Cyclosporine

Cyclosporine, a calcineurin inhibitor, is increasingly used to treat dermatologic and systemic inflammatory and immune-mediated diseases in dogs and cats.1

Overview

• As an immunosuppressive agent affecting primarily T-cells, cyclosporine was originally used for organ transplantation in human and veterinary medicine.1

• A veterinary ophthalmic topical cyclosporine preparation is also available.

• Caution should be used when administering this potent agent.

Formulations

• The only veterinary-approved formulation is ultramicronized modified cyclosporine1 (Atopica).

  • Absorbed more consistently and can lower risks associated with over- or underdosing

• Vegetable oil-based formulation (Sandimmune) is not approved for use in dogs and cats.1

  • Because of variability in oral bioavailability, marked intraindividual and interindividual variation in blood concentrations can be seen.1

  • Atopica and Sandimmune are not bioequivalent.2

 Gastrointestinal Upset & Solutions

• Most commonly cited side effect associated with administration of cyclosporine to dogs and cats is GI upset,1-5 notably

  • Vomiting

  • Diarrhea

  • Inappetence

Administration Options

• Various options for administering oral cyclosporine can help alleviate GI side effects.

  • Administer concurrent antiemetic5 (eg, metoclopramide, maropitant)

  • Administer frozen capsules1,5

    • In dogs, may decrease blood concentrations and jeopardize treatment efficacy

  • Administer capsules with small amount of food1,5

    • In dogs, may decrease blood concentrations and jeopardize treatment efficacy

  • Start at a lower dose (1–2 mg/kg q24h) and gradually increase to final dose5

    • Not appropriate for life-threatening immune-mediated diseases, such as immune-mediated hemolytic anemia

  • Decrease dose1,5

Cyclosporine-Induced Gingival Hyperplasia

• Monitoring

  • Gingival hyperplasia is a known side effect of cyclosporine in dogs and cats, so patients  on cyclosporine should be monitored for the condition.1-5

  • Risk appears dose-dependent, but significant interindividual differences exist in incidence and severity5

• Managing

  • Generally mild and of limited clinical significance5

  • If problematic, hyperplasia often improves with cyclosporine dose reduction.5

  • Significant hyperplasia may require drug discontinuation.5

  • Azithromycin toothpaste and systemic azithromycin have improved the severity of gingival hyperplasia in some dogs.5

Less Common Disorders & Adverse Effects

• Less common adverse effects include3,4

  • Cats only

    • Behavior disorders (eg, hiding, hyperactivity, aggression)

    • Hypersalivation

    • Ocular discharge

    • Sneezing/rhinitis

  • Dogs only

    • Cutaneous papillomatosis

    • Lymphadenopathy

    • Persistent otitis externa

  • Dogs & cats

    • Secondary infection

    • Lethargy

Drug Interactions & Patient Assessment

• Cyclosporine is metabolized by the cytochrome P450 enzyme CYP3A; some drugs can impact CYP3A activity.1

  • Check any medication administered concurrently with cyclosporine for possible drug interactions. 

  • Interactions can increase or decrease cyclosporine blood concentrations and potentially cause drug toxicity or failure.1,2

  • Ketoconazole is the most common drug co-administered to purposefully decrease cyclo-sporine dosages and still achieve adequate cyclosporine blood concentrations.

    • Reduces hepatic metabolism of cyclosporine, allowing decrease of oral cyclosporine doses by as much as 75%1

  • Although much less commonly used in clinical patients, powdered whole grapefruit can also increase blood concentrations in dogs.1

• Because individual patient responses can vary, measuring blood concentrations and/or assessing pharmacodynamics can be beneficial.

  • When measuring blood concentrations, obtaining samples at peak (2 hours after dosing) and trough is recommended.1

    • Laboratory and analysis method for monitoring samples should be consistent for each patient.

      • Some laboratories measure cyclosporine metabolites and the parent drug.1

  • Dogs only: To measure patient immune response by pharmacodynamic assessment, blood samples can be sent to Mississippi State University College of Veterinary Medicine (cvm.msstate.edu).

    • Obtaining test results regarding patient’s immune response can help guide dose decisions (based on authors’ research, samples received from private practitioners, and ongoing clinical trials at MSU).

Potential for Drug Toxicity or Failure

Precautions & Potentially Fatal Outcomes

• Dogs only: Food can decrease oral absorption of the ultramicronized formulation of cyclosporine in dogs, so they should receive cyclosporine on an empty stomach.3

  • Because this effect was not seen in cats, they should receive cyclosporine with a meal.4

• Because safety studies have not been conducted, exercise caution when administering cyclosporine to

  • Dogs or cats younger than 6 months of age3,4

  • Dogs weighing less than 4 pounds3

  • Cats weighing less than 3 pounds4

• Because cyclosporine suppresses the immune system, monitor patients for development of secondary fungal or protozoal infection.

  • Even the label dose used for treating atopic dermatitis may cause significant immune effects with potential risk for increased systemic infection.1,6

• Cats only: Cyclosporine has been associated with potentially fatal toxoplasmosis from acute infection or secondary to reactivation of latent infection.7,8

  • Monitor closely for clinical signs associated with Toxoplasma gondii infection.7,8

Do Not Use

• In breeding, pregnant, or lactating dogs or cats3,4

• In cats with FeLV or FIV infection4

• In cats that are hypersensitive to cyclosporine4

• In dogs or cats with neoplasia or a history of neoplasia3,4