CYCLAVANCE: Product Information (Page 2 of 3)

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.

clinical assessment graph

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)

assembly of dispenser

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.

preparing the dose


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.

dosing the dog

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

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