Atripla 600 mg/200 mg/245 mg film-coated tablets
Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (as fumarate)
Excipient with known effect
Each film-coated tablet contains 1 mmol (23.6 mg) of sodium.
For the full list of excipients, see section 6.1.
Film-coated tablet.
Pink, capsule-shaped, film-coated tablet, of dimensions 20 mm x 10.4 mm, debossed with “123” on one side, plain on the other side.
Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Atripla prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).
The demonstration of the benefit of Atripla is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to Atripla (see section 5.1). No data are currently available from clinical studies with Atripla in treatment-naïve or in heavily pretreated patients.
No data are available to support the combination of Atripla and other antiretroviral agents.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
Adults
The recommended dose of Atripla is one tablet taken orally once daily.
If a patient misses a dose of Atripla within 12 hours of the time it is usually taken, the patient should take Atripla as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Atripla by more than 12 hours and it is almost time for the next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.
If the patient vomits within 1 hour of taking Atripla, another tablet should be taken. If the patient vomits more than 1 hour after taking Atripla he/she does not need to take another dose.
It is recommended that Atripla be taken on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8). In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended (see section 4.8).
It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower following administration of Atripla on an empty stomach as compared to the individual component tenofovir disoproxil fumarate when taken with food (see section 5.2). Data on the clinical translation of the decrease in pharmacokinetic exposure are not available. In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited (see section 5.1).
Where discontinuation of therapy with one of the components of Atripla is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products.
If therapy with Atripla is discontinued, consideration should be given to the long half-life of efavirenz (see section 5.2) and long intracellular half-lives of emtricitabine and tenofovir. Because of interpatient variability in these parameters and concerns regarding development of resistance, HIV treatment guidelines should be consulted, also taking into consideration the reason for discontinuation.
Dose adjustment: If Atripla is co-administered with rifampicin to patients weighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may be considered (see section 4.5).
Special populations
Elderly
Atripla should be administered with caution to elderly patients (see section 4.4).
Renal impairment
Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).
Hepatic impairment
The pharmacokinetics of Atripla have not been studied in patients with hepatic impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated with the normal recommended dose of Atripla (see sections 4.3, 4.4 and 5.2). Patients should be monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz (see sections 4.3 and 4.4).
If Atripla is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).
Paediatric population
The safety and efficacy of Atripla in children under the age of 18 years have not been established (see section 5.2).
Method of administration
Atripla tablets should be swallowed whole with water, once daily.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Severe hepatic impairment (CPT, Class C) (see section 5.2).
Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine). Competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening adverse reactions (for example, cardiac arrhythmias, prolonged sedation or respiratory depression) (see section 4.5).
Co-administration with voriconazole. Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered (see section 4.5).
Co-administration with herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).
Co-administration with other medicinal products
As a fixed combination, Atripla should not be administered concomitantly with other medicinal products containing the same active components, emtricitabine or tenofovir disoproxil fumarate. Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due to similarities with emtricitabine, Atripla should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5). Atripla should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.
Co-administration of Atripla and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal have been reported.
No data are available on the safety and efficacy of Atripla in combination with other antiretroviral agents.
Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5).
Switching from a PI-based antiretroviral regimen
Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switch to Atripla may lead to a reduction of the response to the therapy (see section 5.1). These patients should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions.
Opportunistic infections
Patients receiving Atripla or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Transmission of HIV
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.
Effect of food
The administration of Atripla with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in frequency of adverse reactions (see section 4.8). It is recommended that Atripla be taken on an empty stomach, preferably at bedtime.
Liver disease
The pharmacokinetics, safety and efficacy of Atripla have not been established in patients with significant underlying liver disorders (see section 5.2). Atripla is contraindicated in patients with severe hepatic impairment (see section 4.3) and not recommended in patients with moderate hepatic impairment. Since efavirenz is principally metabolised by the CYP system, caution should be exercised in administering Atripla to patients with mild hepatic impairment. These patients should be carefully monitored for efavirenz adverse reactions, especially nervous system symptoms. Laboratory tests should be performed to eva luate their liver disease at periodic intervals (see section 4.2).
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Atripla needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered (see section 4.8).
In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended.
Hepatic events
Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered for all patients independent of pre-existing hepatic dysfunction or other risk factors.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection
Patients with chronic hepatitis B or C and treated with CART are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.
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.
The safety and efficacy of Atripla have not been studied for the treatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination have shown activity against HBV in pharmacodynamic studies (see section 5.1). Limited clinical experience suggests that emtricitabine and tenofovir disoproxil fumarate have an anti-HBV activity when used in antiretroviral combination therapy to control HIV infection. Discontinuation of Atripla therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Atripla must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Atripla. If appropriate, resumption of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Psychiatric symptoms
Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions and psychosis-like behaviour. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risk of continued therapy outweighs the benefits (see section 4.8).
Nervous system symptoms
Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovir disoproxil fumarate. Headache has been reported in clinical studies with emtricitabine (see section 4.8). Nervous system symptoms associated with efavirenz usually begin during the first one or two days of therapy and generally resolve after the first two to four weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.
Seizures
Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures.
Renal impairment
Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renal impairment require a dose adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.2 and 5.2). Use of Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of Atripla and nephrotoxic agents (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2) is unavoidable, renal function must be monitored weekly (see section 4.5).
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil fumarate and with risk factors for renal dysfunction. If Atripla is co-administered with an NSAID, renal function should be monitored adequately.
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Atripla and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients with a history of renal dysfunction or in patients who are at risk of renal dysfunction, a more frequent monitoring of renal function is required.
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Atripla, renal function must be re-eva luated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Since Atripla is a combination product and the dosing interval of the individual components cannot be altered, treatment with Atripla must be interrupted in patients with confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with Atripla should also be considered in case of progressive decline of renal function when no other cause has been identified. Where discontinuation of therapy with one of the components of Atripla is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil fumarate are available.
Bone effects
In a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in bone mineral density of the hip and spine were observed in both treatment groups. Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in bone mineral density of the hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8). If bone abnormalities are suspected then appropriate consultation should be obtained.
Skin reactions
Mild-to-moderate rash has been reported with the individual components of Atripla. The rash associated with the efavirenz component usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz (see section 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Atripla must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Atripla is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking an NNRTI.
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 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.
Mitochondrial dysfunction following exposure in utero
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome
In HIV infected patients with severe immune deficiency at the time of institution of 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 eva luated 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 occur many months after initiation of treatment.
Osteonecrosis
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients with HIV-1 harbouring mutations
Atripla should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutation (see sections 4.1 and 5.1).
Elderly
Atripla has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased hepatic or renal function, therefore caution should be exercised when treating elderly patients with Atripla (see section 4.2).
Excipients
This medicinal product contains 1 mmol (23.6 mg) of sodium per dose which should be taken into consideration by patients on a controlled sodium diet.
As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil fumarate, any interactions that have been identified with these agents individually may occur with Atripla. Interaction studies with these agents have only been performed in adults.
As a fixed combination, Atripla should not be administered concomitantly with other medicinal products containing the components, emtricitabine or tenofovir disoproxil as fumarate. Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due to similarities with emtricitabine, Atripla should not be administered concomitantly with other cytidine analogues, such as lamivudine. Atripla should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.
Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect of co-administration with substrates of these enzymes is not clear (see section 5.2).
Efavirenz exposure may be increased when given with medicinal products (for example ritonavir) or food (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John's wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John's wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.4).
In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP-mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal products is low.
Cannabinoid test interaction
Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV infected subjects receiving efavirenz. Confirmatory testing by a more specific method such as gas chromatography/mass spectrometry is recommended in such cases.
Contraindications of concomitant use
Atripla must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-threatening events (see section 4.3).
Voriconazole: Co-administration of standard doses of efavirenz and voriconazole is contraindicated. Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and Atripla must not be co-administered (see section 4.3 and Table 1).
St. John's wort (Hypericum perforatum): Co-administration of Atripla and St. John's wort or herbal preparations containing St. John's wort is contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort due to induction of drug metabolising enzymes and/or transport proteins by St. John's wort. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John's wort. The inducing effect of St. John's wort may persist for at least 2 weeks after cessation of treatment (see section 4.3).
Concomitant use not recommended
Atazanavir/ritonavir: Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination with Atripla. Therefore co-administration of atazanavir/ritonavir and Atripla is not recommended (see Table 1).
Didanosine: Co-administration of Atripla and didanosine is not recommended (see section 4.4 and Table 1).
Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Atripla with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.
Use of Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).
Other interactions
Interactions between Atripla or its individual component(s) and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, once daily as “q.d.” and once every 8 hours as “q8h”). If available, 90% confidence intervals are shown in parentheses.
Table 1: Interactions between Atripla or its individual components and other medicinal products
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Medicinal product by therapeutic areas
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Effects on drug levels
Mean percent change in AUC, Cmax, Cmin with 90% confidence intervals if available
(mechanism)
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Recommendation concerning co-administration with Atripla
(efavirenz 600 mg, emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg)
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ANTI-INFECTIVES
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HIV antivirals
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Protease inhibitors
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Atazanavir/ritonavir/Tenofovir disoproxil fumarate
(300 mg q.d./100 mg q.d./300 mg q.d.)
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Atazanavir:
AUC: ↓ 25% (↓ 42 to ↓ 3)
Cmax: ↓ 28% (↓ 50 to ↑ 5)
Cmin: ↓ 26% (↓ 46 to ↑ 10)
Co-administration of atazanavir/ritonavir with tenofovir resulted in increased exposure to tenofovir. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.
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Co-administration of atazanavir/ritonavir and Atripla is not recommended.
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Atazanavir/ritonavir/Efavirenz
(400 mg q.d./100 mg q.d./600 mg q.d., all administered with food)
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Atazanavir (pm):
AUC: ↔* (↓ 9% to ↑ 10%)
Cmax: ↑ 17%* (↑ 8 to ↑ 27)
Cmin: ↓ 42%* (↓ 31 to ↓ 51)
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Atazanavir/ritonavir/Efavirenz
(400 mg q.d./200 mg q.d./600 mg q.d., all administered with food)
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Atazanavir (pm):
AUC: ↔*/** (↓ 10% to ↑ 26%)
Cmax: ↔*/** (↓ 5% to ↑ 26%)
Cmin: ↑ 12%*/** (↓ 16 to ↑ 49)
(CYP3A4 induction).
* When compared to atazanavir 300 mg/ritonavir 100 mg q.d. in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir.
** based on historical comparison.
Co-administration of efavirenz with atazanavir/ritonavir is not recommended.
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Atazanavir/ritonavir/Emtricitabine
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Interaction not studied.
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Darunavir/ritonavir/Efavirenz
(300 mg b.i.d.*/100 mg b.i.d./600 mg q.d.)
*lower than recommended doses; similar findings are expected with recommended doses.
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Darunavir:
AUC: ↓ 13%
Cmin: ↓ 31%
Cmax: ↓ 15%
(CYP3A4 induction)
Efavirenz:
AUC: ↑ 21%
Cmin: ↑ 17%
Cmax: ↑ 15%
(CYP3A4 inhibition)
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Atripla in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin. If Atripla is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Darunavir/ritonavir should be used with caution in combination with Atripla. See ritonavir row below. Monitoring of renal function may be indicated, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
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Darunavir/ritonavir/Tenofovir disoproxil fumarate
(300 mg b.i.d.*/100 mg b.i.d./300 mg q.d.)
*lower than recommended dose
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Darunavir:
AUC: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 22%
Cmin: ↑ 37%
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Darunavir/ritonavir/Emtricitabine
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Interaction not studied. Based on the different elimination pathways, no interaction is expected.
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Fosamprenavir/ritonavir/Efavirenz
(700 mg b.i.d./100 mg b.i.d./600 mg q.d.)
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No clinically significant pharmacokinetic interaction.
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Atripla and fosamprenavir/ritonavir can be co-administered without dose adjustment.
See ritonavir row below.
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Fosamprenavir/ritonavir/Emtricitabine
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Interaction not studied.
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Fosamprenavir/ritonavir/Tenofovir disoproxil fumarate
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Interaction not studied.
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Indinavir/Efavirenz
(800 mg q8h/200 mg q.d.)
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Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Indinavir:
AUC: ↓ 31% (↓ 8 to ↓ 47)
Cmin: ↓ 40%
A similar reduction in indinavir exposures was observed when indinavir 1,000 mg q8h was given with efavirenz 600 mg q.d.
(CYP3A4 induction)
For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.
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Insufficient data are available to make a dosing recommendation for indinavir when dosed with Atripla. While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz, a component of Atripla, and indinavir.
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Indinavir/Emtricitabine
(800 mg q8h/200 mg q.d.)
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Indinavir:
AUC: ↔
Cmax: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
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Indinavir/Tenofovir disoproxil fumarate
(800 mg q8h/300 mg q.d.)
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Indinavir:
AUC: ↔
Cmax: ↔
Tenofovir:
AUC: ↔
Cmax: ↔
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Lopinavir/ritonavir/Tenofovir disoproxil fumarate
(400 mg b.i.d./100 mg b.i.d./300 mg q.d.)
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Lopinavir/Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 32% (↑ 25 to ↑ 38)
Cmax: ↔
Cmin: ↑ 51% (↑ 37 to ↑ 66)
Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.
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Insufficient data are available to make a dosing recommendation for lopinavir/ritonavir when dosed with Atripla. Co-administration of lopinavir/ritonavir and Atripla is not recommended.
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Lopinavir/ritonavir soft capsules or oral solution/Efavirenz
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Substantial decrease in lopinavir exposure, necessitating dosage adjustment of lopinavir/ritonavir. When used in combination with efavirenz and two NRTIs, 533/133 mg lopinavir/ritonavir (soft capsules) twice daily yielded similar lopinavir plasma concentrations as compared to lopinavir/ritonavir (soft capsules) 400/100 mg twice daily without efavirenz (historical data).
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Lopinavir/ritonavir tablets/Efavirenz
(400/100 mg b.i.d./600 mg q.d.)
(500/125 mg b.i.d./600 mg q.d.)
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Lopinavir concentrations: ↓ 30-40%
Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Dosage adjustment of lopinavir/ritonavir is necessary when given with efavirenz. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.
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Lopinavir/ritonavir/Emtricitabine
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Interaction not studied.
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Ritonavir/Efavirenz
(500 mg b.i.d./600 mg q.d.)
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Ritonavir:
Morning AUC: ↑ 18% (↑ 6 to ↑ 33)
Evening AUC: ↔
Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)
Evening Cmax: ↔
Morning Cmin: ↑ 42% (↑ 9 to ↑ 86)
Evening Cmin: ↑ 24% (↑ 3 to ↑ 50)
Efavirenz:
AUC: ↑ 21% (↑ 10 to ↑ 34)
Cmax: ↑ 14% (↑ 4 to ↑ 26)
Cmin: ↑ 25% (↑ 7 to ↑ 46)
(inhibition of CYP-mediated oxidative metabolism)
When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not available.
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Co-administration of ritonavir at doses of 600 mg and Atripla is not recommended. When using Atripla with low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, due to possible pharmacodynamic interaction.
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Ritonavir/Emtricitabine
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Interaction not studied.
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Ritonavir/Tenofovir disoproxil fumarate
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Interaction not studied.
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Saquinavir/ritonavir/Efavirenz
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Interaction not studied. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir above.
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Insufficient data are available to make a dosing recommendation for saquinavir/ritonavir when dosed with Atripla. Co-administration of saquinavir/ritonavir and Atripla is not recommended. Use of Atripla in combination with saquinavir as the sole protease inhibitor is not recommended.
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Saquinavir/ritonavir/Tenofovir disoproxil fumarate
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There |
