Reyataz 200 mg Hard Capsules

  • Name:

    Reyataz 200 mg Hard Capsules

  • Company:
    info
  • Active Ingredients:

    Atazanavir sulfate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 25/02/19

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Summary of Product Characteristics last updated on medicines.ie: 22/2/2019

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Bristol-Myers Squibb Pharma EEIG

Company Products

Medicine NameActive Ingredients
Medicine Name Baraclude 0.05 mg/ml oral solution Active Ingredients Entecavir monohydrate
Medicine Name Baraclude 0.5 mg film coated tablets Active Ingredients Entecavir monohydrate
Medicine Name Baraclude 1.0 mg film coated tablets Active Ingredients Entecavir monohydrate
Medicine Name Empliciti 300 mg and 400 mg powder for concentrate for solution for infusion Active Ingredients Elotuzumab
Medicine Name NULOJIX 250 mg powder for concentrate for solution for infusion Active Ingredients Belatacept
Medicine Name OPDIVO 10 mg/mL concentrate for solution for infusion Active Ingredients Nivolumab
Medicine Name ORENCIA 125 mg solution for injection in pre-filled pen Active Ingredients Abatacept
Medicine Name ORENCIA 250 mg powder for concentrate for solution for infusion Active Ingredients Abatacept
Medicine Name ORENCIA 50 mg, 87.5 mg and 125 mg solution for injection (pre-filled syringe) Active Ingredients Abatacept
Medicine Name Reyataz 150 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Reyataz 200 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Reyataz 300 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Sprycel 10 mg/mL powder for oral suspension Active Ingredients dasatinib monohydrate
Medicine Name Sprycel 20mg, 50mg, 70mg and 100mg Film-Coated Tablets Active Ingredients dasatinib monohydrate
Medicine Name Sustiva 50 mg , 100 mg , 200 mg Hard Capsules Active Ingredients Efavirenz
Medicine Name Sustiva 600 mg Film-coated Tablets Active Ingredients Efavirenz
Medicine Name Yervoy 5mg per ml concentrate for solution for infusion Active Ingredients ipilimumab
Medicine Name Zerit 30 mg capsules Active Ingredients Stavudine
Medicine Name Zerit 40 mg capsules Active Ingredients Stavudine
1 - 0 of 19 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 25 February 2019 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 22 February 2019 SmPC

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The Marketing Authorisation Holder address has been changed.

Updated on 26 November 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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Updated on 10 October 2018 PIL

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  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to date of revision

Updated on 10 October 2018 SmPC

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  • Change to section 4.3 - Contraindications
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Updated on 25 May 2018 SmPC

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To include information on the contraindicated co-administration with lurasidone

  • Section 4.3 Contraindactions
  • Section 4.5 Interaction with other medicinal products and other forms of interaction

Updated on 18 May 2018 PIL

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  • Change to section 2 - what you need to know - contraindications

Updated on 19 January 2018 SmPC

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  • Change to section 10 - Date of revision of the text

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Update to Section 10 'Date of revision of the text' - December 2017

Updated on 19 January 2018 SmPC

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  • New SmPC for new product

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Updated on 13 December 2017 PIL

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  • New PIL for new product

Updated on 13 December 2017 PIL

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  • Change to section 6 - date of revision

Updated on 3 November 2017 SmPC

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  • Change to section 4.3 - Contraindications
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SmPC and PIL update to include information on the contraindicated co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection).
Update to section 4.3 and 4.5

Updated on 2 November 2017 PIL

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  • Change to section 2 - what you need to know - contraindications
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Updated on 8 September 2017 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
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Update to the SmPC and Package Leaflet (PIL) with warnings and precautions of use and post-marketing experience on Chronic Kidney Disease.

·         SmPC Section 4.4 Warnings and Precautions for use

·         SmPC Section 4.8 Undesirable effects

Updated on 8 September 2017 PIL

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Updated on 4 January 2017 PIL

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  • New individual PIL (was previously included in a combined PIL)

Updated on 3 January 2017 SmPC

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  • Change to section 4.6 - Pregnancy and lactation

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Section 4.6 (fertility, pregnancy and lactation), has been updated to indicate that atazanavir has been detected in human milk.

Updated on 23 June 2016 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
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Section 4.2 - change to body weight in regards to dose for patients 6 - 18 years.

Updated on 16 February 2016 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
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4.4     Special warnings and precautions for use

 

Fat redistribution Weight and metabolic disordersparameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral theraphy. Such changes may in part be linked to the disease control and life style. For lipids, there is in some cases eveidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinicallly appropriate.

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.

 

4.8     Undesirable effects

 

Metabolism and nutrition disorders:

uncommon: diabetesa, hyperglycaemiaa,b, weight decreased, weight gain, anorexia, appetite increased

 

c.         Description of selected adverse reactions

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. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

 

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

 

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 sections 4.4 and 5.1).

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

 

10.     DATE OF REVISION OF THE TEXT

 

28 January 2016

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 25 November 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
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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). (See also section 4.4 Withdrawal of ritonavir only under restrictive conditions).


 

In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen (see section 4.4), unboosted REYATAZ could be maintained in patients with mild hepatic impairment at a dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg once daily with food (see section 5.2). Unboosted REYATAZ must not be used in patients with severe hepatic impairment.

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 disoproxil fumarate or H2-receptor antagonists).

§ If tenofovir disoproxil fumarate 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 disoproxil fumarate and an H2-receptor antagonist.

(See section 4.4 Withdrawal of ritonavir only under restrictive conditions). 

4.3     Contraindications

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

 

REYATAZ is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, 4.4 and 5.2). REYATAZ with ritonavir is contraindicated in patients with moderate hepatic insufficiency (see sections 4.2, 4.4 and 5.2).

 

Co-administration of REYATAZ with simvastatin or lovastatin is contraindicated (see section 4.5).

 

Combination of rifampicin and REYATAZ is contraindicated (see section 4.5).

 

4.4     Special warnings and precautions for use

Withdrawal of ritonavir only under restrictive conditions
The recommended standard treatment is REYATAZ boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.
The withdrawal of ritonavir from the boosted regimen of REYATAZ is not recommended, but may be considered in adults patients at the dose of 400 mg once daily with food only under the following combined restrictive conditions:

§ absence of prior virologic failure

§ undetectable viral load during the last 6 months under current regimen

§ viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.

REYATAZ given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil fumarate and with other concomitant medications that reduce atazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen) or in case of perceived challenging compliance.

REYATAZ given without ritonavir should not be used in pregnant patients given that it could result of suboptimal exposure of particular concern for the mother infection and vertical transmission.

4.5 Interaction with other medicinal products and other forms of interaction

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 and other medicinal products are listed in the tables below (increase is indicated as "↑, decrease as , no change as ↔). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved recommended regimen of atazanavir. (see section 4.4).

If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), special attention should be given to atazanavir interactions that may differ in the absence of ritonavir (see information below Table 2).

Medicinal products by therapeutic area

Interaction

Recommendations concerning co-administration

ANTI-RETROVIRALS

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.

Ritonavir 100 mg once daily

(atazanavir 300 mg once daily)

 

Studies conducted in HIV-infected patients.

 

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.

Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.

Indinavir

Indinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.

Co-administration of REYATAZ and indinavir is not recommended (see section 4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily

(atazanavir 400 mg once daily)

No significant effect on lamivudine and zidovudine concentrations was observed.

Based on these data and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of these medicinal products and REYATAZ is not expected to significantly alter the exposure of the co-administered drugs.

Abacavir

The co-administration of abacavir and REYATAZ 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)

Atazanavir, simultaneous administration with ddI+d4T (fasted)

Atazanavir AUC ↓87% (↓92% ↓79%)

Atazanavir Cmax ↓89% (↓94% ↓82%)

Atazanavir Cmin ↓84% (↓90% ↓73%)

 

Atazanavir, dosed 1 hr after ddI+d4T (fasted)

Atazanavir AUC ↔3% (↓36% ↑67%)

Atazanavir Cmax ↑12% (↓33% ↑18%)

Atazanavir Cmin ↔3% (↓39% ↑73%)

 

Atazanavir concentrations were greatly decreased when co-administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets.

No significant effect on didanosine and stavudine concentrations was observed.

Didanosine should be taken at the fasted state 2 hours after REYATAZ taken with food. The co-administration of stavudine with REYATAZ is not expected to significantly alter the exposure of stavudine.

Didanosine (enteric coated capsules) 400 mg single dose

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Didanosine (with food)

Didanosine AUC ↓34% (↓41% ↓27%)

Didanosine Cmax ↓38% (↓48% ↓26%)

Didanosine Cmin ↑25% (↓8% ↑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 once daily

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

 

Studies conducted in HIV-infected patients

 

Atazanavir AUC ↓22% (↓35% ↓6%) *

Atazanavir Cmax ↓16% (↓30% ↔0%) *

Atazanavir Cmin ↓23% (↓43% ↑2%) *

 

* In a combined analysis from several clinical studies, atazanavir/ritonavir 300/100 mg co-administered with tenofovir disoproxil fumarate 300 mg (n=39) was compared to atazanavir/ritonavir 300/100 mg (n=33).

 

The efficacy of REYATAZ/ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naive patients in clinical study 138 (see sections 4.8 and 5.1). The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown.

When co-administered with tenofovir disoproxil fumarate, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir disoproxil fumarate 300 mg (all as a single dose with food).

Tenofovir disoproxil fumarate 300 mg once daily

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Tenofovir disoproxil fumarate AUC ↑37% (↑30% ↑45%)

Tenofovir disoproxil fumarate Cmax ↑34% (↑20% ↑51%)

Tenofovir disoproxil fumarate Cmin ↑29% (↑21% ↑36%)

 

Patients should be closely monitored for tenofovir disoproxil fumarate-associated adverse events, including renal disorders.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

 

Atazanavir (pm): all administered with food

Atazanavir AUC ↔0%(↓9% ↑10%)*

Atazanavir Cmax ↑17%(↑8% ↑27%)*

Atazanavir Cmin ↓42%(↓51% ↓31%)*

 

Co-administration of efavirenz and REYATAZ is not recommended (see section 4.4)

 

Efavirenz 600 mg once daily

(atazanavir 400 mg once daily with ritonavir 200 mg once daily)

Atazanavir (pm): all administered with food

Atazanavir AUC ↔6% (↓10% ↑26%) */**

Atazanavir Cmax ↔9% (↓5% ↑26%) */**

Atazanavir Cmin ↔12% (↓16% ↑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 twice daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

 

Study conducted in HIV infected patients

 

Nevirapine AUC ↑26% (↑17% ↑36%)

Nevirapine Cmax ↑21% (↑11% ↑32%)

Nevirapine Cmin ↑35% (↑25% ↑47%)

 

Atazanavir AUC ↓19% (↓35% ↑2%) *

Atazanavir Cmax ↔2% (↓15% ↑24%) *

Atazanavir Cmin ↓59% (↓73% ↓40%) *

 

* When compared to 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.

Co-administration of nevirapine and REYATAZ is not recommended (see section 4.4)

Integrase Inhibitors

Raltegravir 400 mg twice daily

(atazanavir/ritonavir)

Raltegravir AUC ↑41%

Raltegravir Cmax ↑24%

Raltegravir C12hr ↑77%

 

The mechanism is UGT1A1 inhibition.

No dose adjustment required for raltegravir.

HCV Protease Inhibitors

Boceprevir 800 mg three times daily

(atazanavir 300 mg/ritonavir 100 mg once daily)

boceprevir AUC 5%

boceprevir Cmax 7%

boceprevir Cmin 18%

 

atazanavir AUC 35%

atazanavir Cmax 25%

atazanavir Cmin 49%

 

ritonavir AUC 36%

ritonavir Cmax 27%

ritonavir Cmin ↓ 45%

 

Co-administration of atazanavir/ritonavir with boceprevir resulted in lower exposure of atazanavir which may be associated with lower efficacy and loss of HIV control. This co-administration might be considered on a case by case basis if deemed necessary, in patients with suppressed HIV viral loads and with HIV viral strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring for HIV suppression is warranted.

ANTIBIOTICS

Clarithromycin 500 mg twice daily

(atazanavir 400 mg once daily)

Clarithromycin AUC ↑94% (↑75% ↑116%)

Clarithromycin Cmax ↑50% (↑32% ↑71%)

Clarithromycin Cmin ↑160% (↑135% ↑188%)

 

14-OH clarithromycin

14-OH clarithromycin AUC ↓70% (↓74% ↓66%)

14-OH clarithromycin Cmax ↓72% (↓76% ↓67%)

14-OH clarithromycin Cmin ↓62% (↓66% ↓58%)

 

Atazanavir AUC ↑28% (↑16% ↑43%)

Atazanavir Cmax ↔6% (↓7% ↑20%)

Atazanavir Cmin ↑91% (↑66% ↑121%)

 

A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.

 

No recommendation regarding dose reduction can be made; therefore, caution should be exercised if REYATAZ is co-administered with clarithromycin.

ANTIFUNGALS

Ketoconazole 200 mg once daily

(atazanavir 400 mg once daily)

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.

Itraconazole

Itraconazole, like ketoconazole, is a potent inhibitor as well as a substrate of CYP3A4.

 

Based on data obtained with other boosted PIs and ketoconazole, where ketoconazole AUC showed a 3-fold increase, REYATAZ/ritonavir is expected to increase ketoconazole or itraconazole concentrations.

Voriconazole 200 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily)

 

Subjects with at least one functional CYP2C19 allele.

 

Voriconazole AUC ↓33% (↓42% ↓22%)

Voriconazole Cmax ↓10% (↓22% ↓4%)

Voriconazole Cmin ↓39% (↓49% ↓28%)

 

 

Atazanavir AUC ↓12% (↓18% ↓5%)

Atazanavir Cmax ↓13% (↓20% ↓4%)

Atazanavir Cmin ↓ 20 % (↓28 % ↓10%)

 

 

Ritonavir AUC ↓12% (↓17% ↓7%)

Ritonavir Cmax ↓9% (↓17% ↔0%)

Ritonavir Cmin ↓25% (↓35% ↓14%)

 

In the majority of patients with at least one functional CYP2C19 allele, a reduction in both voriconazole and atazanavir exposures are expected.

 

Co-administration of voriconazole and REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see section 4.4).

 

At the time voriconazole treatment is required, a patient's CYP2C19 genotype should be performed if feasible.

 

Therefore if the combination is unavoidable, the following recomendations are made according to the CYP2C19 status:

 

- in patients with at least one functional CYP2C19 allele, close clinical monitoring for a loss of both voriconazole (clinical signs) and atazanavir (virologic response) efficacy is recommended.

 

- in patients without a functional CYP2C19 allele, close clinical and laboratory monitoring of voriconazole-associated adverse events is recommended.

 

If genotyping is not feasible, full monitoring of safety and efficacy should be performed.

Voriconazole 50 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily)

 

Subjects without a functional CYP2C19 allele.

 

Voriconazole AUC ↑561% (↑451% ↑699%)

Voriconazole Cmax ↑438% (↑355% ↑539%)

Voriconazole Cmin ↑765% (↑571% ↑1,020%)

 

 

Atazanavir AUC ↓20% (↓35% ↓3%)

Atazanavir Cmax ↓19% (↓34% ↔0.2%)

Atazanavir Cmin ↓ 31 % (↓46 % ↓13%)

 

 

Ritonavir AUC ↓11% (↓20% ↓1%)

Ritonavir Cmax ↓11% (↓24% ↑4%)

Ritonavir Cmin ↓19% (↓35% ↑1%)

 

In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected.

 

Fluconazole 200 mg once daily

(atazanavir 300 mg and ritonavir 100 mg once daily)

Atazanavir and fluconazole concentrations were not significantly modified when REYATAZ/ritonavir was co-administered with fluconazole.

No dosage adjustments are needed for fluconazole and REYATAZ.

ANTIMYCOBACTERIAL

Rifabutin 150 mg twice weekly

(atazanavir 300 mg and ritonavir 100 mg once daily)

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.

When given with REYATAZ, 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.

Rifampicin

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.

The combination of rifampicin and REYATAZ is contraindicated (see section 4.3).

ANTIPSYCOTICS

Quetiapine

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

Co-administration of quetiapine with REYATAZ is contraindicated as REYATAZ may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma (see section 4.3).

ACID REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir disoproxil fumarate

In HIV-infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg once daily

For patients not taking tenofovir disoproxil fumarate, 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 (e.g., 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.

Famotidine 20 mg twice daily

Atazanavir AUC ↓18% (↓25% ↑1%)

Atazanavir Cmax ↓20% (↓32% ↓7%)

Atazanavir Cmin ↔1% (↓16% ↑18%)

Famotidine 40 mg twice daily

Atazanavir AUC ↓23% (↓32% ↓14%)

Atazanavir Cmax ↓23% (↓33% ↓12%)

Atazanavir Cmin ↓20% (↓31% ↓8%)

In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg once daily

Famotidine 40 mg twice daily

Atazanavir AUC ↔3% (↓14% ↑22%)

Atazanavir Cmax ↔2% (↓13% ↑8%)

Atazanavir Cmin ↓14% (↓32% ↑8%)

With Tenofovir disoproxil fumarate 300 mg once daily

In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily

For patients who are taking tenofovir disoproxil fumarate, if REYATAZ/ritonavir with both tenofovir disoproxil fumarate and an H2-receptor antagonist are co-administered, a dose increase of REYATAZ to 400 mg with 100 mg of ritonavir is recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.

Famotidine 20 mg twice daily

Atazanavir AUC ↓21% (↓34% ↓4%) *

Atazanavir Cmax ↓21% (↓36% ↓4%) *

Atazanavir Cmin ↓19% (↓37% ↑5%) *

 

Famotidine 40 mg twice daily

Atazanavir AUC ↓24% (↓36% ↓11%)*

Atazanavir Cmax ↓23% (↓36% ↓8%) *

Atazanavir Cmin ↓25% (↓47% ↑7%) *

 

In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400/100 mg once daily

Famotidine 20 mg twice daily

Atazanavir AUC ↑18% (↑6.5% ↑30%)*

Atazanavir Cmax ↑18% (↑6.7% ↑31%)*

Atazanavir Cmin ↑24 % (↑10% ↑39%)*

 

Famotidine 40 mg twice daily

Atazanavir AUC «2.3% (↓13% ↑10%)*

Atazanavir Cmax «5% (↓17% ↑8.4%)*

Atazanavir Cmin «1.3% (↓10% ↑15)*

 

 

* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir disoproxil fumarate, atazanavir concentrations are expected to be additionally decreased by about 20%.

 

The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers.

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 ↓61% (↓65% ↓55%)

Atazanavir Cmax ↓66% (↓62% ↓49%)

Atazanavir Cmin ↓65% (↓71% ↓59%)

 

Co-administration of REYATAZ with ritonavir and proton pump inhibitors is not recommended. If the combination is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of 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 ↓30% (↓43% ↓14%) *

Atazanavir Cmax ↓31% (↓42% ↓17%) *

Atazanavir Cmin ↓31% (↓46% ↓12%) *

 

* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily.

The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of 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.

 

Antacids

Antacids and medicinal products containing buffers

Reduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids, including buffered medicinal products, are administered with REYATAZ.

REYATAZ should be administered 2 hours before or 1 hour after antacids or buffered medicinal products.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Potential for increased alfuzosin concentrations which can result in hypotension. The mechanism of interaction is CYP3A4 inhibition by REYATAZ and/or ritonavir.

Co-administration of alfuzosin with REYATAZ is contraindicated (see section 4.3)

ANTICOAGULANTS

Warfarin

Co-administration with REYATAZ has the potential to increase or decrease warfarin concentrations.

It is recommended that the International Normalised Ratio (INR) be monitored carefully during treatment with REYATAZ, especially when commencing therapy.

ANTIEPILEPTICS

Carbamazepine

REYATAZ may increase plasma levels of carbamazepine due to CYP3A4 inhibition.

Due to carbamazepine inducing effect, a reduction in REYATAZ exposure cannot be ruled out.

Carbamazepine should be used with caution in combination with REYATAZ. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's virologic response should be excercised.

Phenytoin, phenobarbital

Ritonavir may decrease plasma levels of phenytoin and/or phenobarbital due to CYP2C9 and CYP2C19 induction.

Due to phenytoin/phenobarbital inducing effect, a reduction in REYATAZ exposure cannot be ruled out.

Phenobarbital and phenytoin should be used with caution in combination with REYATAZ/ritonavir.

 

When REYATAZ/ritonavir is co-administered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.

 

Close monitoring of patient's virologic response should be exercised.

Lamotrigine

Co-administration of lamotrigine and REYATAZ/ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.

 

 

Lamotrigine should be used with caution in combination with REYATAZ/ritonavir.

 

If necessary, monitor lamotrigine concentrations and adjust the dose accordingly.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Irinotecan

Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.

If REYATAZ is co-administered with irinotecan, patients should be closely monitored for adverse events related to irinotecan.

Immunosuppressants

Cyclosporin

Tacrolimus

Sirolimus

 

Concentrations of these immunosuppressants may be increased when co-administered with REYATAZ due to CYP3A4 inhibition.

More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone,

Systemic lidocaine,

Quinidine

Concentrations of these antiarrhythmics may be increased when co-administered with REYATAZ 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.

Caution is warranted and therapeutic concentration monitoring is recommended when available. The concomitant use of quinidine is contraindicated (see section 4.3).

Calcium channel blockers

Bepridil

REYATAZ 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 contraindicated (see section 4.3)

Diltiazem 180 mg once daily

(atazanavir 400 mg once daily)

Diltiazem AUC ↑125% (↑109% ↑141%)

Diltiazem Cmax ↑98% (↑78% ↑119%)

Diltiazem Cmin ↑142% (↑114% ↑173%)

 

Desacetyl-diltiazem AUC ↑165% (↑145% ↑187%)

Desacetyl-diltiazem Cmax ↑172% (↑144% ↑203%)

Desacetyl-diltiazem Cmin ↑121% (↑102% ↑142%)

 

No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. Co-administration of diltiazem and REYATAZ/ritonavir has not been studied. 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.

Verapamil

Serum concentrations of verapamil may be increased by REYATAZ due to CYP3A4 inhibition.

Caution should be exercised when verapamil is co-administered with REYATAZ.

CORTICOSTEROIDS

Fluticasone propionate intranasal 50 µg 4 times daily for 7 days

(ritonavir 100 mg capsules twice daily)

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 REYATAZ/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.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil

Sildenafil, tadalafil and vardenafil are metabolised by CYP3A4. Co-administration with REYATAZ may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-associated adverse events, including hypotension, visual changes, and priapism. The mechanism of this interaction is CYP3A4 inhibition.

Patients should be warned about these possible side effects when using PDE5 inhibitors for erectile dysfunction with REYATAZ (see section 4.4).

Also see PULMONARY ARTERIAL HYPERTENSION in this table for futher information regarding co-administration of REYATAZ with sildenafil.

HERBAL PRODUCTS

St. John’s wort (Hypericum perforatum)

Concomitant use of St. John's wort with REYATAZ may be expected to result in significant reduction in plasma levels of atazanavir. This effect may be due to an induction of CYP3A4. There is a risk of loss of therapeutic effect and development of resistance (see section 4.3).

Co-administration of REYATAZ with products containing St. John's wort is contraindicated.

HORMONAL CONTRACEPTIVES

Ethinyloestradiol 25 μg + norgestimate

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Ethinyloestradiol AUC ↓19% (↓25% ↓13%)

Ethinyloestradiol Cmax ↓16% (↓26% ↓5%)

Ethinyloestradiol Cmin ↓37% (↓45% ↓29%)

 

Norgestimate AUC ↑85% (↑67% ↑105%)

Norgestimate Cmax ↑68% (↑51% ↑88%)

Norgestimate Cmin ↑102% (↑77% ↑131%)

 

While the concentration of ethinyloestradiol was increased with atazanavir given alone, due to both UGT and CYP3A4 inhibition by atazanavir, the net effect of atazanavir/ritonavir is a decrease in ethinyloestradiol levels because of the inducing effect of ritonavir.

 

The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.

If an oral contraceptive is administered with REYATAZ/ritonavir, it is recommended that the oral contraceptive contain at least 30 μg of ethinyloestradiol and that the patient be reminded of strict compliance with this contraceptive dosing regimen. Co-administration of REYATAZ/ritonavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate has not been studied, and therefore should be avoided. An alternate reliable method of contraception is recommended.

Ethinyloestradiol 35 µg + norethindrone
(atazanavir 400 mg once daily)

Ethinyloestradiol AUC ↑48% (↑31% ↑68%)

Ethinyloestradiol Cmax ↑15% (↓1% ↑32%)

Ethinyloestradiol Cmin ↑91% (↑57% ↑133%)

 

Norethindrone AUC ↑110% (↑68% ↑162%)

Norethindrone Cmax ↑67% (↑42% ↑196%)

Norethindrone Cmin ↑262% (↑157% ↑409%)

 

The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.

LIPID LOWERING AGENTS

HMG-CoA reductase inhibitors

Simvastatin

Lovastatin

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

Co-administration of simvastatin or lovastatin with REYATAZ is contraindicated due to an increased risk of myopathy including rhabdomyolysis. (see section 4.3).

Atorvastatin

The risk of myopathy including rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.

Co-administration of atorvastatin with REYATAZ is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring (see section 4.4).

Pravastatin

Fluvastatin

Although not studied, there is a potential for an increase in pravastatin or fluvastatin exposure when co-administered with protease inhibitors. Pravastatin is not metabolised by CYP3A4. Fluvastatin is partially metabolised by CYP2C9.

Caution should be exercised.

INHALED BETA AGONISTS

Salmeterol

Co-administration with REYATAZ may result in increased concentrations of salmeterol and an increase in salmeterol-associated adverse events.

 

The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

Co-administration of salmeterol with REYATAZ is not recommended (see section 4.4).

OPIOIDS

Buprenorphine, once daily, stable maintenance dose

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Buprenorphine AUC ↑67%

Buprenorphine Cmax ↑37%

Buprenorphine Cmin ↑69%

 

Norbuprenorphine AUC ↑105%

Norbuprenorphine Cmax ↑61%

Norbuprenorphine Cmin ↑101%

 

The mechanism of interaction is CYP3A4 and UGT1A1 inhibition.

Concentrations of atazanavir (when given with ritonavir) were not significantly affected.

Co-administration with REYATAZ with ritonavir warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.

Methadone, stable maintenance dose

(atazanavir 400 mg once daily)

No significant effect on methadone concentrations was observed. Given that low dose ritonavir (100 mg twice daily) has been shown to have no significant effect on methadone concentrations, no interaction is expected if methadone is co-administered with REYATAZ, based on these data.

No dosage adjustment is necessary if methadone is co-administered with REYATAZ.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with REYATAZ may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-inhibitor-associated adverse events.

 

The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

 

A safe and effective dose in combination with REYATAZ has not been established for sildenafil when used to treat pulmonary arterial hypertension. Sildenafil, when used for the treatment of pulmonary arterial hypertension, is contraindicated (see section 4.3).

SEDATIVES

Benzodiazepines

Midazolam

Triazolam

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

Co-administration of REYATAZ with triazolam or orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with co-administration of REYATAZ and parenteral midazolam. If REYATAZ is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen (see section 4.4)

The same recommendations for drug drug interactions would apply except:


§
that co-administration is not recommended with tenofovir, boceprevir, carbamazepine, phenytoin, phenobarbital, proton pump inhibitors, and buprenorphine.

§ that co-administration with famotidine is not recommended but if required, atazanavir without ritonavir should be administered either 2 hours after famotidine or 12 hours before. No single dose of famotidine should exceed 20 mg, and the total daily dose of famotidine should not exceed 40 mg.

§ the need to consider that

§ co-administration of voriconazole and REYATAZ without ritonavir may affect atazanavir concentrations

§ co-administration of fluticasone and REYATAZ without ritonavir may increase fluticasone concentrations relative to fluticasone given alone

§ if an oral contraceptive is administered with REYATAZ without ritonavir, it is recommended that the oral contraceptive contain no more than 30 μ of ethinyloestradiol

§ no dose adjustment of lamotrigine is required


4.7 Effects on ability to drive and use machines

No studies on effects of REYATAZ on the ability to drive and use machines have been performed.
Patients should be informed that dizziness has been reported during treatment with regimens containing REYATAZ (see section 4.8).


 

5.1     Pharmacodynamic properties

Data on withdrawal of ritonavir from atazanavir boosted regimen (see also section 4.4)

Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with REYATAZ 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted REYATAZ 400 mg

once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with REYATAZ + ritonavir and two NRTIs (n=85) in HIV infected subjects with fully suppressed HIV replication, as assessed by the proportion of subjects with HIV RNA < 50 copies/ml: 78% of subjects on unboosted REYATAZ and two NRTIs compared with 75% on REYATAZ + ritonavir and two NRTIs.

Eleven subjects (13%) in the unboosted REYATAZ group and 6 (7%) in the REYATAZ + ritonavir group, had virologic rebound. Four subjects in the unboosted REYATAZ group and 2 in the REYATAZ + ritonavir group had HIV RNA > 500 copies/ml during the maintenance phase. No subject in either group showed emergence of protease inhibitor resistance. The M184V substitution in reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in 2 subjects in the unboosted REYATAZ and 1 subject in the REYATAZ + ritonavir group.

There were fewer treatment discontinuations in the unboosted REYATAZ group (1 vs. 4 subjects in the REYATAZ + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted REYATAZ group compared with the REYATAZ + ritonavir group (18 and 28 subjects, respectively).

 

5.2 Pharmacokinetic properties

 

In HIV-infected patients (n=13), multiple dosing of REYATAZ 400 mg (without ritonavir) once daily with food produced a geometric mean (CV%) for atazanavir Cmax of 2298 (71) ng/ml, with time to Cmax of approximately 2.0 hours. The geometric mean (CV%) for atazanavir Cmin and AUC were 120 (109) ng/ml and 14874 (91) ng•h/ml, respectively.




Special  populations

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. REYATAZ (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

 

10. DATE OF REVISION OF THE TEXT

 

October 2015

Updated on 28 May 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

In section 4.4 the following text has been added :

Cholelithiasis

Cholelithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

 

 

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. In some cases, nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

In section 4.8  the folowing in red has been added :

renal and urinary disorders:

uncommon: nephrolithiasisa, hematuria, proteinuria, pollakiuria, interstitial nephritis;

rare: kidney pain

 


In section 10 the date has been updated to  
April 2014

Updated on 11 April 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

WS-539 variation-This procedure was submitted following the CHMP Class Labelling to update within 2 month our RETAYAZ PI (SmPC section 4.4 Warnings and Precautions and PIL section 1 What Reyataz is and what it is used for) to update information regarding the risk of HIV transmission.

Following text inserted for section 4.4:

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Updated on 15 January 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

A typo has been identified and corrected in Section 4.5. All other changes that were associated with the updated dated 25th November still apply.
The following text has changed: "Due to ohenitoine/phenobarbital..." to "Due to phenitoine/phenobarbital ..."

Updated on 19 December 2013 SmPC

Reasons for updating

  • Removal of black triangle
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Type-II-89 variation aiming to update the Reyataz PI (SmPC section 4.5 Interaction with other medicinal products and other forms of interaction and PIL section 2 Other medicines and Reyataz) with DDI information on several antiepileptic medicines (carbamazepine, phenytoin, phenobarbital and lamotrigine). This variation also includes the quetiapine contra-indication.

 

In addition Section 4.8 was updated to include the most up to date adverse event reporting safety information and Section 10 to update the revision of the text.

Updated on 7 November 2013 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
  • Removal of black triangle
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Type-II-89 variation aiming to update the Reyataz PIL (section 2 Interaction with other medicinal products and other forms of interaction and PIL section 2 Other medicines and Reyataz) with DDI information on several antiepileptic medicines (carbamazepine, phenytoin, phenobarbital and lamotrigine). This variation also includes the quetiapine contra-indication.

 

In addition Section 4.8 was updated to include the most up to date adverse event reporting safety information and Section 10 to update the revision of the text.

 

Updated on 9 August 2013 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Omission of a footnote in Section 1. The following footnote has now been inserted:

* Intensive monitoring is requested only when used for the recently-licensed indication extension to paediatric patients.



Updated on 25 June 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Variation 087 was to update Section 4.8 Undesirable effects of the SmPC and Section 4 Possible side effects of the PI, with Angioedema as an uncommon adverse event, following the CHMP endorsed PRAC recommendation received on December 17th to perform a cumulative review of angioedema and anaphylactic reaction associated with atazanavir.

The class labeling variation was to amend sections 4.4 Special warnings and precautions for use and 4.8 Undesirable effects of the SmPC and section 2 of the Package Leaflet to include information regarding autoimmune disorders under Immune Reactivation Syndrome (IRS).

Updated on 3 May 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

This amendment encompasses:

·         Section 4.4 Special warnings and precautions for use

o   Revise the warning and update drug-drug interaction (DDI) study results (Study AI424383) for the co-administration of atazanavir/ritonavir with voriconazole

·         Section 4.5 Interaction with other medicinal products and other forms of interaction

 

o   Revise the warning and update drug-drug interaction (DDI) study results (Study AI424383) for the co-administration of atazanavir/ritonavir with voriconazole

·         Section 6.1 List of excipients

o   Re-arrangement of excipients to aid clarity


·        
Section 10 Date of Revision of Text

o   Updated to reflect revision date

Updated on 17 December 2012 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Correction of pack sizes and presentations sold.

Updated on 5 September 2012 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 Sections 4.3, 4.4 and 4.5 of the SmPC  have been updated to include information about drug interactions with Reyataz and some statins (simavastatin, lovastatin, pravastatin and fluvastatin)

 

Updated on 11 July 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update to section 4.4 and 4.5 of the SmPC.

Updated on 19 April 2012 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.5 has been updated to include information about drug interactions with Reyataz and Boceprevir.

Updated on 2 December 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
  • Addition of legal category

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.2: addition of subheadings - Posology, Paediatric populations, Special populations and Pregnancy and Postpartum. Updates to Table 1 and subsections - paediatric patients (less than 6 years of age) and addition of text for pregnancy and postpartum subsection.
 
Section 4.5: deletion of text "<->", twice daily as "BID" and once daily as "QD")."<->". Replacement of Table 2.

Section 4.6: Update to section title "Fertility, pregnancy and lactation", addition of subheadings - "Pregnancy", "Breast-feeding" and "Fertility". Text updated under each subsection.

Section 4.7: deletion of "No studies on the effects on the ability to drive and use machines have been performed."

Section 4.8: addtion of subheadings - "a. Summary of the safety profile"; "b. Tabulated list of adverse reactions"; "c. Dscription of selected adverse reactions", "d. Paediatric population" and "e. Other sepcial populations". entire section has been reformatted to add relevant text under each subsection.

Section 5.1: addition of final paragraph "The European Medicines Agency has waived the obligation to submit the results of studies with Reyataz hard capsules in all subsets of the paediatric population in treatment of immunodeficiency virus (HIV-1) infection (see section 4.2 for information on paediatric use).

Section 5.2: addtion of subheadings "Pregnancy" and "Paediatric population". Paediatric text under "Specific populations moved to new  Paediatric subsection. Addition of pregnancy subsection.

Section 6.5: updated to reflect details for product marketed in the UK.

Section 8: updated to reflect details for product marketed in the UK.

Section 10: Updated to reflect approval date of change

Addition of Legal category: POM

Updated on 9 September 2011 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4 and 4.8 have been updated following EMA approval of a Type II variation. This includes the addition of Steven Johnson Syndrome.

Updated on 31 May 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The following text has been deleted from the section 4.2 of the SPC:

Method of administration: for oral administration. The capsules should be swallowed whole. REYATAZ oral powder is available for adult patients who are unable to swallow capsules (see Summary of Product Characteristics for REYATAZ oral powder). REYATAZ oral powder must not be used in paediatric patients unable to swallow capsules due to insufficient data on pharmacokinetics, safety, and efficacy.


The followign text has been deleted from section 5.2:

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non linear disposition. In healthy subjects, the AUC of atazanavir from the capsules and oral powder were similar

Updated on 8 April 2011 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The following text ahs been added to the SPC

SPC:

 

Section 4.3

The following text has been added:

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.

 

 

Section 4.4

The following text has been added

 

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.

 

Section 4.5

The following  text has been added:

 

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Potential for increased alfuzosin concentrations which can result

Co-administration of

 

in hypotension. The mechanism of interaction is CYP3A4

REYATAZ/ritonavir

 

inhibition by atazanavir/ritonavir.

with alfuzosin is contraindicated (see section 4.3)

 

PDE5 Inhibitors

Sildenafil, tadalafil,

Sildenafil, tadalafil, and vardenafil are metabolised by CYP3A4.

Patients should be

vardenafil

Co-administration with REYATAZ/ritonavir may result in

warned about these

 

increased concentrations of the PDE5 inhibitor and an increase in

possible side effects

 

PDE5-associated adverse events, including hypotension, visual

when using PDE5

 

changes, and priapism. The mechanism of this interaction is

inhibitors for erectile

 

CYP3A4 inhibition.

dysfunction with REYATAZ/ritonavir (see section 4.4). Also see

 

 

PULMONARY

 

 

ATERIAL

 

 

HYPERTENSION

 

 

in this table for

 

 

futher information

 

 

regarding co-administration of

 

 

REYATAZ/ritonavir with sildenafil.

 

 

INHALED BETA AGONISTS

Salmeterol

Co-administration with REYATAZ/ritonavir may result in

Co-administration of

 

increased concentrations of salmeterol and an increase in

salmeterol with

 

salmeterol-associated adverse events.

REYATAZ/ritonavir is not recommended

 

The mechanism of interaction is CYP3A4 inhibition by atazanavir/ritonavir.

(see section 4.4).

 

 

 

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with REYATAZ/ritonavir may result in

A safe and effective

 

increased concentrations of the PDE5 inhibitor and an increase in

dose in combination

 

PDE5-inhibitor-associated adverse events.

with

 

 

REYATAZ/ritonavir

 

The mechanism of interaction is CYP3A4 inhibition by

has not been

 

atazanavir/ritonavir.

established for sildenafil when used

 

 

to treat pulmonary arterial hypertension. Sildenafil, when

 

 

used for the

treatment of

pulmonary arterial

hypertension, is

contraindicated (see

section 4.3).

 

Updated on 19 October 2010 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The following text has been added to section 4.5 of the SPC:

Integrase Inhibitors

Raltegravir 400 mg BID

(atazanavir/ritonavir)

raltegravir

↑ 41%

↑ 24%

C12hr↑ 77%

No dose adjustment required for Isentress.

 

The mechanism is UGT1A1 inhibition.

 

Updated on 12 August 2010 SmPC

Reasons for updating

  • Change to paediatric information
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

new paediatric inidcation approved

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 (³ 4 PI mutations). There are very limited data available from children aged 6 to less than 18 years (see sections 4.4 and 5.1).

 

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

 

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 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

Body Weight (kg)

REYATAZ dose

ritonavir dosea

15 to less than 20

150 mg

100 mgb

20 to less than 40

200 mg

100 mg

at least 40

300 mg

100 mg

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): REYAYAZ is not recommended in paediatric patients less than 6 years of age due to insufficient data on pharmacokinetics, safety, and efficacy. REYATAZ has not been studied in children less than 3 months of age and is not recommended especially taking into account the potential risk of kernicterus.

 

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).

 

Method of administration: for oral administration. The capsules should be swallowed whole. REYATAZ oral powder is available for adult patients who are unable to swallow capsules (see Summary of Product Characteristics for REYATAZ oral powder). REYATAZ oral powder must not be used in paediatric patients unable to swallow capsules due to insufficient data on pharmacokinetics, safety, and efficacy.


4.4 Warnings and precautions

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 ³4 PI mutations, in treatment experienced children even lower numbers of PI mutations may be predictive of a lack of benefit (see section 5.1).



Updated on 9 April 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4 spc add :

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).

Section 4.5 spc add:

Rifabutin 150 mg twice weekly

(atazanavir 300 mg and ritonavir 100 mg QD)

rifabutin

↑1.48 **

(1.19, 1.84)

↑2.49 **

(2.03, 3.06)

↑1.40 **

(1.05, 1.87)

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 recommeded 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.

** When compared to rifabutin 150 mg QD alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC: ↑2.19 (1.78, 2.69).

 

In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.

Updated on 25 January 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

 

 

The concomitant use of REYATAZ and oral contraceptives should be avoided (see section 4.5).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Table 1: Interactions between REYATAZ and other medicinal products

 

Co‑administered medicinal products (dose in mg)

Medicinal product assessed

AUC

(90% CI)

Cmax

(90% CI)

Cmin

(90% CI)

 

 

Recommendations concerning co‑administration

HORMONAL CONTRACEPTIVES

 

 

 

 

Ethinyloestradiol 35 μg + norethindrone (atazanavir 400 mg QD)

ethinyloestradiol

↑1.48

(1.31, 1.68)

↑1.15

(0.99, 1.32)

↑1.91

(1.57, 2.33)

The co If an oral contraceptive is administered with REYATAZ/ritonavir, it is recommended that the oral contraceptive contain at least 30 μg of ethinyloestradiol and that the patient be reminded of the need for strict compliance with the contraceptive dosing regimen. Co-administration of REYATAZ/ritonavir and oral with other hormonal contraceptives should be avoided (see section 4.4). Alternateor oral contraceptives containing progestogens other than norethindrone or norgestimate has not been studied; therefore, alternate reliable methods of contraception should be considered.are recommended.

norethindrone

↑2.10

(1.68, 2.62)

↑1.67

(1.42, 1.96)

↑3.62

(2.57, 5.09)

The concentration of oral contraceptives was increased due to UGT inhibition. In contrast, ritonavir may decrease ethinyloestradiol concentrations. The effects of co-administration of oral contraceptives and REYATAZ/ritonavir have not been studied.

 

Ethinyloestradiol 25 μg + norgestimate (atazanavir 300 QD with ritonavir 100 mg QD)

ethinyloestradiol

↓0.81

(0.75, 0.87)

↓0.84

(0.74, 0.95)

↓0.63

(0.55, 0.71)

norgestimate

↑1.85

(1.67, 2.05)

↑1.68

(1.51, 1.88)

↑2.02

(1.77, 2.31)

The concentration of oral contraceptives was increased due to UGT inhibition. In contrast, ritonavir may decrease ethinyloestradiol concentrations. 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.

 

 

Updated on 28 August 2009 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



4.2     Posology and method of administration

 

Patients with renal impairment: no dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sectionsections 4.4 and 5.2).

 

4.4     Special warnings and precautions for use

 

Addition of:

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).

 

(.......)

 

Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.5).

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

(....)

 

Table 1: Interactions between REYATAZ and other medicinal products

 

ACID REDUCING AGENTS

H2‑Receptor antagonists

 

 

 

 

 

Famotidine 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.

Without Tenofovir

 

 

 

 

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 BID should not be exceeded. If a higher dose of an H2‑receptor antagonist is required (eg, famotidine 40 mg BID or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered.

In HIV‑infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg QD

 

 

 

‑ famotidine 20 mg BID

atazanavir

↓0.82

(0.75, 1.01)

 

↓0.80

(0.68, 0.93)

 

↔0.99

(0.84, 1.18)

 

‑ famotidine 40 mg BID

 atazanavir

↓0.77

(0.68, 0.86)

 

↓0.77

(0.67, 0.88)

 

↓0.80

(0.69, 0.92)

 

In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg QD

 

 

 

‑ famotidine 40 mg BID

atazanavir

↔1.03

(0.86, 1.22)

 

↔1.02

(0.87, 1.18)

 

↓0.86

(0.68, 1.08)

 

With Tenofovir 300 mg QD

 

 

 

 

 

In HIV‑infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg QD

 

 

 

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.

 

 

‑ famotidine 20 mg BID

atazanavir

↓0.79*

(0.66, 0.96)

 

↓0.79*

(0.64, 0.96)

 

↓0.81*

(0.63, 1.05)

 

‑ famotidine 40 mg BID

atazanavir

↓0.76*

(0.64, 0.89)

 

↓0.77*

(0.64, 0.92)

 

↓0.75*

(0.53, 1.07)

 

 

* When compared to atazanavir 300 mg QD with ritonavir 100 mg QD 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.

 

 

Proton pump inhibitors

 

 

 

 

 

Omeprazole 40 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)

 

atazanavir (am): 2 hr after omeprazole

0.39

(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 exceeded (see section 4.4).

 

 

 

 

 

Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)

Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)

 

 

 

atazanavir (am): 1 hr after omeprazaoleomeprazole

↓0.70*

(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 QD

 

 

The 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.

 

 

4.8     Undesirable effects

 

REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 48 96°weeks median duration and 101108 weeks maximum duration).

 

(.....)

 

Laboratory abnormalities

The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (8487% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 35% (537% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3‑4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 4896 weeks, 3948% had Grade 3‑4 total bilirubin elevations (see section 4.4).

 

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 creatine kinase (7%), elevated alanine aminotransferase/serum glutamic‑pyruvic transaminase (ALT/SGPT) (45%), low neutrophils (45%), elevated aspartate aminotransferase/serum glutamic‑oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (23%).

 

OneTwo percent of patients treated with REYATAZ experienced concurrent Grade 3‑4 ALT/AST and Grade 3‑4 total bilirubin elevations.

 

 

5.1     Pharmacodynamic properties

 

Antiviral activity in vitro: atazanavir exhibits anti‑HIV‑1 activity (EC50 of 2 to 5 nM) in the absence of human serum against a variety of laboratory(including all clades tested) and clinical anti‑HIV isolates. Atazanavir has‑2 activity against HIV‑1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has activity against HIV‑2 isolates (EC50 of 1.9 to 32 nM). Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, amprenavir, did not result in antagonistic anti‑HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation.

 

Resistance

Antiretroviral treatment naive patients

In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.

 

Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks)

Frequency

de novo PI substitution (n=26)a

>20%

none

10-20%

none

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

 

The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

 

Antiretroviral treatment experienced patients

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.

 

Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks)

Frequency

de novo PI substitution (n=35)a,b

>20%

M36, M46, I54, A71, V82

10-20%

L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)

 

 

None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.

 

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors.

 

Cross‑resistance in vitro in viruses resistant to other protease inhibitors

Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors.

Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir.

 

Clinical results

In antiretroviral naive patients

Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response.

In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%].

 

 (Table 2: 4).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4).

 

Table 4:           Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a

Parameter

REYATAZ/ritonaviraritonavirb (300 mg/100 mg
once daily)

n=440

 

 

lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg
twice daily)

n=443

 

 

HIV RNA <50 copies/ml, % c

All patients

78

76

Baseline Characteristics

 

HIV RNA
  <100,000 copies/ml

82 (n=217d)

81 (n=218)

 

  ≥100,000 copies/ml

74 (n=223)

72 (n=225)

 

CD4 count
  <50 cells/mm3

78 (n=58)

63 (n=48)

 

  50 to <100 cells/mm3

76 (n=45)

69 (n=29)

 

  100 to <200 cells/mm3

75 (n=106)

78 (n=134)

 

  ≥200 cells/mm3

80 (n=222)

80 (n=228)

 

Week 48

Week 96

Week 48

Week 96

HIV RNA <50 copies/ml, %

All patientsd

78

74

76

68

Difference estimate

    [95% CI]d

Week 48: 1.7% [-3.8%, 7.1%]

Week 96: 6.1% [0.3%, 12.0%]

Per protocol analysise

86

(n=392f)

91

(n=352)

89

(n=372)

89

(n=331)

Difference estimatee

     [95% CI]

Week 48: -3% [-7.6%, 1.5%]

Week 96: 2.2% [-2.3%, 6.7%]

HIV RNA <50 copies/ml, % by Baseline Characteristicd  

HIV RNA
    <100,000 copies/ml

82 (n=217)

75 (n=217)

81 (n=218)

70 (n=218)

    ≥100,000 copies/ml

74 (n=223)

74 (n=223)

72 (n=225)