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, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS), contact Virbac AH, Inc. at 1-800-338-3659 or us.virbac.com. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae.
CYCLAVANCE® (cyclosporine oral solution) USP MODIFIED
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.
Modulis® for Dogs (cyclosporine oral solution) USP MODIFIED 100 mg/mL
The clinical safety of ATOPICA for Cats was assessed in a masked, controlled 6-week field study followed by a 12-week open-labeled dose-tapering field study. In these two field studies, 205 cats received treatment with ATOPICA for Cats for up to 126 days.
Two cats died or were euthanized within two weeks following study exit. One cat was diagnosed with the effusive form of feline infectious peritonitis and died following normal study exit, and one cat with pre-existing anemia that worsened during the study was diagnosed with aplastic anemia and euthanized because of a poor prognosis for recovery.
Fourteen of the 205 cats (6.8%) were withdrawn from the studies due to the occurrence of an adverse reaction. Adverse reactions in these 14 cats included weight loss, anorexia, vomiting, diarrhea, hypersalivation, lethargy, hepatic lipidosis and jaundice, upper respiratory signs, ocular discharge, cough, toxoplasmosis, lymphopenia, anemia, bacterial dermatitis, seizure, ataxia, and small cell gastrointestinal lymphoma.
The most commonly reported adverse reaction was vomiting. In most cases, vomiting spontaneously resolved with continued dosing. Adverse reactions occurred most often with daily dosing compared to other dosing regimes.
Adverse reactions reported with greater than 2% frequency in the two field studies.
*Cats may have experienced more than one type or occurrence of a reaction during the studies.
Adverse Reaction*
Number (Percent)
of Cases
n = 205
Vomiting/Retching/Regurgitation
72 (35.1%)
Weight Loss
42 (20.5%)
Diarrhea
31 (15.1%)
Anorexia/Decreased Appetite
29 (14.1%)
Lethargy/Malaise
28 (13.6%)
Hypersalivation
23 (11.2%)
Behavioral Disorder
(hiding, hyperactivity, aggression)
18 (8.8%)
Ocular Discharge/Epiphora/Conjunctivitis
14 (6.8%)
Sneezing/Rhinitis
11 (5.4%)
Gingivitis/Gingival Hyperplasia
9 (4.4%)
Polydipsia
6 (2.9%)
The following adverse reactions were reported in less than or equal to 2% of cats treated with ATOPICA for Cats in the two field studies: bacterial dermatitis, hepatic lipidosis and jaundice, gastrointestinal small cell lymphoma, constipation, cough, toxoplasmosis, muscle wasting, muscle tremors, ataxia, convulsion, polyuria, urinary tract infection, inappropriate urination or defection, seborrhea, worsening otitis externa, papilloma, leukotrichia (whitening of hair) and excessive hair growth, anemia, lymphopenia, worsening monocytosis, worsening neutrophilia, hyperglobulinemia, increased serum creatinine and urea nitrogen, and increased alanine aminotransferase.
Contact Information:
To report suspected adverse drug events or for technical assistance, contact Elanco US Inc. at 1-888-545-5973. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae
Atopica™ for Cats (cyclosporine oral solution) USP MODIFIED 100 mg/mL
ADVERSE REACTIONS: In the KCS clinical field trial, there were 20 adverse reactions reported out of 132 cases enrolled. This corresponds to an adverse reaction rate of 12.9% (13 of 101 cases) for OPTIMMUNE Ophthalmic Ointment treated dogs and 22.6% (7 of 31) for placebo treated dogs. The reactions described were primarily ocular and periocular inflammatory reactions. These were likely a function of therapy being unable to fully control the keratoconjunctivitis, rather than a true "adverse reaction." Similarly, in the CSK trial, of 36 cases evaluated for safety, adverse reactions were noted in 2 animals (5.6%). One involved transient hyperemia, epiphora, and mild discomfort of the eye. The other involved periocular/palpebral inflammation and mild alopecia.
On rare occasion, instillation of OPTIMMUNE Ophthalmic Ointment may be associated with local irritation as manifested by periocular redness, lid spasm, and excessive rubbing. As the eyes of dogs with KCS often demonstrate considerable inflammation, it will be difficult to determine whether this local irritation constitutes a hypersensitivity to OPTIMMUNE Ophthalmic Ointment. If this ocular irritation persists beyond 7 days, hypersensitivity to a component of OPTIMMUNE Ophthalmic Ointment should be suspected and therapeutic options reassessed.
Optimmune® (0.2% Cyclosporine, USP) Ophthalmic Ointment