CYCLAVANCE- cyclosporine oral solution solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
cyclosporine (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D)
Available from:
Virbac AH Inc
Administration route:
ORAL
Prescription type:
PRESCRIPTION
Therapeutic indications:
CYCLAVANCE is indicated for the control of atopic dermatitis in dogs weighing at least 4 lbs (1.8 kg) body weight. CYCLAVANCE is contraindicated for use in dogs with a history of neoplasia. Do not use in dogs with a hypersensitivity to cyclosporine.
Product summary:
CYCLAVANCE is supplied in glass amber vials of 5, 15, 30 and 50 mL at 100 mg/mL. - 5 and 15 mL vials are supplied with a 1 mL Luer Lok® oral dosing syringe. - 30 and 50 mL vials are supplied with a 1 mL and 3 mL Luer Lok® oral dosing syringes
Authorization status:
Abbreviated New Animal Drug Application
Authorization number:
51311-994-15, 51311-994-50

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CYCLAVANCE- cyclosporine oral solution solution

Virbac AH Inc

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CYCLAVANCE™ (cyclosporine oral solution) USP MODIFIED

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:

CYCLAVANCE™ (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].

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

6.8%

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.

CLINICAL PHARMACOLOGY:

Cyclosporine is a 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

depress hematopoiesis or the function of phagocytic cells. A decrease in CD4 and CD8

cells was not seen in dogs receiving 20 mg/kg/day of cyclosporine for 56 days.

Cyclosporine is not a corticosteroid or an antihistamine.

METABOLISM: Cyclosporine is extensively metabolized by the cytochrome P-450

enzyme system in the liver, and to a lesser degree in the gastrointestinal tract and the

kidney. The metabolism of cyclosporine can be altered by the co-administration of a

variety of agents (See Precautions).

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 cyclosporine capsules at 5 mg/kg/day or

placebo capsules. After 30 days, placebo dogs were switched to cyclosporine capsules.

Dogs were treated with cyclosporine 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

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

treated with placebo worsened by 9%. Seventy-four percent (74%) of cyclosporine

capsule 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

cyclosporine capsule 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.

ANIMAL SAFETY:

In a 52-week oral study with dose levels of 0, 1, 3, and 9 times the target initial daily

dose, emesis, diarrhea and weight loss were seen in all cyclosporine treated groups with

increasing frequency as the dose increased.

Multilocular papilloma-like lesions of the skin were observed in 5 out of 8 high dose

animals between weeks 20 and 40. These changes regressed spontaneously after drug

was withdrawn.

Other findings in the mid and high dose animals included swollen gums due to chronic

gingivitis and periodontitis, lower serum albumin and higher cholesterol, triglyceride, IgA

and IgG. Hematological findings consisted of anemia and decreased leukocyte counts in

a few high dose animals. Erythrocyte sedimentation rates were increased at all dose

levels in a dose dependent fashion. Notable histopathological findings were limited to

lymphoid atrophy, hypertrophic gums (from gingivitis) and slight regenerative changes

of the renal tubular epithelium in high dose animals. The findings were shown to be

reversible during a 12-week recovery phase of the study.

In a 90-day study with cyclosporine, dogs were dosed in one of two patterns: either 1,

3, or 5X the maximum recommended target initial daily dose for 90 days, or 1, 3, or 5X

the maximum recommended target initial daily dose for 30 days followed by tapering to

mimic the recommended clinical dosing pattern. The maximum recommended dose,

when administered for 90 days causes callus-like lesions on the footpads, red/swollen

pinnae, mild to moderate gingival proliferation, hyperkeratotic areas on the integument,

hair loss, salivation, vomiting, and diarrhea/ abnormal stools. These clinical signs

lessened in severity or resolved as the drug was tapered to a lower dose. Increased

erythrocyte sedimentation rate, hyperproteinemia, hyperglobulinemia, hypoalbuminemia,

hypocalcemia, hypophosphatemia, and hypomagnesemia were observed at three and

five times the maximum recommended dose. These resolved as the dose was tapered.

When administered at higher than the maximum recommended dose, raised skin

lesions, papilloma-like areas on the integument, popliteal lymph node enlargement, and

weight loss were also seen. There were no cyclosporine related changes in urinalysis,

ECG, blood pressure, or ophthalmologic exams.

Gross necropsy revealed epithelial changes consistent with those seen on physical

examination. Proliferation of gingiva and toe pad epithelium was seen in all cyclosporine

dosed groups, and was seen in a dose dependent fashion. The degree of the

proliferation was greater in dogs in the non-tapered groups as compared to the tapered

groups. Similar changes were noted on histopathologic examination of the cutaneous

changes seen on physical examination. These lesions were characterized by epidermal

hyperplasia, chronic dermatitis and hyperkeratosis.

Methylprednisolone combination: Twenty-four dogs were administered 1 mg/kg/day

methylprednisolone alone for 14 days followed by 20 mg/kg/day cyclosporine either

alone or in combination with methylprednisolone, or placebo for 14 days. There was no

evidence of seizures/convulsions or neurological signs.

Vaccination effect: The effect of cyclosporine administration on the immunological

response to vaccination was evaluated in a study in which 16 dogs were dosed with

either cyclosporine at 20 mg/kg/day (4X the initial daily dose) or placebo for 56 d ays. All

dogs were vaccinated on Day 27 with a killed commercial rabies virus and a multivalent

vaccine (DHLPP) which included a modified live virus. Antibody titers for rabies, canine

distemper, canine adenovirus type 2, parainfluenza, parvovirus, Leptospira canicola, and

Leptospira icterohaemmorrhagiae were examined on Days 0, 27 (prior to vaccination),

42 and 56. Quantification of CD4, CD8, and CD3 T-lymphocytes was analyzed.

Clinical changes included soft stool and dermatologic changes consistent with those

seen in previous studies. Antibody titers did not rise in dogs treated with cyclosporine or

the placebo for any component of the multivalent vaccine which included a modified live

virus while all animals demonstrated a significant increase in antibody rabies titer by Day

42 or 15 days post-revaccination. No effect was seen on T-lymphocytes.

STORAGE INFORMATION:

CYCLAVANCE (cyclosporine oral solution) USP MODIFIED should be stored and

dispensed in the original container at temperatures between 68-86°F (20-30°C). Do not

refrigerate because a precipitate may be observed below 68°F (20°C).

Once opened, use contents within 12 weeks.

HOW SUPPLIED:

CYCLAVANCE is supplied in glass amber vials of 5, 15, 30 and 50 mL at 100 mg/mL.

- 5 and 15 mL vials are supplied with a 1 mL Luer Lok® oral dosing syringe.

- 30 and 50 mL vials are supplied with a 1 mL and 3 mL Luer Lok® oral dosing syringes

Instructions for Assembling the Dispensing System and Preparing a Dose of

CYCLAVANCE™ (cyclosporine oral solution) USP MODIFIED.

Assembling the Dispensing System

The dispensing system consists of three parts:

1. A vial containing the medicine sealed with a rubber stopper

2. A plastic adapter (dispensing system) that you will push onto the top of the vial. The

adapter must always remain on the vial after first use.

3. An oral dosing syringe that fits into the top of the plastic adapter to withdraw the

prescribed dose of medicine from the vial.

(1 mL syringe with the 5 and 15 mL vial sizes; 1 and 3 mL syringes with the 30 and 50

mL vial sizes)

Fitting the Plastic Adapter into the New Bottle of Medicine

1. Remove the plastic lid from the top of the vial.

2. Hold the vial upright on a table and push the plastic adapter firmly onto the top of the

vial until it is firmly and evenly seated.

Note: To prepare a dose, carefully follow the instructions for Preparing a Dose of

Medicine.

Preparing a Dose of Medicine

1. Check that the plunger of the oral dosing syringe is pushed all the way down.

2. Keep the vial upright and push the oral dosing syringe firmly into the plastic adapter

while turning the syringe clockwise to secure the dispensing system.

3. Turn the vial with the attached dosing syringe upside down and slowly pull the plunger

up so that the oral dosing syringe fills with the medicine.

4. Expel any large bubbles by pushing and pulling the plunger a few times.

The presence of a few tiny bubbles is not important

for dosing accuracy.

5. Withdraw the dose of medicine prescribed by your veterinarian.

Note: If the prescribed dose is more than the maximum volume marked on the oral

dosing syringe, you will need to reload the syringe to withdraw the full dose.

6. Return the vial to its upright position and remove the oral dosing syringe by twisting it

counterclockwise out of the plastic dispenser.

You can now introduce the syringe into the mouth of the dog according to your

veterinarian’s instructions, and push the medicine out of the syringe.

See Information for Dog Owners for complete administration instructions.

Do not rinse or clean the oral dosing syringe between uses.

Store the medication and the dosing syringe securely. CYCLAVANCE should be stored

and dispensed in the original container at temperatures between 68-86˚F (20-30˚C). Do

not refrigerate because a precipitate may be observed below 68˚F (20˚C). Once

opened, use contents within 12 weeks.

Keep out of reach of children

Approved by FDA under ANADA # 200-689

Manufactured for:

Virbac AH, Inc.

P.O. Box 162059

Fort Worth, TX 76161

Information for Dog Owners

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

lbs. (1.8 kg) body weight. Dogs with atopic dermatitis scratch, lick and chew their skin

which can cause red, raised crusty bumps, open sores and/or hair loss.

Atopic dermatitis is a common skin disease in dogs and is caused by allergens such as

house dust mites or pollens which stimulate an exaggerated immune response. The

disease is chronic, recurrent, and requires lifelong management.

This summary contains important information about CYCLAVANCE. You should read this

information before starting your dog on CYCLAVANCE. This sheet is provided only as a

summary and does not take the place of instructions from your veterinarian. Talk to

your veterinarian if you do not understand any of this information or you want to know

more about CYCLAVANCE.

What is CYCLAVANCE?

CYCLAVANCE is an oral solution of cyclosporine that lowers the immune response.

CYCLAVANCE selectively acts on the immune cells involved in the allergic reaction.

CYCLAVANCE reduces the inflammation and itching associated with atopic dermatitis.

What kind of results can I expect when my dog takes CYCLAVANCE for the

control of atopic dermatitis? CYCLAVANCE should be given daily until improvement

is seen. This will generally be the case within 30 days. You should contact your

veterinarian if you are not satisfied with your dog’s response. Once the signs of atopic

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