Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

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. In vitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initially increase the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates with 
narrow therapeutic index (see section 4.3). 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).

QT Prolonging Drugs
Efavirenz is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval and 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).

Paediatric population
Interaction studies have only been performed in adults.

Contraindications of concomitant use
Efavirenz 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).

Efavirenz must not be administered with elbasvir/grazoprevir due to the expected significant decreases in elbasvir and grazoprevir plasma concentrations caused by induction of drug metabolising enzymes and/or transport proteins and which are expected to result in the loss of virologic response of elbasvir/grazoprevir (see section 4.5).

St. John’s wort (Hypericum perforatum)
Co-administration of efavirenz 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 and the dose of efavirenz may need adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of treatment (see section 4.3).

Other interactions
Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or “q12h”). If available, 90 % or 95 % confidence intervals are shown in parentheses. Studies were conducted in healthy subjects unless otherwise noted.


Table 2: Interactions between efavirenz and other medicinal products in adults 
Medicinal product by therapeutic areas            Effects on drug levels         Recommendation (dose)                            Mean percent change in             concerning AUC, Cmax, Cmin with         co-administration with confidence intervals if             efavirenz availablea
(mechanism)
ANTI-INFECTIVES
HIV antivirals
Protease inhibitors (PI)
Atazanavir/ ritonavir/Efavirenz                   Atazanavir (pm):               Co-administration of (400 mg once daily/100 mg once daily/600 mg       AUC: ↔* (↓ 9 to ↑ 10)          efavirenz with once daily, all administered with food)           Cmax: ↑ 17 %* (↑ 8 to ↑ 27)    atazanavir/ritonavir is not Cmin: ↓ 42 %* (↓ 31 to ↓ 51)   recommended. If the co-administration of
Atazanavir/ritonavir/Efavirenz                    Atazanavir (pm):               atazanavir with an NNRTI (400 mg once daily/200 mg once daily/600 mg       AUC: ↔*/** (↓ 10 to ↑ 26)      is required, an increase in once daily, all administered with food)           Cmax: ↔*/** (↓ 5 to ↑ 26)      the dose of both atazanavir Cmin: ↑ 12 %*/** (↓ 16 to      and ritonavir to 400 mg
↑ 49)                          and 200 mg, respectively,
(CYP3A4 induction).            in combination with
* When compared to             efavirenz could be atazanavir 300 mg/ritonavir    considered with close
100 mg once daily in the       clinical monitoring.
evening without efavirenz.
This decrease in atazanavir
Cmin might negatively impact the efficacy of atazanavir.
** based on historical comparison

Darunavir/ritonavir/Efavirenz                     Darunavir:                     Efavirenz in combination (300 mg twice daily*/100 mg twice daily/600 mg    AUC : ↓ 13 %                   with darunavir/ritonavir once daily)                                       Cmin : ↓ 31 %                  800/100 mg once daily Cmax: ↓ 15%                    may result in suboptimal
*lower than recommended doses, similar findings   (CYP3A4 induction)             darunavir Cmin. If are expected with recommended doses.              Efavirenz:                     efavirenz is to be used in AUC : ↑ 21 %                   combination with
Cmin: ↑ 17 %                   darunavir/ritonavir, the
Cmax: ↑ 15%                    darunavir/ritonavir
(CYP3A4 inhibition)           600/100 mg twice daily regimen should be used.
This combination should be used with caution.
See also ritonavir row below.
Fosamprenavir/ritonavir/Efavirenz                 No clinically significant      No dose adjustment is (700 mg twice daily/100 mg twice daily/600 mg     pharmacokinetic interaction.   necessary for any of these once daily)                                                                      medicinal products.
See also ritonavir row below.
Fosamprenavir/Nelfinavir/Efavirenz                Interaction not                No dose adjustment is studied                        necessary for any of these medicinal products.
Fosamprenavir/Saquinavir/Efavirenz                Interaction not studied        Not recommended, as the exposure to both PIs is expected to be significantly decreased.


Medicinal product by therapeutic areas          Effects on drug levels          Recommendation (dose)                          Mean percent change in              concerning AUC, Cmax, Cmin with          co-administration with confidence intervals if             efavirenz availablea
(mechanism)
Indinavir/Efavirenz                             Indinavir:                       While the clinical (800 mg q8h/200 mg once daily)                  AUC: ↓ 31 % (↓ 8 to ↓ 47)        significance of decreased Cmin: ↓ 40 %                     indinavir concentrations
A similar reduction in           has not been established,
indinavir exposures was          the magnitude of the observed when indinavir          observed pharmacokinetic
1,000 mg q8h was given with      interaction should be efavirenz 600 mg daily.          taken into consideration
(CYP3A4 induction)               when choosing a regimen
Efavirenz:                       containing both efavirenz
No clinically significant        and indinavir.
pharmacokinetic interaction
No dose adjustment is
Indinavir/ritonavir/Efavirenz                   Indinavir:                       necessary for efavirenz (800 mg twice daily/100 mg twice daily/600 mg   AUC: ↓ 25 % (↓ 16 to ↓ 32) b     when given with indinavir once daily)                                     Cmax: ↓ 17 % (↓ 6 to ↓ 26)b      or indinavir/ritonavir.
Cmin: ↓ 50 % (↓ 40 to ↓ 59)b
Efavirenz:
No clinically significant        See also ritonavir row pharmacokinetic interaction      below.
The geometric mean Cmin for indinavir (0.33 mg/l) when given with ritonavir and efavirenz was higher than the mean historical Cmin
(0.15 mg/l) when indinavir was given alone at 800 mg q8h. In HIV-1 infected patients (n = 6), the pharmacokinetics of indinavir and efavirenz were generally comparable to these uninfected volunteer data.
Lopinavir/ritonavir soft capsules or oral       Substantial decrease in          With efavirenz, an solution/Efavirenz                              lopinavir exposure.              increase of the lopinavir/ritonavir soft capsule or oral solution
Lopinavir/ritonavir tablets/ Efavirenz                                           doses by 33 % should be considered
(4 capsules/~6.5 ml twice
(400/100 mg twice daily/600 mg once daily)      Lopinavir concentrations:        daily instead of ↓ 30-40 %                        3 capsules/5 ml twice daily). Caution is
(500/125 mg twice daily/600 mg once daily)      Lopinavir concentrations:        warranted since this dose similar to lopinavir/ritonavir   adjustment might be
400/100 mg twice daily           insufficient in some without efavirenz                patients. The dose of lopinavir/ritonavir tablets should be increased to
500/125 mg twice daily when co-administered with efavirenz 600 mg once daily.
See also ritonavir row below.


Medicinal product by therapeutic areas       Effects on drug levels           Recommendation (dose)                       Mean percent change in               concerning AUC, Cmax, Cmin with          co-administration with confidence intervals if              efavirenz availablea
(mechanism)
Nelfinavir/Efavirenz                        Nelfinavir:                       No dose adjustment is (750 mg q8h/600 mg once daily)              AUC: ↑ 20 % (↑ 8 to ↑ 34)         necessary for either Cmax: ↑ 21 % (↑ 10 to ↑ 33)       medicinal product.
The combination was generally well tolerated.
Ritonavir/Efavirenz                         Ritonavir:                        When using efavirenz (500 mg twice daily/600 mg once daily)      Morning AUC: ↑ 18 % (↑ 6 to       with low-dose ritonavir, ↑ 33)                             the possibility of an
Evening AUC: ↔                    increase in the incidence
Morning Cmax: ↑ 24 % (↑ 12 to     of efavirenz-associated
↑ 38)                             adverse events should be
Evening Cmax: ↔                   considered, due to
Morning Cmin: ↑ 42 % (↑ 9 to      possible
↑ 86)b                            pharmacodynamic
Evening Cmin: ↑ 24 % (↑ 3 to      interaction.
↑ 50)b
Efavirenz:
AUC: ↑ 21 % (↑ 10 to ↑ 34)
Cmax: ↑ 14 % (↑ 4 to ↑ 26)
Cmin: ↑ 25 % (↑ 7 to ↑ 46)b
(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.
Saquinavir/ritonavir/Efavirenz              Interaction not studied.          No data are available to make a dose recommendation. See also ritonavir row above. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz                         Maraviroc:                        Refer to the Summary of (100 mg twice daily/600 mg once daily)      AUC12: ↓ 45 % (↓ 38 to            Product Characteristics for ↓ 51)                             the medicinal product
Cmax: ↓ 51 % (↓ 37 to ↓ 62)       containing maraviroc.
Efavirenz concentrations not measured, no effect is expected.


Medicinal product by therapeutic areas      Effects on drug levels           Recommendation (dose)                      Mean percent change in               concerning AUC, Cmax, Cmin with           co-administration with confidence intervals if               efavirenz availablea
(mechanism)
Integrase strand transfer inhibitor
Raltegravir/Efavirenz                       Raltegravir:                     No dose adjustment is (400 mg single dose/ - )                    AUC: ↓ 36 %                      necessary for raltegravir.
C12: ↓ 21 %
Cmax: ↓ 36 %
(UGT1A1 induction)
NRTIs and NNRTIs
NRTIs/Efavirenz                             Specific interaction studies     No dose adjustment is have not been performed with     necessary for either efavirenz and NRTIs other        medicinal product.
than lamivudine, zidovudine,
and tenofovir disoproxil.
Clinically significant interactions are not expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to 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 efavirenz and another
NNRTI is not recommended.
Hepatitis C antivirals
Boceprevir/Efavirenz                        Boceprevir:                      Plasma trough (800 mg 3 times daily/600 mg once daily)    AUC: ↔ 19%*                      concentrations of Cmax: ↔ 8%                       boceprevir were decreased
Cmin: ↓ 44%                      when administered with
Efavirenz:                       efavirenz. The clinical
AUC: ↔ 20%                       outcome of this observed
Cmax: ↔ 11%                      reduction of boceprevir
(CYP3A induction - effect on     trough concentrations has boceprevir)                      not been directly assessed.
*0-8 hours
No effect (↔) equals a decrease in mean ratio estimate of ≤20% or increase in mean ratio estimate of
≤25%
Telaprevir/Efavirenz                        Telaprevir (relative to 750 mg   If efavirenz and telaprevir (1,125 mg q8h/600 mg once daily)            q8h):                            are co-administered, AUC: ↓ 18% (↓ 8 to ↓ 27)         telaprevir 1,125 mg every
Cmax: ↓ 14% (↓ 3 to ↓ 24)        8 hours should be used.
Cmin: ↓ 25% (↓ 14 to ↓ 34)%
Efavirenz:
AUC: ↓ 18% (↓ 10 to ↓ 26)
Cmax: ↓ 24% (↓ 15 to ↓ 32)
Cmin: ↓ 10% (↑ 1 to ↓ 19)%
(CYP3A induction by efavirenz)

Medicinal product by therapeutic areas       Effects on drug levels       Recommendation (dose)                       Mean percent change in           concerning AUC, Cmax, Cmin with      co-administration with confidence intervals if          efavirenz availablea
(mechanism)
Simeprevir/Efavirenz                        Simeprevir:                   Concomitant (150 mg once daily /600 mg once daily)      AUC: ↓ 71% (↓ 67 to ↓ 74)     administration of Cmax: ↓ 51% (↓ 46 to ↓ 56)    simeprevir with efavirenz
Cmin: ↓ 91% (↓ 88 to ↓ 92)    resulted in significantly
Efavirenz:                    decreased plasma
AUC: ↔                        concentrations
Cmax: ↔                       of simeprevir due to
Cmin: ↔                       CYP3A
No effect (↔) equals a        induction by efavirenz,
decrease in                   which may result in loss of mean ratio estimate of ≤20%   therapeutic or increase in mean ratio     effect of simeprevir. Co- estimate of≤25% (CYP3A4       administration enzyme induction)             of simeprevir with efavirenz is not recommended.
Elbasvir/grazoprevir                        Elbasvir:                     Concomitant AUC: ↓54%                     administration of
Cmax: ↓45%                    STOCRIN with elbasvir/grazoprevir is
Grazoprevir:                  contraindicated (see
AUC: ↓83%                     section 4.3) because it may lead to loss of virologic
Cmax: ↓87% response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by
CYP3A4 or P-gp induction (refer to the
Summary of Product
Characteristics for elbasvir/grazoprevir for additional information).


Medicinal product by therapeutic areas      Effects on drug levels         Recommendation (dose)                      Mean percent change in             concerning AUC, Cmax, Cmin with        co-administration with confidence intervals if            efavirenz availablea
(mechanism)
Sofosbuvir/velpatasvir                      Sofosbuvir:                    Coadministration of sofosbuvir/velpatasvir/voxilaprevir         Cmax ↑38%                      efavirenz/emtricitabine/ tenofovir disoproxil with
Velpatasvir                    sofosbuvir/velpatasvir has
AUC ↓53%                       been shown to
Cmax ↓47%                      significantly decrease plasma concentrations of
Cmin ↓57% velpatasvir due to CYP3A induction by efavirenz,
Expected: which may result in loss of
↓ Voxilaprevir                 therapeutic effect of velpatasvir. Although not studied, a similar decrease in voxilaprevir exposure is anticipated.
Coadministration of
STOCRIN with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/ voxilaprevir is not recommended (refer to the
Summary of Product
Characteristics for sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/ voxilaprevir for additional information).
Glecaprevir/pibrentasvir                    ↓glecaprevir                   Concomitant ↓pibrentasvir                  administration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Co-administration of glecaprevir/pibrentasvir with efavirenz is not recommended.
Refer to the prescribing information for glecaprevir/pibrentasvir for more information.
Antibiotics
Azithromycin/Efavirenz                      No clinically significant      No dose adjustment is (600 mg single dose/400 mg once daily)      pharmacokinetic interaction.   necessary for either medicinal product.


Medicinal product by therapeutic areas       Effects on drug levels       Recommendation (dose)                       Mean percent change in           concerning AUC, Cmax, Cmin with       co-administration with confidence intervals if          efavirenz availablea
(mechanism)
Clarithromycin/Efavirenz                     Clarithromycin:               The clinical significance (500 mg q12h/400 mg once daily)              AUC: ↓ 39 % (↓ 30 to ↓ 46)    of these changes in Cmax: ↓ 26 % (↓ 15 to ↓ 35)   clarithromycin plasma
Clarithromycin                levels is not known.
14-hydroxymetabolite:         Alternatives to
AUC: ↑ 34 % (↑ 18 to ↑ 53)    clarithromycin (e.g.
Cmax: ↑ 49 % (↑ 32 to ↑ 69)   azithromycin) may be
Efavirenz:                    considered. No dose
AUC: ↔                        adjustment is necessary
Cmax: ↑ 11 % (↑ 3 to ↑ 19)    for efavirenz.
(CYP3A4 induction)
Rash developed in 46 % of uninfected volunteers receiving efavirenz and clarithromycin.
Other macrolide antibiotics (e.g.,           Interaction not studied.      No data are available to erythromycin)/Efavirenz                                                    make a dose recommendation.
Antimycobacterials
Rifabutin/Efavirenz                          Rifabutin:                     The daily dose of (300 mg once daily/600 mg once daily)        AUC: ↓ 38 % (↓ 28 to ↓ 47)     rifabutin should be Cmax: ↓ 32 % (↓ 15 to ↓ 46)    increased by 50 % when
Cmin: ↓ 45 % (↓ 31 to ↓ 56)    administered with
Efavirenz:                     efavirenz. Consider
AUC: ↔                         doubling the rifabutin
Cmax: ↔                        dose in regimens where
Cmin: ↓ 12 % (↓ 24 to ↑ 1)     rifabutin is given 2 or
(CYP3A4 induction)             3 times a week in combination with efavirenz. The clinical effect of this dose adjustment has not been adequately evaluated.
Individual tolerability and virological response should be considered when making the dose adjustment (see section
5.2).


Medicinal product by therapeutic areas       Effects on drug levels       Recommendation (dose)                      Mean percent change in            concerning AUC, Cmax, Cmin with       co-administration with confidence intervals if           efavirenz availablea
(mechanism)
Rifampicin/Efavirenz                        Efavirenz:                     When taken with (600 mg once daily/600 mg once daily)       AUC: ↓ 26 % (↓ 15 to ↓ 36)     rifampicin in patients Cmax: ↓ 20 % (↓ 11 to ↓ 28)    weighing 50 kg or
Cmin: ↓ 32 % (↓ 15 to ↓ 46)    greater, increasing
(CYP3A4 and CYP2B6             efavirenz daily dose to induction)                     800 mg may provide exposure similar to a daily dose of 600 mg,
when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated.
Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2). No dose adjustment is necessary for rifampicin including
600 mg.

As the 600 mg tablet is the only dose form available in the local marketplace, the recommended dose adjustments for co- administration of efavirenz and rifampicin for patients weighing 50 kg or greater is not possible.

Antifungals
Itraconazole/Efavirenz                      Itraconazole:                 Since no dose (200 mg q12h/600 mg once daily)             AUC: ↓ 39 % (↓ 21 to ↓ 53)    recommendation for Cmax: ↓ 37 % (↓ 20 to ↓ 51)   itraconazole can be made,
Cmin: ↓ 44 % (↓ 27 to ↓ 58)   alternative antifungal
(decrease in itraconazole     treatment should be concentrations: CYP3A4        considered.
induction)
Hydroxyitraconazole:
AUC: ↓ 37 % (↓ 14 to ↓ 55)
Cmax: ↓ 35 % (↓ 12 to ↓ 52)
Cmin: ↓ 43 % (↓ 18 to ↓ 60)
Efavirenz:
No clinically significant pharmacokinetic change.


Medicinal product by therapeutic areas         Effects on drug levels         Recommendation (dose)                         Mean percent change in             concerning AUC, Cmax, Cmin with         co-administration with confidence intervals if            efavirenz availablea
(mechanism)
Posaconazole/Efavirenz                         Posaconazole:                  Concomitant use of --/400 mg once daily                           AUC: ↓ 50 %                    posaconazole and Cmax: ↓ 45 %                   efavirenz should be
(UDP-G induction)              avoided unless the benefit to the patient outweighs the risk.



Voriconazole/Efavirenz                         Voriconazole:                  When efavirenz is (200 mg twice daily/400 mg once daily)         AUC: ↓ 77 %                    co-administered with Cmax: ↓ 61 %                   voriconazole, the
Efavirenz:                     voriconazole maintenance
AUC: ↑ 44 %                    dose must be increased to
Voriconazole/Efavirenz                         Cmax: ↑ 38 %                   400 mg twice daily and (400 mg twice daily/300 mg once daily)         Voriconazole:                  the efavirenz dose must be AUC: ↓ 7 % (↓ 23 to ↑ 13) *    reduced by 50 %, i.e., to
Cmax: ↑ 23 % (↓ 1 to ↑ 53) *   300 mg once daily. When
Efavirenz:                     treatment with
AUC: ↑ 17 % (↑ 6 to ↑ 29) **   voriconazole is stopped,
Cmax: ↔**                      the initial dose of
*compared to 200 mg twice      efavirenz should be daily alone                    restored.
** compared to 600 mg once daily alone                    As the 600 mg tablet is
(competitive inhibition of     the only dose form oxidative metabolism)          available in the local marketplace, the recommended dose adjustments for co- administration of efavirenz and voriconazole are not possible.


Fluconazole/Efavirenz                          No clinically significant      No dose adjustment is (200 mg once daily/400 mg once daily)          pharmacokinetic interaction    necessary for either medicinal product.
Ketoconazole and other imidazole antifungals   Interaction not studied        No data are available to make a dose recommendation.


Medicinal product by therapeutic areas               Effects on drug levels          Recommendation (dose)                               Mean percent change in              concerning AUC, Cmax, Cmin with          co-administration with confidence intervals if              efavirenz availablea
(mechanism)
ANTIMALARIAL
Artemether/lumefantrine/                            Artemether:                      Since decreased Efavirenz                                           AUC: ↓ 51%                       concentrations of (20/120 mg tablet, 6 doses of 4 tablets each over   Cmax: ↓ 21%                      artemether, 3 days/600 mg once daily)                           Dihydroartemisinin:              dihydroartemisinin, or AUC: ↓ 46%                       lumefantrine may result in
Cmax: ↓ 38%                      a decrease of antimalarial
Lumefantrine:                    efficacy, caution is
AUC: ↓ 21%                       recommended when
Cmax: ↔                          efavirenz and
Efavirenz:                       artemether/lumefantrine
AUC: ↓ 17%                       tablets are coadministered
Cmax: ↔
(CYP3A4 induction)
Atovaquone and proguanil                            Atovaquone:                      Concomitant hydrochloride/Efavirenz                             AUC: ↓ 75% (↓ 62 to ↓ 84)        administration of (250/100 mg single dose/600 mg once daily)          Cmax: ↓ 44% (↓ 20 to ↓ 61)       atovaquone/proguanil with efavirenz should be
Proguanil:                       avoided.
AUC: ↓ 43% (↓ 7 to ↓ 65)
Cmax: ↔

ACID REDUCING AGENTS
Aluminium hydroxide-magnesium hydroxide-             Neither                         Co-administration of simethicone antacid/Efavirenz                        aluminium/magnesium             efavirenz with medicinal (30 mL single dose/400 mg single dose)               hydroxide antacids nor          products that alter gastric Famotidine/Efavirenz                                 famotidine altered the          pH would not be expected (40 mg single dose/400 mg single dose)               absorption of efavirenz.        to affect efavirenz absorption.
ANTIANXIETY AGENTS
Lorazepam/Efavirenz                                  Lorazepam:                      No dose adjustment is (2 mg single dose/600 mg once daily)                 AUC: ↑ 7 % (↑ 1 to ↑ 14)        necessary for either Cmax: ↑ 16 % (↑ 2 to ↑ 32)      medicinal product.
These changes are not considered clinically significant.
ANTICOAGULANTS
Warfarin/Efavirenz                                   Interaction not studied.        Dose adjustment of Acenocoumarol/Efavirenz                              Plasma concentrations and       warfarin or effects of warfarin or          acenocoumarol may be acenocoumarol are potentially   required.
increased or decreased by efavirenz.


Medicinal product by therapeutic areas          Effects on drug levels             Recommendation (dose)                          Mean percent change in                 concerning AUC, Cmax, Cmin with             co-administration with confidence intervals if                 efavirenz availablea
(mechanism)
ANTICONVULSANTS
Carbamazepine/Efavirenz                         Carbamazepine:                      No dose recommendation (400 mg once daily/600 mg once daily)           AUC: ↓ 27 % (↓ 20 to ↓ 33)          can be made. An Cmax: ↓ 20 % (↓ 15 to ↓ 24)         alternative
Cmin: ↓ 35 % (↓ 24 to ↓ 44)         anticonvulsant should be
Efavirenz:                          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)
The steady-state AUC, Cmax and
Cmin of the active carbamazepine epoxide metabolite remained unchanged. Co-administration of higher doses of either efavirenz or carbamazepine has not been studied.
Phenytoin, Phenobarbital, and other             Interaction not studied. There is   When efavirenz is anticonvulsants that are substrates of CYP450   a potential for reduction or        co-administered with an isoenzymes                                      increase in the plasma              anticonvulsant that is a concentrations of phenytoin,        substrate of CYP450 phenobarbital and other             isoenzymes, periodic anticonvulsants that are            monitoring of substrates of CYP450                anticonvulsant levels isoenzymes when                     should be conducted.
co-administered with efavirenz.
Valproic acid/Efavirenz                         No clinically significant effect    No dose adjustment is (250 mg twice daily/600 mg once daily)          on efavirenz pharmacokinetics.      necessary for efavirenz.
Limited data suggest there is no    Patients should be clinically significant effect on    monitored for seizure valproic acid pharmacokinetics.     control.
Vigabatrin/Efavirenz                            Interaction not studied.            No dose adjustment is Gabapentin/Efavirenz                            Clinically significant              necessary for any of interactions are not expected       these medicinal products.
since vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.


Medicinal product by therapeutic areas             Effects on drug levels         Recommendation (dose)                             Mean percent change in             concerning AUC, Cmax, Cmin with         co-administration with confidence intervals if             efavirenz availablea
(mechanism)
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz                            Sertraline:                       Sertraline dose increases (50 mg once daily/600 mg once daily)           AUC: ↓ 39 % (↓ 27 to ↓ 50)         should be guided by Cmax: ↓ 29 % (↓ 15 to ↓ 40)        clinical response.
Cmin: ↓ 46 % (↓ 31 to ↓ 58)        No dose adjustment is
Efavirenz:                        necessary for efavirenz.
AUC: ↔
Cmax: ↑ 11 % (↑ 6 to ↑ 16)
Cmin: ↔
(CYP3A4 induction)
Paroxetine/Efavirenz                            No clinically significant         No dose adjustment is (20 mg once daily/600 mg once daily)            pharmacokinetic interaction       necessary for either medicinal product.
Fluoxetine/Efavirenz                             Interaction not studied. Since   No dose adjustment is fluoxetine shares a similar      necessary for either metabolic profile with           medicinal product.
paroxetine, i.e. a strong
CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.
Norepinephrine and dopamine reuptake inhibitor
Bupropion/Efavirenz                             Bupropion:                        Increases in bupropion [150 mg single dose (sustained release)/600 mg AUC: ↓ 55% (↓ 48 to ↓ 62)          dosage should be guided once daily]                                    Cmax: ↓ 34% (↓ 21 to ↓ 47)         by clinical response, but Hydroxybupropion:                 the maximum
AUC: ↔                            recommended dose of
Cmax: ↑ 50% (↑ 20 to ↑ 80)        bupropion should not be
(CYP2B6 induction)                exceeded. No dose adjustment is necessary for efavirenz.
ANTIHISTAMINES
Cetirizine/Efavirenz                              Cetirizine:AUC: ↔               No dose adjustment is (10 mg single dose/600 mg once daily)             Cmax: ↓ 24 % (↓ 18 to ↓ 30)     necessary for either These changes are not           medicinal product.
considered clinically significant.
Efavirenz:
No clinically significant pharmacokinetic interaction.


Medicinal product by therapeutic areas       Effects on drug levels          Recommendation (dose)                       Mean percent change in              concerning AUC, Cmax, Cmin with          co-administration with confidence intervals if              efavirenz availablea
(mechanism)
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz                          Diltiazem:                       Dose adjustments of (240 mg once daily/600 mg once daily)       AUC: ↓ 69 % (↓ 55 to ↓ 79)        diltiazem should be Cmax: ↓ 60 % (↓ 50 to ↓ 68)       guided by clinical
Cmin: ↓ 63 % (↓ 44 to ↓ 75)       response (refer to the
Desacetyl diltiazem:              Summary of Product
AUC: ↓ 75 % (↓ 59 to ↓ 84)        Characteristics for
Cmax: ↓ 64 % (↓ 57 to ↓ 69)       diltiazem). No dose
Cmin: ↓ 62 % (↓ 44 to ↓ 75)       adjustment is necessary
N-monodesmethyl diltiazem:        for efavirenz.
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.
Verapamil, Felodipine, Nifedipine and        Interaction not studied. When    Dose adjustments of Nicardipine                                  efavirenz is co-administered     calcium channel blockers with a calcium channel blocker   should be guided by that is a substrate of the       clinical response (refer to
CYP3A4 enzyme, there is a        the Summary of Product potential for reduction in the   Characteristics for the plasma concentrations of the     calcium channel calcium channel blocker.         blocker).
LIPID LOWERING MEDICINAL PRODUCTS
HMG Co-A Reductase Inhibitors
Atorvastatin/Efavirenz                       Atorvastatin:                    Cholesterol levels should (10 mg once daily/600 mg once daily)        AUC: ↓ 43 % (↓ 34 to ↓ 50)        be periodically Cmax: ↓ 12 % (↓ 1 to ↓ 26)       monitored. Dose
2-hydroxy atorvastatin:           adjustments of
AUC: ↓ 35 % (↓ 13 to ↓ 40)        atorvastatin may be
Cmax: ↓ 13 % (↓ 0 to ↓ 23)        required (refer to the
4-hydroxy atorvastatin:           Summary of Product
AUC: ↓ 4 % (↓ 0 to ↓ 31)          Characteristics for the
Cmax: ↓ 47 % (↓ 9 to ↓ 51)        atorvastatin). No dose
Total active HMG Co-A            adjustment is necessary reductase inhibitors:            for efavirenz.
AUC: ↓ 34 % (↓ 21 to ↓ 41)
Cmax: ↓ 20 % (↓ 2 to ↓ 26)


Medicinal product by therapeutic areas       Effects on drug levels             Recommendation (dose)                       Mean percent change in                 concerning AUC, Cmax, Cmin with            co-administration with confidence intervals if                efavirenz availablea
(mechanism)
Pravastatin/Efavirenz                        Pravastatin:                        Cholesterol levels should (40 mg once daily/600 mg once daily)        AUC: ↓ 40 % (↓ 26 to ↓ 57)           be periodically Cmax: ↓ 18 % (↓ 59 to ↑ 12)         monitored. Dose adjustments of pravastatin may be required (refer to the
Summary of Product
Characteristics for pravastatin). No dose adjustment is necessary for efavirenz.
Simvastatin/Efavirenz                        Simvastatin:                        Cholesterol levels should (40 mg once daily/600 mg once daily)         AUC: ↓ 69 % (↓ 62 to ↓ 73)          be periodically Cmax: ↓ 76 % (↓ 63 to ↓ 79)         monitored. Dose
Simvastatin acid:                   adjustments of
AUC: ↓ 58 % (↓ 39 to ↓ 68)          simvastatin may be
Cmax: ↓ 51 % (↓ 32 to ↓ 58)         required (refer to the
Total active HMG Co-A               Summary of Product reductase inhibitors:               Characteristics for
AUC: ↓ 60 % (↓ 52 to ↓ 68)          simvastatin). No dose
Cmax: ↓ 62 % (↓ 55 to ↓ 78)         adjustment is necessary
(CYP3A4 induction)                 for efavirenz.
Co-administration of efavirenz with atorvastatin, pravastatin,
or simvastatin did not affect efavirenz AUC or Cmax values.
Rosuvastatin/Efavirenz                       Interaction not studied.            No dose adjustment is Rosuvastatin is largely excreted    necessary for either unchanged via the faeces,           medicinal product.
therefore interaction with efavirenz is not expected.
HORMONAL CONTRACEPTIVES
Oral:                                        Ethinyloestradiol:                  A reliable method of Ethinyloestradiol+Norgestimate/ Efavirenz    AUC: ↔                              barrier contraception (0.035 mg+0.25 mg once daily/600 mg once     Cmax: ↔                             must be used in addition daily)                                       Cmin: ↓ 8 % (↑ 14 to ↓ 25)          to hormonal Norelgestromin (active              contraceptives 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.


Medicinal product by therapeutic areas         Effects on drug levels            Recommendation (dose)                         Mean percent change in                concerning AUC, Cmax, Cmin with            co-administration with confidence intervals if               efavirenz availablea
(mechanism)
Injection: Depo-medroxyprogesterone acetate   In a 3-month drug interaction       Because of the limited (DMPA)/Efavirenz                              study, no significant differences   information available, a (150 mg IM single dose DMPA)                  in MPA pharmacokinetic              reliable method of barrier parameters were found between       contraception must be subjects receiving efavirenz-       used in addition to containing antiretroviral           hormonal contraceptives therapy and subjects receiving      (see section 4.6).
no antiretroviral therapy.
Similar results 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.
Implant: Etonogestrel/Efavirenz               Decreased exposure of               A reliable method of etonogestrel may be expected        barrier contraception
(CYP3A4 induction). There           must be used in addition have been occasional                to hormonal postmarketing reports of            contraceptives contraceptive failure with          (see section 4.6).
etonogestrel in efavirenz- exposed patients.
IMMUNOSUPPRESSANTS
Immunosuppressants metabolized by CYP3A4      Interaction not studied.            Dose adjustments of the (e.g., cyclosporine, tacrolimus,              Decreased exposure of the           immunosuppressant may sirolimus)/Efavirenz                          immunosuppressant may be            be required. Close expected (CYP3A4 induction).        monitoring of
These immunosuppressants are        immunosuppressant not anticipated to affect           concentrations for at exposure of efavirenz.              least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
OPIOIDS
Methadone/Efavirenz                           Methadone:                          Concomitant (stable maintenance, 35-100 mg once           AUC: ↓ 52 % (↓ 33 to ↓ 66)          administration with daily/600 mg once daily)                      Cmax: ↓ 45 % (↓ 25 to ↓ 59)         efavirenz should be (CYP3A4 induction)                  avoided due
In a study of HIV infected          to the risk for QTc intravenous drug users,             prolongation co-administration of efavirenz      (see section 4.3).
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.


Medicinal product by therapeutic areas        Effects on drug levels        Recommendation (dose)                        Mean percent change in            concerning AUC, Cmax, Cmin with       co-administration with confidence intervals if           efavirenz availablea
(mechanism)
Buprenorphine/naloxone/Efavirenz                 Buprenorphine:                 Despite the decrease in AUC: ↓ 50 %                    buprenorphine exposure,
Norbuprenorphine:              no patients exhibited
AUC: ↓ 71 %                    withdrawal symptoms.
Efavirenz:                     Dose adjustment of
No clinically significant      buprenorphine or pharmacokinetic interaction    efavirenz may not be necessary when co-administered.

 a
90 % confidence intervals unless otherwise noted.
b
95 % confidence intervals.

Other interactions: 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.