Compendium February 1999

Compendium February 1999

20TH ANNIVERSARY

Small Animal/Exotics

PHARM PROFILE

ITRACONAZOLE Stephen Martin, BS, RPh, MBA Iowa State University

TABLE ONE Itraconazole—Recommended Dosinga Species

I

traconazole (Sporanox®, Janssen Pharmaceutica, Titusville, NJ), an antifungal agent labeled for human use, belongs to the triazolederivative azole group of synthetic antifungal agents, other members of which include fluconazole and terconazole.

Pharmacology Itraconazole and the other triazoles increase fungal cell membrane permeability by inhibiting the fungal cytochrome P-450 enzyme system in the production of ergosterol, a building block of fungal cell walls.1,2 Itraconazole is lipophilic, and concentrations of the drug in fatty tissues, omentum, liver, kidney, and skin tissues are 2 to 20 times the corresponding plasma concentration. Measurable amounts can also be found in the hair, sebum, and fingernails; only negligible amounts are found in cerebrospinal fluid.2 Indications Itraconazole has demonstrated in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, H. capsulatum var. duboisii, Aspergillus flavus, Aspergillus fumigatus, and Cryptococcus neoformans. 2 Animal models have also shown itraconazole to be active against Candida albicans,

Dogs

Dosage

Infection

5-mg/kg loading dose twice daily or 10-mg/kg loading dose once daily for 3 to 4 days,7 then 5 mg/kg once daily3,7

Blastomycosis

5 mg/kg twice daily7,8

Cryptococcosis, histoplasmosis, aspergillosis, sporotrichosis

5–10 mg/kg once or twice daily9

Malassezia dermatitis

5 mg/kg twice daily3

Blastomycosis, histoplasmosis

50 mg/day for cats weighing <3.2 kg5

Cryptococcosis

100 mg/day for cats weighing >3.2 kg5

Cryptococcosis

Birds

10 mg/kg every 24 hours6

Aspergillosis or candidiasis in raptors, psittacines, and waterfowlb

Horses

3 mg/kg twice daily10

Aspergillus nasal infection

Cats

a The dosages presented here are meant for the capsule form and must be given with food for maximum absorption. b Absorption in birds is improved by administering a dose made by dissolving the capsule contents (beads) in 2 ml of 0.1 N hydrochloric acid and diluting with 18 ml of orange juice to make a final solution of 20 mg/ml. The appropriate dose should be followed by a gruel gavage.6

Pharm Profile introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like Pharm Profile to cover a particular agent, please contact column editor GiGi Davidson, BS, RPh, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email [email protected].

Small Animal/Exotics

20TH ANNIVERSARY

Client Counseling Information ■ Itraconazole is an antifungal agent used to treat fungal infections; it is very important to give this medication for the full course of treatment even if clinical signs begin to clear up. Early discontinuation of treatment could cause signs to return. ■ Itraconazole capsules and the compounded suspension should be given with food, whereas the oral solution should be given on an empty stomach. This drug should be administered 2 hours before drugs that can reduce stomach acidity (e.g., antacids, omeprazole, cimetidine, ranitidine). ■ Although itraconazole is generally well tolerated, your veterinarian should be notified immediately if loss of appetite, lethargy, dark urine, or pale stools are observed. ■ Itraconazole can interact with various other medications; check with your veterinarian before giving other medications. ■ Capsules should be stored at controlled room temperature (59˚F to 77˚F) and protected from light and moisture. The following preparation can be helpful for doses less than 100 mg: Itraconazole 40-mg/ml suspension11—24 itraconazole capsules (100 mg); 5 ml ethyl alcohol 95%; simple syrup, USP (as much as needed to make 60 ml) 1. Empty capsules into glass mortar and add alcohol; wait about 5 minutes. 2. Begin to grind the beads (capsule contents) into a fine paste; continue grinding until all alcohol has evaporated and a fine powder remains. 3. Gradually add about 15 ml of syrup, stirring constantly, and transfer the mixture to an amber glass bottle. Wash the mortar with the syrup and transfer to the bottle until a final volume of 60 ml is reached. 4. Keep refrigerated and shake well before use; the refrigerated suspension will remain stable for 35 days. 5. Give with food. Coccidioides immitis, Paracoccidioides brasiliensis, and Sporothrix schenckii.1 Itraconazole is indicated in humans for the treatment of blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. It has also been used to treat other superficial, systemic, and miscellaneous mycotic infections. The oral solution is labeled for oropharyngeal and esophageal candidiasis in humans. Itraconazole has been used in veterinary medicine to treat several fungal infections, including blastomycosis, histoplasmosis, aspergillosis, various forms of tinea, candidiasis (vaginal and systemic), cryptococcal infections, and fungal keratitis.

Cautions Although generally well tolerated, some of the more common adverse effects associated with itraconazole use in humans are nausea, vomiting, diarrhea, rash, and elevated liver enzymes.2,3 The same gastrointestinal events and elevated liver enzymes have been observed in dogs, as have anorexia, lethargy, increased blood urea nitrogen, and skin ulcerations.4 In cats, anorexia, weight loss, and increased serum ALT concentrations have been observed; hepatotoxicity leading to death has occurred in a cat at a dose of 27.8 mg/kg/day for several weeks.5 Itraconazole is suspected

Compendium February 1999

of causing anorexia and lethargy in African grey parrots.6 Side effects are usually dose related and generally develop after 30 days of therapy. If necessary because of an adverse reaction or toxicity, treatment can be discontinued and then resumed at half the original dose after the problem has resolved.7 Liver enzymes should be checked monthly when an animal is being treated with itraconazole.5,7 Patients with hepatic impairment should be carefully monitored if placed on itraconazole; renal insufficiency does not affect itraconazole plasma levels.2 At doses 5 to 20 times the maximum human dose (400 mg/day) in rats and mice, itraconazole produced maternal toxicity, embryotoxicity, and teratogenicity. Unless benefits outweigh risks, use of this drug in pregnancy should be avoided. The drug is excreted in human breast milk.2

Acute Toxicity Increased ALT concentrations and drug-induced anorexia are signs of itraconazole toxicity.3,7 Itraconazole treatment should be discontinued in dogs with serum ALT concentrations higher than 250 IU/L or if the dog becomes anorexic8 (see Cautions). Drug Interactions Because itraconazole inhibits the cytochrome P-450 3A4 enzyme system, caution should be used when drugs that are metabolized by this system are given concurrently because adverse effects could result from an increase in the plasma concentration of itraconazole. Concurrent administration of terfenadine or cisapride with itraconazole is contraindicated; these combinations have resulted in severe cardiovascular adverse effects (including death). Cardiovascular effects may also be seen when itraconazole and astemizole are given concurrently.2,3 Itraconazole will also cause elevated plasma levels of calcium-channel blockers (e.g., amlodipine, nifedip-

Compendium February 1999

20TH ANNIVERSARY

ine), digoxin, midazolam, quinidine, cyclosporine, and warfarin. Dosage adjustments may be necessary for these drugs. Rifampin and H2 antagonists given concurrently with itraconazole will result in lower itraconazole plasma levels.2

Dosage Although the use of itraconazole is extralabel in veterinary medicine, the drug has been prescribed for several species (Table One). Treatment with itraconazole tends to be lengthy; depending on the infection, the course of treatment may run 30 to 90 days or longer. To avoid relapse and failure, treatment should be continued until the patient is clinically free of infection for 1 to 2 months. For severe or lifethreatening mycotic infections, amphotericin B may be given with itraconazole at the onset of treatment or itraconazole can be given as a loading dose for the first 3 to 4 days. Preparations Itraconazole is commercially available only as Sporanox® 100-mg capsules and Sporanox® 10-mg/ml solution. The bioavailability of itraconazole depends on whether the capsules or solution is administered. For maximum absorption, Sporanox® capsules should be given with food and Sporanox® solution without food. The manufacturer does not recommend using these dose forms interchangeably because the bioavailability of the solution is higher than that of the capsules. Treatment with itraconazole can be expensive. The average wholesale price for a bottle of 30 capsules is about $190; a 120-ml bottle of solution costs about $100. Storage and Handling The capsules should be stored at controlled room tem-

Small Animal/Exotics

perature (59˚F to 77˚F) and protected from light and moisture. The solution should be stored at room temperature and protected from freezing. The extemporaneous compounded suspension should be refrigerated and any remaining suspension discarded after 35 days.

References 1. Reynolds JEF: Martindale: The Extra Pharmacopoeia, ed 30. London, Pharmaceutical Press, 1993, p 325. 2. Kastrup GK (ed): Drug Facts and Comparisons. St. Louis, Facts and Comparisons, 1998, pp 359f–359k. 3. McEvoy GK (ed): AHFS-98 Drug Information. Bethesda, American Society of Health-System Pharmacists, 1998, pp 112–116. 4. Legendre AM, Rohrbach BW, Toal RL, et al: Treatment of blastomycosis with itraconazole in 112 dogs. J Vet Intern Med 10:365–371, 1996. 5. Medleau L, Gilbert JJ, Marks MA: Itraconazole for the treatment of cryptococcosis in cats. J Vet Intern Med 9:39–42, 1995. 6. Orosz SE, Frazier DL: Antifungal agents: A review of their pharmacology and therapeutic indications. J Avian Med Surg 9:8–18, 1995. 7. Bonagura JD (ed): Kirk’s Veterinary Therapy XII. Philadelphia, WB Saunders Co, 1995, pp 329–331. 8. Berthelin CF, Legendre AM, Bailey CS: Cryptococcosis of the nervous system in dogs: Part 2. Diagnosis, treatment, monitoring, and prognosis. Prog Vet Neurol 5:136–145, 1994. 9. Morgan RV: Handbook of Small Animal Practice, ed 3. Philadelphia, WB Saunders Co, 1997, p 899. 10. Korenek NL, Legendre AM, Andrews FM: Treatment of mycotic rhinitis in three horses. J Vet Intern Med 8:224–227, 1994. 11. Pesko LJ: Itraconazole antifungal in suspension. Am Druggist May:52, 1997.

About the Author Mr. Martin is the pharmacist at the Veterinary Teaching Hospital, Iowa State University, Ames, Iowa.