Interactions : אינטראקציות

4.5       Interaction with other medicinal products and other forms of interaction

As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil, 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. 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).

Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and efavirenz are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

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 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).

Elbasvir/grazoprevir: Co-administration of Atripla with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir (see section 4.3 and Table 1).

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).

QT Prolonging Drugs: Atripla is contraindicated with concomitant use of drugs that are known to prolong the QTc interval and could lead to Torsade de Pointes, such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (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 Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir: Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir 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 
Medicinal product by therapeutic areas             Effects on drug levels             Recommendation Mean percent change in AUC, Cmax,            concerning
Cmin with 90% confidence intervals     co-administration with if available                       Atripla
(mechanism)                   (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
ANTI-INFECTIVES
HIV antivirals
Protease inhibitors
Atazanavir/ritonavir/Tenofovir disoproxil   Atazanavir:                            Co-administration of (300 mg q.d./100 mg q.d./245 mg q.d.)       AUC: ↓ 25% (↓ 42 to ↓ 3)               atazanavir/ritonavir and Cmax: ↓ 28% (↓ 50 to ↑ 5)              Atripla is not
Cmin: ↓ 26% (↓ 46 to ↑ 10)             recommended.

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.
Atazanavir/ritonavir/Efavirenz              Atazanavir (pm):
(400 mg q.d./100 mg q.d./600 mg q.d., all   AUC: ↔* (↓ 9% to ↑ 10%) administered with food)                     Cmax: ↑ 17%* (↑ 8 to ↑ 27) Cmin: ↓ 42%* (↓ 31 to ↓ 51)

Atazanavir/ritonavir/Efavirenz              Atazanavir (pm):
(400 mg q.d./200 mg q.d./600 mg q.d., all   AUC: ↔*/** (↓ 10% to ↑ 26%) administered with food)                     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.
Atazanavir/ritonavir/Emtricitabine          Interaction not studied.
Darunavir/ritonavir/Efavirenz               Darunavir:                             Atripla in combination (300 mg b.i.d.*/100 mg b.i.d./600 mg        AUC: ↓ 13%                             with darunavir/ritonavir q.d.)                                       Cmin: ↓ 31%                            800/100 mg once daily Cmax: ↓ 15%                            may result in suboptimal
*lower than recommended doses; similar      (CYP3A4 induction)                     darunavir Cmin. If Atripla findings are expected with recommended                                             is to be used in doses.                                      Efavirenz:                             combination with AUC: ↑ 21%                             darunavir/ritonavir, the
Cmin: ↑ 17%                            darunavir/ritonavir
Cmax: ↑ 15%                            600/100 mg twice daily
(CYP3A4 inhibition)                    regimen should be used.


Medicinal product by therapeutic areas             Effects on drug levels                 Recommendation Mean percent change in AUC, Cmax,                concerning
Cmin with 90% confidence intervals        co-administration with if available                           Atripla
(mechanism)                       (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Darunavir/ritonavir/Tenofovir disoproxil   Darunavir:                                Darunavir/ritonavir (300 mg b.i.d.*/100 mg b.i.d./245 mg q.d.) AUC: ↔                                    should be used with Cmin: ↔                                   caution in combination
*lower than recommended dose                                                         with Atripla. See Tenofovir:                                ritonavir row below.
AUC: ↑ 22%                                Monitoring of renal
Cmin: ↑ 37%                               function may be
Darunavir/ritonavir/Emtricitabine          Interaction not studied. Based on the     indicated, particularly in different elimination pathways, no        patients with underlying interaction is expected.                  systemic or renal disease,
or in patients taking nephrotoxic agents.
Fosamprenavir/ritonavir/Efavirenz           No clinically significant                Atripla and (700 mg b.i.d./100 mg b.i.d./600 mg q.d.)   pharmacokinetic interaction.             fosamprenavir/ritonavir Fosamprenavir/ritonavir/Emtricitabine       Interaction not studied.                 can be co-administered Fosamprenavir/ritonavir/Tenofovir           Interaction not studied.                 without dose adjustment.
disoproxil                                                                           See ritonavir row below.
Indinavir/Efavirenz                         Efavirenz:                               Insufficient data are (800 mg q8h/200 mg q.d.)                    AUC: ↔                                   available to make a Cmax: ↔                                  dosing recommendation
Cmin: ↔                                  for indinavir when dosed with Atripla. While the
Indinavir:                               clinical significance of
AUC: ↓ 31% (↓ 8 to ↓ 47)                 decreased indinavir
Cmin: ↓ 40%                              concentrations has not been established, the
A similar reduction in indinavir         magnitude of the exposures was observed when              observed indinavir 1,000 mg q8h was given         pharmacokinetic with efavirenz 600 mg q.d.               interaction should be
(CYP3A4 induction)                       taken into consideration
For co-administration of efavirenz       when choosing a regimen with low-dose ritonavir in               containing both combination with a protease inhibitor,   efavirenz, a component see section on ritonavir below.          of Atripla, and indinavir.
Indinavir/Emtricitabine                     Indinavir:
(800 mg q8h/200 mg q.d.)                    AUC: ↔
Cmax: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Indinavir/Tenofovir disoproxil              Indinavir:
(800 mg q8h/245 mg q.d.)                    AUC: ↔
Cmax: ↔

Tenofovir:
AUC: ↔
Cmax: ↔


Medicinal product by therapeutic areas             Effects on drug levels                 Recommendation Mean percent change in AUC, Cmax,                concerning
Cmin with 90% confidence intervals        co-administration with if available                           Atripla
(mechanism)                       (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Lopinavir/ritonavir/Tenofovir disoproxil    Lopinavir/Ritonavir:                     Insufficient data are (400 mg b.i.d./100 mg b.i.d./245 mg q.d.)   AUC: ↔                                   available to make a Cmax: ↔                                  dosing recommendation
Cmin: ↔                                  for lopinavir/ritonavir when dosed with Atripla.
Tenofovir:                               Co-administration of
AUC: ↑ 32% (↑ 25 to ↑ 38)                lopinavir/ritonavir and Cmax: ↔                                  Atripla is not
Cmin: ↑ 51% (↑ 37 to ↑ 66)               recommended.

Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.
Lopinavir/ritonavir soft capsules or oral   Substantial decrease in lopinavir solution/Efavirenz                          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).

Lopinavir/ritonavir tablets/Efavirenz       Lopinavir concentrations: ↓ 30-40% (400/100 mg b.i.d./600 mg q.d.)

(500/125 mg b.i.d./600 mg q.d.)             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.
Lopinavir/ritonavir/Emtricitabine           Interaction not studied.


Medicinal product by therapeutic areas             Effects on drug levels                 Recommendation Mean percent change in AUC, Cmax,                concerning
Cmin with 90% confidence intervals        co-administration with if available                           Atripla
(mechanism)                       (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Ritonavir/Efavirenz                         Ritonavir:                               Co-administration of (500 mg b.i.d./600 mg q.d.)                 Morning AUC: ↑ 18% (↑ 6 to ↑ 33)         ritonavir at doses of Evening AUC: ↔                           600 mg and Atripla is not
Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)       recommended. When
Evening Cmax: ↔                          using Atripla with
Morning Cmin: ↑ 42% (↑ 9 to ↑ 86)        low-dose ritonavir, the Evening Cmin: ↑ 24% (↑ 3 to ↑ 50)        possibility of an increase in the incidence of
Efavirenz:                               efavirenz-associated
AUC: ↑ 21% (↑ 10 to ↑ 34)                adverse events should be Cmax: ↑ 14% (↑ 4 to ↑ 26)                considered, due to
Cmin: ↑ 25% (↑ 7 to ↑ 46)                possible
(inhibition of CYP-mediated              pharmacodynamic oxidative metabolism)                    interaction.

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.
Ritonavir/Emtricitabine                     Interaction not studied.
Ritonavir/Tenofovir disoproxil              Interaction not studied.
Saquinavir/ritonavir/Efavirenz              Interaction not studied. For             Insufficient data are co-administration of efavirenz with      available to make a low-dose ritonavir in combination        dosing recommendation with a protease inhibitor, see section   for saquinavir/ritonavir on ritonavir above.                      when dosed with Atripla.
Saquinavir/ritonavir/Tenofovir disoproxil   There were no clinically significant     Co-administration of pharmacokinetic interactions when        saquinavir/ritonavir and tenofovir disoproxil was                 Atripla is not co-administered with ritonavir           recommended. Use of boosted saquinavir.                      Atripla in combination
Saquinavir/ritonavir/Emtricitabine          Interaction not studied.                 with saquinavir as the sole protease inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz                         Maraviroc:                               Refer to the Summary of (100 mg b.i.d./600 mg q.d.)                 AUC12h: ↓ 45% (↓ 38 to ↓ 51)             Product Characteristics Cmax: ↓ 51% (↓ 37 to ↓ 62)               for the medicinal product containing maraviroc.
Efavirenz concentrations not measured, no effect is expected.
Maraviroc/Tenofovir disoproxil              Maraviroc:
(300 mg b.i.d./245 mg q.d.)                 AUC12h: ↔
Cmax: ↔

Tenofovir concentrations not measured, no effect is expected.
Maraviroc/Emtricitabine                     Interaction not studied.

Medicinal product by therapeutic areas          Effects on drug levels               Recommendation Mean percent change in AUC, Cmax,              concerning
Cmin with 90% confidence intervals       co-administration with if available                         Atripla
(mechanism)                     (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Integrase strand transfer inhibitor
Raltegravir/Efavirenz                    Raltegravir:                             Atripla and raltegravir (400 mg single dose/-)                   AUC: ↓ 36%                               can be co-administered C12h: ↓ 21%                              without dose adjustment.
Cmax: ↓ 36%
(UGT1A1 induction)
Raltegravir/Tenofovir disoproxil         Raltegravir:
(400 mg b.i.d./-)                        AUC: ↑ 49%
C12h: ↑ 3%
Cmax: ↑ 64%
(mechanism of interaction unknown)

Tenofovir:
AUC: ↓ 10%
C12h: ↓ 13%
Cmax: ↓ 23%
Raltegravir/Emtricitabine                Interaction not studied.
NRTIs and NNRTIs
NRTIs/Efavirenz                          Specific interaction studies have not    Due to the similarity been performed with efavirenz and        between lamivudine and
NRTIs other than lamivudine,             emtricitabine, a zidovudine and tenofovir disoproxil.     component of Atripla,
Clinically significant interactions      Atripla should not be have not been found and would not be     administered expected since the NRTIs are             concomitantly with metabolised via a different route than   lamivudine efavirenz and would be unlikely to       (see section 4.4).
compete for the same metabolic enzymes and elimination pathways.
NNRTIs/Efavirenz                         Interaction not studied.                 Since use of two NNRTIs proved not beneficial in terms of efficacy and safety, co-administration of Atripla and another
NNRTI is not recommended.
Didanosine/Tenofovir disoproxil          Co-administration of tenofovir           Co-administration of disoproxil and didanosine results in a   Atripla and didanosine is
40-60% increase in systemic exposure     not recommended.
to didanosine.                           Increased systemic
Didanosine/Efavirenz                     Interaction not studied.                 exposure to didanosine 

Medicinal product by therapeutic areas          Effects on drug levels             Recommendation Mean percent change in AUC, Cmax,            concerning
Cmin with 90% confidence intervals    co-administration with if available                       Atripla
(mechanism)                   (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Didanosine/Emtricitabine                 Interaction not studied.             may increase didanosine related adverse reactions.
Rarely, pancreatitis and lactic acidosis,
sometimes fatal, have been reported.
Co-administration of tenofovir disoproxil and didanosine at a dose of
400 mg daily has been associated with a significant decrease in
CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e.
active) didanosine. A decreased dosage of
250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of
HIV-1 infection.
Hepatitis C antivirals
Elbasvir/Grazoprevir +                   Elbasvir:                            Co-administration of Efavirenz                                AUC: ↓ 54%                           Atripla with Cmax: ↓ 45%                          elbasvir/grazoprevir is
(CYP3A4 or P-gp induction - effect   contraindicated because it on elbasvir)                         may lead to loss of virologic response to
Grazoprevir:                         elbasvir/grazoprevir.
AUC: ↓ 83%                           This loss is due to
Cmax: ↓ 87%                          significant decreases in
(CYP3A4 or P-gp induction - effect   elbasvir/grazoprevir on grazoprevir)                      plasma concentrations caused by CYP3A4 or
Efavirenz:                           P-gp induction. Refer to
AUC: ↔                               the Summary of Product
Cmax: ↔                              Characteristics for elbasvir/grazoprevir for more information.


Medicinal product by therapeutic areas          Effects on drug levels             Recommendation Mean percent change in AUC, Cmax,            concerning
Cmin with 90% confidence intervals    co-administration with if available                       Atripla
(mechanism)                   (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Glecaprevir/Pibrentasvir/Efavirenz       Expected:                            Concomitant Glecaprevir: ↓                       administration of
Pibrentasvir: ↓                      glecaprevir/pibrentasvir with efavirenz, a component of Atripla,
may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Coadministration of glecaprevir/pibrentasvir with Atripla is not recommended. Refer to the prescribing information for glecaprevir/pibrentasvir for more information.
Ledipasvir/Sofosbuvir                    Ledipasvir:                          No dose adjustment is (90 mg/400 mg q.d.) +                    AUC: ↓ 34% (↓ 41 to ↓ 25)            recommended. The Efavirenz/Emtricitabine/Tenofovir        Cmax: ↓ 34% (↓ 41 to ↑ 25)           increased exposure of disoproxil                               Cmin: ↓ 34% (↓ 43 to ↑ 24)           tenofovir could potentiate (600 mg/200 mg/245 mg q.d.)                                                   adverse reactions Sofosbuvir:                          associated with tenofovir
AUC: ↔                               disoproxil, including
Cmax: ↔                              renal disorders. Renal function should be
GS-3310071:                          closely monitored (see
AUC: ↔                               section 4.4).
Cmax: ↔
Cmin: ↔

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 98% (↑ 77 to ↑ 123)
Cmax: ↑ 79% (↑ 56 to ↑ 104)
Cmin: ↑ 163% (↑ 137 to ↑ 197)


Medicinal product by therapeutic areas          Effects on drug levels             Recommendation Mean percent change in AUC, Cmax,            concerning
Cmin with 90% confidence intervals    co-administration with if available                       Atripla
(mechanism)                   (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Sofosbuvir/Velpatasvir                   Sofosbuvir:                          Concomitant (400 mg/100 mg q.d.) +                   AUC: ↔                               administration of Atripla Efavirenz/Emtricitabine/Tenofovir        Cmax: ↑ 38% (↑ 14 to ↑ 67)           and disoproxil                                                                    sofosbuvir/velpatasvir or (600 mg/200 mg/245 mg q.d.)              GS-3310071:                          sofosbuvir/velpatasvir/ AUC: ↔                               voxilaprevir is expected
Cmax: ↔                              to decrease plasma
Cmin: ↔                              concentrations of velpatasvir and
Velpatasvir:                         voxilaprevir.
AUC: ↓ 53% (↓ 61 to ↓ 43)            Co-administration of
Cmax: ↓ 47% (↓ 57 to ↓ 36)           Atripla with
Cmin: ↓ 57% (↓ 64 to ↓ 48)           sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/
Efavirenz:                           voxilaprevir is not
AUC: ↔                               recommended (see
Cmax: ↔                              section 4.4).
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↑ 81% (↑ 68 to ↑ 94)
Cmax: ↑ 77% (↑ 53 to ↑ 104)
Cmin: ↑ 121% (↑ 100 to ↑ 143)
Sofosbuvir/Velpatasvir/Voxilaprevir      Interaction only studied with (400 mg/100 mg/100 mg q.d.) +            sofosbuvir/velpatasvir.
Efavirenz/Emtricitabine/Tenofovir disoproxil                               Expected:
(600 mg/200 mg/245 mg q.d.)              Voxilaprevir:↓
Sofosbuvir                               Sofosbuvir:                          Atripla and sofosbuvir (400 mg q.d.) +                          AUC: ↔                               can be co-administered Efavirenz/Emtricitabine/Tenofovir        Cmax: ↓ 19% (↓ 40 to ↑ 10)           without dose adjustment.
disoproxil
(600 mg/200 mg/245 mg q.d.)              GS-3310071:
AUC: ↔
Cmax: ↓ 23% (↓ 30 to ↑ 16)

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↔
Cmax: ↑ 25% (↑ 8 to ↑ 45)
Cmin: ↔
Medicinal product by therapeutic areas          Effects on drug levels            Recommendation Mean percent change in AUC, Cmax,           concerning
Cmin with 90% confidence intervals    co-administration with if available                      Atripla
(mechanism)                  (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)


Antibiotics
Clarithromycin/Efavirenz                 Clarithromycin:                       The clinical significance (500 mg b.i.d./400 mg q.d.)              AUC: ↓ 39% (↓ 30 to ↓ 46)             of these changes in Cmax: ↓ 26% (↓ 15 to ↓ 35)            clarithromycin plasma levels is not known.
Clarithromycin                        Alternatives to
14-hydroxymetabolite:                 clarithromycin (e.g.
AUC: ↑ 34% (↑ 18 to ↑ 53)             azithromycin) may be
Cmax: ↑ 49% (↑ 32 to ↑ 69)            considered. Other macrolide antibiotics,
Efavirenz:                            such as erythromycin,
AUC: ↔                                have not been studied in
Cmax: ↑ 11% (↑ 3 to ↑ 19)             combination with Atripla.
(CYP3A4 induction)

Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.
Clarithromycin/Emtricitabine             Interaction not studied.
Clarithromycin/Tenofovir disoproxil      Interaction not studied.
Antimycobacterials
Rifabutin/Efavirenz                      Rifabutin:                            The daily dose of (300 mg q.d./600 mg q.d.)                AUC: ↓ 38% (↓ 28 to ↓ 47)             rifabutin should be Cmax: ↓ 32% (↓ 15 to ↓ 46)            increased by 50% when
Cmin: ↓ 45% (↓ 31 to ↓ 56)            given with Atripla.
Consider doubling the
Efavirenz:                            rifabutin dose in
AUC: ↔                                regimens where rifabutin
Cmax: ↔                               is given 2 or 3 times a
Cmin: ↓ 12% (↓ 24 to ↑ 1)             week in combination
(CYP3A4 induction)                    with Atripla. The clinical
Rifabutin/Emtricitabine                  Interaction not studied.              effect of this dose Rifabutin/Tenofovir disoproxil           Interaction not studied.              adjustment has not been adequately evaluated.
Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2).
Rifampicin/Efavirenz                     Efavirenz:                            When Atripla is taken (600 mg q.d./600 mg q.d.)                AUC: ↓ 26% (↓ 15 to ↓ 36)             with rifampicin in Cmax: ↓ 20% (↓ 11 to ↓ 28)            patients weighing 50 kg
Cmin: ↓ 32% (↓ 15 to ↓ 46)            or greater, an additional (CYP3A4 and CYP2B6 induction)         200 mg/day (800 mg


Medicinal product by therapeutic areas          Effects on drug levels             Recommendation Mean percent change in AUC, Cmax,            concerning
Cmin with 90% confidence intervals    co-administration with if available                       Atripla
(mechanism)                   (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Rifampicin/Tenofovir disoproxil          Rifampicin:                          total) of efavirenz may (600 mg q.d./245 mg q.d.)                AUC: ↔                               provide exposure similar Cmax: ↔                              to a daily efavirenz dose of 600 mg when taken
Tenofovir:                           without rifampicin. The
AUC: ↔                               clinical effect of this dose
Cmax: ↔                              adjustment has not been
Rifampicin/Emtricitabine                 Interaction not studied.             adequately evaluated.
Individual tolerability and virological response should be considered when making the dose adjustment
(see section 5.2). No dose adjustment of rifampicin is recommended when given with Atripla.
Antifungals
Itraconazole/Efavirenz                   Itraconazole:                        Since no dose (200 mg b.i.d./600 mg q.d.)              AUC: ↓ 39% (↓ 21 to ↓ 53)            recommendation can be Cmax: ↓ 37% (↓ 20 to ↓ 51)           made for itraconazole
Cmin: ↓ 44% (↓ 27 to ↓ 58)           when used with Atripla,
(decrease in itraconazole            an alternative antifungal concentrations: CYP3A4 induction)    treatment should be considered.
Hydroxyitraconazole:
AUC: ↓ 37% (↓ 14 to ↓ 55)
Cmax: ↓ 35% (↓ 12 to ↓ 52)
Cmin: ↓ 43% (↓ 18 to ↓ 60)

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Itraconazole/Emtricitabine               Interaction not studied.
Itraconazole/Tenofovir disoproxil        Interaction not studied.
Posaconazole/Efavirenz                   Posaconazole:                        Concomitant use of (-/400 mg q.d.)                          AUC: ↓ 50%                           posaconazole and Atripla Cmax: ↓ 45%                          should be avoided unless
(UDP-G induction)                    the benefit to the patient
Posaconazole/Emtricitabine               Interaction not studied.             outweighs the risk.
Posaconazole/Tenofovir disoproxil        Interaction not studied.


Medicinal product by therapeutic areas           Effects on drug levels               Recommendation Mean percent change in AUC, Cmax,              concerning
Cmin with 90% confidence intervals      co-administration with if available                         Atripla
(mechanism)                     (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Voriconazole/Efavirenz                    Voriconazole:                          Since Atripla is a fixed- (200 mg b.i.d./400 mg q.d.)               AUC: ↓ 77%                             dose combination Cmax: ↓ 61%                            product, the dose of efavirenz cannot be
Efavirenz:                             altered; therefore,
AUC: ↑ 44%                             voriconazole and Atripla
Cmax: ↑ 38%                            must not be
(competitive inhibition of oxidative   co-administered.
metabolism)

Co-administration of standard doses of efavirenz and voriconazole is contraindicated (see section 4.3).
Voriconazole/Emtricitabine                Interaction not studied.
Voriconazole/Tenofovir disoproxil         Interaction not studied.
Antimalarials
Artemether/Lumefantrine/Efavirenz         Artemether:                            Since decreased (20/120 mg tablet, 6 doses of 4 tablets   AUC: ↓ 51%                             concentrations of each over 3 days/600 mg q.d.)             Cmax: ↓ 21%                            artemether, dihydroartemisinin, or
Dihydroartemisinin (active             lumefantrine may result metabolite):                           in a decrease of
AUC: ↓ 46%                             antimalarial efficacy,
Cmax: ↓ 38%                            caution is recommended when Atripla and
Lumefantrine:                          artemether/lumefantrine
AUC: ↓ 21%                             tablets are
Cmax: ↔                                co-administered.

Efavirenz:
AUC: ↓ 17%
Cmax: ↔
(CYP3A4 induction)
Artemether/Lumefantrine/Emtricitabine     Interaction not studied.
Artemether/Lumefantrine/Tenofovir         Interaction not studied.
disoproxil
Atovaquone and proguanil                  Atovaquone:                            Concomitant hydrochloride/Efavirenz                   AUC: ↓ 75% (↓ 62 to ↓ 84)              administration of (250/100 mg single dose/600 mg q.d.)      Cmax: ↓ 44% (↓ 20 to ↓ 61)             atovaquone/proguanil with Atripla should be
Proguanil:                             avoided.
AUC: ↓ 43% (↓ 7 to ↓ 65)
Cmax: ↔
Atovaquone and proguanil                  Interaction not studied.
hydrochloride/Emtricitabine
Atovaquone and proguanil                  Interaction not studied.
hydrochloride/Tenofovir disoproxil


Medicinal product by therapeutic areas              Effects on drug levels                Recommendation Mean percent change in AUC, Cmax,               concerning
Cmin with 90% confidence intervals        co-administration with if available                          Atripla
(mechanism)                      (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
ANTICONVULSANTS
Carbamazepine/Efavirenz                      Carbamazepine:                            No dose recommendation (400 mg q.d./600 mg q.d.)                    AUC: ↓ 27% (↓ 20 to ↓ 33)                 can be made for the use Cmax: ↓ 20% (↓ 15 to ↓ 24)                of Atripla with
Cmin: ↓ 35% (↓ 24 to ↓ 44)                carbamazepine. An alternative anticonvulsant
Efavirenz:                                should be considered.
AUC: ↓ 36% (↓ 32 to ↓ 40)                 Carbamazepine plasma
Cmax: ↓ 21% (↓ 15 to ↓ 26)                levels should be
Cmin: ↓ 47% (↓ 41 to ↓ 53)                monitored periodically.
(decrease in carbamazepine concentrations: CYP3A4 induction;
decrease in efavirenz concentrations:
CYP3A4 and CYP2B6 induction)

Co-administration of higher doses of either efavirenz or carbamazepine has not been studied.
Carbamazepine/Emtricitabine                  Interaction not studied.
Carbamazepine/Tenofovir disoproxil           Interaction not studied.
Phenytoin, Phenobarbital, and other          Interaction not studied with efavirenz,   When Atripla is co- anticonvulsants that are substrates of CYP   emtricitabine, or tenofovir disoproxil.   administered with an isozymes                                     There is a potential for reduction or     anticonvulsant that is a increase in the plasma concentrations     substrate of CYP of phenytoin, phenobarbital and other     isozymes, periodic anticonvulsants that are substrates of    monitoring of
CYP isozymes with efavirenz.              anticonvulsant levels should be conducted.
Valproic acid/Efavirenz                      No clinically significant effect on       Atripla and valproic acid (250 mg b.i.d./600 mg q.d.)                  efavirenz pharmacokinetics. Limited       can be co-administered data suggest there is no clinically       without dose adjustment.
significant effect on valproic acid       Patients should be pharmacokinetics.                         monitored for seizure
Valproic acid/Emtricitabine                  Interaction not studied.                  control.
Valproic acid/Tenofovir disoproxil           Interaction not studied.
Vigabatrin/Efavirenz                         Interaction not studied. Clinically       Atripla and vigabatrin or Gabapentin/Efavirenz                         significant interactions are not          gabapentin can be co- expected since vigabatrin and             administered without gabapentin are exclusively eliminated     dose adjustment.
unchanged in the urine and are unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.
Vigabatrin/Emtricitabine                     Interaction not studied.
Gabapentin/Emtricitabine
Vigabatrin/Tenofovir disoproxil              Interaction not studied.
Gabapentin/Tenofovir disoproxil
ANTICOAGULANTS
Warfarin/Efavirenz                           Interaction not studied. Plasma           Dose adjustment of Acenocoumarol/Efavirenz                      concentrations and effects of warfarin    warfarin or or acenocoumarol are potentially          acenocoumarol may be increased or decreased by efavirenz.      required when co-administered with
Atripla.
Medicinal product by therapeutic areas           Effects on drug levels            Recommendation Mean percent change in AUC, Cmax,           concerning
Cmin with 90% confidence intervals    co-administration with if available                      Atripla
(mechanism)                  (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz                      Sertraline:                           When co-administered (50 mg q.d./600 mg q.d.)                  AUC: ↓ 39% (↓ 27 to ↓ 50)             with Atripla, sertraline Cmax: ↓ 29% (↓ 15 to ↓ 40)            dose increases should be
Cmin: ↓ 46% (↓ 31 to ↓ 58)            guided by clinical response.
Efavirenz:
AUC: ↔
Cmax: ↑ 11% (↑ 6 to ↑ 16)
Cmin: ↔
(CYP3A4 induction)
Sertraline/Emtricitabine                  Interaction not studied.
Sertraline/Tenofovir disoproxil           Interaction not studied.
Paroxetine/Efavirenz                      Paroxetine:                           Atripla and paroxetine (20 mg q.d./600 mg q.d.)                  AUC: ↔                                can be co-administered Cmax: ↔                               without dose adjustment.
Cmin: ↔

Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Paroxetine/Emtricitabine               Interaction not studied.
Paroxetine/Tenofovir disoproxil        Interaction not studied.
Fluoxetine/Efavirenz                   Interaction not studied. Since           Atripla and fluoxetine fluoxetine shares a similar metabolic    can be co-administered profile with paroxetine, i.e. a strong   without dose adjustment.
CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.
Fluoxetine/Emtricitabine               Interaction not studied.
Fluoxetine/Tenofovir disoproxil        Interaction not studied.
Norepinephrine and dopamine reuptake inhibitor
Bupropion/Efavirenz                    Bupropion:                               Increases in bupropion [150 mg single dose (sustained         AUC: ↓ 55% (↓ 48 to ↓ 62)                dosage should be guided release)/600 mg q.d.]                  Cmax: ↓ 34% (↓ 21 to ↓ 47)               by clinical response, but the maximum
Hydroxybupropion:                     recommended dose of
AUC: ↔                                bupropion should not be
Cmax: ↑ 50% (↑ 20 to ↑ 80)            exceeded. No dose
(CYP2B6 induction)                    adjustment is necessary
Bupropion/Emtricitabine                   Interaction not studied.              for efavirenz.
Bupropion/Tenofovir disoproxil            Interaction not studied.


Medicinal product by therapeutic areas          Effects on drug levels                  Recommendation Mean percent change in AUC, Cmax,                 concerning
Cmin with 90% confidence intervals          co-administration with if available                            Atripla
(mechanism)                        (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz                      Diltiazem:                                  Dose adjustments of (240 mg q.d./600 mg q.d.)                AUC: ↓ 69% (↓ 55 to ↓ 79)                   diltiazem when co- Cmax: ↓ 60% (↓ 50 to ↓ 68)                  administered with Atripla Cmin: ↓ 63% (↓ 44 to ↓ 75)                  should be guided by clinical response (refer to
Desacetyl diltiazem:                        the Summary of Product
AUC: ↓ 75% (↓ 59 to ↓ 84)                   Characteristics for Cmax: ↓ 64% (↓ 57 to ↓ 69)                  diltiazem).
Cmin: ↓ 62% (↓ 44 to ↓ 75)

N-monodesmethyl diltiazem:
AUC: ↓ 37% (↓ 17 to ↓ 52)
Cmax: ↓ 28% (↓ 7 to ↓ 44)
Cmin: ↓ 37% (↓ 17 to ↓ 52)

Efavirenz:
AUC: ↑ 11% (↑ 5 to ↑ 18)
Cmax: ↑ 16% (↑ 6 to ↑ 26)
Cmin: ↑ 13% (↑ 1 to ↑ 26)
(CYP3A4 induction)
The increase in efavirenz pharmacokinetic parameters is not considered clinically significant.
Diltiazem/Emtricitabine                  Interaction not studied.
Diltiazem/Tenofovir disoproxil           Interaction not studied.
Verapamil, Felodipine, Nifedipine and    Interaction not studied with efavirenz,     Dose adjustments of Nicardipine                              emtricitabine, or tenofovir disoproxil.     calcium channel blockers When efavirenz is co-administered           when co-administered with a calcium channel blocker that is      with Atripla should be a substrate of the CYP3A4 enzyme,           guided by clinical there is a potential for reduction in the   response (refer to the plasma concentrations of the calcium        Summary of Product channel blocker.                            Characteristics for the calcium channel blocker).
LIPID LOWERING MEDICINAL PRODUCTS
HMG Co-A Reductase Inhibitors
Atorvastatin/Efavirenz        Atorvastatin:                                          Cholesterol levels should (10 mg q.d./600 mg q.d.)      AUC: ↓ 43% (↓ 34 to ↓ 50)                              be periodically Cmax: ↓ 12% (↓ 1 to ↓ 26)                              monitored. Dosage adjustments of
2-hydroxy atorvastatin:                     atorvastatin may be
AUC: ↓ 35% (↓ 13 to ↓ 40)                   required when
Cmax: ↓ 13% (↓ 0 to ↓ 23)                   co-administered with Atripla (refer to the
4-hydroxy atorvastatin:                     Summary of Product
AUC: ↓ 4% (↓ 0 to ↓ 31)                     Characteristics for Cmax: ↓ 47% (↓ 9 to ↓ 51)                   atorvastatin).

Total active HMG Co-A reductase inhibitors:
AUC: ↓ 34% (↓ 21 to ↓ 41)
Cmax: ↓ 20% (↓ 2 to ↓ 26)

Medicinal product by therapeutic areas          Effects on drug levels              Recommendation Mean percent change in AUC, Cmax,             concerning
Cmin with 90% confidence intervals      co-administration with if available                        Atripla
(mechanism)                    (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Atorvastatin/Emtricitabine               Interaction not studied.
Atorvastatin/Tenofovir disoproxil        Interaction not studied.
Pravastatin/Efavirenz                    Pravastatin:                            Cholesterol levels should (40 mg q.d./600 mg q.d.)                 AUC: ↓ 40% (↓ 26 to ↓ 57)               be periodically Cmax: ↓ 18% (↓ 59 to ↑ 12)              monitored. Dosage
Pravastatin/Emtricitabine                Interaction not studied.                adjustments of Pravastatin/Tenofovir disoproxil         Interaction not studied.                pravastatin may be required when co-administered with
Atripla (refer to the
Summary of Product
Characteristics for pravastatin).
Simvastatin/Efavirenz                    Simvastatin:                            Cholesterol levels should (40 mg q.d./600 mg q.d.)                 AUC: ↓ 69% (↓ 62 to ↓ 73)               be periodically Cmax: ↓ 76% (↓ 63 to ↓ 79)              monitored. Dosage adjustments of
Simvastatin acid:                       simvastatin may be
AUC: ↓ 58% (↓ 39 to ↓ 68)               required when
Cmax: ↓ 51% (↓ 32 to ↓ 58)              co-administered with
Atripla (refer to the
Total active HMG Co-A reductase         Summary of Product inhibitors:                             Characteristics for
AUC: ↓ 60% (↓ 52 to ↓ 68)               simvastatin).
Cmax: ↓ 62% (↓ 55 to ↓ 78)
(CYP3A4 induction)

Co-administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz
AUC or Cmax values.
Simvastatin/Emtricitabine                Interaction not studied.
Simvastatin/Tenofovir disoproxil         Interaction not studied.
Rosuvastatin/Efavirenz                   Interaction not studied. Rosuvastatin   Atripla and rosuvastatin is largely excreted unchanged via the   can be co-administered faeces, therefore interaction with      without dose adjustment.
efavirenz is not expected.
Rosuvastatin/Emtricitabine               Interaction not studied.
Rosuvastatin/Tenofovir disoproxil        Interaction not studied.


Medicinal product by therapeutic areas            Effects on drug levels                Recommendation Mean percent change in AUC, Cmax,               concerning
Cmin with 90% confidence intervals        co-administration with if available                          Atripla
(mechanism)                      (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
HORMONAL CONTRACEPTIVES
Oral:                                      Ethinyloestradiol:                        A reliable method of Ethinyloestradiol+Norgestimate/Efavirenz   AUC: ↔                                    barrier contraception (0.035 mg+0.25 mg q.d./600 mg q.d.)        Cmax: ↔                                   must be used in addition Cmin: ↓ 8% (↑ 14 to ↓ 25)                 to hormonal contraceptives
Norelgestromin (active metabolite):       (see section 4.6).
AUC: ↓ 64% (↓ 62 to ↓ 67)
Cmax: ↓ 46% (↓ 39 to ↓ 52)
Cmin: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (active metabolite):
AUC: ↓ 83% (↓ 79 to ↓ 87)
Cmax: ↓ 80% (↓ 77 to ↓ 83)
Cmin: ↓ 86% (↓ 80 to ↓ 90)
(induction of metabolism)

Efavirenz: no clinically significant interaction.
The clinical significance of these effects is not known.
Ethinyloestradiol/Tenofovir disoproxil     Ethinyloestradiol:
(-/245 mg q.d.)                            AUC: ↔
Cmax: ↔
Tenofovir:
AUC: ↔
Cmax: ↔
Norgestimate/Ethinyloestradiol/            Interaction not studied.
Emtricitabine
Injection:                                 In a 3-month drug interaction study,      Because of the limited Depomedroxyprogesterone acetate            no significant differences in MPA         information available, a (DMPA)/Efavirenz                           pharmacokinetic parameters were           reliable method of barrier (150 mg IM single dose DMPA)               found between subjects receiving          contraception must be efavirenz-containing antiretroviral       used in addition to therapy and subjects receiving no         hormonal contraceptives antiretroviral therapy. Similar results   (see section 4.6).
were found by other investigators,
although the MPA plasma levels were more variable in the second study. In both studies, plasma progesterone levels for subjects receiving efavirenz and DMPA remained low consistent with suppression of ovulation.
DMPA/Tenofovir disoproxil                  Interaction not studied.
DMPA/Emtricitabine                         Interaction not studied.
Implant:                                   Decreased exposure of etonogestrel        A reliable method of Etonogestrel/Efavirenz                     may be expected (CYP3A4                   barrier contraception induction). There have been               must be used in addition occasional post-marketing reports of      to hormonal contraceptive failure with etonogestrel   contraceptives in efavirenz-exposed patients.            (see section 4.6).
Etonogestrel/Tenofovir disoproxil          Interaction not studied.
Etonogestrel/Emtricitabine                 Interaction not studied.
Medicinal product by therapeutic areas          Effects on drug levels               Recommendation Mean percent change in AUC, Cmax,              concerning
Cmin with 90% confidence intervals       co-administration with if available                         Atripla
(mechanism)                     (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
IMMUNOSUPPRESSANTS
Immunosuppressants metabolised by        Interaction not studied.                 Dose adjustments of the CYP3A4 (e.g. cyclosporine, tacrolimus,   ↓ exposure of the immunosuppressant      immunosuppressant may sirolimus)/Efavirenz                     may be expected (CYP3A4                  be required. Close induction).                              monitoring of
These immunosuppressants are not         immunosuppressant anticipated to impact exposure of        concentrations for at least efavirenz.                               two weeks (until stable
Tacrolimus/Emtricitabine/Tenofovir       Tacrolimus:                              concentrations are disoproxil                               AUC: ↔                                   reached) is recommended (0.1 mg/kg q.d./200 mg/245 mg q.d.)      Cmax: ↔                                  when starting or stopping C24h: ↔                                  treatment with Atripla.

Emtricitabine:
AUC: ↔
Cmax: ↔
C24h: ↔

Tenofovir disoproxil:
AUC: ↔
Cmax: ↔
C24h: ↔
OPIOIDS
Methadone/Efavirenz                      Methadone:                               Concomitant (35-100 mg q.d./600 mg q.d.)             AUC: ↓ 52% (↓ 33 to ↓ 66)                administration with Cmax: ↓ 45% (↓ 25 to ↓ 59)               Atripla should be avoided (CYP3A4 induction)                       due to the risk for QTc prolongation (see section
In a study of HIV infected intravenous   4.3).
drug users, co-administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.
Methadone/Tenofovir disoproxil           Methadone:
(40-110 mg q.d./245 mg q.d.)             AUC: ↔
Cmax: ↔
Cmin: ↔

Tenofovir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Methadone/Emtricitabine                  Interaction not studied.


Medicinal product by therapeutic areas                  Effects on drug levels            Recommendation Mean percent change in AUC, Cmax,           concerning
Cmin with 90% confidence intervals    co-administration with if available                      Atripla
(mechanism)                  (efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
245 mg)
Buprenorphine/naloxone/Efavirenz                 Buprenorphine:                       Despite the decrease in AUC: ↓ 50%                           buprenorphine exposure,
no patients exhibited
Norbuprenorphine:                    withdrawal symptoms.
AUC: ↓ 71%                           Dose adjustment of buprenorphine may not
Efavirenz:                           be necessary when
No clinically significant            co-administered with pharmacokinetic interaction.         Atripla.
Buprenorphine/naloxone/Emtricitabine             Interaction not studied.
Buprenorphine/naloxone/Tenofovir                 Interaction not studied.
disoproxil
1 The predominant circulating metabolite of sofosbuvir.

Studies conducted with other medicinal products

There were no clinically significant pharmacokinetic interactions when efavirenz was administered with azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, zidovudine, aluminium/magnesium hydroxide antacids, famotidine or fluconazole. The potential for interactions with efavirenz and other azole antifungals, such as ketoconazole, has not been studied.

There were no clinically significant pharmacokinetic interactions when emtricitabine was administered with stavudine, zidovudine or famciclovir. There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine or ribavirin.