Chemical formula: C₃₈H₅₂N₆O₇ Molecular mass: 704.856 g/mol PubChem compound: 148192
Atazanavir interacts in the following cases:
Dose related asymptomatic prolongations in PR interval with atazanavir have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), atazanavir should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing atazanavir in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances).
Atazanavir is metabolised principally by CYP3A4. Co-administration of atazanavir and medicinal products that induce CYP3A4 is not recommended.
Atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir with ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir with ritonavir must not be used in patients with moderate to severe hepatic impairment.
In case of withdrawal of ritonavir form the initial recommended ritonavir boosted regimen, unboosted atazanavir could be maintained in patients with mild hepatic impairment at a dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg once daily with food. Unboosted atazanavir must not be used in patients with severe hepatic impairment.
Atazanavir should be administered 2 hours before or 1 hour after antacids or buffered medicinal products. Reduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids, including buffered medicinal products, are administered with atazanavir.
Co-administration of atazanavir with proton pump inhibitors is not recommended. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.
Co-administration of atazanavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided.
Caution is warranted and therapeutic concentration monitoring is recommended when available. Concentrations of these antiarrhythmics may be increased when co-administered with atazanavir. The mechanism of amiodarone or systemic lidocaine/atazanavir interaction is CYP3A inhibition.
Co-administration of atorvastatin with atazanavir is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring.
The risk of myopathy including rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.
Co-administration of atazanavir/ritonavir with boceprevir resulted in lower exposure of atazanavir which may be associated with lower efficacy and loss of HIV control. This co-administration might be considered on a case by case basis if deemed necessary, in patients with suppressed HIV viral loads and with HIV viral strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring for HIV suppression is warranted.
Boceprevir AUC: ↔5%
Boceprevir Cmax: ↔7%
Boceprevir Cmin: ↔18%
Atazanavir AUC: ↓35%
Atazanavir Cmax: ↓25%
Atazanavir Cmin: ↓49%
Ritonavir AUC: ↓36%
Ritonavir Cmax: ↓27%
Ritonavir Cmin: ↓45%
Co-administration with atazanavir with ritonavir warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.
Buprenorphine AUC: ↑67%
Buprenorphine Cmax: ↑37%
Buprenorphine Cmin: ↑69%
Norbuprenorphine AUC: ↑105%
Norbuprenorphine Cmax: ↑61%
Norbuprenorphine Cmin: ↑101%
The mechanism of interaction is CYP3A4 and UGT1A1 inhibition.
Concentrations of atazanavir (when given with ritonavir) were not significantly affected.
Carbamazepine should be used with caution in combination with atazanavir. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient’s virologic response should be excercised.
Atazanavir may increase plasma levels of carbamazepine due to CYP3A4 inhibition. Due to carbamazepine inducing effect, a reduction in atazanavir exposure cannot be ruled out.
More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.
Concentrations of these immunosuppressants may be increased when co-administered with atazanavir due to CYP3A4 inhibition.
No recommendation regarding dose reduction can be made; therefore, caution should be exercised if atazanavir is co-administered with clarithromycin.
Clarithromycin AUC: ↑94% (↑75% ↑116%)
Clarithromycin Cmax: ↑50% (↑32% ↑71%)
Clarithromycin Cmin: ↑160% (↑135% ↑188%)
14-OH clarithromycin
14-OH clarithromycin AUC: ↓70% (↓74% ↓66%)
14-OH clarithromycin Cmax: ↓72% (↓76% ↓67%)
14-OH clarithromycin Cmin: ↓62% (↓66% ↓58%)
Atazanavir AUC: ↑28% (↑16% ↑43%)
Atazanavir Cmax: ↔6% (↓7% ↑20%)
Atazanavir Cmin: ↑91% (↑66% ↑121%)
A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.
Didanosine should be taken at the fasted state 2 hours after atazanavir taken with food. The co-administration of stavudine with atazanavir is not expected to significantly alter the exposure of stavudine.
Atazanavir, simultaneous administration with ddI+d4T (fasted):
Atazanavir AUC: ↓87% (↓92% ↓79%)
Atazanavir Cmax: ↓89% (↓94% ↓82%)
Atazanavir Cmin: ↓84% (↓90% ↓73%)
Atazanavir, dosed 1 hr after ddI+d4T (fasted):
Atazanavir AUC: ↔3% (↓36% ↑67%)
Atazanavir Cmax: ↑12% (↓33% ↑18%)
Atazanavir Cmin: ↔3% (↓39% ↑73%)
Atazanavir concentrations were greatly decreased when co-administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets.
No significant effect on didanosine and stavudine concentrations was observed.
An initial dose reduction of diltiazem by 50% is recommended, with subsequent titration as needed and ECG monitoring.
Diltiazem AUC: ↑125% (↑109% ↑141%)
Diltiazem Cmax: ↑98% (↑78% ↑119%)
Diltiazem Cmin: ↑142% (↑114% ↑173%)
Desacetyl-diltiazem AUC: ↑165% (↑145% ↑187%)
Desacetyl-diltiazem Cmax: ↑172% (↑144% ↑203%)
Desacetyl-diltiazem Cmin: ↑121% (↑102% ↑142%)
No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. Co-administration of diltiazem and atazanavir/ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition.
Co-administration of efavirenz and atazanavir is not recommended.
Atazanavir (pm): all administered with food
Atazanavir AUC: ↔0% (↓9% ↑10%)*
Atazanavir Cmax: ↑17% (↑8% ↑27%)*
Atazanavir Cmin: ↓42% (↓51% ↓31%)*
Atazanavir (pm): all administered with food
Atazanavir AUC: ↔6% (↓10% ↑26%)/*
Atazanavir Cmax: ↔9% (↓5% ↑26%)/*
Atazanavir Cmin: ↔12% (↓16% ↑49%)/*
* When compared to atazanavir 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin, might negatively impact the efficacy of atazanavir. The mechanism of efavirenz/atazanavir interaction is CYP3A4 induction.
** Based on historical comparison.
If an oral contraceptive is administered with atazanavir/ritonavir, it is recommended that the oral contraceptive contain at least 30 μg of ethinyloestradiol and that the patient be reminded of strict compliance with this contraceptive dosing regimen. Co-administration of atazanavir/ritonavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate has not been studied, and therefore should be avoided. An alternate reliable method of contraception is recommended.
Ethinyloestradiol 25 μg + norgestimate (atazanavir 300 mg once daily with ritonavir 100 mg once daily):
Ethinyloestradiol AUC: ↓19% (↓25% ↓13%)
Ethinyloestradiol Cmax: ↓16% (↓26% ↓5%)
Ethinyloestradiol Cmin: ↓37% (↓45% ↓29%)
Norgestimate AUC: ↑85% (↑67% ↑105%)
Norgestimate Cmax: ↑68% (↑51% ↑88%)
Norgestimate Cmin: ↑102% (↑77% ↑131%)
While the concentration of ethinyloestradiol was increased with atazanavir given alone, due to both UGT and CYP3A4 inhibition by atazanavir, the net effect of atazanavir/ritonavir is a decrease in ethinyloestradiol levels because of the inducing effect of ritonavir.
The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.
Ethinyloestradiol 35 µg + norethindrone (atazanavir 400 mg once daily):
Ethinyloestradiol AUC: ↑48% (↑31% ↑68%)
Ethinyloestradiol Cmax: ↑15% (↓1% ↑32%)
Ethinyloestradiol Cmin: ↑91% (↑57% ↑133%)
Norethindrone AUC: ↑110% (↑68% ↑162%)
Norethindrone Cmax: ↑67% (↑42% ↑196%)
Norethindrone Cmin: ↑262% (↑157% ↑409%)
The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.
For patients not taking tenofovir, if atazanavir 300 mg/ritonavir 100 mg and H2-receptor antagonists are co-administered, a dose equivalent to famotidine 20 mg twice daily should not be exceeded. If a higher dose of an H2-receptor antagonist is required (e.g. famotidine 40 mg twice daily or equivalent) an increase of the atazanavir/ritonavir dose from 300/100 mg to 400/100 mg can be considered.
In HIV-infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg once daily:
Famotidine 20 mg twice daily:
Atazanavir AUC: ↓18% (↓25% ↑1%)
Atazanavir Cmax: ↓20% (↓32% ↓7%)
Atazanavir Cmin: ↔1% (↓16% ↑18%)
Famotidine 40 mg twice daily:
Atazanavir AUC: ↔3% (↓14% ↑22%)
Atazanavir Cmax: ↔2% (↓13% ↑8%)
Atazanavir Cmin: ↓14% (↓32% ↑8%)
In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg once daily:
Famotidine 40 mg twice daily:
Atazanavir AUC: ↔3% (↓14% ↑22%)
Atazanavir Cmax: ↔2% (↓13% ↑8%)
Atazanavir Cmin: ↓14% (↓32% ↑8%)
For patients who are taking tenofovir disoproxil fumarate, if atazanavir/ritonavir with both tenofovir disoproxil fumarate and an H2-receptor antagonist are co-administered, a dose increase of atazanavir to 400 mg with 100 mg of ritonavir is recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.
In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily:
Famotidine 20 mg twice daily:
Atazanavir AUC: ↓21% (↓34% ↓4%)*
Atazanavir Cmax: ↓21% (↓36% ↓4%)*
Atazanavir Cmin: ↓19% (↓37% ↑5%)*
Famotidine 40 mg twice daily:
Atazanavir AUC: ↓24% (↓36% ↓11%)*
Atazanavir Cmax: ↓23% (↓36% ↓8%)*
Atazanavir Cmin: ↓25% (↓47% ↑7%)*
In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400/100 mg once daily:
Famotidine 20 mg twice daily:
Atazanavir AUC: ↑18% (↑6.5% ↑30%)*
Atazanavir Cmax: ↑18% (↑6.7% ↑31%)*
Atazanavir Cmin: ↑24 % (↑10% ↑39%)*
Famotidine 40 mg twice daily:
Atazanavir AUC: ↔2.3% (↓13% ↑10%)*
Atazanavir Cmax: ↔5% (↓17% ↑8.4%)*
Atazanavir Cmin: ↔1.3% (↓10% ↑15)*
* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir disoproxil fumarate, atazanavir concentrations are expected to be additionally decreased by about 20%.
The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2-blockers.
Concomitant use of atazanavir/ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.
A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.
The fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82%-89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway, e.g. budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are yet unknown. The mechanism of interaction is CYP3A4 inhibition.
Co-administration of atazanavir and indinavir is not recommended. Indinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.
If atazanavir is co-administered with irinotecan, patients should be closely monitored for adverse events related to irinotecan. Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Ketoconazole and itraconazole should be used cautiously with atazanavir/ritonavir, high doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.
No significant effect on atazanavir concentrations was observed.
Itraconazole, like ketoconazole, is a potent inhibitor as well as a substrate of CYP3A4.
Based on data obtained with other boosted PIs and ketoconazole, where ketoconazole AUC showed a 3-fold increase, atazanavir/ritonavir is expected to increase ketoconazole or itraconazole concentrations.
Lamotrigine should be used with caution in combination with atazanavir/ritonavir. If necessary, monitor lamotrigine concentrations and adjust the dose accordingly.
Co-administration of lamotrigine and atazanavir/ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.
Co-administration of nevirapine and atazanavir is not recommended.
Nevirapine AUC: ↑26% (↑17% ↑36%)
Nevirapine Cmax: ↑21% (↑11% ↑32%)
Nevirapine Cmin: ↑35% (↑25% ↑47%)
Atazanavir AUC: ↓19% (↓35% ↑2%)*
Atazanavir Cmax: ↔2% (↓15% ↑24%)*
Atazanavir Cmin: ↓59% (↓73% ↓40%)*
* When compared to atazanavir 300 mg and ritonavir 100 mg without nevirapine. This decrease in atazanavir Cmin, might negatively impact the efficacy of atazanavir. The mechanism of nevirapine/atazanavir interaction is CYP3A4 induction.
Co-administration of atazanavir with ritonavir and proton pump inhibitors is not recommended. If the combination is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.
Omeprazole 40 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily):
Atazanavir (am): 2 hr after omeprazole
Atazanavir AUC: ↓61% (↓65% ↓55%)
Atazanavir Cmax: ↓66% (↓62% ↓49%)
Atazanavir Cmin: ↓65% (↓71% ↓59%)
Omeprazole 20 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily):
Atazanavir (am): 1 hr after omeprazole
Atazanavir AUC: ↓30% (↓43% ↓14%)*
Atazanavir Cmax ↓31% (↓42% ↓17%)*
Atazanavir Cmin ↓31% (↓46% ↓12%)*
* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily.
The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of atazanavir/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. Although not studied, similar results are expected with other proton pump inhibitors. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with proton pump inhibitors.
Phenobarbital and phenytoin should be used with caution in combination with atazanavir/ritonavir. When atazanavir/ritonavir is co-administered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required. Close monitoring of patient’s virologic response should be exercised.
Although not studied, there is a potential for an increase in pravastatin or fluvastatin exposure when coadministered with protease inhibitors. Pravastatin is not metabolised by CYP3A4. Fluvastatin is partially metabolised by CYP2C9. Caution should be exercised.
No dose adjustment required for raltegravir.
Raltegravir AUC: ↑41%
Raltegravir Cmax: ↑24%
Raltegravir C12hr: ↑77%
The mechanism is UGT1A1 inhibition.
When given with atazanavir, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommended for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for atazanavir.
Rifabutin AUC: ↑48% (↑19% ↑84%)**
Rifabutin Cmax: ↑149% (↑103% ↑206%)**
Rifabutin Cmin: ↑40% (↑5% ↑87%)**
25-O-desacetyl-rifabutin AUC: ↑990% (↑714% ↑1361%)**
25-O-desacetyl-rifabutin Cmax: ↑677% (↑513% ↑883%)**
25-O-desacetyl-rifabutin Cmin: ↑1045% (↑715% ↑1510%)**
** When compared to rifabutin 150 mg once daily alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC ↑119% (↑78% ↑169%). In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.
Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.
Atazanavir AUC: ↑250% (↑144% ↑403%)*
Atazanavir Cmax: ↑120% (↑56% ↑211%)*
Atazanavir Cmin: ↑713% (↑359% ↑1339%)*
* In a combined analysis, atazanavir 300 mg and ritonavir 100 mg (n=33) was compared to atazanavir 400 mg without ritonavir (n=28).
The mechanism of interaction between atazanavir and ritonavir is CYP3A4 inhibition.
Concomitant use of salmeterol and atazanavir may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and atazanavir is not recommended. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.
Patients should be warned about these possible side effects when using PDE5 inhibitors for erectile dysfunction with atazanavir.
Sildenafil, tadalafil and vardenafil are metabolised by CYP3A4. Coadministration with atazanavir may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-associated adverse events, including hypotension, visual changes, and priapism. The mechanism of this interaction is CYP3A4 inhibition.
Co-administration of atazanavir with voxilaprevir-containing products is expected to increase the concentration of voxilaprevir. Co-administration of atazanavir with voxilaprevir-containing regimens is not recommended.
Sofosbuvir AUC: ↑40% (↑25% ↑57%)
Sofosbuvir Cmax: ↑29% (↑9% ↑52%)
Velpatasvir AUC: ↑93% (↑58% ↑136%)
Velpatasvir Cmax: ↑29% (↑7% ↑56%)
Voxilaprevir AUC: ↑331% (↑276% ↑393%)
Voxilaprevir Cmax: ↑342% (↑265% ↑435%)
* Lack of pharmacokinetics interaction bounds 70-143%.
Effect on atazanavir and ritonavir exposure has not been studied.
Expected:
↔ Atazanavir
↔ Ritonavir
The mechanism of interaction between atazanavir/ritonavir and sofosbuvir/velpatasvir/voxilaprevir is inhibition of OATP1B, Pgp, and CYP3A.
When co-administered with tenofovir disoproxil fumarate, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir disoproxil fumarate 300 mg (all as a single dose with food).
Atazanavir AUC: ↓22% (↓35% ↓6%)*
Atazanavir Cmax: ↓16% (↓30% ↔0%)*
Atazanavir Cmin: ↓23% (↓43% ↑2%)*
* In a combined analysis from several clinical studies, atazanavir/ritonavir 300/100 mg co-administered with tenofovir disoproxil fumarate 300 mg (n=39) was compared to atazanavir/ritonavir 300/100 mg (n=33).
The efficacy of atazanavir/ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naive patients in clinical study 138. The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown.
Caution should be exercised when verapamil is coadministered with atazanavir. Serum concentrations of verapamil may be increased by atazanavir due to CYP3A4 inhibition.
Co-administration of voriconazole and atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
At the time voriconazole treatment is required, a patient’s CYP2C19 genotype should be performed if feasible.
Therefore if the combination is unavoidable, the following recommendations are made according to the CYP2C19 status:
If genotyping is not feasible, full monitoring of safety and efficacy should be performed.
Subjects with at least one functional CYP2C19 allele.
Voriconazole AUC: ↓33% (↓42% ↓22%)
Voriconazole Cmax: ↓10% (↓22% ↓4%)
Voriconazole Cmin ↓39% (↓49% ↓28%)
Atazanavir AUC: ↓12% (↓18% ↓5%)
Atazanavir Cmax: ↓13% (↓20% ↓4%)
Atazanavir Cmin: ↓ 20% (↓28% ↓10%)
Ritonavir AUC: ↓12% (↓17% ↓7%)
Ritonavir Cmax: ↓9% (↓17% ↔0%)
Ritonavir Cmin: ↓25% (↓35% ↓14%)
In the majority of patients with at least one functional CYP2C19 allele, a reduction in both voriconazole and atazanavir exposures are expected.
Subjects without a functional CYP2C19 allele.
Voriconazole AUC ↑561% (↑451% ↑699%)
Voriconazole Cmax ↑438% (↑355% ↑539%)
Voriconazole Cmin ↑765% (↑571% ↑1,020%)
Atazanavir AUC: ↓20% (↓35% ↓3%)
Atazanavir Cmax: ↓19% (↓34% ↔0.2%)
Atazanavir Cmin: ↓31% (↓46% ↓13%)
Ritonavir AUC: ↓11% (↓20% ↓1%)
Ritonavir Cmax: ↓11% (↓24% ↑4%)
Ritonavir Cmin: ↓19% (↓35% ↑1%)
In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected.
It is recommended that the International Normalised Ratio (INR) be monitored carefully during treatment with atazanavir, especially when commencing therapy. Co-administration with atazanavir has the potential to increase or decrease warfarin concentrations.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving atazanavir. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving atazanavir should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to the disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
In clinical studies, atazanavir (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators.
Cholelithiasis has been reported in patients receiving atazanavir. Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with atazanavir.
Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving atazanavir. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. Atazanavir should be discontinued if severe rash develops.
The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of atazanavir, atazanavir may not be restarted.
Atazanavir with ritonavir is not recommended in patients undergoing haemodialysis.
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occurs many months after initiation of treatment.
Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment. The safety and efficacy of atazanavir has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration.
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Nephrolithiasis has been reported in patients receiving atazanavir. Some patients required hospitalization for additional management and some had complications. In some cases, nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.
A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity. The use of atazanavir with ritonavir may be considered during pregnancy only if the potential benefit justifies the potential risk.
In clinical trial AI424-182 atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.
The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include atazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with atazanavir/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with atazanavir/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.
It is not known whether atazanavir with ritonavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.
Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.
In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility.
Patients should be informed that dizziness has been reported during treatment with regimens containing atazanavir.
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