Atazanavir label updated in the US relating to drug interactions with NNTRIs, hormonal contraceptives, midazolam, H2 receptor antagonists and other drugs
The US atazanavir (Reyataz) package insert has been updated to include important drug-drug interaction information regarding the administration of atazanavir with or without ritonavir and nevirapine, efavirenz, hormonal contraceptives, orally and parenterally administered midazolam, H2-receptor antagonists, and drugs that are substrates of cytochrome P450 2C8. Below is a summary of the changes.
Do not coadminister atazanavir with nevirapine because:
- nevirapine substantially decreases atazanavir exposures, and
- potential risk exists for nevirapine associated toxicity due to increased nevirapine exposures
Efavirenz decreases atazanavir exposure:
For treatment-naive patients: the recommended dose is atazanavir 400 mg with ritonavir 100 mg and efavirenz 600 mg once daily. Efavirenz should be taken on an empty stomach preferably at bedtime
For treatment-experienced patients: do not coadminister atazanavir with efavirenz because efavirenz decreases atazanavir exposure
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 effect of increases in the concentration of the progestational agent are unknown, and could include risk of insulin resistance, dyslipidemia and acne.
Coadministration of atazanavir or atazanavir/ritonavir with other hormonal contraceptives (eg, 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.
Coadministration of oral midazolam with atazanavir is contraindicated. Concomitant use of parenteral midazolam with atazanavir may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
The packaged insert already contains the following dosing information for treatment naive patients: atazanavir 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. H2-receptor antagonist dose comparable to famotidine 40 mg twice daily can be used with atazanavir 300 mg with ritonavir 100 mg in treatment-naive patients.
The label was updated to add the following:
For treatment-naive patients unable to tolerate ritonavir, atazanavir 400 mg 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 famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
Substrates of CYP2C8
Atazanavir is a weak inhibitor of CY2C8. Caution should be used when atazanavir without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g. paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.
The complete, revised label is available on the FDA website:
Source: FDA list serve: