Veterinary Medicine - May 2008 - (Page 267) TABLE 1 the microemulsion (modified) forms (Atopica—Novartis Animal Health, Neoral—Novartis Pharmaceuticals) since they have improved absorption in animals. Unmodified formulations (e.g. Sandimmune—Novartis Pharmaceuticals, generic cyclosporine capsules) have poor bioavailability and extreme variability in their treatment efficacy in animals,4 so we do not recommend them. The pharmacokinetics of modi ed cyclosporine (5 mg/kg orally daily) was studied in normal fasted beagles. Peak blood concentrations were reached after a mean of 1.4 hours, and the terminal half-life was determined to be roughly 9.4 hours. Based on these ndings, oncedaily dosing was deemed suf cient.5 Less Common and Rare Adverse Effects* of Cyclosporine in Dogs and Cats Acute toxoplasmosis4,21 Bacterial infection9 Bone marrow suppression4 Epidermal hamartomas and squamous cell carcinoma in situ (1 dog)22 Excessive shedding9 Gingival hyperplasia1,4,9 Hepatitis9 Hirsutism4 Lymphoma (cat)4 Lymphoproliferative disorders (cat)4 Nephropathy4 Papillomatosis9 Psoriasiform-lichenoid-like dermatosis (3 dogs)23 Renal arterial resistance (experimentally induced)4 Seizures9 Sodium retention4 *And those noted at higher dosages. ADVERSE EFFECTS Most studies show that adverse effects from cyclosporine are rare in dogs and cats at the dosages used for most dermatologic conditions. The most common side effects in dogs receiving cyclosporine at a therapeutic dosage of 5 mg/kg once daily or less are gastrointestinal problems (diarrhea, nausea, vomiting, anorexia).1,3,4,6 These side effects may occur within the rst few weeks of administration and are generally transient. By starting at a lower dosage and gradually increasing to a therapeutic dosage or by administering the medication with food, the side effects may be minimized. Metoclopramide may also be administered 30 to 60 minutes before cyclosporine to help reduce gastrointestinal side effects in patients exhibiting nausea or vomiting.7 Diarrhea or soft stool is the most common side effect noted in cats receiving cyclosporine.4 Field study data from the manufacturer and a recent retrospective study on the long-term use (six to 30 months) of cyclosporine in dogs showed that cyclosporine administration may cause abnormalities on routine blood work (e.g. elevated alkaline phosphatase and alanine aminotransferase activities, increased cholesterol concentrations, hypoalbuminemia).8,9 However, these changes were not associated with clinical signs of disease. In addition, urinary tract infections may occur. Whether these infections are related to the medication is unknown. Some evidence suggests that atopic dogs are generally more prone to urinary tract infections.8,10 In people, cyclosporine is considered to be nephrotoxic, hepatotoxic, and associated with hypertension. These effects have not been observed in dogs or cats receiving therapeutic doses for dermatologic conditions.4 Other adverse effects and those noted at higher dosages of cyclosporine in dogs and cats are summarized in Table 1. Species Species differences also account for variability in cyclosporine metabolism and distribution. In dogs, hepatic metabolism is rapid, and the drug is primarily concentrated in tissue (skin, liver, kidneys, fat). In rats, however, hepatic metabolism is much slower, and cyclosporine is concentrated in the plasma and tissues, which increases rats’ susceptibility to hepatotoxicosis and nephrotoxicosis.4 Less is known about the speci c pharmacokinetics of cyclosporine in cats. Concurrent medications Marked individual variation in peak and trough cyclosporine concentrations has been noted in both people and dogs.4 Since cyclosporine is primarily metabolized by the cytochrome P-450 enzymes in the liver, hepatic function likely plays an important role in that variation. Concurrently administering other medications that also are metabolized by the hepatic P-450 enzyme system (e.g. ketoconazole) may alter cyclosporine concentrations in the blood. This effect may be clinically useful as concurrent administration of ketoconazole and cyclosporine often allows for a lower dose of cyclosporine to be administered with similar clinical effects.3,4 However, administer cyclosporine with care in dogs receiving medications primarily metabolized by cytochrome P-450 (e.g. ketoconazole, diltiazem, cimetidine, phenobarbital, rifampin) for other conditions. Closely monitor hepatic function in these patients.4 Weight Alison Diesel, DVM Karen A. Moriello, DVM, DACVD Department of Medical Sciences School of Veterinary Medicine University of Wisconsin Madison, WI 53706 Obesity may also in uence the pharmacokinetics of cyclosporine in various species. The concentration in adipose tissue and the hydrophobic nature of the compound lend support to dosing based on a patient’s ideal weight rather than its actual weight.4,6 CAUTIONS The safety and ef cacy of cyclosporine in dogs < 6 months old or < 4 lb are unknown. The drug is contraindicated for use in dogs with a history of malignant neoplasia and VETERINARY MEDICINE May 2008 267
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.