Food and Drug Administration - March 30, 2005
Richard Klein, Kimberly Struble

The Norvir (ritonavir) and Kaletra (lopinavir/ritonavir) package inserts (product labeling) were recently updated to include information regarding interactions with fluticasone (a synthetic corticosteroid, the active component of Flonase nasal Spray) and trazodone (Desyrel, a non-tricyclic antidepressant). In addition, alfuzosin (an alpha-blocker used to increase the flow of urine in people with benign prostatic hypertrophy (BPH)) was added to the Contraindications section of the Norvir package insert.

Listed below are labeling revisions for the Norvir and Kaletra package inserts.

Summary of Label Changes

NORVIR

Clinical Pharmacology:

Results of the drug interaction studies with NORVIR and fluticasone propionate aqueous nasal spray and trazodone were included:

NORVIR increased fluticasone AUC and Cmax by approximately 350-fold and 25-fold respectively. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.

NORVIR increased trazodone AUC and Cmax by 2.4 fold and 34%, respectively.

CONTRAINDICATIONS:

The Alpha₁-adrenoreceptor antagonist drug, alfuzosin HCL, was added to the contraindicated list.

WARNINGS:

The following Warning regarding fluticasone was included:

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. (see PRECAUTIONS: Drug Interactions)

PRECAUTIONS:

In the PRECAUTIONS section, the following clinical comment was included regarding the fluticasone interaction:

Concomitant use of fluticasone propionate and NORVIR increases plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS)

The following clinical comments were included regarding the trazodone interaction:

Concomitant use of trazadone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

KALETRA

WARNINGS:

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of KALETRA and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. (see PRECAUTIONS: Drug Interactions)

PRECAUTIONS:

In the PRECAUTIONS section, the following clinical comment was included regarding the fluticasone interaction:

Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS).

The following clinical comments were included regarding the trazodone interaction:

Concomitant use of trazodone and KALETRA may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Richard Klein, Office of Special Health Issues

Food and Drug Administration

Kimberly Struble, Division of Antiviral Drug Products

Food and Drug Administration

050330
FD050303

SOURCE: Food and Drug Administration (FDA).

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