November 14, 2016
The U.S. Food and Drug Administration (FDA) recently approved ITRAFUNGOL, an itraconazole oral solution for treating dermatophytosis caused by Microsporum canis in cats (New Animal Drug Application 141-474). FDA wants to remind you of the benefits of using FDA-approved drugs in your clinic and also inform you of the risks associated with oral formulations of itraconazole compounded from bulk drug substances.
Manufactured for Elanco US Inc., ITRAFUNGOL is a prescription animal drug and comes with a graduated dosing oral syringe. Please refer to the Freedom of Information Summary and package insert for ITRAFUNGOL before using it.
Benefits of FDA Approval
FDA rigorously evaluates an animal drug before approving it. As part of the approval process, the drug company must prove to FDA that:
- The drug is safe and effective for a specific use in a specific animal species;
- The manufacturing process is adequate to preserve the drug’s identity, strength, quality, and purity; and
- The drug’s labeling is truthful and not misleading.
FDA’s role does not stop after the agency approves an animal drug. As long as the drug company markets the animal drug, the agency continues to monitor:
- The drug’s safety and effectiveness. Sometimes, the agency’s post-approval monitoring uncovers safety and effectiveness issues that were unknown at the time of approval;
- The manufacturing process to ensure quality and consistency are maintained;
- The drug’s labeling to make sure the information remains truthful and not misleading; and
- The company’s marketing communications related to the drug to make sure the information is truthful and not misleading.
Adverse Drug Events and Drug Interactions Associated with ITRAFUNGOL
While itraconazole is considered less toxic than many other drugs in the same class, such as ketoconazole and clotrimazole, there’s still a risk for adverse drug events and drug interactions. Adverse drug events reported for ITRAFUNGOL in cats include decreased appetite, vomiting, diarrhea, increased salivation, and elevated hepatic enzymes.1
ITRAFUNGOL is a cytochrome p-450 inhibitor and may increase or prolong plasma concentrations of other drugs metabolized by this pathway, such as amitriptyline, amlodipine, benzodiazepines, buspirone, cisapride, corticosteroids, cyclosporine, ivermectin, and macrolide antibiotics.2
Concerns about Oral Formulations of Itraconazole Compounded from Bulk Drug Substances
FDA is aware that itraconazole is currently the treatment of choice for many systemic fungal infections in animals and alternative oral treatments are lacking.3 The agency is also aware that oral formulations of itraconazole compounded from bulk drug substances are available through many compounding pharmacies. FDA-approved drugs have data demonstrating that the drugs are safe, effective, and properly manufactured so they have the intended quality and effect. Itraconazole products compounded from bulk drug substances for animals are unapproved animal drugs. Of particular concern is that several published studies show significant differences in the bioavailability of oral itraconazole products compounded from bulk drug substances for animals.
Itraconazole is highly lipophilic and practically insoluble in water.4 To be absorbed, the drug must dissolve in the acidic environment of the gastrointestinal tract, which is difficult to accomplish. The pharmacokinetics of compounded oral itraconazole formulations are unknown. Substantial variations in drug absorption are seen between oral formulations of itraconazole compounded by different pharmacies, the same pharmacy at different times, or manufactured under different conditions.5,6,7 These variations can cause clinical effects, including a lack of effectiveness and adverse drug events. Substantial differences in bioavailability may result in you inadvertently under- or over-dosing patients when you start them on compounded itraconazole or switch them from one compounded formulation to another.
A study published in 2014 by Mawby et al found that a compounded oral formulation of itraconazole had very low absorption and bioavailability in a group of nine healthy Beagles.8 The compounded product used in the study resulted in AUC and CMAX concentrations that were approximately 5% of the values measured after the same dose of Sporanox, an FDA-approved oral itraconazole capsule used to treat certain fungal infections in people. (AUC is the plasma concentration versus time curve and CMAX is the peak concentration.)
Because of the documented variations in drug absorption and poor bioavailability of oral formulations of itraconazole compounded from bulk drug substances, FDA recommends that you prescribe FDA-approved ITRAFUNGOL for cats that need to be treated with itraconazole. The labeling for ITRAFUNGOL is written specifically for cats and includes all necessary information, including associated risks, so you can use the drug safely and effectively in cats. Oral formulations of itraconazole compounded from bulk drug substances are unapproved animal drugs and don’t have the same assurances of safety and effectiveness as ITRAFUNGOL.
FDA’s Center for Veterinary Medicine (CVM) is committed to promoting and protecting animal health by ensuring safe and effective drugs are available for animals. For more information, please contact CVM’s Education & Outreach Staff at 240-402-7002 or AskCVM@fda.hhs.gov.
FDA’s Center for Veterinary Medicine
- Elanco US Inc. Package insert for Itrafungol (itraconazole oral solution), New Animal Drug Application 141-474. Greenfield, Ind:Elanco US Inc., 2016.
- Plumb DC. Plumb’s veterinary drug handbook. 8th ed. Stockholm, Wis: PharmaVet Inc., 2015;583-586, 1148-1149.
- Davis JL, Papich MG, Heit MC. Antifungal and antiviral drugs. In: Riviere JE, Papich MG, eds. Veterinary pharmacology and therapeutics. 9th ed. Ames, IA: Wiley-Blackwell, 2009;1013-1049.
- Christensen KJ, Gubbins PO, Gurley BJ, et al. Relative bioavailability of itraconazole from an extemporaneously prepared suspension and from the marketed capsules. Am J Health Syst Pharm 1998;55:261-265.
- Swaminathan S, Sangwai M, Wawdhane S, et al. Soluble itraconazole in tablet form using disordered drug delivery approach: critical scale-up considerations and bio-equivalence studies. AAPS PharmSciTech 2013;14:360-374.
- Mawby DI, Whittemore JC, Genger S, et al. Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs. J Vet Intern Med 2014;28:72-77.