United States - English - NLM (National Library of Medicine)
CYCLAVANCE- cyclosporine oral solution solution
Virbac AH Inc
CYCLAVANCE™ (cyclosporine oral solution) USP MODIFIED
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.
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-
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.)
CYCLAVANCE is contraindicated for use in dogs with a history of neoplasia. Do not use
in dogs with a hypersensitivity to cyclosporine.
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
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
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
Killed vaccines are recommended for dogs receiving CYCLAVANCE because the impact
of cyclosporine on the immune response to modified live vaccines is unknown (See
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
% out of
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:
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
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
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),
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,
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
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
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.
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
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.
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.
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
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
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