The co-administration of atazanavir/ritonavir with abacavir is not expected to significantly alter the exposure of abacavir.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of abacavir (600 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) was studied in 12 HIV+ subjects. There was no effect on atazanavir or ritonavir pharmacokinetics, but abacavir AUC decreased by 17% and Cmax decreased by 20%.
Abacavir plasma pharmacokinetics in the absence and the presence of atazanavir/ritonavir or lopinavir/ritonavir) and vice versa in HIV+ patients. Waters L, et al. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract 557.

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In a sequential pharmacokinetic study, healthy male volunteers (n=8) were administered a single oral dose of 400 mg albendazole, in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg twice daily. Pharmacokinetic parameters of albendazole and  its metabolite albendazole sulfoxide, were not changed by short-term administration of ritonavir. However long-term administration resulted in significant changes in albendazole disposition, with a significant decrease in albendazole and albendazole sulfoxide AUC0-24 (73% and 59% respectively) and Cmax (74% and 48% respectively). Tmax and the terminal half-life were not significantly changed. The observation is most likely due to a ritonavir-mediated induction of metabolising enzymes (CYP2C9, CYP1A2, UGTs) or transporters, although changes in absorption are also possible. These findings need to be replicated with a key boosted PI such as lopinavir/ritonavir. 
Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers. Corti N, Heck A, Rentsch K, et al.Eur J Clin Pharmacol. 2009;65:999-1006.

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Concentrations of amiodarone may be increased when co-administered with atazanavir/ritonavir. The mechanism of amiodarone/atazanavir interaction is CYP3A inhibition. Caution is warranted and therapeutic concentration monitoring is recommended when available.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of atazanavir has not been studied, but may increase amiodarone concentrations and has the potential to produce serious and/or life-threatening adverse events. Caution is warranted and concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Coadministration of tricyclic antidepressants with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Caution is warranted as atazanavir could increase concentrations of the calcium channel blocker. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Reduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids are administered with atazanavir with ritonavir. Atazanavir with ritonavir should be administered 2 hours before or 1 hour after antacids.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if antacids are administered with atazanavir. Atazanavir should be administered 2 h before or 1 h after these medications.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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LHPG Comment: Artemisinin, and its derivatives such as artesunate and artemether, are rapidly metabolized via CYP3A4 to a biologically active metabolite, dihydroartemisinin (the metabolism of artesunate is so rapid that it may be considered a pro-drug for dihydroartemisinin). Although the parent drugs and dihydroartemisinin all have antimalarial activity, dihydroartemisinin has greater potency than the parent drugs. Inhibition of CYP3A4 would reduce dihydroartemisinin, but increase concentrations of the parent drug and potentially increase the half life of the parent drug. The effects of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are unclear.

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Atazanavir with ritonavir should not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows, such as astemizole.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

No clinically significant drug interaction was observed when atazanavir was coadministered with atenolol. In a pharmacokinetic study (n=19) between atazanavir 400 mg once daily and atenolol 50 mg once daily, no clinically significant additive effect of atazanavir and atenolol on the PR interval was observed. There was no change in atazanavir Cmax, a 7% decrease in AUC and a 26% decrease in Cmin. Atenolol Cmax, AUC and Cmin increased by 34%, 25% and 2%, respectively.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration may increase atorvastatin concentrations. Titrate atorvastatin dose carefully and use the lowest necessary dose. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including atazanavir, are used in combination with these drugs
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and azithromycin.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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LHPG Comment: The charts reflect a more cautious option that may be appropriate for when atazanavir is boosted with ritonavir.

Co-administration with bepridil is contraindicated. Atazanavir/ritonavir should not be used in combination with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of atazanavir has not been studied, but may increase bepridil concentrations and has the potential to produce serious and/or life-threatening adverse events. Caution is warranted and concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Coadministration of atazanavir/ritonavir (300/100 mg once daily) to subjects stable on a buprenorphine maintenance dose increased buprenorphine AUC, Cmax and Cmin by 67%, 37% and 69%, respectively. The AUC, Cmax and Cmin of norbuprenorphine increased by 2.05-fold, 1.61-fold and 2.01-fold, respectively. Concentrations of atazanavir were not significantly affected. The mechanism of interaction is CYP3A4 and UGT1A1 inhibition. Co-administration warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Three case reports have recently been published on a pharmacokinetic interaction between buprenorphine and ritonavir-boosted atazanavir.
The first subject had been titrated to a stable dose of buprenorphine 14 mg/day prior to the commencement of ddI (250 mg), tenofovir (300 mg) and atazanavir/ritonavir (300/100 mg), all given once daily. The next day the subject began to experience daytime somnolence and decreased mental functioning. After two weeks, during which the subject was offered additional counselling, buprenorphine was decreased to 8 mg/day and this resulted in tolerance to the sedative effects after 7 days. The subject was finally stabilised on buprenorphine 10 mg/day.
The second subject was stable on once daily ddI (250 mg), tenofovir (300 mg), atazanavir/ritonavir (300/100 mg) and twice daily olanzepine (5 mg) prior to induction with buprenorphine (8 mg/day). On the second day of induction, the subject reported feeling “doped up“, and required a dose reduction of buprenorphine to 8 mg every other day to improve the feelings of opiate excess.
The third subject had been receiving lamivudine (300 mg), tenofovir (300 mg) and atazanavir/ritonavir (300/100 mg) once daily prior to the initiation of buprenorphine (8 mg/day). Following the commencement of buprenorphine, the subject reported feeling dizzy, “high“ and “over medicated“. Buprenorphine was reduced to 8 mg every other day; however, though this improved the dizziness the corresponding opiate cravings required dose modification to 8 mg daily and a further dose increase to 12 mg daily. At this dose, the subject experienced hypersomnolence but elected to remain on the higher dose as it suppressed the opiate craving. Tolerance developed over a week and the hypersomnolence gradually ceased.
Phase I metabolism of buprenorphine is primarily by CYP3A4 to norbuprenorphine, with phase II metabolism being mainly through glucuronidation. The authors postulate that atazanavir and/or ritonavir inhibited CYP3A4-mediated metabolism, with atazanavir having an additional inhibitory effect on glucuronidation, resulting in increased concentrations of buprenorphine and clinical symptoms of opiate excess. They recommend caution if using buprenorphine with atazanavir or ritonavir and suggest beginning with reduced doses of buprenorphine and slower dose escalation to allow for assessment of opiate excess.
Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir.
Bruce RD, Altice FL. AIDS, 2006, 20: 783-784.

When administered with a potent inhibitor of CYP3A4, a low dose of buspirone, used cautiously, is recommended. When used in combination with a potent inducer of CYP3A4, e.g. phenobarbital, phenytoin, carbamazepine, St. John's wort, an adjustment of the dosage of buspirone may be necessary to maintain buspirone’s anxiolytic effect.
Buspirone Summary of Product Characteristics, Actavis UK Ltd, August 2012.

Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect.
Buspar Prescribing Information, Bristol Myers Squibb, November 2010.

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Atazanavir trough concentrations were evaluated in 32 HIV+ subjects with substance-related disorders (SRDs) and 35 HIV+ subjects without SRDs. The median atazanavir trough concentrations in the SRD groups were significantly lower with cannabis (0.238 vs 0.593 µg/ml). Trough concentrations in the SRD group were below the therapeutic range in 50% of marijuana users. There was no significant direct effect of SRD on viral load or CD4 count.
Tobacco and marijuana uses significantly decrease atazanavir trough concentrations in HIV-infected individuals. Ma Q, Fehintola F, Zingman B, et al. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009, abstract H-231.

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Increased concentrations of atazanavir, saquinavir and ritonavir were reported in a patient taking Cat’s claw whilst being treated with atazanavir (300 mg once daily), saquinavir (2000 mg once daily), ritonavir (100 mg once daily), abacavir and lamivudine. Trough concentrations of the protease inhibitors were determined and found to be supratherapeutic (atazanavir 1.22 µg/ml; saquinavir 3.4 µg/ml; ritonavir 6.13 µg/ml), though no signs or symptoms of overdosage were observed. Concentrations were evaluated 15 days after stopping Cat’s claw and were found to have normalised (atazanavir 0.3 µg/ml; saquinavir 0.64 µg/ml; ritonavir 0.92 µg/ml). 
Interaction between cat's claw and protease inhibitors atazanavir, ritonavir and saquinavir. Lopez Galera RM, Ribera Pascuet E, Esteban Mur JI, et al. Eur J Clin Pharmacol. 2008, 64(12):1235-6.

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In vitro data indicate that CYP3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide M1 in man. In a drug-drug interaction study at steady state with ciclesonide and ketoconazole as a potent CYP3A4 inhibitor, the exposure to the active metabolite M1 increased approximately 3.5-fold, whereas the exposure to ciclesonide was not affected. Therefore the concomitant administration of potent inhibitors of CYP 3A4 (e.g. ketoconazole, itraconazole and ritonavir or nelfinavir) should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids.
Alvesco Summary of Product Characteristics, Nycomed UK Ltd, February 2009.

Concentrations of ciclosporin, tacrolimus, or sirolimus may be increased when co-administered with atazanavir with ritonavir due to CYP3A4 inhibition. More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration may increase ciclosporin concentrations. Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with atazanavir. Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

• H2-RAs increase intragastric pH and reduce atazanavir absorption. However,
• H2-RAs are less potent than proton pump inhibitors in suppressing intragastric pH and may be used with atazanavir.
• Atazanavir/ritonavir at 300/100 mg may be used concomitantly with H2-RAs although temporal separation (giving ATV/r 10 hours after or 2 hours before the H2-RA) should be considered in treatment experienced patients.
• Local prescribing information may vary.
Based on current data the above approach to managing the interaction is appropriate although some may feel that temporal separation of the H2-RA and atazanavir/ritonavir would be safer in all patients. Note: The authors clearly state that due to the magnitude of the decrease in exposure, atazanavir should NOT be used concomitantly with proton pump inhibitors (PPIs).
Further information on the administration of H2-receptor antagonists with atazanavir. Agarwala S, Thal G, Nettles R, Bertz R. J Acquir Immune Defic Syndr, 2006, 42: 516.

Trough atazanavir concentrations were available in 15 patients receiving a proton pump inhibitor (PPI) and 19 patients receiving an H2 receptor antagonist (H2). The mean atazanavir trough concentration in the PPI group was 0.65 µg/ml (range <0.05 to 1.85 µg/ml) compared to 1.12 µg/ml (range <0.05 to 3.17 µg/ml) in the H2 group. Concentrations were below target (0.27 µg/ml) in 6/15 in the PPI group, even though 5 of these were receiving boosted atazanavir. Inadequate levels were observed in 4/20 in the H2 group, 2 of whom were receiving boosted atazanavir. These results suggest a negative effect of proton pump inhibitors and H2 receptor antagonists on atazanavir concentrations and that boosting with ritonavir does not ensure adequate concentrations. Further study of this important issue is warranted.
Coadministration of atazanavir with proton-pump inhibitors and H2-blockers. Farthing C, Khanlou H. 7th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2004, abstract P289.

Atazanavir with ritonavir should not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows, such as cisapride.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of cisapride and atazanavir is contraindicated due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Coadministration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) increased atazanavir AUC, Cmax and Cmin by 28%, 6% and 91%, respectively. The AUC, Cmax and Cmin of clarithromycin increased by 94%, 50% and 160%, respectively, but AUC, Cmax and Cmin of 14-OH clarithromycin decreased by 70%, 72% and 62%, respectively. A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition. No recommendation regarding dose reduction can be made; therefore, caution should be exercised if atazanavir/ritonavir is co-administered with clarithromycin. 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).
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of atazanavir (400 mg once daily) and clarithromycin (500 mg once daily) resulted in no change in atazanavir Cmax, a 1.28-fold increase in AUC and a 1.91 fold increase in Cmin (n=29). Cmax, AUC and Cmin of clarithromycin were increased by 1.5-, 1.94-fold, and 2.64-fold (n=21); Cmax, AUC and Cmin of the active metabolite (14-OH clarithromycin) decreased by 72%, 70% and 62% respectively. Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of atazanavir/ritonavir with clarithromycin has not been studied.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Coadministration of atazanavir (400 mg once daily) and clarithromycin (500 mg twice daily) was studied in 30 healthy subjects. The steady state Cmax and AUC of atazanavir were higher in the presence of clarithromycin (Cmax, 5136 and 5421 ng/ml, 6% increase; AUC 29493 and 37790 ng/ml.h, 28% increase). The steady state Cmax and AUC of clarithromycin were 50% and 94% higher in the presence of atazanavir; this was accompanied by a 70% decrease in exposure of 14-OH clarithromycin.
Steady state pharmacokinetic interaction study of atazanavir with clarithromycin in healthy subjects. Mummaneni V, Randall D, Chabuel D, et al. 42nd ICAAC, San Diego, September 2002, abstract H-1717.

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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. 

Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

The impact of boosted antiretroviral therapies on the pharmacokinetics of clopidogrel and prasugrel active metabolites (AM) and on the efficacy of prasugrel and clopidogrel were evaluated in a randomized crossover study. A significantly lower exposure of clopidogrel AM (69% decrease) and prasugrel AM (52% decrease) were demonstrated in HIV-infected patients treated sequentially with a loading dose of clopidogrel (300 mg) and prasugrel (60 mg) while on a ritonavir- or cobicistat- containing antiretroviral regimen compared to healthy volunteers receiving only the corresponding antiplatelet agent. Of interest, the coadministration with ritonavir or cobicistat had a differential impact on clopidogrel and prasugrel pharmacodynamics effect. Treatment with clopidogrel resulted in adequate platelet inhibition in all healthy volunteers (no coadministration of ritonavir- or cobicistat-boosted regimens) while 44% of HIV-infected patients were shown to have insufficient platelet inhibition (coadministration with ritonavir- or cobicistat-boosted regimens). On the contrary, treatment with prasugrel resulted in a potent platelet inhibition in both healthy and HIV-infected subjects. The authors conclude that prasugrel remains an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.
Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Marsousi N, Daali Y, Fontana P, et al. Clin Pharmacokinet, 2018 [epub ahead of print].

The impact of ritonavir on the pharmacokinetics of clopidogrel active metabolite (AM) and the pharmacodynamic effect was evaluated in a randomized, placebo-controlled, crossover study in 12 healthy volunteers. Subjects ingested either placebo or clopidogrel (300 mg followed by 75 mg the two following days) alone and together with ritonavir (100 mg twice daily). Ritonavir significantly decreased the exposure of clopidogrel AM by 51% and average platelet inhibition significantly decreased from 51% without ritonavir to 31% with ritonavir (mean difference 90% CI -27% to -12%). The maximal platelet inhibition by clopidogrel was also reduced from 60% to 40% during concurrent ritonavir (mean difference 90% CI -29% to -11%). The authors conclude that patients receiving ritonavir are at risk for diminished clopidogrel response and consequently increased risk for atherothrombotic events if the two drugs are used concurrently. The authors recommend to avoid concomitant administration of clopidogrel with ritonavir.
Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Itkonen MK, Tornio A, Lapatto-Reiniluoto O, et al. Clin Pharmacol Ther, 2018, [epub ahead of print].

A 45-year-old HIV infected patient treated with darunavir/ritonavir plus emtricitabine/tenofovir. The patient underwent coronary stenting as he presented a significant stenosis of the coronary artery. The patient was subsequently started on dual antiplatelet therapy with aspirin and clopidogrel while his actual antiretroviral treatment was maintained. Six month later, the patient presented an episode of chest pain with electrocardiographic signs of acute anterior myocardial infarction, and evidence of thrombosis of the implanted stent. He underwent thromboaspiration and implantation of a novel stent. Clopidogrel was replaced by prasugrel while the darunavir/ritonavir regimens was maintained. No novel stent thrombosis episodes occurred while on prasugrel.
Recurrent coronary disease in HIV-infected patients: role of drug-drug interactions. Bravo I, Alvarez H, Marino A, Clotet B, Molto J. Br J Clin Pharmacol 2018 [epub ahead of print].

A 64-year-old man presented with increasing shortness of breath, fatigue and chest pain radiating to his left shoulder and neck. His home medications included darunavir, ritonavir, emtricitabine-tenofovir, isoniazid, pyridoxine, clopidogrel, aspirin, carvedilol, rosuvastatin, valsartan, sertraline, tamsulosin and esomeprazole. Potential drug-drug interactions between isoniazid and clopidogrel, and ritonavir and clopidogrel were identified that could interfere with clopidogrel activation. Based on this, platelet function testing was completed and impaired clopidogrel response was seen on two platelet function tests. There was no genetic cause (i.e., CYP2C19 genotype) for the impaired clopidogrel response.
A patient with HIV and tuberculosis with diminished clopidogrel response. Metzger NL, Momary KN. Int J STD AIDS, 2013, 25(7): 532-534.

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Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before ritonavir alone (100 mg once daily administered at steady state) was studied in 16 HIV negative subjects. Simultaneous administration did not significantly change dabigatran PK (possibly due to mixed induction and inhibition of P-gp by ritonavir). Administration 2 hours before ritonavir decreased dabigatran AUC by 29% and Cmax by 27%. These results suggests that dabigatran can be administered simultaneously with ritonavir used as a once daily pharmacokinetic enhancer.
Cobicistat, but not ritonavir, increases dabigatran exposure. Brooks KM, Gordon LA, Penzak S, et al. Conference on Retroviruses and Opportunistic Infections (CROI) Seattle, February 2017, abstract 409.

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LHPG Comment: Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Clinically significant interactions are unlikely, but can not be excluded.

Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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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).
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

An in vitro study determined CYP3A4 activities in human liver microsomes from 2 donors using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC. Daunorubicin hydrochloride showed an inhibitory effect on CYP3A4, IC50 value for the 2 microsome sample was 206/200 micromol/l. Comparing IC50 values with plasma concentrations present during antineoplastic therapy, potential for daunorubicin to cause clinical drug interactions by inhibition of CYP3A4 was thought to be relatively low.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA, Böcker R, Beckurts KT, Zaigler M, Barthold D, Fuhr U. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

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Atazanavir with ritonavir should not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows, such as ergot derivatives.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of dihydroergotamine and atazanavir is contraindicated due to potential for serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Co-administration of diltiazem and atazanavir/ritonavir has not been studied. Coadministration of diltiazem (180 mg once daily) and atazanavir (400 mg once daily) increased the AUC, Cmax and Cmin of diltiazem by 2.25-fold, 1.98-fold and 2.42-fold, respectively. Desacetyl diltiazem AUC increased by 2.65-fold, Cmax increased by 2.72-fold and Cmin increased by 2.21-fold. No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition. An initial dose reduction of diltiazem by 50% is recommended, with subsequent titration as needed and ECG monitoring.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

When atazanavir (400 mg once daily) was coadministered with diltiazem (180 mg once daily), there was a 1.98-, a 2.25-, and a 2.42-fold increase in diltiazem Cmax, AUC, and Cmin respectively. Desacetyl-diltiazem Cmax, AUC, and Cmin were increased 2.72-, 2.65- and 2.21-fold, respectively (n=28). There was no significant change in the pharmacokinetics of atazanavir (n=30). Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of atazanavir/ritonavir with diltiazem has not been studied.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals). A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel may occur, even at lower doses.
Taxotere (docetaxel) Summary of Product Characteristics, Sanofi-Aventis, December 2009.

Three cases have been reported where administration of IV docetaxel to HIV+ patients on ritonavir-containing regimens resulted in severe haematological and cutaneous toxicity 3-7 days after the first infusion of docetaxel (70-100 mg/m2), despite patients having normal baseline liver function and blood cell counts. Each patient recovered following the withdrawal of docetaxel.
Severe toxicity related to a pharmacokinetic interaction between docetaxel and ritonavir in HIV-infected patients. Mir O, Dessard-Diana B, Louet AL, et al. Br J Clin Pharmacol, 2010, 69(1): 99-101.

A study was carried out in 12 patients with solid tumours. One cohort of patients (n=4) received 10 mg of oral docetaxel and a subsequent cohort (n=8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized to simultaneous administration or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. Docetaxel AUC in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The AUC in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 ± 1.5 and 2.8 ± 1.4 mg/L.h, respectively, compared with 1.9 ± 0.4 mg/L.h after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was >100% (i.e. 131 ± 90% and 161 ± 91%, respectively), indicating marked inhibition by ritonavir of gut wall and/or hepatic metabolism. Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel and caution is essential when giving docetaxel with boosted PIs.
Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors. Oostendorp RL, Huitema A, Rosing H, et al. Clin Cancer Res, 2009, 15(12): 4228-4233.

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Coadministration of tricyclic antidepressants with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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(See Summary)

(See Summary)

(See Summary)

The effect of echinacea on CYP activity was assessed by use of a number of CYP probe drugs (caffeine for CYP1A2; tolbutamide for CYP2C9; dextromethorphan for CYP2D6 and midazolam for both hepatic and intestinal CYP3A) in a study in 12 healthy volunteers. The data demonstrated that echinacea caused inhibition of CYP1A2 and intestinal CYP3A activity and induction of hepatic CYP3A activity. The authors indicate that for CYP3A substrates (such as protease inhibitors), the type of drug interaction observed with echinacea will be dependent on the relative extraction of the drugs at hepatic and intestinal sites and will not be readily predicted. Certainly echinacea could contribute to inter-patient variability in protease inhibitor levels.
The effect of echinacea (Echinacea purpurea) root on cytochrome P450 activity in vivo. Gorski JC, Huang SM, Pinto A, et al. Clin Pharmacol Ther, 2004, 75: 89-100.

(See Summary)

Co-administration of efavirenz with atazanavir/ritonavir is not recommended. When compared to atazanavir/ritonavir (300/100 mg once daily in the evening) without efavirenz, coadministration of efavirenz (600 mg once daily) and atazanavir/ritonavir (400/100 mg once daily in the evening) had no effect on atazanavir AUC, increased Cmax by 17% and decreased Cmin by 42%. Based on historical comparison with atazanavir/ritonavir (300/100 mg once daily in the evening) without efavirenz, coadministration of efavirenz (600 mg once daily) and atazanavir/ritonavir (400/200 mg once daily in the evening) increased atazanavir AUC, Cmax and Cmin by 6%, 9% and 12%, respectively. The decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. The mechanism of efavirenz/atazanavir interaction is CYP3A4 induction.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Atazanavir without ritonavir should not be coadministered with efavirenz. Coadministration of efavirenz (600 mg once daily) with atazanavir (400 mg once daily), in 27 subjects, resulted in a 59%, 74% and 93% decrease in atazanavir Cmax, AUC and Cmin, respectively. Coadministration of efavirenz (600 mg once daily) with atazanavir/ritonavir (300/100 mg once daily), in 13 subjects, caused a 14%, 39% and 48% increase in atazanavir Cmax, AUC and Cmin, respectively. If atazanavir is combined with efavirenz in treatment-naïve patients, atazanavir 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered on an empty stomach, preferably at bedtime. Coadministration of atazanavir with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Coadministration of atazanavir/ritonavir (400/100 mg once daily) and efavirenz (600 mg once daily) decreased atazanavir Cmin by 42%, had no effect on AUC and increased Cmax by 17%, when compared to atazanavir/ritonavir 300/100 mg once daily alone. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. Coadministration of atazanavir and a higher dose of ritonavir (400/200 mg once daily) and efavirenz had no effect on AUC or Cmax and increased Cmin by 12% when compared to historical data from subjects receiving atazanavir/ritonavir 300/100 mg once daily alone. Co-administration of efavirenz with atazanavir/ritonavir is not recommended. If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.
Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2015.

Coadministration of atazanavir (400 mg once daily) and efavirenz (600 mg once daily) to 27 subjects resulted in a 59% decrease in atazanavir Cmax, a 74% decrease in AUC and a 93% decrease in Cmin. A study in 13 patients showed that boosting atazanavir with ritonavir (300/100 mg once daily) with co-administered efavirenz (600 mg once daily) increased Cmax, AUC and Cmin by 14%, 39% and 48%, respectively, compared to unboosted atazanavir (400 mg once daily) without efavirenz. Coadministration of atazanavir/ritonavir (400/100 mg once daily) and efavirenz (600 mg once daily) had no effect on atazanavir AUC, increased atazanavir Cmax by 17% and decreased Cmin by 42% (n=14). When co-administered with efavirenz in treatment naïve patients, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime). Coadministration of efavirenz and atazanavir in treatment-experienced patients is not recommended.
Sustiva Prescribing Information, Bristol-Myers Squibb Company, March 2015.

Atazanavir trough concentrations (24 ± 4 h post dose) were determined in HIV+ patients receiving atazanavir/ritonavir (300/100mg once daily n=12 or 400/100 once daily n=20) with an NNRTI (efavirenz or nevirapine) or atazanavir/ritonavir alone (300/100 mg once daily n=154). Coadministration of an NNRTI resulted in a 5.5-fold decrease in atazanavir trough concentrations; increasing the dose to 400/100 mg decreased the magnitude of the reduction to 1.7-fold, but did not overcome the inducer effect of the NNRTI on atazanavir metabolism. In the presence of an NNRTI, median (range) atazanavir troughs were 92 (24-415) ng/ml and 290 (71-2069) ng/ml for the 300/100 and 400/100 mg doses, respectively. Trough concentrations obtained in the absence of an NNRTI were 506 (26-2657) ng/ml.
Critical drug interaction between ritonavir-boosted atazanavir regimen and non-nucleoside reverse transcriptase inhibitors. Poirier JM, Guiard-Schmid JB, Meynard JL, et al. AIDS, 2006, 20(7): 1087-1089.

Comparison of switching from atazanavir alone (400 mg) to coadministration of 600 mg atazanavir and 600 mg efavirenz versus 300 mg atazanavir, 100 mg ritonavir and 600 mg efavirenz showed atazanavir AUC was decreased (21%) when given without ritonavir but maintained (increased 39%) when boosted with ritonavir.
Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. Tackett D, Child M, Agarwala S, et al. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 2003, abstract 543.

Coadministration of atazanavir (400 mg once daily) and efavirenz (600 mg once daily) to healthy subjects (n=27) resulted in decreases in atazanavir Cmax (3369 to 1375 ng/ml, 59%) and AUC (20656 to 5462 ng/ml.h, 74%). Mean efavirenz pharmacokinetic parameters were similar to literature values in HIV+ patients.
Evaluation of steady-state interaction between atazanavir and efavirenz. Preston S, Piliero P, O’Mara E, et al. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 2002, abstract 443-W.

LHPG Comment: Note the different dosing advice from Europe (400/100 mg atazanavir/ritonavir) and America (300/100 mg atazanavir/ritonavir).

(See Summary)

Genvoya should not be co-administered with other antiretroviral medicinal products.
Genvoya Summary of Product Characteristics, Gilead Sciences International Ltd, November 2015.

Genvoya is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of Genvoya with other antiretroviral medications for treatment of HIV-1 infection should be avoided.
Genvoya US Prescribing Information, Gilead Sciences Inc, November 2015.

Coadministration of Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) and atazanavir (300 mg once daily) was studied in seven HIV+ patients with documented antiretroviral resistance. Two of the seven patients were also started on abacavir (600 mg once daily) in addition to Stribild and atazanavir. Of the seven patients, one had ART changed due to concerns of resistance based on a genotype, and one experienced a decline in renal function that warranted a change in therapy. Five patients remained virologically suppressed after 9-16 months of treatment: four on Stribild and atazanavir, and one on Stribild, atazanavir and abacavir.
Co-administration of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine and atazanavir in treatment-experienced HIV patients. Biagi M, Badowski ME, Chiampas T et al. Int J STD AIDS, 2017, 28(8): 766-772.

Stribild is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products.
Stribild Summary of Product Characteristics, Gilead Sciences International Ltd, May 2015.

Stribild is a complete regimen for the treatment of HIV-1 infection; therefore, Stribild should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Stribild should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. Stribild should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.
Stribild Prescribing Information, Gilead Sciences Inc, July 2015.

Coadministration of Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) and atazanavir (300 mg once daily) was studied in seven HIV+ patients with documented antiretroviral resistance. Two of the seven patients were also started on abacavir (600 mg once daily) in addition to Stribild and atazanavir. Of the seven patients, one had ART changed due to concerns of resistance based on a genotype, and one experienced a decline in renal function that warranted a change in therapy. Five patients remained virologically suppressed after 9-16 months of treatment: four on Stribild and atazanavir, and one on Stribild, atazanavir and abacavir.
Co-administration of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine and atazanavir in treatment-experienced HIV patients. Biagi M, Badowski ME, Chiampas T et al. Int J STD AIDS, 2017, 28(8): 766-772.

Healthy volunteers received atazanavir (300 mg once daily) with ritonavir (100 mg once daily for 10 days) or with elvitegravir/cobicistat (85/150 mg once daily for 10 days). Elvitegravir AUC and Cmax following the lower dose with atazanavir were comparable to values obtained with the standard dose alone, but Ctrough was higher in the lower dose + atazanavir (83% increase). Atazanavir Cmax and Ctrough decreased by 24% and 20%, respectively, relative to values obtained in the presence of ritonavir, but remained many-fold above the atazanavir protein-binding adjusted IC95.
Pharmacokinetics and drug interaction profile of cobicistat boosted-EVG with atazanavir, rosuvastatin or rifabutin. Ramanathan S et al. 13th International Workshop on Clinical Pharmacology of HIV Therapy, Barcelona 2012, abstract O_03.

(See Summary)

In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Summary of Product Characteristics, Gilead Sciences International Ltd, November 2016.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP 2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Prescribing Information, Gilead Sciences Inc, November 2012.

When given with atazanavir with ritonavir or cobicistat, the dose of Descovy is 200/10 mg once daily. Co-administration of Descovy with medicinal products that inhibit P-gp (e.g., cobicistat or ritonavir) are expected to increase the absorption and plasma concentration of tenofovir alafenamide. Coadministration with atazanavir/cobicistat (300/150 mg once daily) increased tenofovir alafenamide AUC and Cmax by 75% and 80%; there was no change in atazanavir AUC, Cmax or Cmin. Coadministration of tenofovir alafenamide (10 mg) and atazanavir/ritonavir (300/100 mg once daily) increased tenofovir alafenamide AUC and Cmax by 91% and 77%, with no change in atazanavir AUC, Cmax or Cmin.

Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2016.

Based on drug interaction studies conducted with the components of Descovy, no clinically significant drug interactions have been either observed or are expected when Descovy is combined with atazanavir with ritonavir or cobicistat. Coadministration of atazanavir/ritonavir (300/100 mg once daily) and tenofovir alafenamide (10 mg once daily) was studied in 10 subjects. Cmax and AUC of tenofovir alafenamide increased by 77% and 91%; atazanavir Cmax and AUC decreased by 2% and 1% and there was no change in Cmin.
Descovy US Prescribing Information, Gilead Sciences Inc, April 2016.

(See Summary)

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(See Summary)

Atazanavir with ritonavir should not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows, such as ergot derivatives.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of ergometrine and atazanavir is contraindicated due to potential for serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Atazanavir with ritonavir should not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows, such as ergot derivatives.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of ergotamine and atazanavir is contraindicated due to potential for serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and erythromycin.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

(See Summary)

Coadministration of an oral contraceptive containing 25 microgram ethinylestradiol and norgestimate with atazanavir/ritonavir (300/100 mg once daily) decreased ethinylestradiol AUC, Cmax and Cmin by 19%, 16% and 37%, respectively.  The AUC, Cmax and Cmin of norgestimate increased by 1.85-fold, 1.68-fold and 2.02-fold, respectively. While the concentration of ethinylestradiol 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 ethinylestradiol 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. If an oral contraceptive is administered with atazanavir/ritonavir, it is recommended that the oral contraceptive contain at least 30 microgram of ethinylestradiol 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.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Use with caution if coadministration of atazanavir or atazanavir/ritonavir with oral contraceptives is considered. Coadministration of atazanavir (400 mg once daily) with ethinylestradiol and norethindrone, in 19 subjects, caused a 15%, 48% and 91% increase in ethinylestradiol Cmax, AUC and Cmin, respectively; norethindrone Cmax, AUC and Cmin increased by 1.67-, 2.1- and a 3.62-fold, respectively. Coadministration of atazanavir/ritonavir (300/100 mg once daily) with ethinylestradiol and norgestimate was studied in 14 subjects. Ethinylestradiol AUC, Cmax and Cmin decreased by 19%, 16% and 37%, respectively; AUC, Cmax and Cmin of 17-desacteyl norgestimate increased by 85%, 68% and 102%, respectively. If an oral contraceptive is administered with atazanavir/ritonavir, it is recommended that 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 increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of atazanavir or atazanavir/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable 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 contraception are recommended.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

Co-administration of ethinylestradiol/levonorgestrel with atazanavir/cobicistat was studied in 6 healthy female subjects. Ethinylestradiol Cmax and AUC increased by 5% and 1%, and C24 reduced by 25% when co-administered with atazanavir/cobicistat. No significant changes were seen in levonorgestrel PK when co-administered with atazanavir/cobicistat (Cmax and AUC decreased by 17% and 8%, and C24h increased by 1%).
Elliot ER, Bisdomini E, Else L, et al. Pharmacokinetics (PK) of ethinylestradiol/levonorgestrel with atazanavir/cobicistat. Conference on Retroviruses and Opportunistic Infections, March 2018, Boston, Abstract 469.

An open-label, three-period, single-sequence study assessed the pharmacokinetics of an oral contraceptive when give alone (35 µg ethinyl estradiol plus norgestimate) or with atazanavir/ritonavir (300/100 mg once daily with 25 µg ethinyl estradiol plus norgestimate).  Dose normalised results showed ethinylestradiol AUC, Cmax and Cmin decreased by 19%, 16% and 37%, respectively, whereas the AUC, Cmax and Cmin of 17-deacetyl norgestimate (active metabolite) increased by 85%, 68% and 102%, respectively.  The authors concluded that increasing the ethinyl estradiol component to 30-35 µg when co-administered with atazanavir/ritonavir might be desirable to minimise breakthrough bleeding.
The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women. Zhang J, Chung E, Yones C, et al. Antivir Ther, 2011, 16(2): 157-164.

Coadministration of atazanavir (400 mg once daily) with an oral contraceptive containing ethinyl estradiol (35 µg) and norethindrone (1000 µg) was studied in 22 women. Co-administration of daily doses of the oral contraceptive and 400 mg atazanavir produced 67% and 110% increases in Cmax and AUC of norethindrone, respectively, and 15% and 48% increases in the Cmax and AUC of ethinylestradiol, respectively, compared to the administration alone. Co-administration of will not impact contraceptive effectiveness. No dose adjustment of the oral contraceptive is recommended.
Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. Tackett D, Child M, Agarwala S, et al. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 2003, abstract 543.

(See Summary)

Co-administration of atazanavir/ritonavir with oral contraceptives containing progestogens other than norgestimate, or other hormonal contraceptives, has not been studied, and therefore should be avoided. An alternate reliable method of contraception is recommended.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Coadministration of atazanavir or atazanavir/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

The use of a vaginal ring releasing etonogestrel/ethinylestradiol (120/15 µg/day) in HIV positive women treated with an ATV/r (300/100 mg) containing regimen showed an increase in etonogestrel exposure of 71-79% and a decrease in ethinylestradiol exposure of 29-35% compared to exposure of hormones in HIV positive women not yet on ART. Since no dosage adjustment of ethinylestradiol is possible with the CVR, alternative forms of contraception or barrier contraception in addition to the vaginal ring should be used until the clinical relevance of these pharmacokinetic changes is better understood. 
Vaginal contraceptive hormone exposure profoundly altered by EFV- and ATV/r-based ART. Scarsi KK, Cramer YS, Gingrich D, et al. Conference on Retroviruses and Opportunistic Infections (CROI), Washington, March 2018, abstract 141.

Coadministration of atazanavir/ritonavir (300/100 mg once daily with an etonogestrel/ethinyl estradiol vaginal ring (120/15 µg/day) was studied in 23 HIV+ women. After 21 days of contraceptive steroid coadministration, atazanavir Cmin and AUC decreased by 30% and 33%, ritonavir Cmin and AUC decreased by 33% and 37%. The change in ritonavir, but not atazanavir, exposures were statistically significantly different, but Cmin values for both remained within the expected range. The authors conclude that the observed decreases in exposure are unlikely to be clinically significant.
Scarsi K , Cramer Y, Campbell K, et al., Intraindividual comparison of efavirenz, atazanavir, or ritonavir plasma pharmacokinetics before and during 21 days of vaginally administered hormone contraception. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy, Baltimore, May 2018, Abstract 10.

LHPG Comment: The US Prescribing Information indicates that etravirine should NOT be coadministered with atazanavir or atazanavir/ritonavir. whereas the European SPC says that they can be used without dose adjustment. Given the decrease in etravirine Cmin, we recommend caution.

Etravirine and atazanavir/ritonavir can be used without dose adjustment. Coadministration with atazanavir/ritonavir (300/100 mg once daily) decreased atazanavir AUC (14%), Cmax (3%) and Cmin (38%). Etravirine AUC and Cmax increased by 30% and Cmin increased by 26%.
Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, March 2012.

Etravirine should not be co-administered with atazanavir without low-dose ritonavir. Concomitant use of etravirine with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. Etravirine and atazanavir/ritonavir should not be co-administered. Concomitant use of etravirine with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of etravirine with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine and darunavir/ritonavir (as part of the background regimen). Coadministration of atazanavir (400 mg once daily) and etravirine was studied in 14 subjects. Etravirine Cmax, AUC and Cmin increased by 47%, 50% and 58%, respectively; atazanavir Cmax, AUC and Cmin decreased by 3%, 17% and 47%, respectively. Coadministration of atazanavir/ritonavir (300/100 mg once daily) and etravirine was studied in 14 subjects. Etravirine Cmax and AUC increased by 30%, Cmin increased by 26%. Data from 13 subjects showed that atazanavir Cmax, AUC and Cmin decreased by 3%, 14%, and 38%, respectively.
Intelence Prescribing Information, Tibotec Pharmaceuticals Ltd, March 2012.

The pharmacokinetics of TMC125 were determined in 2 groups of HIV- subjects (n=16) after administration of TMC125 (800 mg twice daily) with atazanavir (400 mg once daily) or atazanavir/ritonavir (300/100 mg once daily). Exposure to TMC125 increased when given with atazanavir (Cmin increased by 58%, Cmax by 47%, AUC by 50%) and to a lesser extent with atazanavir/ritonavir (Cmin increased by 26%, Cmax by 30%, AUC by 30%). When atazanavir was coadministered with TMC125, atazanavir Cmin decreased by 47%, Cmax by 3% and AUC by 17%. Coadministration of TMC125 to atazanavir/ritonavir decreased atazanavir Cmin by 38%, Cmax by 3% and AUC by 14%. The increase in TMC exposure is not considered to be clinically relevant; however, due to the decrease in atazanavir Cmin, atazanavir should only be used with TMC125 in the presence of low dose ritonavir.
Pharmacokinetics of TMC125 with atazanavir and atazanavir/ritonavir. Scholler-Gyure M, Woodfall B, De Marez T,et al. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2006, abstract 278.

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The effect of famotidine (20 or 40 mg twice daily) on the steady state pharmacokinetics of atazanavir/ritonavir (300/100 mg once daily, alone or with tenofovir 300 mg once daily) was studied in HIV+ subjects. The lower famotidine dose when administered simultaneously in the absence of tenofovir had no effect on atazanavir Cmin, but decreased atazanavir AUC by 13%. The same dose administered temporally separated in the presence of tenofovir decreased atazanavir Cmax, AUC and Cmin by 21%, 21% and 19%, respectively. The higher dose of famotidine, administered either simultaneously or temporally separated reduced atazanavir exposure by 20-23% in subjects not receiving tenofovir and by 23-25% in subjects receiving tenofovir.
Effects of famotidine on the pharmacokinetics of atazanavir when given with ritonavir with or without tenofovir in HIV-infected subjects. Wang X, Chung E, Mahnke L,et al. 10th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, April 2009, abstract P30.

The effect of famotidine (20 mg twice daily dosed with or 2 h apart, 40 mg once daily dosed 12 h apart, or 40 mg twice daily) on atazanavir/ritonavir (300/100 mg once daily) was studied in 20 HIV- subjects. Atazanavir exposures were similar when given alone or with famotidine 20 mg twice daily (both together and apart) or with 40 mg once daily. Decreases in atazanavir exposure (AUC 21%, Cmax 26%, Cmin 28%) were seen when famotidine 40 mg was given twice daily.
Effect of famotidine 20 and 40 mg dosing regimens on the bioavailability of atazanavir with ritonavir in combination with tenofovir in healthy subjects. Agarwala S, et al. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract 568.

The Bristol Myers Squibb perspective on the administration of H2-receptor antagonists (H2-RA) and atazanavir was published in an article in JAIDS in mid 2006. In summary they state:
• H2-RAs increase intragastric pH and reduce atazanavir absorption. However,
• H2-RAs are less potent than proton pump inhibitors in suppressing intragastric pH and may be used with atazanavir.
• Atazanavir/ritonavir at 300/100 mg may be used concomitantly with H2-RAs although temporal separation (giving ATV/r 10 hours after or 2 hours before the H2-RA) should be considered in treatment experienced patients.
• Local prescribing information may vary.
Based on current data the above approach to managing the interaction is appropriate although some may feel that temporal separation of the H2-RA and atazanavir/ritonavir would be safer in all patients. Note: The authors clearly state that due to the magnitude of the decrease in exposure, atazanavir should NOT be used concomitantly with proton pump inhibitors (PPIs).
Further information on the administration of H2-receptor antagonists with atazanavir. Agarwala S, Thal G, Nettles R, Bertz R. J Acquir Immune Defic Syndr, 2006, 42: 516.

Two studies were designed to evaluate the effect of the H2 antagonist famotidine (40 mg twice daily) on the pharmacokinetics of ATV in groups of healthy subjects (n=16). In one study, subjects received ATV 400 mg alone for 6 days, followed by either ATV + famotidine together, ATV + famotidine + cola together, ATV + famotidine separated (10 h post morning ATV dose and 2 h prior to evening ATV dose), or ATV 300 mg twice daily + famotidine + RTV (100 mg twice daily). In the second study, following 10 days of ATV/RTV (300/100 mg twice daily), subjects received ATV/RTV + famotidine, ATV/RTV + famotidine + cola, or ATV/RTV (400/100 mg) + famotidine. When compared to ATV 400 mg alone, the addition of famotidine reduced ATV AUC and Cmin by 41% and 42% respectively. Separating the administration of ATV and famotidine reduced the effect on AUC and Cmin (GMR 0.95 and 0.79 respectively). The addition of RTV to ATV 300 mg with famotidine resulted in increased AUC (79%) and Cmin (546%). Relative to a boosted 300/100 mg regimen, famotidine reduced ATV AUC and Cmin by 18% and 28% respectively. Increasing ATV to 400 mg when given with famotidine and RTV produced similar AUC and Cmin (GMR 1.03 and 0.86 respectively). The administration of cola did not mitigate the effects of famotidine in either study. The authors concluded that patients receiving ATV 400 mg unboosted and who require famotidine can either switch to ATV/RTV 300/100 mg twice daily, or remain on an unboosted regimen, but take famotidine 10 h after and 2 h prior to ATV. Patients on boosted ATV regimens (ATV/RTV 300/100 mg twice daily) should increase ATV to 400/100 mg when given with famotidine.
Pharmacokinetic effect of famotidine on atazanavir with and without ritonavir in healthy subjects. Agarwala, S et al. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, April 2005, abstract 11.

Trough atazanavir concentrations were available in 15 patients receiving a proton pump inhibitor (PPI) and 19 patients receiving an H2 receptor antagonist (H2). The mean atazanavir trough concentration in the PPI group was 0.65 µg/ml (range <0.05 to 1.85 µg/ml) compared to 1.12 µg/ml (range <0.05 to 3.17 µg/ml) in the H2 group. Concentrations were below target (0.27 µg/ml) in 6/15 in the PPI group, even though 5 of these were receiving boosted atazanavir. Inadequate levels were observed in 4/20 in the H2 group, 2 of whom were receiving boosted atazanavir. These results suggest a negative effect of proton pump inhibitors and H2 receptor antagonists on atazanavir concentrations and that boosting with ritonavir does not ensure adequate concentrations. Further study of this important issue is warranted.
Coadministration of atazanavir with proton-pump inhibitors and H2-blockers. Farthing C, Khanlou H. 7th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2004, abstract P289.

Caution is warranted as atazanavir could increase concentrations of the calcium channel blocker. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Atazanavir and fluconazole concentrations were not significantly modified when atazanavir/ritonavir (300/100 mg once daily) was co-administered with fluconazole (200 mg once daily). No dosage adjustments are needed for atazanavir/ritonavir and fluconazole.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

No clinically significant drug interactions were observed when atazanavir was coadministered with fluconazole.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

In an open label, randomised sequential crossover study in healthy volunteers, the interaction of atazanavir/ritonavir (300/100 mg once daily) and fluconazole (200 mg once daily) was assessed. There were no changes in exposure to atazanavir or fluconazole with all geometric mean ratios of pharmacokinetic parameters within the equivalence range of 0.8-1.25.
Lack of pharmacokinetic interaction between atazanavir, ritonavir and fluconazole dosed to steady state in healthy volunteers. Agarwala S, Gray K, Nettle R, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2006, abstract A-382.

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Coadministration of intranasal fluticasone ( 50 µg 4 times daily for 7 days) and ritonavir (100 mg twice daily) was studied. 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 metabolized 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/ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). 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.
Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2014.

Concomitant use of fluticasone propionate and atazanavir (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Concomitant use of fluticasone propionate and atazanavir/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced 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. Coadministration of fluticasone propionate and atazanavir/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Reyataz Prescribing Information, Bristol-Myers Squibb Co, September 2015.

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Virological failure was detected in an HIV+ patient taking atazanavir/ritonavir (300/100 mg once daily) and tenofovir/emtricitabine. The patient reported consuming garlic cloves (six garlic cloves three times weekly) and trough atazanavir concentrations were found to be sub-optimal (178 and 121 ng/ml). A trough atazanavir concentration following a single dose of atazanavir/ritonavir taken ~16 weeks after stopping garlic was found to be 609 ng/ml. The ~70% reduction in atazanavir exposure has been attributed to induction of intestinal CYP3A4 and/or P-gp by garlic.
An unusual case of HIV virologic failure during treatment with boosted atazanavir. Duncan A, Mills J. AIDS. 2013, 27(8):1361-2.

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The effect of Ginkgo biloba extract (120 mg twice daily for 4 weeks) on the steady state pharmacokinetics of lopinavir/ritonavir (400/100 mg twice daily) or single doses of midazolam (8 mg) was studied in 14 HIV- subjects. Coadministration had no effect on lopinavir or ritonavir concentrations, but decreased midazolam AUC by 34% and Cmax by 31%. The results suggest that Gingko biloba extract is unlikely to reduce exposure of ritonavir-boosted protease inhibitors, but unboosted regimens may be affected.
Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Robertson SM, Davey RT, Voell J, et al. Curr Med Res Opin, 2008, 24(2): 591-599.

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This study showed hop extracts to induce the expression of drug metabolism and excretion proteins. mRNA levels for CYP3A4, CYP2B6 and MDR1 were increased in a concentration dependent manner by activating PXR. The efficacy with which hops activated PXR was comparable to that of St John's wort.
Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Teotico DG, Bischof JJ, Peng L, et al. Mol Pharmacol, 2008, 74: 1512-1520.

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Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; ketoconazole, itraconazole; erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window. Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs.
Glivec Summary of Product Characteristics, Novartis Pharmaceuticals UK Ltd, October 2012.

There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40% respectively) in healthy subjects when imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir). Substances that inhibit CYP3A4 activity may decrease metabolism and increase imatinib concentrations. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib. Particular caution is recommended when administering imatinib with CYP3A4 substrates that have a narrow therapeutic window.
Gleevec Prescribing Information, Novartis, January 2013.

Imatinib pharmacokinetics alone and in combination with ritonavir (600 mg once daily for 3 days) were evaluated in 11 cancer patients receiving imatinib for at least 2 months (400-800 mg). The dose of imatinib was decreased by 50% during coadministration with ritonavir (for safety reasons) and pharmacokinetic parameters were normalised to an imatinib dose of 400 mg. Coadministration had no significant effect on imatinib AUC or Cmax (decreases of 3% and 13%, respectively). However, plasma exposure of CGP74588 (an active metabolite) was increased by approximately 40%. A population analysis with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. The authors suggest that at steady state imatinib is insensitive to acute CYP3A4 inhibition by ritonavir and relies on alternate elimination pathways.
Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. van Erp NP, Gelderblom H, Karlsson MO et al. Clin Cancer Res, 2007, 13(24): 7394-7400.

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