1. Name Of The Medicinal Product
REYATAZ
REYATAZ
REYATAZ
* Intensive monitoring is requested only when used for the recently-licensed indication extension to paediatric patients.
2. Qualitative And Quantitative Composition
Each capsule contains 150 mg, 200 mg or 300 mg of atazanavir (as sulphate)
Excipient: 82.18 mg of lactose per 150 mg capsule.
Excipient: 109.57 mg of lactose per 200 mg capsule.
Excipient: 164.36 mg of lactose per 300 mg capsule.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Hard capsule
REYATAZ 150 mg capsules are blue and powder blue capsule 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 capsule printed with white ink, with "BMS 200 mg" on one half and with "3631" on the other half.
REYATAZ 300 mg capsules are opaque red and blue capsule printed with white ink, with "BMS 300 mg" on one half and with "3622" on the other half.
4. Clinical Particulars
4.1 Therapeutic Indications
REYATAZ capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.
Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (
The choice of REYATAZ in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history (see sections 4.4 and 5.1).
4.2 Posology And Method Of Administration
Posology
Therapy should be initiated by a physician experienced in the management of HIV infection.
Adults: the recommended dose of REYATAZ capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1).
Paediatric population
Paediatric patients (6 years to less than 18 years of age): The dose of REYATAZ capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. REYATAZ capsules must be taken with ritonavir and have to be taken with food.
Table 1: Dose for Paediatric Patients (6 years to less than 18 years of age) for REYATAZ capsules with ritonavir
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|
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Body Weight (kg)
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REYATAZ once daily dose
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ritonavir once daily dosea
|
15 to less than 20
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150 mg
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100 mgb
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20 to less than 40
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200 mg
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100 mg
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at least 40
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300 mg
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100 mg
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a Ritonavir capsules, tablets or oral solution.
b Ritonavir oral solution no lower than 80 mg and not more than 100 mg may be used for paediatric patients from 15 kg to less than 20 kg who cannot swallow ritonavir capsules/tablets.
The available data do not support the use of REYATAZ in combination with low dose ritonavir in paediatric patients weighing less than 15 kg.
Paediatric patients (less than 6 years of age): The safety and efficacy of REYAYAZ in children aged 3 months to 6 years has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. REYATAZ should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.
Special populations
Patients with renal impairment: no dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).
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 must not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4, and 5.2).
Pregnancy and Postpartum
During the second and third trimesters of pregnancy:
REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.
The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g., tenofovir or H2-receptor antagonists).
• If tenofovir or an H2-receptor antagonist is needed, a dose increase to REYATAZ 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).
• It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receiving both tenofovir and an H2-receptor antagonist.
During postpartum:
Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.
• During this time, postpartum patients should follow the same dose recommendation as for non-pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).
Method of administration: for oral administration. The capsules should be swallowed whole.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Patients with moderate to severe hepatic insufficiency (see sections 4.2 and 4.4).
Combination of rifampicin and REYATAZ with concomitant low-dose ritonavir is contraindicated (see section 4.5).
The PDE5 inhibitor sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see section 4.4 and section 4.5.
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., alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).
REYATAZ must not be used in combination with products containing St. John's wort (Hypericum perforatum) (see section 4.5).
4.4 Special Warnings And Precautions For Use
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 at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).
Patients with coexisting conditions
Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). 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 (see section 4.8).
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.
No dosage adjustment is needed in patients with renal impairment. However, REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).
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 (see section 5.1). 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 (see sections 4.8 and 5.3).
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 disorders
Combination 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 evaluation 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 (see section 4.8).
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.
Hyperglycaemia
New 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.
Hyperbilirubinaemia
Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be evaluated 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 (see section 4.5).
Nephrolithiasis
Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Osteonecrosis
Although 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.
Rash and associated syndromes
Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.
Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. REYATAZ should be discontinued if severe rash develops.
The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of REYATAZ, REYATAZ may not be restarted.
Interactions with other medicinal products
Co-administration of REYATAZ with simvastatin or lovastatin is not recommended (see section 4.5).
Co-administration of REYATAZ with nevirapine or efavirenz is not recommended (see section 4.5).
If the co-administration 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 (see sections 4.3 and 4.5).
PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile dysfunction in patients receiving REYATAZ with concomitant low-dose ritonavir. Co-administration of REYATAZ with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse events such as hypotension, visual changes and priapism (see section 4.5).
Co-administration of voriconazole and REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole (see section 4.5).
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 (see section 4.5).
Concomitant use of salmeterol and REYATAZ/ritonavir may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and REYATAZ is not recommended (see section 4.5).
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 (see section 4.5). 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.
Co-administration of REYATAZ/ritonavir in combination with tenofovir and an H2-receptor antagonist should be avoided (see section 4.5).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric population
Safety
Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric 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. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).
Efficacy
Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance. While in adults no benefit can be expected in patients with
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 (see section 4.3).
Other interactions
Interactions 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 “
Table 2: Interactions between REYATAZ and other medicinal products
Medicinal products by therapeutic area
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Interaction
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Recommendations concerning co-administration
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ANTI-RETROVIRALS
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Protease 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.
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Ritonavir 100 mg once daily
(atazanavir 300 mg once daily)
Studies conducted in HIV-infected patients.
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Atazanavir AUC: ↑250% (↑144% ↑403%)*
Atazanavir Cmax: ↑120% (↑56% ↑211%)*
Atazanavir Cmin: ↑713% (↑359% ↑1339%)*
* In a combined analysis, atazanavir 300 mg and ritonavir 100 mg (n=33) was compared to atazanavir 400 mg without ritonavir (n=28).
The mechanism of interaction between atazanavir and ritonavir is CYP3A4 inhibition.
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Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.
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Indinavir
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Indinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.
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Co-administration of REYATAZ/ritonavir and indinavir is not recommended (see section 4.4).
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Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
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Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily
(atazanavir 400 mg once daily)
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No significant effect on lamivudine and zidovudine concentrations was observed.
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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.
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Abacavir
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The co-administration of REYATAZ/ ritonavir with abacavir is not expected to significantly alter the exposure of abacavir.
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Didanosine (buffered tablets) 200 mg/stavudine 40 mg, both single dose
(atazanavir 400 mg single dose)
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Atazanavir, simultaneous administration with ddI+d4T (fasted)
Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
Atazanavir, dosed 1 hr after ddI+d4T (fasted)
Atazanavir AUC ↔3% (
Atazanavir Cmax↑12% (
Atazanavir Cmin ↔3% (
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.
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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.
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Didanosine (enteric coated capsules) 400 mg single dose
(atazanavir 300 mg once daily with ritonavir 100 mg once daily)
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Didanosine (with food)
Didanosine AUC
Didanosine Cmax
Didanosine Cmin↑25% (
No significant effect on atazanavir concentrations was observed when administered with enteric-coated didanosine, but administration with food decreased didanosine concentrations.
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Tenofovir disoproxil fumarate 300 mg once daily
(atazanavir 300 mg once daily with ritonavir 100 mg once daily)
Studies conducted in HIV-infected patients
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Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
* 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 (see sections 4.8 and 5.1). The mechanism of interaction between atazanavir and tenofovir is unknown.
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Tenofovir disoproxil fumarate 300 mg once daily
(atazanavir 300 mg once daily with ritonavir 100 mg once daily)
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Tenofovir disoproxil fumarate AUC ↑37% (↑30% ↑45%)
Tenofovir disoproxil fumarate Cmax↑34% (↑20% ↑51%)
Tenofovir disoproxil fumarate Cmin↑29% (↑21% ↑36%)
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Patients should be closely monitored for tenofovir-associated adverse events, including renal disorders.
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
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Efavirenz 600 mg once daily
(atazanavir 400 mg once daily with ritonavir 100 mg once daily)
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Atazanavir (pm): all administered with food
Atazanavir AUC ↔0%(
Atazanavir Cmax↑17%(↑8% ↑27%)*
Atazanavir Cmin
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Co-administration of efavirenz with REYATAZ/ritonavir is not recommended (see section 4.4)
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Efavirenz 600 mg once daily
(atazanavir 400 mg once daily with ritonavir 200 mg once daily)
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Atazanavir (pm): all administered with food
Atazanavir AUC ↔6% (
Atazanavir Cmax ↔9% (
Atazanavir Cmin ↔12% (
* 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.
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Nevirapine 200 mg twice daily
(atazanavir 400 mg once daily with ritonavir 100 mg once daily)
Study conducted in HIV infected patients
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Nevirapine AUC ↑26% (↑17% ↑36%)
Nevirapine Cmax↑21% (↑11% ↑32%)
Nevirapine Cmin↑35% (↑25% ↑47%)
Atazanavir AUC
Atazanavir Cmax ↔2% (
Atazanavir Cmin
* 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.
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Co-administration of nevirapine with REYATAZ/ritonavir is not recommended (see section 4.4)
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Integrase Inhibitors
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Raltegravir 400 mg twice daily
(atazanavir/ritonavir)
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Raltegravir AUC↑ 41%
Raltegravir Cmax ↑ 24%
Raltegravir C12hr ↑ 77%
The mechanism is UGT1A1 inhibition.
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No dose adjustment required for Isentress.
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ANTIBIOTICS
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Clarithromycin 500 mg twice daily
(atazanavir 400 mg once daily)
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Clarithromycin AUC ↑94% (↑75% ↑116%)
Clarithromycin Cmax↑50% (↑32% ↑71%)
Clarithromycin Cmin↑160% (↑135% ↑188%)
14-OH clarithromycin
14-OH clarithromycin AUC
14-OH clarithromycin Cmax
14-OH clarithromycin Cmin
Atazanavir AUC ↑28% (↑16% ↑43%)
Atazanavir Cmax ↔6% (
Atazanavir Cmin↑91% (↑66% ↑121%)
A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.
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No recommendation regarding dose reduction can be made; therefore, caution should be exercised if REYATAZ/ritonavir is co-administered with clarithromycin.
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ANTIFUNGALS
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Ketoconazole 200 mg once daily
(atazanavir 400 mg once daily)
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No significant effect on atazanavir concentrations was observed.
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Ketoconazole and itraconazole should be used cautiously with REYATAZ/ritonavir. High doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.
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Itraconazole
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Itraconazole, like ketoconazole, is a potent inhibitor as well as a substrate of CYP3A4.
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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.
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Voriconazole
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Co-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 twice daily) decreased the Cmax and AUC of voriconazole (90% CI) by an average of 24% (max and AUC of ritonavir (90% CI) with an average of 24% (
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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 (see section 4.4). Patients should be carefully monitored for adverse events and/or loss of efficacy during the co-administration of voriconazole and REYATAZ/ritonavir.
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Fluconazole 200 mg once daily
(atazanavir 300 mg and ritonavir 100 mg once daily)
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Atazanavir and fluconazole concentrations were not significantly modified when REYATAZ/ritonavir was co-administered with fluconazole.
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No dosage adjustments are needed for REYATAZ/ritonavir and fluconazole.
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ANTIMYCOBACTERIAL
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Rifabutin 150 mg twice weekly
(atazanavir 300 mg and ritonavir 100 mg once daily)
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Rifabutin AUC ↑48% (↑19% ↑84%) **
Rifabutin Cmax↑149% (↑103% ↑206%) **
Rifabutin Cmin↑40% (↑5% ↑87%) **
25-O-desacetyl-rifabutin AUC ↑990% (↑714% ↑1361%) **
25-O-desacetyl-rifabutin Cmax↑677% (↑513% ↑883%) **
25-O-desacetyl-rifabutin Cmin↑1045% (↑715% ↑1510%) **
** When compared to rifabutin 150 mg once daily alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC ↑119% (↑78% ↑169%).
In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.
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When given with REYATAZ/ritonavir, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommended for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for REYATAZ/ritonavir.
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Rifampicin
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Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of REYATAZ or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.
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The combination of rifampicin and REYATAZ with concomitant low-dose ritonavir is contraindicated (see section 4.3).
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ACID REDUCING AGENTS
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H2-Receptor antagonists
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Without Tenofovir
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In HIV-infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg once daily
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For patients not taking tenofovir, if REYATAZ 300 mg/ritonavir 100 mg and H2-receptor antagonists are co-administered, a dose equivalent to famotidine 20 mg twice daily should not be exceeded. If a higher dose of an H2-receptor antagonist is required (eg, famotidine 40 mg twice daily or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered.
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Famotidine 20 mg twice daily
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Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin ↔1% (
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Famotidine 40 mg twice daily
|
Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
|
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In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg once daily
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|
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Famotidine 40 mg twice daily
|
Atazanavir AUC ↔3% (
Atazanavir Cmax ↔2% (
Atazanavir Cmin
|
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With Tenofovir 300 mg once daily
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|
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In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily
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For patients who are taking tenofovir,
Co-administration of REYATAZ/ritonavir in combination with tenofovir and an H2-receptor antagonist should be avoided (see section 4.4). If the combination of REYATAZ/ritonavir with both tenofovir and an H2-receptor antagonist is judged unavoidable, close clinical monitoring is recommended. A dose increase of REYATAZ to 400 mg with 100 mg of ritonavir may be considered but is still under evaluation.
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Famotidine 20 mg twice daily
|
Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
|
|
Famotidine 40 mg twice daily
|
Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
|
|
|
* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir, atazanavir concentrations are expected to be additionally decreased by about 20%.
The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers.
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|
Proton pump inhibitors
|
|
|
Omeprazole 40 mg once daily
(atazanavir 400 mg once daily with ritonavir 100 mg once daily)
|
Atazanavir (am): 2 hr after omeprazole
Atazanavir AUC
Atazanavir Cmax
Atazanavir Cmin
|
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 exceeded (see section 4.4).
|
Omeprazole 20 mg once daily
(atazanavir 400 mg once daily with ritonavir 100 mg once daily)
|
Atazanavir (am): 1 hr after omeprazole
Atazanavir AUC
Atazanavir Cmax
Ataz
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