Ataben 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 (see section 4.2).

Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations).

The choice of Ataben capsules, 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).

Therapy should be initiated by a physician experienced in the management of HIV infection. Posology

Adults

 

The recommended dose of Ataben 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).

Paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg)

 

The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. Ataben 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 and weighing at least 15 kg) for Ataben with ritonavir
Body Weight (kg)	Ataben once daily dose	Ritonavir once daily dosea
15 to less than 35	200 mg	100mg

 

 

at least 35	300 mg	100mg
Ritonavir capsules, tablets or oral solution.

Paediatric patients (at least 3 months of age and weighing at least 5 kg): Ataben oral powder is available for paediatric patients at least 3 months of age and weighing at least 5 kg (see Summary of Product Characteristics for Ataben oral powder).

Switching to Ataben capsules from Ataben oral powder is encouraged as soon as patients are able to consistently swallow capsules.

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation (see Summary of Product Characteristics for Ataben oral powder).

Special populations Renal impairment

No dosage adjustment is needed. Ataben with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).

Hepatic impairment

Ataben with ritonavir has not been studied in patients with hepatic impairment Ataben with ritonavir should be used with caution in patients with mild hepatic impairment. Ataben with ritonavir must not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen (see section 4.4), unboosted Ataben 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 Ataben must not be used in patients with severe hepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

Ataben 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 or H -receptor antagonists).

▪  If tenofovir disoproxil or an H -receptor antagonist is needed, a dose increase to Ataben 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

▪   It is not recommended to use Ataben with ritonavir for pregnant patients who are receiving both Tenofovir disoproxil and an H -receptor antagonist. (See section 4.4 Withdrawal of ritonavir only under restrictive conditions).

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

During this time, postpartum patients should follow the same dose recommendation as for non- pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

 

Ataben should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.

Method of administration:

 

For oral use. The capsules should be swallowed whole.

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Ataben is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, 4.4 and 5.2). Ataben with ritonavir is contraindicated in patients with moderate hepatic insufficiency (see sections 4.2, 4.4 and 5.2). Co-administration with simvastatin or lovastatin (see section 4.5). Combination of rifampicin (see section 4.5). Combination of the PDE5 inhibitor sildenafil 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 sections 4.4 and 4.5. Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5). Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (see section 4.5). Co-administration with glecaprevir/pibrentasvir fixed dose combination (see section 4.5) Co-administration with products containing St. John's wort (Hypericum perforatum) (see section 4.5).

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.

Co-administration of Ataben with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).

 

 

Patients with coexisting conditions

 

Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The

safety and efficacy of Ataben has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Renal impairment: No dosage adjustment is needed in patients with renal impairment. However, Ataben is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

QT prolongation: Dose related asymptomatic prolongations in PR interval with Ataben have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), Ataben should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing Ataben in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action

 

 

has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

 

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

In clinical studies, Ataben (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators.

Hyperbilirubinaemia

 

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP- glucuronosyl transferase (UGT) have occurred in patients receiving Ataben (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Ataben should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to Ataben may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of Ataben and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Withdrawal of ritonavir only under restrictive conditions

 

The recommended standard treatment is Ataben boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.

 

 

The withdrawal of ritonavir from the boosted regimen of Ataben 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.

Ataben given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil 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.

Ataben 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. Cholelithiasis

Cholelithiasis has been reported in patients receiving Ataben (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.

Chronic kidney disease

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.8).

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving Ataben (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.

Immune reactivation syndrome

 

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occurs many months after initiation of treatment.

Osteonecrosis

 

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Rash and associated syndromes

 

Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with Ataben.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving Ataben. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. Ataben should be discontinued if severe rash develops.

 

 

The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of Ataben, Ataben may not be restarted.

Interactions with other medicinal products

 

The combination of Ataben with atorvastatin is not recommended (see section 4.5).

 

Co-administration of Ataben with nevirapine or efavirenz is not recommended (see section 4.5).

 

If the co-administration of Ataben with an NNRTI is required, an increase in the dose of both Ataben and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of Ataben 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 Ataben. Co-administration of Ataben with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and Ataben with ritonavir is not recommended, unless an assessment of the benefit/risk justifies the use of voriconazole.

In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected (see section 4.5).

Concomitant use of Ataben /ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5). Concomitant use of salmeterol and Ataben may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and Ataben is not recommended (see section 4.5).

 

 

The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.

Co-administration of Ataben with proton pump inhibitors is not recommended (see section 4.5). If the combination of Ataben with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of Ataben to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.

Co-administration of Ataben with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided (see section 4.5).

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), Ataben 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. Excipients

Lactose

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

 

When Ataben and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with Ataben and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, Ataben is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Co-administration of Ataben with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevir concentrations (see section 4.3). Co- administration of Ataben with glecaprevir/pibrentasvir fixed dose combination is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecapreir and pibrentasvir plasma concentrations (see section 4.3).

Other interactions

 

Interactions between atazanavir and other medicinal products are listed in the table 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 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).

 

 

Table 2: Interactions between Ataben and other medicinal products

 

Medicinal      products     by therapeutic area	Interaction	Recommendations concerning                      co- administration
ANTI-HCV AGENTS
Grazoprevir 200 mg once	Atazanavir    AUC   ↑43%    (↑30%	Co-administration              of
daily (atazanavir 300 mg /	↑57%)	Ataben                             and
ritonavir 100 mg once daily)	Atazanavir    Cmax    ↑12%    (↑1%	elbasvir/grazoprevir            is
	↑24%)	contraindicated because of a
	Atazanavir Cmin   ↑23%   (↑13%	significant       increase       in
	↑134%)	grazoprevir                 plasma
	Grazoprevir AUC: ↑958% (↑678%	concentrations       and      an
	↑1339%)	associated potential increase
	Grazoprevir        Cmax:        ↑524%	in     the     risk      of     ALT
	(↑342% ↑781%)	elevations (see section 4.3).
	Grazoprevir       Cmin:       ↑1064%
	(↑696% ↑1602%)
	Grazoprevir concentrations were
	greatly      increased      when     co-
	administered                             with
	atazanavir/ritonavir
Elbasvir 50 mg once daily	Atazanavir     AUC     ↑7%     (↓2%
(atazanavir      300      mg      /	↑17%)
ritonavir 100 mg once daily)	Atazanavir Cmax ↑2% (↓4% ↑8%)
	Atazanavir    Cmin    ↑15%    (↑2%
	↑29%)
	Elbasvir AUC:   ↑376%   (↑307%
	↑456%)
	Elbasvir Cmax: ↑315% (↑246%
	↑397%)

 

 

	Elbasvir Cmin: ↑545% (↑451% ↑654%) Elbasvir concentrations were increased when co-administered with atazanavir/ritonavir.
Sofosbuvir     400     mg     /	Sofosbuvir AUC : ↑40% (↑25%
velpatasvir         100        mg	↑57%)
/voxilaprevir 100 mg single	Sofosbuvir Cmax : ↑29% (↑9%
dose*	↑52%)
(atazanavir      300      mg      /	Velpatasvir AUC: ↑93% (↑58%
ritonavir 100 mg once daily)	↑136%)
	Velpatasvir Cmax : ↑29% (↑7%
	↑56%)
	Voxilaprevir      AUC     :     ↑331%
	(↑276% 393%)
	Voxilaprevir       Cmax:       ↑342%
	(↑265% ↑435%)
	*Lack       of       pharmacokinetics
	interaction bounds
	70-143%
	Effect on atazanavir and ritonavir
	exposure has not been studied.
	Expected:
	↔ Atazanavir
	↔ Ritonavir
	The    mechanism    of    interaction
	between Ataben /ritonavir and
	sofosbuvir/velpatasvir/voxilaprevir
	is inhibition of OATP1B, Pgp, and

 

 

	CYP3A.
Glecaprevir     300     mg     /	Glecaprevir      AUC     :      ↑553%	Co-administration              of
pibrentasvir 120 mg once	(↑424% ↑714%)	Ataben                           with
daily	Glecaprevir      Cmax     :     ↑306%	glecaprevir/pibrentasvir      is
(atazanavir      300      mg      /	(↑215% ↑423%)	contraindicated because of
ritonavir     100     mg     once	Glecaprevir     Cmin     :     ↑1330%	the potential increase in the
daily*)	(↑885% ↑1970%)	risk of ALT elevations due
	Pibrentasvir AUC : ↑64% (↑48%	to a significant increase  in
	↑82%)	glecaprevir and pibrentasvir
	Pibrentasvir Cmax : ↑29% (↑15%	plasma concentrations (see
	↑45%)	section 4.3)
	Pibrentasvir Cmin: ↑129% (↑95%
	↑168%)
	* Effect of atazanavir and ritonavir
	on the first dose of glecaprevir and
	pibrentasvir is reported.
ANTI-RETROVIRALS
Protease inhibitors: The co-administration of Ataben /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	Atazanavir AUC: ↑250% (↑144%	Ritonavir 100 mg once daily
daily	↑403%)*	is used   as   a   booster   of
(atazanavir    300   mg    once	Atazanavir Cmax: ↑120% (↑56%	atazanavir
daily)	↑211%)*	pharmacokinetics.
Studies conducted in HIV-	Atazanavir Cmin: ↑713% (↑359%
infected patients	↑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.
Indinavir	Indinavir is associated with indirect                                   unconjugated hyperbilirubinaemia due to inhibition of UGT.	Co-administration              of Ataben 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 Ataben is not expected to significantly alter the exposure of the co- administered medicinal products.
Abacavir	The co-administration of abacavir and Ataben 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%)	Didanosine should be taken at the fasted state 2 hours after Ataben taken with food. The co-administration of stavudine with Ataben is not expected to significantly alter the exposure of stavudine.

 

 

	Atazanavir concentrations were greatly decreased when co- administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets. No significant effect on didanosine and stavudine concentrations was observed.
Didanosine (enteric coated	Didanosine (with food)
capsules) 400   mg   single	Didanosine AUC   ↓34%   (↓41%
dose	↓27%)
(atazanavir    300   mg    once	Didanosine Cmax ↓38% (↓48%
daily with ritonavir 100 mg	↓26%)
once daily)	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	Atazanavir    AUC   ↓22%    (↓35%	When co-administered with
fumarate    300    mg    once	↓6%) *	tenofovir               disoproxil
daily	Atazanavir Cmax   ↓16%   (↓30%	fumarate, it is recommended
(atazanavir    300   mg    once	↔0%) *	that   Ataben   300    mg    be
daily with ritonavir 100 mg	Atazanavir Cmin   ↓23%   (↓43%	given with ritonavir 100 mg
once daily)	↑2%) *	and     tenofovir     disoproxil
300 mg tenofovir disoproxil	* In a combined analysis from	fumarate 300 mg (all as a
fumarate is   equivalent   to	several           clinical           studies,	single dose with food).

 

 

245 mg tenofovir disoproxil.	atazanavir/ritonavir 300/100   mg
Studies conducted in HIV-	co-administered    with    tenofovir
infected patients	disoproxil     fumarate     300     mg
	(n=39)       was       compared       to
	atazanavir/ritonavir 300/100   mg
	(n=33).
	The efficacy of Ataben /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.
Tenofovir             disoproxil	Tenofovir     disoproxil     fumarate	Patients should be closely
fumarate    300    mg    once	AUC ↑37% (↑30% ↑45%)	monitored     for     tenofovir
daily	Tenofovir     disoproxil     fumarate	disoproxil               fumarate-
(Atazanavir 300 mg once	Cmax ↑34% (↑20% ↑51%)	associated                 adverse
daily with ritonavir 100 mg	Tenofovir     disoproxil     fumarate	reactions,    including    renal
once daily)	Cmin ↑29% (↑21% ↑36%)	disorders.
300 mg tenofovir disoproxil
fumarate is   equivalent   to
245 mg tenofovir disoproxil.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz    600    mg    once	Atazanavir (pm): all administered	Co-administration of
daily (Atazanavir 400 mg	with food	efavirenz and Ataben is not
once daily with ritonavir 100	Atazanavir      AUC      ↔0%(↓9%	recommended (see section

 

 

mg once daily)	↑10%)*			4.4)
	Atazanavir	Cmax	↑17%(↑8%
	↑27%)*
	Atazanavir	Cmin	↓42%(↓51%
	↓31%)*
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 Ataben 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	Nevirapine    AUC ↑26%   (↑17%			Co-administration              of
daily	↑36%)			nevirapine and Ataben   is
(Atazanavir 400 mg once	Nevirapine Cmax ↑21% (↑11%			not      recommended      (see
daily with ritonavir 100 mg	↑32%)			section 4.4)
once daily)	Nevirapine Cmin   ↑35%   (↑25%
Study conducted in HIV	↑47%)
infected patients	Atazanavir    AUC   ↓19%    (↓35%
	↑2%) *

 

 

	Atazanavir Cmax   ↔2%   (↓15% ↑24%) * Atazanavir Cmin   ↓59%   (↓73% ↓40%) * * When compared to Ataben 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.
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.
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	No              recommendation regarding dose reduction can be made; therefore, caution should be exercised if Ataben is co-administered with clarithromycin.

 

 

	↓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.
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 Ataben/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, Ataben /ritonavir is expected            to            increase ketoconazole or itraconazole concentrations.
Voriconazole 200 mg twice	Voriconazole AUC ↓33% (↓42%	Co-administration              of
daily (Atazanavir             300	↓22%)	voriconazole     and    Ataben
mg/ritonavir 100 mg once	Voriconazole Cmax ↓10%   (↓22%	with      ritonavir      is      not
daily)	↓4%)	recommended     unless     an
Subjects with at least one	Voriconazole    Cmin ↓39%   (↓49%	assessment           of          the
functional CYP2C19 allele.	↓28%)	benefit/risk to the patient
	Atazanavir    AUC   ↓12%    (↓18%	justifies       the       use       of
	↓5%)	voriconazole    (see    section
	Atazanavir     Cmax ↓13%     (↓20%	4.4).
	↓4%)	At the   time   voriconazole
	Atazanavir Cmin ↓ 20 % (↓28 %	treatment    is    required,    a
	↓10%)	patient's                 CYP2C19
	Ritonavir    AUC    ↓12%    (↓17%	genotype         should         be
	↓7%)	performed if feasible.
	Ritonavir Cmax ↓9% (↓17% ↔0%)	Therefore if the combination
	Ritonavir       Cmin ↓25%       (↓35%	is         unavoidable,         the
	↓14%)	following recommendations
	In the majority of patients with at	are made according to the
	least    one    functional    CYP2C19	CYP2C19 status:
	allele,     a     reduction     in     both	- in patients with at least one
	voriconazole       and       atazanavir	functional CYP2C19 allele,
	exposures are expected.	close clinical monitoring for
		a loss of both voriconazole
Voriconazole 50 mg twice	Voriconazole        AUC       ↑561%	(clinical          signs)         and
daily (Atazanavir             300	(↑451% ↑699%)	atazanavir              (virologic
mg/ritonavir 100 mg once	Voriconazole Cmax ↑438% (↑355%	response)        efficacy        is

 

 

daily)				↑539%)	recommended.
Subjects	without		a	Voriconazole Cmin ↑765% (↑571%	-    in    patie	nts    without    a
functional CYP2C19 allele.				↑1,020%)	functional CYP2C19 allele,
				Atazanavir    AUC   ↓20%    (↓35%	close clinical and laboratory
				↓3%)	monitoring of voriconazole-
				Atazanavir     Cmax ↓19%     (↓34%	associated adverse events is
				↔0.2%)	recommended.
				Atazanavir Cmin ↓ 31 % (↓46 %	If genotyping is not feasible,
				↓13%)	full monitoring of safety and
				Ritonavir    AUC    ↓11%    (↓20%	efficacy	should         be
				↓1%)	performed.
				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				Atazanavir       and       fluconazole	No dosage adjustments are
daily				concentrations          were          not	needed for fluconazole and
(Atazanavir	300	mg	and	significantly       modified      when	Ataben
ritonavir 100 mg once daily)				Ataben      /ritonavir       was      co-
				administered with fluconazole.
ANTIMYCOBACTERIAL
Rifabutin   150 mg   twice				Rifabutin    AUC    ↑48%    (↑19%	When given with Ataben,
weekly				↑84%) **	the recommended dose of
(Atazanavir	300	mg	and	Rifabutin    Cmax ↑149%    (↑103%	rifabutin is 150 mg 3 times
ritonavir 100 mg once daily)				↑206%) **	per week on set days (for
				Rifabutin Cmin ↑40% (↑5% ↑87%)	example	Monday-

 

 

	**	Wednesday-Friday).
	25-O-desacetyl-rifabutin        AUC	Increased    monitoring     for
	↑990% (↑714% ↑1361%) **	rifabutin-associated adverse
	25-O-desacetyl-rifabutin	reactions                 including
	Cmax ↑677% (↑513% ↑883%) **	neutropenia and uveitis is
	25-O-desacetyl-rifabutin	warranted      due      to      an
	Cmin ↑1045% (↑715% ↑1510%) **	expected        increase        in
	** When compared to rifabutin	exposure       to       rifabutin.
	150 mg once daily alone. Total	Further dosage reduction of
	rifabutin      and     25-O-desacetyl-	rifabutin to 150 mg twice
	rifabutin    AUC    ↑119%    (↑78%	weekly    on    set    days    is
	↑169%).	recommended for patients in
	In       previous        studies,       the	whom the 150 mg dose 3
	pharmacokinetics     of    atazanavir	times    per    week    is    not
	was not altered by rifabutin.	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
		Ataben.
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	The combination of rifampicin and Ataben is contraindicated (see section 4.3).

 

 

		attempts to overcome the decreased exposure by increasing the dose of Ataben or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.
ANTIPSYCHOTICS
Quetiapine		Due to CYP3A4 inhibition	by	Co-administration              of
		Ataben,        concentrations	of	quetiapine with Ataben is
		quetiapine      are      expected	to	contraindicated as   Ataben
		increase.		may    increase     quetiapine-
				related   toxicity.    Increased
				plasma     concentrations    of
				quetiapine may lead to coma
				(see section 4.3).
Lurasidone		Ataben is expected to increase plasma levels of lurasidone due to CYP3A4 inhibition.		Co-administration              of lurasidone with Ataben is contra-ndicated as this may increase lurasidone-related toxicity (see section 4.3).
ACID REDUCING AGENTS
H2-Receptor antagonists
Without Tenofovir
In     HIV-infected    patients     with     atazanavir/ritonavir     at			the		For patients not taking
recommended dose 300/100 mg once daily					tenofovir, if Ataben 300
Famotidine 20 mg twice	Atazanavir AUC ↓18% (↓25% ↑1%)				mg/ritonavir 100 mg and
daily	Atazanavir Cmax ↓20% (↓32% ↓7%)				H2-receptor     antagonists
	Atazanavir Cmin ↔1% (↓16% ↑18%)				are    co-administered,    a
					dose       equivalent        to
Famotidine 40 mg twice	Atazanavir AUC ↓23% (↓32% ↓14%)
daily	Atazanavir Cmax ↓23% (↓33% ↓12%)				famotidine 20 mg twice

 

 

	Atazanavir Cmin ↓20% (↓31% ↓8%)				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 Ataben /ritonavir dose from 300/100 mg to 400/100 mg can be considered.
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 (equivalent to 245 mg tenofovir disoproxil)
In     HIV-infected    patients     with     atazanavir/ritonavir recommended dose of 300/100 mg once daily			at	the	For patients who are taking                tenofovir disoproxil fumarate, if Ataben /ritonavir with both tenofovir disoproxil fumarate and an H2- receptor antagonist are co-administered, a dose increase of Ataben 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 ↑30%)* Atazanavir ↑31%)* Atazanavir ↑39%)*	AUC     ↑18%     Cmax ↑18%     Cmin ↑24      %	(↑6.5% (↑6.7% (↑10%
Famotidine 40 mg twice	Atazanavir	AUC    ↔2.3%	(↓13%

 

 

daily	↑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	Atazanavir      (am):      2      hr      after	Co-administration
daily	omeprazole	ofAtaben    with ritonavir
(Atazanavir 400 mg once	Atazanavir AUC ↓61% (↓65% ↓55%)	and        proton        pump
daily with ritonavir 100 mg	Atazanavir Cmax ↓66% (↓62% ↓49%)	inhibitors          is          not
once daily)	Atazanavir Cmin ↓65% (↓71% ↓59%)	recommended.     If     the
Omeprazole 20 mg once	Atazanavir      (am):      1      hr      after	combination     is    judged
daily	omeprazole	unavoidable,             close
(Atazanavir 400 mg once	Atazanavir AUC ↓30% (↓43% ↓14%)	clinical     monitoring     is
daily with ritonavir 100 mg	*	recommended                in
once daily)	Atazanavir Cmax ↓31% (↓42% ↓17%)	combination      with     an
	*	increase in the dose of
	Atazanavir Cmin ↓31% (↓46% ↓12%)	Ataben   to 400 mg with

 

 

	*	100    mg    of    ritonavir;
	* When compared to atazanavir 300	doses of   proton   pump
	mg once daily with ritonavir 100 mg	inhibitors comparable to
	once daily.	omeprazole 20 mg should
	The decrease   in   AUC,   Cmax,   and	not    be    exceeded    (see
	Cmin was    not    mitigated    when    an	section 4.4).
	increased dose   ofAtaben   /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	Reduced plasma   concentrations   of	Ataben        should        be
products            containing	atazanavir may be the consequence of	administered     2     hours
buffers	increased    gastric    pH    if    antacids,	before or 1 hour after
	including         buffered        medicinal	antacids      or      buffered
	products,     are     administered     with	medicinal products.
	Ataben.
ALPHA 1-ADRENORECEPTOR ANTAGONIST
Alfuzosin	Potential for increased alfuzosin concentrations which can result in hypotension.    The    mechanism    of interaction is CYP3A4 inhibition by	Co-administration of alfuzosin with Ataben is contraindicated (see section 4.3)

 

 

	Ataben and/or ritonavir.
ANTICOAGULANTS
Direct-acting oral anticoagulants (DOACs)
Apixaban Rivaroxaban	Potential for increased apixaban and rivaroxaban concentrations which can result in a higher risk of bleeding. The mechanism of interaction is inhibition of CYP3A4 / and P-gp by REYATAZ/ritonavir. Ritonavir is a strong inhibitor of both CYP3A4 and P-gp. REYATAZ is an inhibitor of CYP3A4. The potential inhibition of P-gp by REYATAZ is unknown and cannot be excluded.	Co-administration of apixaban or rivaroxaban and REYATAZ with ritonavir is not recommended
Dabigatran	Potential for increased dabigatran concentrations which can result in a higher risk of bleeding. The mechanism of interaction is P-gp inhibition. Ritonavir is a strong P-gp inhibitor. Potential P-gp inhibition by Ataben is unknown and cannot be excluded.	Co-administration of dabigatran and Ataben with ritonavir is not recommended.
Edoxaban	Potential for increased edoxaban concentrations which can result in a higher risk of bleeding. The mechanism of interaction is P-gp inhibition by Ataben /ritonavir. Ritonavir is a strong P-gp inhibitor.	Exercise caution when edoxaban is used with Ataben. Please refer to edoxaban SmPC section 4.2 and 4.5 for appropriate edoxaban

 

 

	Potential P-gp inhibition by Ataben is unknown and cannot be excluded.	dosage recommendations for coadministration with P-gp inhibitors.
Vitamin K antagonists
Warfarin	Co-administration with Ataben has the potential to increase or decrease warfarin concentrations.	It is recommended that the                 International Normalized Ratio (INR) be monitored carefully during treatment with Ataben, especially when commencing therapy.
ANTIEPILEPTICS
Carbamazepine	ATABEN may increase plasma levels of carbamazepine due to CYP3A4 inhibition. Due to carbamazepine inducing effect, a reduction in Ataben exposure cannot be ruled out.	Carbamazepine should be used with caution in combination with Ataben. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's              virologic response should be exercised.
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 Ataben exposure cannot be ruled out.	Phenobarbital              and phenytoin should be used with caution in combination with Ataben /ritonavir. When Ataben /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 Ataben /ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.	Lamotrigine should be used with caution in combination with Ataben /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 Ataben 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	More frequent therapeutic concentration monitoring of       these       medicinal

 

 

	Ataben due to CYP3A4 inhibition.	products is recommended until plasma levels have been stabilized.
CARDIOVASCULAR AGENTS
Antiarrhythmics
Amiodarone, Systemic lidocaine, Quinidine	Concentrations             of             these antiarrhythmics may be increased when co-administered with Ataben. 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 Ataben .	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	ATABEN 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%	An initial dose reduction of diltiazem by 50% is recommended,           with subsequent titration as needed and ECG monitoring.

 

 

	(↑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 Ataben /ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition.
Verapamil	Serum concentrations of verapamil may be increased by Ataben due to CYP3A4 inhibition.	Caution should be exercised when verapamil is co-administered with Ataben.
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   metabolised   via   the	Co-administration of Ataben /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

 

 

	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.	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 Ataben 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 Ataben (see section 4.4). Also see PULMONARY ARTERIAL HYPERTENSION in this table for further information regarding co- administration of Ataben with sildenafil.
HERBAL PRODUCTS
St.           John's           wort (Hypericum perforatum)	Concomitant use of St. John's wort with Ataben may be expected to result	Co-administration          of Ataben     with     products

 

 

	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).	containing St. John's wort is contraindicated.
HORMONAL CONTRACEPTIVES
thinyloestradiol 25 μg +	Ethinyloestradiol AUC ↓19% (↓25%	If an oral contraceptive is
norgestimate	↓13%)	administered with Ataben
(atazanavir 300 mg once	Ethinyloestradiol Cmax ↓16%   (↓26%	/ritonavir,           it          is
daily with ritonavir 100 mg	↓5%)	recommended    that    the
once daily)	Ethinyloestradiol Cmin ↓37%   (↓45%	oral contraceptive contain
	↓29%)	at     least     30     μg     of
	Norgestimate    AUC    ↑85%    (↑67%	ethinyloestradiol and that
	↑105%)	the patient be reminded
	Norgestimate      Cmax ↑68%      (↑51%	of strict compliance with
	↑88%)	this contraceptive dosing
	Norgestimate      Cmin ↑102%     (↑77%	regimen.                      Co-
	↑131%)	administration of Ataben
	While        the       concentration        of	/ritonavir      with      other
	ethinyloestradiol was increased with	hormonal contraceptives
	atazanavir given alone, due to both	or     oral     contraceptives
	UGT    and   CYP3A4   inhibition    by	containing    progestogens
	atazanavir,      the      net      effect     of	other than nor estimate
	atazanavir/ritonavir is a decrease in	has not been studied, and
	ethinyloestradiol levels because of the	therefore       should      be
	inducing effect of ritonavir.	avoided.     An     alternate
	The increase in progestin exposure	reliable        method       of
	may lead to related side-effects (e.g.	contraception                 is
	insulin resistance, dyslipidemia, acne	recommended.

 

 

	and spotting), thus possibly affecting the compliance.
Ethinyloestradiol 35 µg +	Ethinyloestradiol AUC ↑48% (↑31%
norethindrone	↑68%)
(atazanavir 400 mg once	Ethinyloestradiol    Cmax ↑15%    (↓1%
daily)	↑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	Simvastatin and lovastatin are highly					Co-administration          of
Lovastatin	dependent   on    CYP3A4   for    their					simvastatin or lovastatin
	metabolism     and    co-administration					with          Ataben          is
	with Ataben may result in increased					contraindicated due to an
	concentrations.					increased         risk         of
						myopathy           including
						rhabdomyolysis          (see
						section 4.3).
Atorvastatin	The	risk	of	myopathy	including	Co-administration	of

 

 

	rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.	atorvastatin with Ataben 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.
Lomitapide	Lomitapide is highly dependent on CYP3A4 for metabolism and co- administration with Ataben with ritonavir may result in increased concentrations.	Co-administration of limitative and Ataben with ritonavir is contraindicated due to a potential risk of markedly increased transaminase levels and hepatotoxicity (see section 4.3).
INHALED BETA AGONISTS
Salmeterol	Co-administration with Ataben may result in increased concentrations of salmeterol    and    an    increase    in salmeterol-associated adverse events.	Co-administration of salmeterol with Ataben is not recommended (see section 4.4).

 

 

	The    mechanism    of   interaction    is CYP3A4    inhibition    by    atazanavir and/or ritonavir.
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 Ataben 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 Ataben, based on these data.	No dosage adjustment is necessary if methadone is co-administered with Ataben.
PULMONARY ARTERIAL HYPERTENSION
PDE5 Inhibitors
Sildenafil	Co-administration with Ataben may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-inhibitor-associated       adverse	A safe and effective dose in combination with Ataben   has   not   been established for sildenafil

 

 

	events. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.	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 metabolised by CYP3A4. Co-administration with Ataben may cause a large increase in the concentration              of              these benzodiazepines. No drug interaction study has been performed for the co- administration of Ataben 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 Ataben with triazolam or orally            administered midazolam                      is contraindicated          (see section 4.3), whereas caution should be used with co-administration of Ataben and parenteral midazolam. If Ataben 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   Ataben   without   ritonavir    may    affect     atazanavir concentrations

▪      co-administration of fluticasone and Ataben without ritonavir may increase fluticasone concentrations relative to fluticasone given alone

▪     if an oral contraceptive is administered with Ataben without ritonavir, it is recommended that the oral contraceptive contain no more than 30 µg of ethinyloestradiol

▪    no dose adjustment of lamotrigine is required

Paediatric population

 

Interaction studies have only been performed in adults.

Pregnancy

 

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of Ataben with ritonavir may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182Ataben /ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on Ataben /ritonavir 300/100 mg and 13 of 21 (62%) women on Ataben /ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include Ataben) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with Ataben /ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with Ataben /ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

 

It is not known whether Ataben with ritonavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.

Breast-feeding

 

Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

 

Fertility

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).

Patients should be informed that dizziness has been reported during treatment with regimens containing Ataben  (see section 4.8).

Summary of the safety profile

 

Ataben has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving Ataben 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or Ataben 300 mg with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received Ataben 400 mg once daily and patients who received Ataben 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with Ataben plus ritonavir.

Among patients who received Ataben 400 mg once daily or Ataben 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing Ataben and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving Ataben 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir

 

 

disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.4).

Tabulated list of adverse reactions

 

Assessment of adverse reactions for Ataben is based on safety data from clinical studies and post-marketing experience. Frequency is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Immune system disorders:	uncommon: hypersensitivity
Metabolism and nutrition disorders:	uncommon: weight decreased, weight gain, anorexia, appetite increased
Psychiatric disorders:	uncommon: depression, disorientation, anxiety, insomnia, sleep disorder, abnormal dream
Nervous system disorders:	common: headache; uncommon: peripheral neuropathy, syncope, amnesia, dizziness, somnolence, dysgeusia
Eye disorders:	common: ocular icterus
Cardiac disorders:	uncommon: torsades de pointesa rare: QTc prolongationa, oedema, palpitation
Vascular disorders:	uncommon: hypertension
Respiratory, thoracic and mediastinal disorders:	uncommon: dyspnoea
Gastrointestinal disorders:	common:     vomiting,     diarrhoea,     abdominal     pain,                    nausea, dyspepsia; uncommon:     pancreatitis,     gastritis,     abdominal     distension, stomatitis aphthous, flatulence, dry mouth
Hepatobiliary disorders:	common: jaundice;

 

 

	uncommon: hepatitis, cholelithiasisa, cholestasisa; rare: hepatosplenomegaly, cholecystitisa
Skin and subcutaneous tissue disorders:	common: rash; uncommon: erythemia multiformea,b, toxic skin eruptionsa,b, drug rash with eosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa, urticaria, alopecia, pruritus; rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation
Musculoskeletal and connective tissue disorders:	uncommon: muscle atrophy, arthralgia, myalgia; rare: myopathy
Renal and urinary disorders:	uncommon: nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis, chronic kidney diseasea; rare: kidney pain
Reproductive      system      and      breast disorders:	uncommon: gynaecomastia
General disorders and administration site conditions:	common: fatigue; uncommon: chest pain, malaise, pyrexia, asthenia; rare: gait disturbance

^a These adverse reactions were identified through post-marketing surveillance; however, the frequencies were estimated from a statistical calculation based on the total number of patients exposed to Ataben in randomised controlled and other available clinical trials (n = 2321).

^b See description of selected adverse reactions for more details. 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).

Metabolic parameters

 

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

Rash and associated syndromes

 

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with Ataben.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of Ataben (see section 4.4).

Laboratory abnormalities

 

The most frequently reported laboratory abnormality in patients receiving regimens containing Ataben and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (6% Grade 4). Among experienced patients treated with Ataben 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 Ataben 300 mg once daily with 100 mg ritonavir once daily for a median duration of 96 weeks, 48% 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 Ataben and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

 

 

Two percent of patients treated with Ataben experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

 

In a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received either the oral powder or capsule formulation had a mean duration of treatment with Ataben of 115 weeks. The safety profile in this study was overall comparable to that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The most frequently reported laboratory abnormality in paediatric patients receiving Ataben was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3- 4) which occurred in 45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had a mean duration of treatment with Ataben oral powder of 80 weeks. No deaths were reported. The safety profile in these studies was overall comparable to that seen in previous paediatric and adult studies. The most frequently reported laboratory abnormalities in paediatric patients receiving Ataben oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatric patients in these studies than in adults.

Other special populations

 

Patients co-infected with hepatitis B and/or hepatitis C virus

 

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co- infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between Ataben and comparator regimens (see section 4.4).

 

 

Reporting of suspected adverse reactions

 

•  Saudi Arabia:

 

 

 

2.                     o Other GCC States:

 

Please contact the relevant competent authority.

Human experience of acute overdose with Ataben is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with Ataben should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Ataben. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE08

 

 

Mechanism of action

 

Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti- HIV-2 activity in cell culture.

Resistance

 

Antiretroviral treatment naive adult 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. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (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 3. 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 5/26Ataben /ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

 

 

Antiretroviral treatment experienced adult 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 4. 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 4) 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 major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.

Clinical results

 

In antiretroviral naive adult patients

 

Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïve patients comparing Ataben /ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg tablets once daily). The Ataben /ritonavir arm showed

 

 

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 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

Table 5: Efficacy Outcomes in Study 138 a

 

Parameter	ATABEN/ritonavirb (300      mg/100 mg once daily) n=440		Lopinavir/ritonavirc (400 mg/100 mg twice daily) n=443
	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)	66 (n=225)
CD4 count <50 cells/mm3	78 (n=58)	78 (n=58)	63 (n=48)	58 (n=48)
50 to <100 cells/mm3	76 (n=45)	71 (n=45)	69 (n=29)	69 (n=29)
100 to <200 cells/mm3	75 (n=106)	71 (n=106)	78 (n=134)	70 (n=134)
≥ 200 cells/mm3	80 (n=222)	76 (n=222)	80 (n=228)	69 (n=228)

 

 

HIV RNA Mean Change from Baseline, log10 copies/ml
All patients	-3.09 (n=397)	-3.21 (n=360)	-3.13 (n=379)	-3.19 (n=340)
CD4 Mean Change from Baseline, cells/mm3
All patients	203 (n=370)	268 (n=336)	219 (n=363)	290 (n=317)
CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic
HIV RNA <100,000 copies/ml	179 (n=183)	243 (n=163)	194 (n=183)	267 (n=152)
≥100,000 copies/ml	227 (n=187)	291 (n=173)	245 (n=180)	310 (n=165)

^a 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)

^bAtaben /RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^d Intent-to-treat analysis, with missing values considered as failures.

 

^e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.

 

^f Number of patients evaluable.

 

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 Ataben 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted Ataben 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with Ataben + 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 Ataben and two NRTIs compared with 75% on Ataben + ritonavir and two NRTIs.

 

 

 

Eleven subjects (13%) in the unboosted Ataben group and 6 (7%) in the Ataben + ritonavir group, had virologic rebound. Four subjects in the unboosted Ataben group and 2 in the Ataben

+ 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 Ataben  and 1 subject in the Ataben + ritonavir group.

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

In antiretroviral experienced adult patients

 

Study 045 is a randomised, multicenter trial comparing Ataben /ritonavir (300/100 mg once daily) and Ataben /saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the Ataben + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks (Table 6).

Table 6: Efficacy Outcomes at Week 48a and at Week 96 (Study 045)

 

Parameter

ATV/RTVb (300   mg/    100 mg once daily) n=120

LPV/RTVc (400    mg/    100 mg twice daily) n=123

Time-averaged                              difference ATV/RTV-LPV/RTV [97.5% CId]

 

 

	Week 48	Week 96	Week 48	Week 96	Week 48	Week 96
HIV RNA Mean Change from Baseline, log10 copies/ml
All patients	-1.93 (n=90 e)	-2.29 (n=64)	-1.87 (n=99)	-2.08 (n=65)	0.13 [-0.12, 0.39]	0.14 [-0.13, 0.41]
HIV RNA <50 copies/ml, %f (responder/evaluable)
All patients	36 (43/120)	32 (38/120)	42 (52/123)	35 (41/118)	NA	NA
HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable)
0-2	44 (28/63)	41 (26/63)	56 (32/57)	48 (26/54)	NA	NA
3	18 (2/11)	9 (1/11)	38 (6/16)	33 (5/15)	NA	NA
≥ 4	27 (12/45)	24 (11/45)	28 (14/50)	20 (10/49)	NA	NA
CD4 Mean Change from Baseline, cells/mm3
All patients	110 (n=83)	122 (n=60)	121 (n=94)	154 (n=60)	NA	NA

^a The mean baseline CD4 cell count was 337 cells/mm³ (range: 14 to 1,543 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml).

^b ATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^c LPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

^d Confidence interval.

 

^e Number of patients evaluable.

 

^f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.

 

 

^g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

 

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for Ataben

+ ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the Ataben + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for Ataben + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for Ataben + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall remained on study.

ATABEN + saquinavir was shown to be inferior to lopinavir + ritonavir.

 

Paediatric population

 

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of Ataben is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to 21 years of age. Overall, in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily Ataben (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received Ataben with ritonavir are presented in Table 7. For treatment-naive paediatric patients,

 

 

baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm³ (range: 100 to 1157 cells/ mm³) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 log10 copies/ml).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study AI424-020)

 

Parameter	Treatment-Naïve Ataben Capsules/ritonavir (300 mg/100 mg once daily) n=16	Treatment-Experienced Ataben Capsules/ritonavir (300 mg/100 mg once daily) n=25
HIV RNA <50 copies/ml, % a
All patients	81 (13/16)	24 (6/25)
HIV RNA <400 copies/ml, % a
All patients	88 (14/16)	32 (8/25)
CD4 Mean Change from Baseline, cells/mm3
All patients	293 (n=14b)	229 (n=14b)
HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled)
0-2	NA	27 (4/15)
3	NA	-
≥ 4	NA	0 (0/3)

^a Intent-to-treat analysis, with missing values considered as failures.

 

^b Number of patients evaluable.

 

^c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

 

 

^d Includes patients with baseline resistance data. NA = not applicable.

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.

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of Ataben 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) mg/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) mg/ml, respectively.

In HIV-infected patients (n=13), multiple dosing of Ataben 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) mg/ml and 14874 (91) mg/ml, respectively.

Food effect: co-administration of Ataben and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of Ataben and 100 mg dose of ritonavir with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of Ataben with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, Ataben is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a

 

 

multiple-dose study in HIV-infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400 mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

Special populations

 

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for Ataben with ritonavir in patients with renal insufficiency. Ataben (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. Ataben (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

 

 

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).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

 

The pharmacokinetic data from HIV-infected pregnant women receiving Ataben with ritonavir are presented in Table 8.

Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State

 

	atazanavir 300 mg with ritonavir 100 mg
Pharmacokinetic Parameter	2nd Trimester (n=9)	3rd Trimester (n=20)	postpartuma (n=36)
Cmax ng/mL	3729.09	3291.46	5649.10
Geometric mean (CV%)	(39)	(48)	(31)
AUC ng•h/mL	34399.1	34251.5	60532.7
Geometric mean (CV%)	(37)	(43)	(33)
Cmin ng/mLb	663.78	668.48	1420.64
Geometric mean (CV%)	(36)	(50)	(47)
a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period

 

 

 

Paediatric population

 

There is a trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed, however at recommended doses, geometric mean atazanavir exposures (Cmin, Cmax and AUC) in paediatric patients are expected to be similar to those observed in adults.

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single-cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were

 

 

observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.

5.1  Ataben Capsules 150mg:

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V),Empty Hard Gelatin Capsules (Size 1, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A6” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Black.

 

 

Ataben Capsules 200mg:

 

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V), Empty Hard Gelatin Capsules (Size 0, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A7” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.

Ataben Capsules 300mg:

 

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V), Empty Hard Gelatin Capsules (Size 00, Orange opaque Cap Imprinted with “H” in black color, Green opaque body imprinted with “A8” in black color) Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.

NA

24 months

Store below 30ºC.

6 X 10’s Alu- Alu blister pack

NA