Atazanavir

Atazanavir, co-administered with low dose ritonavir, is indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.

Atazanavir, co-administered with low dose ritonavir, is indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.

Co-administration with products containing St. John’s wort (Hypericum perforatum).

Concomitant use of St. John’s wort with atazanavir may be expected to result in significant reduction in plasma levels of atazanavir. This effect may be due to an induction of CYP3A4. There is a risk of loss of therapeutic effect and development of resistance.

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g. quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine).

Atazanavir is contraindicated in patients with severe hepatic insufficiency.

Co-administration of alfuzosin with atazanavir is contraindicated. Potential for increased alfuzosin concentrations which can result in hypotension. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

Co-administration of atazanavir with bepridil is contraindicated. Atazanavir should not be used in combination with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index.

Co-administration of atazanavir with glecaprevir/pibrentasvir is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecaprevir and pibrentasvir plasma concentrations.

Glecaprevir AUC: ↑553% (↑424% ↑714%)
Glecaprevir C_max: ↑306% (↑215% ↑423%)
Glecaprevir C_min: ↑1330% (↑885% ↑1970%)

Pibrentasvir AUC: ↑64% (↑48% ↑82%)
Pibrentasvir C_max: ↑29% (↑15% ↑45%)
Pibrentasvir C_min: ↑129% (↑95% ↑168%)

* Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.

Co-administration of atazanavir with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevir concentrations. Co-administration of atazanavir with glecaprevir/pibrentasvir fixed dose combination is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecapreir and pibrentasvir plasma concentrations.

Atazanavir AUC: ↑43% (↑30% ↑57%)
Atazanavir C_max: ↑12% (↑1% ↑24%)
Atazanavir C_min: ↑23% (↑13% ↑134%)

Grazoprevir AUC: ↑958% (↑678% ↑1339%)
Grazoprevir C_max: ↑524% (↑342% ↑781%)
Grazoprevir C_min: ↑1064% (↑696% ↑1602%)

Grazoprevir concentrations were greatly increased when co-administered with atazanavir/ritonavir.

Atazanavir AUC: ↑7% (↓2% ↑17%)
Atazanavir C_max: ↑2% (↓4% ↑8%)
Atazanavir C_min: ↑15% (↑2% ↑29%)

Elbasvir AUC: ↑376% (↑307% ↑456%)
Elbasvir C_max: ↑315% (↑246% ↑397%)
Elbasvir C_min: ↑545% (↑451% ↑654%)

Elbasvir concentrations were increased when co-administered with atazanavir/ritonavir.

Co-administration of lurasidone with atazanavir is contra-indicated as this may increase lurasidone-related toxicity. Atazanavir is expected to increase plasma levels of lurasidone due to CYP3A4 inhibition.

Co-administration of atazanavir with triazolam or orally administered midazolam is contraindicated, whereas caution should be used with coadministration of atazanavir and parenteral midazolam. If atazanavir is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Midazolam and triazolam are extensively metabolised by CYP3A4. Co-administration with atazanavir may cause a large increase in the concentration of these benzodiazepines. No drug interaction study has been performed for the coadministration of atazanavir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.

Co-administration of quetiapine with atazanavir is contraindicated as atazanavir may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma.

Due to CYP3A4 inhibition by atazanavir, concentrations of quetiapine are expected to increase.

The concomitant use of quinidine is contraindicated. Quinidine has a narrow therapeutic window and is contraindicated due to potential inhibition of CYP3A by atazanavir.

Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of atazanavir or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.

The combination of rifampicin and atazanavir is contraindicated.

Atazanavir with ritonavir is contraindicated in patients with moderate hepatic insufficiency.

A safe and effective dose in combination with atazanavir has not been established for sildenafil when used to treat pulmonary arterial hypertension. Sildenafil, when used for the treatment of pulmonary arterial hypertension, is contraindicated.

Co-administration with atazanavir may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-inhibitor-associated adverse events. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

Co-administration of simvastatin or lovastatin with atazanavir is contraindicated due to an increased risk of myopathy including rhabdomyolysis.

Simvastatin and lovastatin are highly dependent on CYP3A4 for their metabolism and co-administration with atazanavir may result in increased concentrations.