FDA Announces Updates to Atazanavir (Reyataz) Package Insert Concerning Drug Interactions

Reyataz Capsule

The FDA last week announced that the atazanavir (Reyataz) package insert has been updated to include important information about drug-drug interactions regarding the co-administration of atazanavir (with or without ritonavir (Norvir) boosting) and nevirapine (Viramune), efavirenz (Sustiva), hormonal contraceptives, orally and parenterally administered midazolam, H2-receptor antagonists, and drugs that are substrates of cytochrome P450 2C8 (CYP2C8). Below is a summary of the changes.

Nevirapine Tablet

Nevirapine:

Do NOT co-administer atazanavir with nevirapine because:

• Nevirapine substantially decreases atazanavir exposure;

• Potential risk exists for nevirapine-associated toxicity due to increased nevirapine exposure.

Efavirenz Tablet

Efavirenz:

Efavirenz decreases atazanavir exposure:

• For treatment-naive patients the recommended dose is 400 mg atazanavir with 100 mg ritonavir and 600 mg efavirenz once daily; efavirenz should be taken on an empty stomach, preferably at bedtime

• For treatment-experienced patients: do not co-administer atazanavir with efavirenz because efavirenz decreases atazanavir exposure.

Norvir Capsule

Hormonal Contraceptives:

Use with caution if co-administration of atazanavir or atazanavir/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with atazanavir/ritonavir, it is recommended the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If atazanavir is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.

Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could include risk of insulin resistance, dyslipidemia (abnormal blood fat levels), and acne.

Co-administration of atazanavir or atazanavir/ritonavir with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectible contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of non-hormonal contraception are recommended.

Midazolam

Midazolam (Versed and others):

Co-administration of oral midazolam with atazanavir is contraindicated. Concomitant use of parenteral midazolam with atazanavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Midazolam dose reduction should be considered, especially if more than a single dose of midazolam is administered.

H2-receptor Antagonists (Cimetidine [Tagamet], Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid]):

The packaged insert already contains the following dosing information for treatment-naive patients: 300 mg atazanavir with 100 mg ritonavir once daily with food should be administered simultaneously with, and/or at least 10 hours after, H2-receptor antagonists. A H2-receptor antagonist dose comparable to 40 mg famotidine twice daily can be used with 300 mg atazanavir plus 100 mg ritonavir in treatment-naïve patients.

The label was updated to add the following: For treatment-naive patients unable to tolerate ritonavir, 400 mg atazanavir once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to 20 mg famotidine, and the total daily dose should not exceed a dose comparable to 40 mg famotidine.

Substrates of CYP2C8:

Atazanavir is a weak inhibitor of the CYP2C8 enzyme. Caution should be used when atazanavir without ritonavir is co-administered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g., paclitaxel [Taxol], repaglinide [Prandin]). When atazanavir with ritonavir is co-administered with substrates of CYP2C8, clinically significant interactions are not expected.

The complete, revised label will be available soon on the FDA website through at http://www.accessdata.fda.gov.

8/26/08

Source
R Klein and K Struble (U.S. Food and Drug Administration). Recent Updates to the Atazanavir (Reyataz) Product Label. August 24, 2008.