CYCLAVANCE: Product Information

CYCLAVANCE- cyclosporine solution
Virbac AH Inc

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:

CYCLAVANCEâ„¢ (cyclosporine oral solution) USP MODIFIED is an oral form of cyclosporine that immediately forms a microemulsion in an aqueous environment. Cyclosporine, the active ingredient in CYCLAVANCE, 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 Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methylL-leucyl-L-valyl-Nmethyl-L-leucyl-L-alanyl-D-ananyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl].

structural formula
(click image for full-size original)

INDICATIONS:

CYCLAVANCE is indicated for the control of atopic dermatitis in dogs weighing at least 4 lbs (1.8 kg) body weight.

DOSAGE AND ADMINISTRATION:

Always Provide the Instructions for Assembling the Dispensing System and Preparing a Dose of CYCLAVANCE and the Information for Dog Owners with the prescription. The initial dose of CYCLAVANCE is 5 mg/kg/day as a single daily dose for 30 days. Following this initial daily treatment period, the dose of CYCLAVANCE may be tapered by decreasing the frequency of dosing to every other day or twice weekly, until a minimum frequency is reached which will maintain the desired therapeutic effect. CYCLAVANCE 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. The dispensing system for the 5 and 15 mL vial sizes includes a 1 mL oral dosing syringe graduated in 0.01 mL increments. To dose the dog, administer 0.05 mL of CYCLAVANCE per 2.2 lbs of body weight. The dispensing system for the 30 and 50 mL vial sizes includes both a 1 mL oral dosing syringe graduated in 0.01 mL increments, and a 3 mL oral dosing syringe graduated in 0.1 mL increments. To dose the dog, administer 0.1 mL of CYCLAVANCE per 4.4 lbs of body weight. Do not rinse or clean the oral dosing syringe between uses. (See Instructions for Assembling the Dispensing System and Preparing a Dose of CYCLAVANCE.)

CONTRAINDICATIONS:

CYCLAVANCE is contraindicated for use in dogs with a history of neoplasia. Do not use in dogs with a hypersensitivity to cyclosporine.

WARNINGS:

CYCLAVANCE (cyclosporine oral solution) is a systemic immunosuppressant that may increase the susceptibility to infection and the development of neoplasia.

HUMAN WARNINGS: Not for human use. Keep this and all drugs out of reach of children. For use only in dogs. Special precautions to be taken when administering CYCLAVANCE in dogs: Do not eat, drink, smoke, or use smokeless tobacco while handling CYCLAVANCE. Wear gloves during administration. Wash hands after administration. In case of accidental ingestion, seek medical advice immediately and provide the package insert or the label to the physician.

People with known hypersensitivity to cyclosporine should avoid contact with CYCLAVANCE.

PRECAUTIONS:

The safety and effectiveness of cyclosporine has not been established in dogs less than 6 months of age or less than 4 lbs body weight. CYCLAVANCE is not for use in breeding dogs, pregnant or lactating bitches. As with any immunomodulation regimen, exacerbation of sub-clinical neoplastic and infectious conditions may occur. Gastrointestinal problems and gingival hyperplasia may occur at the initial recommended dose (See Animal Safety).

CYCLAVANCE may cause elevated levels of serum glucose, and should be used with caution in cases with diabetes mellitus. If signs of diabetes mellitus develop following the use of CYCLAVANCE, consideration should be given to tapering or discontinuing the dose.

CYCLAVANCE should be used with caution with drugs that affect the P-450 enzyme system. Simultaneous administration of CYCLAVANCE with drugs that suppress the P-450 enzyme system, such as azoles (e.g. ketoconazole), may lead to increased plasma levels of cyclosporine.

Since the effect of cyclosporine use on dogs with compromised renal function has not been studied, CYCLAVANCE 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 CYCLAVANCE because the impact of cyclosporine on the immune response to modified live vaccines is unknown (See Animal Safety).

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 cyclosporine 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 cyclosporine. 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 cyclosporine. However, the incidence rate was lower with cyclosporine 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
Clinical sign % out of 265
Vomiting 30.9%
Diarrhea 20.0%
Persistent Otitis Externa 6.8%
Urinary Tract Infection 3.8%
Anorexia 3.0%
Lethargy 2.3%
Gingival Hyperplasia 2.3%
Lymphadenopathy 2.3%

The following clinical signs were reported in less than 2% of dogs treated with cyclosporine 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 cyclosporine, as described in the following table:

Clinical Chemistry % Affected (out of 265)
Elevated Creatinine 7.8%
Hyperglobulinemia 6.4%
Hyperphosphatemia 5.3%
Hyperproteinemia 3.4%
Hypercholesterolemia 2.6%
Hypoalbuminemia 2.3%
Hypocalcemia 2.3%
Elevated BUN 2.3%

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: The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse reactions are reported to FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using this data. The following adverse events are grouped by body system and are presented in decreasing order of reporting frequency.

Gastrointestinal: Emesis, diarrhea, gingival hyperplasia, hemorrhagic diarrhea, abdominal pain, hematemesis, digestive tract hemorrhage, hypersalivation, retching, flatulence, tenesmus, intestinal stasis, digestive tract hypermotility, melena, pancreatitis, involuntary defecation

General: Lethargy, anorexia, weight loss, polydipsia, hyperthermia, pale mucous membrane, general pain, collapse, dehydration, edema

Dermatologic: Pruritus, dermatitis and eczema, alopecia, erythema, papilloma, bacterial skin infection, skin lesion, skin and/or appendage neoplasm, pigmentation disorder, hair change, hyperkeratosis, histiocytoma, fungal skin infection, dermal cyst(s), desquamation

Behavioral: Hyperactivity, behavioral changes, anxiety, vocalization, aggression, inappropriate urination, disorientation

Neurologic: Muscle tremor, convulsion, ataxia, paresis

Respiratory: Tachypnea, dyspnea, cough

Urologic: Polyuria, urine abnormalities (hematuria, urinary tract infection, proteinuria, glucosuria, decreased urine concentration) urinary incontinence, cystitis, renal failure, renal insufficiency

Immune: Urticaria, anaphylaxis, allergic edema

Blood and lymphatic: Lymphadenopathy, anemia, hypoalbuminemia, leukopenia

Hepatic: Elevated Liver Enzymes, hepatopathy, hepatomegaly, hepatitis

Musculoskeletal: Lameness, limb weakness, myositis

Ear and labyrinth: Otitis externa

Cardio-vascular: Tachycardia

Endocrine: Diabetes mellitus, hyperglycemia

In some cases, death/euthanasia has been reported as an outcome of the adverse events listed above.

Neoplasms have been reported in dogs taking cyclosporine, including reports of lymphoma/lymphosarcoma and mast cell tumor. It is unknown if these were preexisting or developed de novo while on cyclosporine.

Diabetes mellitus has been reported; West Highland White Terriers are the most frequently reported breed.

To report suspected adverse drug events or for technical assistance, contact Virbac AH, Inc. 1-800-338-3659. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/AnimalVeterinary/SafetyHealth.

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