Drug Class Description
Protease Inhibitor

Generic Name
Atazanavir Sulphate

Drug Description
REYATAZ 150 mg hard capsulesREYATAZ 200 mg hard capsulesREYATAZ 300 mg hard capsules

Presentation
Hard capsuleREYATAZ 150 mg capsules are opaque blue and powder blue. They are printed with white and blue inks, with "BMS 150 mg" on one half and with "3624" on the other half.REYATAZ 200 mg capsules are opaque blue. They are printed with white ink, with "BMS 200 mg " on one half and with "3631" on the other half.REYATAZ 300mg capsules are opaque red and blue. They are printed with white ink, with "BMS 300 mg" on one half and with "3622" on the other half.

Indications
REYATAZ is indicated for the treatment of HIV-1 infected adults in combination with other antiretroviral medicinal products.In antiretroviral treatment experienced patients, the demonstration of efficacy is based on a study comparing REYATAZ 300 mg once daily in combination with ritonavir 100 mg once daily with lopinavir/ritonavir, each regimen in combination with tenofovir (see sections 4.8 and 5.1). Based on available virological and clinical data, no benefit is expected in patients with strains resistant to multiple protease inhibitors ( 4 PI mutations). The choice of REYATAZ in treatment experienced patients should be based on individual viral resistance testing and the patient's treatment history

Adult Dosage
Therapy should be initiated by a physician experienced in the management of HIV infection.Adults: the recommended dose of REYATAZ is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics.If REYATAZ with ritonavir is co-administered with didanosine, it is recommended that didanosine be taken 2 hours after REYATAZ with ritonavir. REYATAZ with ritonavir must be taken with food.Infants, toddlers, children, and adolescents: the safety and efficacy of REYATAZ in paediatric patients has not been established.Patients with renal impairment: no dosage adjustment is needed.Patients with hepatic impairment: REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ with ritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ should not be used in patients with moderate to severe hepatic impairment.Method of administration: for oral administration. The capsules should be swallowed whole. REYATAZ oral powder is available for patients who are unable to swallow capsules (see Summary of Product Characteristics for REYATAZ oral powder).

Child Dosage
Infants, toddlers, children, and adolescents: the efficacy and safety of REYATAZ have not been established in this population.

Elderly Dosage
See Adult Dosage

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Patients with moderate to severe hepatic insufficiency.Combination of rifampicin and REYATAZ with concomitant low-dose ritonavir is contraindicated.REYATAZ with ritonavir must not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine).REYATAZ must not be used in combination with products containing St. John's wort (Hypericum perforatum).

Special Precautions
Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.Co-administration of REYATAZ with ritonavir in doses greater than 100 mg once daily has not been clinically eva luated. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended.Patients with coexisting conditionsAtazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment. The safety and efficacy of REYATAZ 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. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products .Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.Dose related asymptomatic prolongations in PR interval with REYATAZ 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), REYATAZ should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing REYATAZ 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.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.Fat redistribution and metabolic disordersCombination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution.Combination antiretroviral therapy (CART), including REYATAZ (with or without ritonavir)-based CART, is associated with dyslipidaemia. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.In clinical studies, REYATAZ (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators. The clinical impact of such findings has not been demonstrated in the absence of specific studies on cardiovascular risk. The selection of antiretroviral therapy must be guided principally by antiviral efficacy. Consultation with standard guidelines for management of dyslipidaemia is recommended.HyperglycaemiaNew onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with development of diabetes or hyperglycaemia.HyperbilirubinaemiaReversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be eva luated for alternative etiologies. Alternative antiretroviral therapy to REYATAZ 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.Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of REYATAZ and indinavir have not been studied and co-administration of these medicinal products is not recommended.NephrolithiasisNephrolithiasis has been reported in patients receiving REYATA. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.Immune reactivation syndromeIn 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 carinii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary.OsteonecrosisAlthough the etiology 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.Interactions with other medicinal productsCo-administration of REYATAZ with simvastatin or lovastatin is not recommended.Co-administration of REYATAZ with nevirapine or efavirenz is not recommended.If the coadministration of REYATAZ with an NNRTI is required, an increase in the dose of both REYATAZ and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ with ritonavir and medicinal products that induce CYP3A4 is not recommended.The concomitant use of REYATAZ and oral contraceptives should be avoided.Co-administration of voriconazole and REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole.Concomitant use of REYATAZ/ritonavir and fluticasone or other glucocorticoids that are metabolized 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.The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.Co-administration of REYATAZ with proton pump inhibitors is not recommended. If the combination of REYATAZ with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.LactosePatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interactions
When REYATAZ and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with REYATAZ and ritonavir.Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, REYATAZ with ritonavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine.Other interactionsInteractions between atazanavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “”, no change as “↔”, twice daily as “BID” and once daily as “QD”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 1 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved regimen of atazanavir.Table 1: Interactions between REYATAZ and other medicinal productsCo-administered medicinal products (dose in mg)Medicinal product assessedAUC(90% CI)Cmax(90% CI)Cmin(90% CI)Recommendations concerning co-administrationANTI-INFECTIVESAntiretroviralsProtease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration is not recommended.Ritonavir 100 mg QD (atazanavir 300 mg QD) studies conducted in HIV-infected patientsatazanavir↑3.50*(2.44, 5.03)↑2.20*(1.56, 3.11)↑8.13*(4.59, 14.39)Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.* 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.IndinavirIndinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.Coadministration of REYATAZ/ritonavir and indinavir is not recommended.Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)Lamivudine 150 mg BID + zidovudine 300 mg BID (atazanavir 400 mg QD)Based on these data and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of REYATAZ/ritonavir with these medicinal products is not expected to significantly alter the exposure of the co-administered drugs.No significant effect on lamivudine and zidovudine concentrations was observed.AbacavirThe co-administration of REYATAZ/ ritonavir with abacavir is not expected to significantly alter the exposure of abacavir.Didanosine (buffered tablets) 200 mg/stavudine 40 mg, both single dose (atazanavir 400 mg single dose)Didanosine should be taken at the fasted state 2 hours after REYATAZ/ritonavir taken with food. The co-administration of REYATAZ/ritonavir with stavudine is not expected to significantly alter the exposure of stavudine.atazanavir, simultaneous administration with ddI+d4T (fasted)0.13(0.08, 0.21)0.11(0.06, 0.18)0.16(0.10, 0.27)atazanavir, dosed 1 hr after ddI+d4T (fasted)↔1.03(0.64, 1.67)↑1.12(0.67, 1.18)↔1.03(0.61, 1.73)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.Didanosine (enteric coated capsules) 400 mg single dose (atazanavir 300 mg QD with ritonavir 100 mg QD)Didanosine (with food)0.66(0.59, 0.73)0.62(0.52, 0.74)↑1.25(0.92, 1.69)No significant effect on atazanavir concentrations was observed when administered with enteric-coated didanosine, but administration with food decreased didanosine concentrations.Tenofovir disoproxil fumarate 300 mg QD (atazanavir 300 mg QD with ritonavir 100 mg QD) studies conducted in HIV-infected patientsatazanavir0.78 *(0.65, 0.94)0.84 *(0.70, 1.00)0.77 *(0.57-1.02)* 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 REYATAZ/ritonavir in combination with tenofovir 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 is unknown.Tenofovir disoproxil fumarate 300 mg QD (atazanavir 300 mg QD with ritonavir 100 mg QD)tenofovir disoproxil fumarate↑1.37(1.30, 1.45)↑1.34(1.20, 1.51)↑1.29(1.21, 1.36)Patients should be closely monitored for tenofovir-associated adverse events, including renal disorders.Non-nucleoside reverse transcriptase inhibitors (NNRTIs)Efavirenz 600 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)atazanavir (pm): all administered with food↔1.00*(0.91, 1.10)↑1.17*(1.08, 1.27)0.58*(0.49, 0.69)Co-administration of efavirenz with REYATAZ/ritonavir is not recommendedEfavirenz 600 mg QD (atazanavir 400 mg QD with ritonavir 200 mg QD)atazanavir (pm): all administered with food↔1.06*/**(0.90, 1.26)↔1.09*/**(0.95, 1.26)↔1.12*/**(0.84, 1.49)* When compared to REYATAZ 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.Nevirapine 200 mg BID (atazanavir 400 mg QD with ritonavir 100 mg QD) study conducted in HIV infected patientsnevirapine↑1.26(1.17, 1.36)↑1.21(1.11, 1.32)↑1.35(1.25, 1.47)Co-administration of nevirapine with REYATAZ/ritonavir is not recommendedatazanavir0.81*(0.65, 1.02)↔1.02*(0.85, 1.24)0.41*(0.27, 0.60)* When compared to REYATAZ 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.AntibioticsClarithromycin 500 mg BID (atazanavir 400 mg QD)clarithromycin↑1.94(1.75, 2.16)↑1.50(1.32, 1.71)↑2.60(2.35, 2.88)No recommendation regarding dose reduction can be made; therefore, caution should be exercised if REYATAZ/ritonavir is co-administered with clarithromycin.14-OH clarithromycin0.30(0.26, 0.34)0.28(0.24, 0.33)0.38(0.34, 0.42)atazanavir↑1.28(1.16, 1.43)↔1.06(0.93, 1.20)↑1.91(1.66, 2.21)A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.AntifungalsKetoconazole 200 mg QD (atazanavir 400 mg QD)No significant effect on atazanavir concentrations was observed.Ketoconazole and itraconazole should be used cautiously with REYATAZ/ritonavir. High doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.ItraconazoleItraconazole, 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, REYATAZ/ritonavir is expected to increase ketoconazole or itraconazole concentrations.VoriconazoleCo-administration of REYATAZ/ritonavir and voriconazole has not been studied.The effect of co-administration of oral voriconazole and low dose (100 mg) oral ritonavir was investigated in healthy volunteers. Low doses of ritonavir (100 mg BID) decreased the Cmax and AUC of voriconazole (90% CI) by an average of 24% (9% to 36%) and 39% (22% to 52%), respectively. Administration of voriconazole resulted in a minor decrease in steady state Cmax and AUC of ritonavir (90% CI) with an average of 24% (6% to 39%) and 14% (26% to ↑1%), respectively.Co-administration of voriconazole and REYATAZ/ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for adverse events and/or loss of efficacy during the co-administration of voriconazole and REYATAZ/ritonavir.Fluconazole 200 mg QD (atazanavir 300 mg and ritonavir 100 mg QD)Atazanavir and fluconazole concentrations were not significantly modified when REYATAZ/ritonavir was co-administered with fluconazole.No dosage adjustments are needed for REYATAZ/ritonavir and fluconazole.AntimycobacterialRifabutin 150 mg QD (atazanavir 400 mg QD)atazanavir↑1.15(0.98, 1.34)↑1.34(1.14, 1.59)↑1.13(0.68, 1.87)A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended when rifabutin is administered with REYATAZ/ritonavir. No dose adjustment is needed for REYATAZ/ritonavir.Rifabutin 150 mg QD (atazanavir 600 mg QD)This is not the recommended therapeutic dose of atazanavir.rifabutin↑2.10(1.57, 2.79)↑1.18(0.94, 1.48)↑3.43(1.98, 5.96)25-O-desacetyl-rifabutin↑22.01*(15.97, 30.34)↑8.20*(5.90, 11.40)↑75.6*(30.1, 190.0)* When compared to rifabutin 300 mg QD.The mechanism of rifabutin and atazanavir interaction is CYP3A4 inhibitionRifampicinRifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of REYATAZ or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.The combination of rifampicin and REYATAZ with concomitant low -dose ritonavir is contraindicatedACID REDUCING AGENTSH2 -Receptor antagonistsFamotidine 40 mg BID (atazanavir 300 mg QD with ritonavir 100 mg QD)atazanavir 0.82(0.75, 0.89)0.86(0.79, 0.94)0.72(0.64, 0.81)No dosage adjustment of REYATAZ/ ritonavir is required when co-administered with an H2-receptor antagonist, all as a single daily dose with food. Reductions in atazanavir concentrations may be avoided by temporal separation of REYATAZ and an H2-receptor antagonist as follows: REYATAZ 300 mg with ritonavir 100 mg once daily with food, 2 hours before and at least 10 hours following the administration of an H2-receptor antagonist.Although not studied, similar results are expected with other H2 -receptor antagonists. The relevance of these data for HIV infected patients is unknown since the intragastric pH may be higher in this population. Therefore, the magnitude of this effect may be more pronounced. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers.Proton pump inhibitorsOmeprazole 40 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)atazanavir (am): 2 hr after omeprazole0.39(0.35, 0.45)0.44(0.38, 0.51)0.35(0.29, 0.41)Co-administration of REYATAZ/ritonavir with proton pump inhibitors is not recommended. If the combination of REYATAZ/ritonavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceededOmeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)atazanavir (am): 1 hr after omeprazaole0.70*(0.57, 0.86)0.69*(0.58, 0.83)0.69*(0.54, 0.88)* When compared to atazanavir 300 mg QD with ritonavir 100 mg QDThe decrease in AUC, Cmax , and Cmin was not mitigated when an increased dose of REYATAZ/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.AntacidsAntacids and medicinal products containing buffersReduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids, including buffered medicinal products, are administered with REYATAZ/ritonavir.REYATAZ/ritonavir should be administered 2 hours before or 1 hour after antacids or buffered medicinal products.ANTICOAGULANTSWarfarinCo-administration with REYATAZ/ritonavir has the potential to produce a decrease or, less often, an increase in INR (International Normalised Ratio).It is recommended that the INR be monitored carefully during treatment with REYATAZ/ritonavir, especially when commencing therapy.ANTINEOPLASTICS AND IMMUNOSUPRESSANTSAntineoplasticsIrinotecanAtazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.If REYATAZ/ritonavir is co-administered with irinotecan, patients should be closely monitored for adverse events related to irinotecan.ImmunosuppressantsCyclosporinTacrolimusSirolimusConcentrations of these immunosuppressants may be increased when co-administered with REYATAZ/ritonavir due to CYP3A4 inhibition.More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.CARDIOVASCULAR AGENTSAntiarrhythmicsAmiodarone,Systemic lidocaine,QuinidineConcentrations of these antiarrhythmics may be increased when co-administered with REYATAZ/ritonavir. The mechanism of amiodarone or systemic lidocaine/atazanavir interaction is CYP3A inhibition. Quinidine has a narrow therapeutic window and is contraindicated due to potential inhibition of CYP3A by REYATAZ/ritonavir.Caution is warranted and therapeutic concentration monitoring is recommended when available. The concomitant use of quinidine is contraindicated.Calcium channel blockersBepridilREYATAZ/ritonavir should not be used in combination with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index.Co-administration with bepridil is contraindicatedDiltiazem 180 mg QD (atazanavir 400 mg QD)diltiazem↑2.25(2.09, 2.41↑1.98(1.78, 2.19)↑2.42(2.14, 2.73)An initial dose reduction of diltiazem by 50% is recommended, with subsequent titration as needed and ECG monitoringdesacetyl-diltiazem↑2.65(2.45, 2.87)↑2.72(2.44, 3.03)↑2.21(2.02, 2.42)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 REYATAZ/ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition.VerapamilSerum concentrations of verapamil may be increased by REYATAZ/ritonavir due to CYP3A4 inhibition..Caution should be exercised when verapamil is co-administered with REYATAZ/ritonavirCORTICOSTEROIDSFluticasone propionate intranasal 50 µg 4 times daily for 7 days (ritonavir 100 mg capsules BID)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, eg, 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 REYATAZ/ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring o

Adverse Reactions
Data on the safety and tolerability of REYATAZ 300 mg with ritonavir 100 mg once daily are limited, as this combination has only been eva luated in 119 patients in Study 045 in a regimen that also included tenofovir 300 mg once daily and a nucleoside reverse transcriptase inhibitor. Considering that tenofovir has been shown to decrease the plasma levels of atazanavir (with or without concomitant ritonavir), the safety data derived from this study may not fully reflect the safety profile of REYATAZ plus ritonavir when used in clinical practice within antiretroviral combinations that exclude tenofovir. An alteration of the safety profile of REYATAZ cannot be excluded in this context. REYATAZ has been eva luated for safety and tolerability in combination therapy with other antiretroviral medicinal products in Phase II and III trials in 1,597 adult patients. The majority of patients (1,047) received REYATAZ 400 mg once daily without ritonavir. The median duration of treatment was 102 weeks in Phase II trials and 48 weeks in the Phase III trials. Adverse events were comparable between patients who received REYATAZ 300 mg with ritonavir 100 mg once daily and patients who received REYATAZ 400 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with REYATAZ plus ritonavir. Among patients who received 400 mg once daily or 300 mg with ritonavir 100 mg once daily, the only adverse events of any severity reported very commonly with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (24%), headache (10%), and jaundice (10%). Among patients receiving REYATAZ 300 mg with ritonavir 100 mg, the frequency of jaundice was 16%. Jaundice was reported within a few days to a few months after the initiation of treatment (See Special Precautions). Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation (buffalo hump). Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (See Special Precautions). Adult patients The following adverse events of moderate intensity or greater with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs have also been reported. The frequency of adverse reactions listed below is defined using the following convention: very common (= 1/10), common (= 1/100, < 1/10), uncommon (= 1/1,000, < 1/100), rare (= 1/10,000, < 1/1,000), or very rare (< 1/10,000). Immune system disorders: uncommon: allergic reactionMetabolism and nutritiondisorders:common: lipodystrophy;uncommon: anorexia, appetite increased, weightdecreased, weight gainPsychiatric disorders:uncommon: anxiety, depression, sleep disorderNervous system disorders: common: headache, insomnia, peripheral neurologicsymptoms;uncommon: abnormal dream, amnesia, confusion,dizziness, somnolence;rare: abnormal gaitEye disorders: common: scleral icterusCardiac disorders and vasculardisorders:uncommon: hypertension, syncope;rare: oedema, palpitationRespiratory, thoracic andmediastinal disorders:uncommon: dyspneaGastrointestinal disorders: common: abdominal pain, diarrhoea, dyspepsia, nausea,vomiting;uncommon: dysgeusia, flatulence, gastritis, pancreatitis,stomatitis aphthous;rare: abdominal distensionHepatobiliary disorders: common: jaundice;uncommon: hepatitis;rare: hepatosplenomegalySkin and subcutaneous tissuedisorders:common: rash;uncommon: alopecia, pruritus, urticaria;rare: eczema, vasodilatation, vesiculobullous rashMusculoskeletal and connectivetissue disorders:uncommon: arthralgia, muscle atrophy, myalgia;rare: myopathyRenal and urinary disorders: uncommon: hematuria, nephrolithiasis, pollakiuria,proteinuria;rare: kidney painReproductive system and breastdisorders:uncommon: gynecomastiaGeneral disorders andadministration site conditions:common: asthenia, fatigue;uncommon: chest pain, fever, malaiseRenal and urinary disorders: uncommon: hematuria, nephrolithiasis, pollakiuria, proteinuria; rare: kidney pain Reproductive system and breast disorders: uncommon: gynecomastia General disorders and administration site conditions: common: asthenia, fatigue; uncommon: chest pain, fever, malaise In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (See Special Precautions). Laboratory abnormalities The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin (84% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 33% (28% Grade 3, 5% Grade 4, reported predominantly as elevated indirect [unconjugated] bilirubin). Among patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily, 49% had Grade 3-4 total bilirubin elevations (See Special Precautions). Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in = 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated amylase (12%), elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%). One percent of patients treated with REYATAZ experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations. Patients co-infected with hepatitis B and/or hepatitis C virus Among 585 patients receiving atazanavir 400 mg once daily, 74 patients were co-infected with chronic hepatitis B or C, and among 119 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 20 were co-infected with chronic hepatitis B or C. Co-infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between REYATAZ and comparator regimens (See Special Precautions).

Manufacturer
Bristol-Myers Squibb

Drug Availability
(POM)

Updated
12 August 2009