA. In one dog, seizures were the result of a

brain tumor diagnosed one month into the study. Another dog experienced seizures

before and after the study.

Otitis externa, allergic otitis, or pinna erythema, with or without exudates, commonly

accompanies atopy. Many dogs entered the study with otitis externa, which did not

resolve without otic treatment. New cases of otitis externa, allergic otitis, or pinna

erythema developed while dogs were receiving ATOPICA. However, the incidence rate

was lower with ATOPICA compared to placebo. A change in the dose frequency was

not necessary when new cases occurred.

Number of Dogs Displaying Each Clinical Observation in the Field Study

The following clinical signs were reported in less than 2% of dogs treated with ATOPICA

in the field study: constipation, flatulence, Clostridial organisms in the feces, nausea,

regurgitation, polyuria/polydipsia, strong urine odor, proteinuria, pruritus, erythema/flushed

appearance, pyoderma, sebaceous adenitis, crusty dermatitis, excessive shedding,

coarse coat, alopecia, papillomas, histiocytoma, granulomatous mass or lesion,

cutaneous cyst, epulis, benign epithelial tumor, multiple hemangioma, raised nodule on

pinna, seizure, shaking/trembling, hind limb twitch, panting, depression, irritability,

hyperactivity, quieter, increased light sensitivity, reluctance to go outside, weight loss,

hepatitis.

The following clinical signs were observed in 1.5-4.5% of dogs while receiving the

placebo: vomiting, diarrhea and urinary tract infection. The following clinical signs were

observed in less than 1% of dogs receiving the placebo: anorexia, otitis externa, cutaneous

cysts, corneal opacity, lymphadenopathy, erythema/flushed appearance.

Clinical Pathology Changes: During the study, some dogs experienced changes in

clinical chemistry parameters while receiving ATOPICA, as described in the following

table:

 

In addition, the following changes in clinical chemistry parameters were noted in less

than 2% of dogs: hypernatremia; hyperkalemia, elevated ALT, elevated ALP, hypercalcemia

and hyperchloremia. These clinical pathology changes were generally not associated

with clinical signs.

Post-approval Experience:

Neoplasms have been reported in dogs taking ATOPICA, including reports of lymphosarcoma

and mast cell tumor. It is unknown if these were preexisting or developed de novo 

while on ATOPICA.

In post-approval drug experience reporting, the following additional adverse reactions have

been associated with ATOPICA administration in dogs: vomiting, diarrhea, depression/

lethargy, anorexia, pruritus, liver enzyme elevations, trembling, convulsions, polydipsia,

polyuria, weight loss, hyperactivity, nervousness, neoplasia.

To report suspected adverse reactions or for technical assistance, call 1-800-332-2761.

Clinical Pharmacology:

Cyclosporine is a potent immunosuppressive agent that has been shown to work via

suppression of T-helper and T-suppressor cells and inhibition of interleukin-2. It does

not impair the hematopoietic system or cell-mediated immunologic responses. A

decrease in CD4 and CD8 cells was not seen in dogs receiving 20 mg/kg/day of

cyclosporine for 56 days. ATOPICA is not a corticosteroid or an antihistamine.

Storage Conditions:

ATOPICA should be stored and dispensed in the original unit-dose container at

controlled room temperature between 59 and 77°F (15-25°C).

How Supplied:

ATOPICA soft gelatin capsules (cyclosporine capsules, USP) MODIFIED are supplied in

packages of 15 unit-dose blisters as follows:

10 mg: oval, white capsules imprinted with red “NVR 10”.

25 mg: oval, blue-gray capsules imprinted with red “NVR 25mg”.

50 mg: oval, white capsules imprinted with red “NVR 50mg”.

100 mg: oval, blue-gray capsules imprinted with red “NVR 100mg”.

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

NADA 141-218, Approved by FDA

© 2008 Novartis Animal Health US, Inc.

Atopica is a registered trademark of Novartis AG.

NAH/ATO-GC/VI/5 11/08

PRINCIPAL DISPLAY PANEL

Package Label – 10 mg

ATOPICA (cyclosporine capsules, USP) MODIFIED

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

An immunosuppressant for use in dogs only. For dogs 4 to 9 pounds.

Net contents: 15 capsules, 10 mg cyclosporine each.

Product # 43511

NADA # 141-218, Approved by the FDA.

PRINCIPAL DISPLAY PANEL

Package Label – 25 mg

ATOPICA (cyclosporine capsules, USP) MODIFIED

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

An immunosuppressant for use in dogs only. For dogs 9.1 to 16 pounds.

Net contents: 15 capsules, 25 mg cyclosporine each.

Product # 43521

NADA # 141-218, Approved by the FDA.

PRINCIPAL DISPLAY PANEL

Package Label – 50 mg

ATOPICA (cyclosporine capsules, USP) MODIFIED

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

An immunosuppressant for use in dogs only. For dogs 16.1 to 33 pounds.

Net contents: 15 capsules, 50 mg cyclosporine each.

Product # 43531

NADA # 141-218, Approved by the FDA.

PRINCIPAL DISPLAY PANEL

Package Label – 100 mg

ATOPICA (cyclosporine capsules, USP) MODIFIED

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

An immunosuppressant for use in dogs only. For dogs 33.1 to 64 pounds. For dogs greater than 64 pounds, see product insert for the appropriate combination of capsules.

Net contents: 15 capsules, 100 mg cyclosporine each.

Product # 43541

NADA # 141-218, Approved by the FDA.