Atripla

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Atripla 600 mg/200 mg/245 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of 
tenofovir disoproxil (as fumarate). 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink, capsule-shaped, film-coated tablet, of dimensions 20 mm x 10.4 mm, debossed with “123” on 
one side, plain on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate.  It is 
indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 
18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current 
combination antiretroviral therapy for more than three months.  Patients must not have experienced 
virological failure on any prior antiretroviral therapy and must be known not to have harboured virus 
strains with mutations conferring significant resistance to any of the three components contained in 
Atripla prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1). 
 
The demonstration of the benefit of Atripla is primarily based on 48-week data from a clinical study in 
which patients with stable virologic suppression on a combination antiretroviral therapy changed to 
Atripla (see section 5.1).  No data are currently available from clinical studies with Atripla in 
treatment-naïve or in heavily pretreated patients. 
 
No data are available to support the combination of Atripla and other antiretroviral agents. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection. 
 
Posology 
 
Adults 
The recommended dose of Atripla is one tablet taken orally once daily. 
 
If a patient misses a dose of Atripla within 12 hours of the time it is usually taken, the patient should 
take Atripla as soon as possible and resume the normal dosing schedule.  If a patient misses a dose of 
Atripla by more than 12 hours and it is almost time for the next dose, the patient should not take the 
missed dose and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Atripla, another tablet should be taken.  If the patient 
vomits more than 1 hour after taking Atripla he/she does not need to take another dose. 
 



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It is recommended that Atripla be taken on an empty stomach since food may increase efavirenz 
exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8).  
In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous 
system, bedtime dosing is recommended (see section 4.8). 
 
It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower following 
administration of Atripla on an empty stomach as compared to the individual component tenofovir 
disoproxil when taken with food (see section 5.2).  Data on the clinical translation of the decrease in 
pharmacokinetic exposure are not available.  In virologically suppressed patients, the clinical 
relevance of this reduction can be expected to be limited (see section 5.1). 
 
Where discontinuation of therapy with one of the components of Atripla is indicated or where dose 
modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil 
are available.  Please refer to the Summary of Product Characteristics for these medicinal products. 
 
If therapy with Atripla is discontinued, consideration should be given to the long half-life of efavirenz 
(see section 5.2) and long intracellular half-lives of emtricitabine and tenofovir.  Because of 
interpatient variability in these parameters and concerns regarding development of resistance, HIV 
treatment guidelines should be consulted, also taking into consideration the reason for discontinuation. 
 
Dose adjustment: If Atripla is co-administered with rifampicin to patients weighing 50 kg or more, an 
additional 200 mg/day (800 mg total) of efavirenz may be considered (see section 4.5). 
 
Special populations 
 
Elderly 
Atripla should be administered with caution to elderly patients (see section 4.4). 
 
Renal impairment 
Atripla is not recommended for patients with moderate or severe renal impairment (creatinine 
clearance (CrCl) < 50 ml/min).  Patients with moderate or severe renal impairment require dose 
interval adjustment of emtricitabine and tenofovir disoproxil  that cannot be achieved with the 
combination tablet (see sections 4.4 and 5.2). 
 
Hepatic impairment 
The pharmacokinetics of Atripla have not been studied in patients with hepatic impairment.  Patients 
with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated with the normal 
recommended dose of Atripla (see sections 4.3, 4.4 and 5.2).  Patients should be monitored carefully 
for adverse reactions, especially nervous system symptoms related to efavirenz (see sections 4.3 
and 4.4). 
 
If Atripla is discontinued in patients co-infected with HIV and HBV, these patients should be closely 
monitored for evidence of exacerbation of hepatitis (see section 4.4). 
 
Paediatric population 
The safety and efficacy of Atripla in children under the age of 18 years have not been established 
(see section 5.2). 
 
Method of administration 
 
Atripla tablets should be swallowed whole with water, once daily. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Severe hepatic impairment (CPT, Class C) (see section 5.2). 



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Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, 
or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine).  
Competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolism 
and create the potential for serious and/or life-threatening adverse reactions (for example, cardiac 
arrhythmias, prolonged sedation or respiratory depression) (see section 4.5). 
 
Co-administration with elbasvir/grazoprevir due to the expected significant decreases in plasma 
concentrations of elbasvir and grazoprevir.  This effect is due to induction of CYP3A4 or P-gp by 
efavirenz and may result in loss of therapeutic effect of elbasvir/grazoprevir (see section 4.5). 
 
Co-administration with voriconazole.  Efavirenz significantly decreases voriconazole plasma 
concentrations while voriconazole also significantly increases efavirenz plasma concentrations.  Since 
Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered (see section 4.5). 
 
Co-administration with herbal preparations containing St. John’s wort (Hypericum perforatum) due to 
the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5). 
 
Administration to patients with: 

- a family history of sudden death or of congenital prolongation of the QTc interval on 
electrocardiograms, or with any other clinical condition known to prolong the QTc interval. 

- a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with 
congestive cardiac failure accompanied by reduced left ventricle ejection fraction. 

- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia. 
 
Co-administration with drugs that are known to prolong the QTc interval (proarrhythmic).  
These drugs include: 

- antiarrhythmics of classes IA and III, 
- neuroleptics, antidepressive agents, 
- certain antibiotics including some agents of the following classes: macrolides, 

fluoroquinolones, imidazole and triazole antifungal agents, 
- certain non-sedating antihistamines (terfenadine, astemizole), 
- cisapride, 
- flecainide, 
- certain antimalarials,  
- methadone (see sections 4.4, 4.5 and 5.1). 

 
4.4 Special warnings and precautions for use 
 
Co-administration with other medicinal products 
 
As a fixed combination, Atripla should not be administered concomitantly with other medicinal 
products containing the same active components, emtricitabine or tenofovir disoproxil.  Atripla should 
not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with 
rifampicin (see section 4.2).  Due to similarities with emtricitabine, Atripla should not be administered 
concomitantly with other cytidine analogues, such as lamivudine (see section 4.5).  Atripla should not 
be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir 
alafenamide. 
 
Co-administration of Atripla and didanosine is not recommended (see section 4.5). 
 
Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not 
recommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decrease 



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following co-administration with efavirenz leading to reduced therapeutic effect of 
sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.5). 
 
No data are available on the safety and efficacy of Atripla in combination with other antiretroviral 
agents. 
 
Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5). 
 
Switching from a PI-based antiretroviral regimen 
 
Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switch 
to Atripla may lead to a reduction of the response to the therapy (see section 5.1).  These patients 
should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs 
from that of protease inhibitors, for adverse reactions. 
 
Opportunistic infections 
 
Patients receiving Atripla or any other antiretroviral therapy may continue to develop opportunistic 
infections and other complications of HIV infection, and therefore should remain under close clinical 
observation by physicians experienced in the treatment of patients with HIV associated diseases. 
 
Transmission of HIV 
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent transmission 
should be taken in accordance with national guidelines. 
 
Effect of food 
 
The administration of Atripla with food may increase efavirenz exposure (see section 5.2) and may 
lead to an increase in frequency of adverse reactions (see section 4.8).  It is recommended that Atripla 
be taken on an empty stomach, preferably at bedtime. 
 
Liver disease 
 
The pharmacokinetics, safety and efficacy of Atripla have not been established in patients with 
significant underlying liver disorders (see section 5.2).  Atripla is contraindicated in patients with 
severe hepatic impairment (see section 4.3) and not recommended in patients with moderate hepatic 
impairment.  Since efavirenz is principally metabolised by the CYP system, caution should be 
exercised in administering Atripla to patients with mild hepatic impairment.  These patients should be 
carefully monitored for efavirenz adverse reactions, especially nervous system symptoms.  Laboratory 
tests should be performed to evaluate their liver disease at periodic intervals (see section 4.2). 
 
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy (CART) and 
should be monitored according to standard practice.  If there is evidence of worsening liver disease or 
persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal 
range, the benefit of continued therapy with Atripla needs to be weighed against the potential risks of 
significant liver toxicity.  In such patients, interruption or discontinuation of treatment must be 
considered (see section 4.8).  
 
In patients treated with other medicinal products associated with liver toxicity, monitoring of liver 
enzymes is also recommended. 
 



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Hepatic events 
Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic disease 
or other identifiable risk factors (see section 4.8).  Liver enzyme monitoring should be considered for 
all patients independent of pre-existing hepatic dysfunction or other risk factors. 
 
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection 
Patients with chronic hepatitis B or C and treated with CART are at an increased risk for severe and 
potentially fatal hepatic adverse reactions.  
 
Physicians should refer to current HIV treatment guidelines for the optimal management of 
HIV infection in patients co-infected with HBV. 
 
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary 
of Product Characteristics for these medicinal products. 
 
The safety and efficacy of Atripla have not been studied for the treatment of chronic HBV infection.  
Emtricitabine and tenofovir individually and in combination have shown activity against HBV in 
pharmacodynamic studies (see section 5.1).  Limited clinical experience suggests that emtricitabine 
and tenofovir disoproxil have an anti-HBV activity when used in antiretroviral combination therapy to 
control HIV infection.  Discontinuation of Atripla therapy in patients co-infected with HIV and HBV 
may be associated with severe acute exacerbations of hepatitis.  Patients co-infected with HIV and 
HBV who discontinue Atripla must be closely monitored with both clinical and laboratory follow-up 
for at least four months after stopping treatment with Atripla.  If appropriate, resumption of anti-
hepatitis B therapy may be warranted.  In patients with advanced liver disease or cirrhosis, treatment 
discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic 
decompensation. 
 
QTc Prolongation 
 
QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1). For patients 
at increased risk of Torsade de Pointes or who are receiving drugs with a known risk for Torsade de 
Pointes, consider alternatives to Atripla. 
 
Psychiatric symptoms 
 
Psychiatric adverse reactions have been reported in patients treated with efavirenz.  Patients with a 
prior history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse 
reactions.  In particular, severe depression was more common in those with a history of depression.  
There have also been post-marketing reports of severe depression, death by suicide, delusions, 
psychosis-like behaviour, and catatonia.  Patients should be advised that if they experience symptoms 
such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately 
to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to 
determine whether the risk of continued therapy outweighs the benefits (see section 4.8). 
 
Nervous system symptoms 
 
Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and 
abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg 
daily in clinical studies.  Dizziness was also seen in clinical studies with emtricitabine and tenofovir 
disoproxil.  Headache has been reported in clinical studies with emtricitabine (see section 4.8).  
Nervous system symptoms associated with efavirenz usually begin during the first one or two days of 
therapy and generally resolve after the first two to four weeks.  Patients should be informed that if they 
do occur, these common symptoms are likely to improve with continued therapy and are not predictive 
of subsequent onset of any of the less frequent psychiatric symptoms. 
 



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Seizures 
 
Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known 
medical history of seizures.  Patients who are receiving concomitant anticonvulsant medicinal products 
primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require 
periodic monitoring of plasma levels.  In a drug interaction study, carbamazepine plasma 
concentrations were decreased when carbamazepine was co-administered with efavirenz 
(see section 4.5).  Caution must be taken in any patient with a history of seizures. 
 
Renal impairment 
 
Atripla is not recommended for patients with moderate or severe renal impairment (creatinine 
clearance < 50 ml/min).  Patients with moderate or severe renal impairment require a dose adjustment 
of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet 
(see sections 4.2 and 5.2).  Use of Atripla should be avoided with concurrent or recent use of a 
nephrotoxic medicinal product.  If concomitant use of Atripla and nephrotoxic agents (e.g. 
aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, 
interleukin-2) is unavoidable, renal function must be monitored weekly (see section 4.5). 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If Atripla is co-administered with an NSAID, renal function should be 
monitored adequately. 
 
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy 
(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil  in clinical 
practice (see section 4.8). 
 
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with 
Atripla and renal function (creatinine clearance and serum phosphate) is also monitored after two to 
four weeks of treatment, after three months of treatment and every three to six months thereafter in 
patients without renal risk factors.  In patients with a history of renal dysfunction or in patients who 
are at risk of renal dysfunction, a more frequent monitoring of renal function is required. 
 
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in 
any patient receiving Atripla, renal function must be re-evaluated within one week, including 
measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, 
proximal tubulopathy).  Since Atripla is a combination product and the dosing interval of the 
individual components cannot be altered, treatment with Atripla must be interrupted in patients with 
confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl 
(0.32 mmol/l).  Interrupting treatment with Atripla should also be considered in case of progressive 
decline of renal function when no other cause has been identified.  Where discontinuation of therapy 
with one of the components of Atripla is indicated or where dose modification is necessary, separate 
preparations of efavirenz, emtricitabine and tenofovir disoproxil  are available. 
 
Bone effects 
 
In a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in bone 
mineral density of the hip and spine were observed in both treatment groups.  Decreases in bone 
mineral density of spine and changes in bone biomarkers from baseline were significantly greater in 
the tenofovir disoproxil treatment group at 144 weeks.  Decreases in bone mineral density of the hip 
were significantly greater in this group until 96 weeks.  However, there was no increased risk of 
fractures or evidence for clinically relevant bone abnormalities over 144 weeks. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 



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inhibitor.  Alternative treatment regimens should be considered for patients with osteoporosis that are 
at a high risk for fractures. 
 
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal 
tubulopathy (see section 4.8).  If bone abnormalities are suspected then appropriate consultation 
should be obtained. 
 
Skin reactions 
 
Mild-to-moderate rash has been reported with the individual components of Atripla.  The rash 
associated with the efavirenz component usually resolves with continued therapy.  Appropriate 
antihistamines and/or corticosteroids may improve tolerability and hasten the resolution of rash.  
Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 
1% of patients treated with efavirenz (see section 4.8).  The incidence of erythema multiforme or 
Stevens-Johnson syndrome was approximately 0.1%.  Atripla must be discontinued in patients 
developing severe rash associated with blistering, desquamation, mucosal involvement or fever.  
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class 
is limited.  Atripla is not recommended for patients who have had a life-threatening cutaneous reaction 
(e.g., Stevens-Johnson syndrome) while taking an NNRTI. 
 
Weight and metabolic parameters 
 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Mitochondrial dysfunction following exposure in utero 
 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine. The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such 
neurological disorders are transient or permanent is currently unknown. These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings. These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
Immune Reactivation Syndrome 
 
In HIV infected patients with severe immune deficiency at the time of institution of CART, an 
inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause 
serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed 
within the first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment. 
 



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Osteonecrosis 
 
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV disease and/or long-term exposure to CART.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
Patients with HIV-1 harbouring mutations 
 
Atripla should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutation 
(see sections 4.1 and 5.1). 
 
Elderly 
 
Atripla has not been studied in patients over the age of 65. Elderly patients are more likely to have 
decreased hepatic or renal function, therefore caution should be exercised when treating elderly 
patients with Atripla (see section 4.2). 
 
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). 
 
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. 
 



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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. 
 



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Table 1: Interactions between Atripla or its individual components and other medicinal products 
 
Medicinal product by therapeutic areas Effects on drug levels 

Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
ANTI-INFECTIVES 
HIV antivirals 
Protease inhibitors 
Atazanavir/ritonavir/Tenofovir disoproxil 
(300 mg q.d./100 mg q.d./245 mg q.d.) 

Atazanavir: 
AUC: ↓ 25% (↓ 42 to ↓ 3) 
Cmax: ↓ 28% (↓ 50 to ↑ 5) 
Cmin: ↓ 26% (↓ 46 to ↑ 10) 
 
Co-administration of 
atazanavir/ritonavir with tenofovir 
resulted in increased exposure to 
tenofovir.  Higher tenofovir 
concentrations could potentiate 
tenofovir-associated adverse events, 
including renal disorders. 

Co-administration of 
atazanavir/ritonavir and 
Atripla is not 
recommended. 

Atazanavir/ritonavir/Efavirenz 
(400 mg q.d./100 mg q.d./600 mg q.d., all 
administered with food) 
 
 
Atazanavir/ritonavir/Efavirenz 
(400 mg q.d./200 mg q.d./600 mg q.d., all 
administered with food) 

Atazanavir (pm): 
AUC: ↔* (↓ 9% to ↑ 10%) 
Cmax: ↑ 17%* (↑ 8 to ↑ 27) 
Cmin: ↓ 42%* (↓ 31 to ↓ 51) 
 
Atazanavir (pm): 
AUC: ↔*/** (↓ 10% to ↑ 26%) 
Cmax: ↔*/** (↓ 5% to ↑ 26%) 
Cmin: ↑ 12%*/** (↓ 16 to ↑ 49) 
(CYP3A4 induction). 
* When compared to atazanavir 
300 mg/ritonavir 100 mg q.d. in the 
evening without efavirenz.  This 
decrease in atazanavir Cmin might 
negatively impact the efficacy of 
atazanavir. 
** based on historical comparison. 
 
Co-administration of efavirenz with 
atazanavir/ritonavir is not 
recommended. 

Atazanavir/ritonavir/Emtricitabine Interaction not studied. 
Darunavir/ritonavir/Efavirenz 
(300 mg b.i.d.*/100 mg b.i.d./600 mg 
q.d.) 
 
*lower than recommended doses; similar 
findings are expected with recommended 
doses. 

Darunavir: 
AUC: ↓ 13% 
Cmin: ↓ 31% 
Cmax: ↓ 15% 
(CYP3A4 induction) 
 
Efavirenz: 
AUC: ↑ 21% 
Cmin: ↑ 17% 
Cmax: ↑ 15% 
(CYP3A4 inhibition) 

Atripla in combination 
with darunavir/ritonavir 
800/100 mg once daily 
may result in suboptimal 
darunavir Cmin.  If Atripla 
is to be used in 
combination with 
darunavir/ritonavir, the 
darunavir/ritonavir 
600/100 mg twice daily 
regimen should be used.  



12 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Darunavir/ritonavir/Tenofovir disoproxil 
(300 mg b.i.d.*/100 mg b.i.d./245 mg q.d.) 
 
*lower than recommended dose 

Darunavir: 
AUC: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

Darunavir/ritonavir 
should be used with 
caution in combination 
with Atripla.  See 
ritonavir row below.  
Monitoring of renal 
function may be 
indicated, particularly in 
patients with underlying 
systemic or renal disease, 
or in patients taking 
nephrotoxic agents. 

Darunavir/ritonavir/Emtricitabine Interaction not studied.  Based on the 
different elimination pathways, no 
interaction is expected. 

Fosamprenavir/ritonavir/Efavirenz 
(700 mg b.i.d./100 mg b.i.d./600 mg q.d.) 

No clinically significant 
pharmacokinetic interaction. 

Atripla and 
fosamprenavir/ritonavir 
can be co-administered 
without dose adjustment. 
See ritonavir row below. 

Fosamprenavir/ritonavir/Emtricitabine Interaction not studied. 
Fosamprenavir/ritonavir/Tenofovir 
disoproxil 

Interaction not studied. 

Indinavir/Efavirenz 
(800 mg q8h/200 mg q.d.) 

Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Indinavir: 
AUC: ↓ 31% (↓ 8 to ↓ 47) 
Cmin: ↓ 40% 
 
A similar reduction in indinavir 
exposures was observed when 
indinavir 1,000 mg q8h was given 
with efavirenz 600 mg q.d. 
(CYP3A4 induction) 
For co-administration of efavirenz 
with low-dose ritonavir in 
combination with a protease inhibitor, 
see section on ritonavir below. 

Insufficient data are 
available to make a 
dosing recommendation 
for indinavir when dosed 
with Atripla.  While the 
clinical significance of 
decreased indinavir 
concentrations has not 
been established, the 
magnitude of the 
observed 
pharmacokinetic 
interaction should be 
taken into consideration 
when choosing a regimen 
containing both 
efavirenz, a component 
of Atripla, and indinavir. 

Indinavir/Emtricitabine 
(800 mg q8h/200 mg q.d.) 

Indinavir: 
AUC: ↔ 
Cmax: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 

Indinavir/Tenofovir disoproxil 
(800 mg q8h/245 mg q.d.) 

Indinavir: 
AUC: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 



13 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Lopinavir/ritonavir/Tenofovir disoproxil 
(400 mg b.i.d./100 mg b.i.d./245 mg q.d.) 

Lopinavir/Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 32% (↑ 25 to ↑ 38) 
Cmax: ↔ 
Cmin: ↑ 51% (↑ 37 to ↑ 66) 
 
Higher tenofovir concentrations could 
potentiate tenofovir-associated 
adverse events, including renal 
disorders. 

Insufficient data are 
available to make a 
dosing recommendation 
for lopinavir/ritonavir 
when dosed with Atripla.  
Co-administration of 
lopinavir/ritonavir and 
Atripla is not 
recommended. 

Lopinavir/ritonavir soft capsules or oral 
solution/Efavirenz 
 
 
 
 
 
 
 
 
 
 
Lopinavir/ritonavir tablets/Efavirenz 
(400/100 mg b.i.d./600 mg q.d.) 
 
(500/125 mg b.i.d./600 mg q.d.) 

Substantial decrease in lopinavir 
exposure, necessitating dosage 
adjustment of lopinavir/ritonavir.  
When used in combination with 
efavirenz and two NRTIs, 533/133 mg 
lopinavir/ritonavir (soft capsules) 
twice daily yielded similar lopinavir 
plasma concentrations as compared to 
lopinavir/ritonavir (soft capsules) 
400/100 mg twice daily without 
efavirenz (historical data). 
 
Lopinavir concentrations: ↓ 30-40% 
 
 
Lopinavir concentrations: similar to 
lopinavir/ritonavir 400/100 mg twice 
daily without efavirenz.  Dosage 
adjustment of lopinavir/ritonavir is 
necessary when given with efavirenz.  
For co-administration of efavirenz 
with low-dose ritonavir in 
combination with a protease inhibitor, 
see section on ritonavir below. 

Lopinavir/ritonavir/Emtricitabine Interaction not studied. 



14 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Ritonavir/Efavirenz 
(500 mg b.i.d./600 mg q.d.) 

Ritonavir: 
Morning AUC: ↑ 18% (↑ 6 to ↑ 33) 
Evening AUC: ↔ 
Morning Cmax: ↑ 24% (↑ 12 to ↑ 38) 
Evening Cmax: ↔ 
Morning Cmin: ↑ 42% (↑ 9 to ↑ 86) 
Evening Cmin: ↑ 24% (↑ 3 to ↑ 50) 
 
Efavirenz: 
AUC: ↑ 21% (↑ 10 to ↑ 34) 
Cmax: ↑ 14% (↑ 4 to ↑ 26) 
Cmin: ↑ 25% (↑ 7 to ↑ 46) 
(inhibition of CYP-mediated 
oxidative metabolism) 
 
When efavirenz was given with 
ritonavir 500 mg or 600 mg twice 
daily, the combination was not well 
tolerated (for example, dizziness, 
nausea, paraesthesia and elevated 
liver enzymes occurred).  Sufficient 
data on the tolerability of efavirenz 
with low-dose ritonavir (100 mg, once 
or twice daily) are not available. 

Co-administration of 
ritonavir at doses of 
600 mg and Atripla is not 
recommended.  When 
using Atripla with 
low-dose ritonavir, the 
possibility of an increase 
in the incidence of 
efavirenz-associated 
adverse events should be 
considered, due to 
possible 
pharmacodynamic 
interaction. 

Ritonavir/Emtricitabine Interaction not studied. 
Ritonavir/Tenofovir disoproxil Interaction not studied. 
Saquinavir/ritonavir/Efavirenz Interaction not studied.  For 

co-administration of efavirenz with 
low-dose ritonavir in combination 
with a protease inhibitor, see section 
on ritonavir above. 

Insufficient data are 
available to make a 
dosing recommendation 
for saquinavir/ritonavir 
when dosed with Atripla.  
Co-administration of 
saquinavir/ritonavir and 
Atripla is not 
recommended.  Use of 
Atripla in combination 
with saquinavir as the 
sole protease inhibitor is 
not recommended. 

Saquinavir/ritonavir/Tenofovir disoproxil There were no clinically significant 
pharmacokinetic interactions when 
tenofovir disoproxil was 
co-administered with ritonavir 
boosted saquinavir. 

Saquinavir/ritonavir/Emtricitabine Interaction not studied. 

CCR5 antagonist 
Maraviroc/Efavirenz 
(100 mg b.i.d./600 mg q.d.) 

Maraviroc: 
AUC12h: ↓ 45% (↓ 38 to ↓ 51) 
Cmax: ↓ 51% (↓ 37 to ↓ 62) 
 
Efavirenz concentrations not 
measured, no effect is expected. 

Refer to the Summary of 
Product Characteristics 
for the medicinal product 
containing maraviroc. 

Maraviroc/Tenofovir disoproxil 
(300 mg b.i.d./245 mg q.d.) 

Maraviroc: 
AUC12h: ↔ 
Cmax: ↔ 
 
Tenofovir concentrations not 
measured, no effect is expected. 

Maraviroc/Emtricitabine Interaction not studied. 



15 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Integrase strand transfer inhibitor 
Raltegravir/Efavirenz 
(400 mg single dose/-) 

Raltegravir: 
AUC: ↓ 36% 
C12h: ↓ 21% 
Cmax: ↓ 36% 
(UGT1A1 induction) 

Atripla and raltegravir 
can be co-administered 
without dose adjustment. 

Raltegravir/Tenofovir disoproxil 
(400 mg b.i.d./-) 

Raltegravir: 
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 

been performed with efavirenz and 
NRTIs other than lamivudine, 
zidovudine and tenofovir disoproxil.  
Clinically significant interactions 
have not been found and would not be 
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. 

Due to the similarity 
between lamivudine and 
emtricitabine, a 
component of Atripla, 
Atripla should not be 
administered 
concomitantly with 
lamivudine 
(see section 4.4). 

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 
disoproxil and didanosine results in a 
40-60% increase in systemic exposure 
to didanosine.  

Co-administration of 
Atripla and didanosine is 
not recommended. 
Increased systemic 
exposure to didanosine Didanosine/Efavirenz Interaction not studied. 



16 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(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 + 
Efavirenz 
 

Elbasvir: 
AUC: ↓ 54% 
Cmax: ↓ 45% 
(CYP3A4 or P-gp induction - effect 
on elbasvir) 
 
Grazoprevir: 
AUC: ↓ 83% 
Cmax: ↓ 87% 
(CYP3A4 or P-gp induction - effect 
on grazoprevir) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
 

Co-administration of 
Atripla with 
elbasvir/grazoprevir is 
contraindicated because it 
may lead to loss of 
virologic response to 
elbasvir/grazoprevir.  
This loss is due to 
significant decreases in 
elbasvir/grazoprevir 
plasma concentrations 
caused by CYP3A4 or 
P-gp induction.  Refer to 
the Summary of Product 
Characteristics for 
elbasvir/grazoprevir for 
more information. 



17 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Glecaprevir/Pibrentasvir/Efavirenz Expected: 

Glecaprevir: ↓ 
Pibrentasvir: ↓ 

Concomitant 
administration of 
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 
(90 mg/400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Ledipasvir: 
AUC: ↓ 34% (↓ 41 to ↓ 25) 
Cmax: ↓ 34% (↓ 41 to ↑ 25) 
Cmin: ↓ 34% (↓ 43 to ↑ 24) 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310071: 
AUC: ↔ 
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) 

No dose adjustment is 
recommended.  The 
increased exposure of 
tenofovir could potentiate 
adverse reactions 
associated with tenofovir 
disoproxil, including 
renal disorders.  Renal 
function should be 
closely monitored (see 
section 4.4). 



18 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Sofosbuvir/Velpatasvir 
(400 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 38% (↑ 14 to ↑ 67) 
 
GS-3310071: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↓ 53% (↓ 61 to ↓ 43) 
Cmax: ↓ 47% (↓ 57 to ↓ 36) 
Cmin: ↓ 57% (↓ 64 to ↓ 48) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 81% (↑ 68 to ↑ 94) 
Cmax: ↑ 77% (↑ 53 to ↑ 104) 
Cmin: ↑ 121% (↑ 100 to ↑ 143) 

Concomitant 
administration of Atripla 
and 
sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/ 
voxilaprevir is expected 
to decrease plasma 
concentrations of 
velpatasvir and 
voxilaprevir.  
Co-administration of 
Atripla with 
sofosbuvir/velpatasvir or 
sofosbuvir/velpatasvir/ 
voxilaprevir is not 
recommended (see 
section 4.4). 

Sofosbuvir/Velpatasvir/Voxilaprevir  
(400 mg/100 mg/100 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Interaction only studied with 
sofosbuvir/velpatasvir. 
 
Expected: 
Voxilaprevir:↓ 

Sofosbuvir 
(400 mg q.d.) + 
Efavirenz/Emtricitabine/Tenofovir 
disoproxil 
(600 mg/200 mg/245 mg q.d.) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↓ 19% (↓ 40 to ↑ 10) 
 
GS-3310071: 
AUC: ↔ 
Cmax: ↓ 23% (↓ 30 to ↑ 16) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↑ 25% (↑ 8 to ↑ 45) 
Cmin: ↔ 

Atripla and sofosbuvir 
can be co-administered 
without dose adjustment. 



19 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Antibiotics 
Clarithromycin/Efavirenz 
(500 mg b.i.d./400 mg q.d.) 

Clarithromycin: 
AUC: ↓ 39% (↓ 30 to ↓ 46) 
Cmax: ↓ 26% (↓ 15 to ↓ 35) 
 
Clarithromycin 
14-hydroxymetabolite: 
AUC: ↑ 34% (↑ 18 to ↑ 53) 
Cmax: ↑ 49% (↑ 32 to ↑ 69) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↑ 11% (↑ 3 to ↑ 19) 
(CYP3A4 induction) 
 
Rash developed in 46% of uninfected 
volunteers receiving efavirenz and 
clarithromycin. 

The clinical significance 
of these changes in 
clarithromycin plasma 
levels is not known.   
Alternatives to 
clarithromycin (e.g. 
azithromycin) may be 
considered.  Other 
macrolide antibiotics, 
such as erythromycin, 
have not been studied in 
combination with Atripla. 

Clarithromycin/Emtricitabine Interaction not studied. 
Clarithromycin/Tenofovir disoproxil Interaction not studied. 
Antimycobacterials 
Rifabutin/Efavirenz 
(300 mg q.d./600 mg q.d.) 

Rifabutin: 
AUC: ↓ 38% (↓ 28 to ↓ 47) 
Cmax: ↓ 32% (↓ 15 to ↓ 46) 
Cmin: ↓ 45% (↓ 31 to ↓ 56) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 12% (↓ 24 to ↑ 1) 
(CYP3A4 induction) 

The daily dose of 
rifabutin should be 
increased by 50% when 
given with Atripla.  
Consider doubling the 
rifabutin dose in 
regimens where rifabutin 
is given 2 or 3 times a 
week in combination 
with Atripla.  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). 

Rifabutin/Emtricitabine Interaction not studied. 
Rifabutin/Tenofovir disoproxil Interaction not studied. 

Rifampicin/Efavirenz 
(600 mg q.d./600 mg q.d.) 

Efavirenz: 
AUC: ↓ 26% (↓ 15 to ↓ 36) 
Cmax: ↓ 20% (↓ 11 to ↓ 28) 
Cmin: ↓ 32% (↓ 15 to ↓ 46) 
(CYP3A4 and CYP2B6 induction) 

When Atripla is taken 
with rifampicin in 
patients weighing 50 kg 
or greater, an additional 
200 mg/day (800 mg 
total) of efavirenz may 
provide exposure similar 
to a daily efavirenz dose 
of 600 mg when taken 
without rifampicin.  The 
clinical effect of this dose 
adjustment has not been 

Rifampicin/Tenofovir disoproxil 
(600 mg q.d./245 mg q.d.) 

Rifampicin: 
AUC: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 



20 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
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 
(200 mg b.i.d./600 mg q.d.) 

Itraconazole: 
AUC: ↓ 39% (↓ 21 to ↓ 53) 
Cmax: ↓ 37% (↓ 20 to ↓ 51) 
Cmin: ↓ 44% (↓ 27 to ↓ 58) 
(decrease in itraconazole 
concentrations: CYP3A4 induction) 
 
Hydroxyitraconazole: 
AUC: ↓ 37% (↓ 14 to ↓ 55) 
Cmax: ↓ 35% (↓ 12 to ↓ 52) 
Cmin: ↓ 43% (↓ 18 to ↓ 60) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

Since no dose 
recommendation can be 
made for itraconazole 
when used with Atripla, 
an alternative antifungal 
treatment should be 
considered. 

Itraconazole/Emtricitabine Interaction not studied. 
Itraconazole/Tenofovir disoproxil Interaction not studied. 
Posaconazole/Efavirenz 
(-/400 mg q.d.) 

Posaconazole: 
AUC: ↓ 50% 
Cmax: ↓ 45% 
(UDP-G induction) 

Concomitant use of 
posaconazole and Atripla 
should be avoided unless 
the benefit to the patient 
outweighs the risk. Posaconazole/Emtricitabine Interaction not studied. 

Posaconazole/Tenofovir disoproxil Interaction not studied. 
Voriconazole/Efavirenz 
(200 mg b.i.d./400 mg q.d.) 

Voriconazole: 
AUC: ↓ 77% 
Cmax: ↓ 61% 
 
Efavirenz: 
AUC: ↑ 44% 
Cmax: ↑ 38% 
(competitive inhibition of oxidative 
metabolism) 
 
Co-administration of standard doses 
of efavirenz and voriconazole is 
contraindicated (see section 4.3). 

Since Atripla is a fixed-
dose combination 
product, the dose of 
efavirenz cannot be 
altered; therefore, 
voriconazole and Atripla 
must not be 
co-administered. 

Voriconazole/Emtricitabine Interaction not studied. 
Voriconazole/Tenofovir disoproxil Interaction not studied. 



21 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Antimalarials 
Artemether/Lumefantrine/Efavirenz 
(20/120 mg tablet, 6 doses of 4 tablets 
each over 3 days/600 mg q.d.) 

Artemether: 
AUC: ↓ 51% 
Cmax: ↓ 21%  
 
Dihydroartemisinin (active 
metabolite): 
AUC: ↓ 46% 
Cmax: ↓ 38%  
 
Lumefantrine: 
AUC: ↓ 21% 
Cmax: ↔ 
 
Efavirenz: 
AUC: ↓ 17% 
Cmax: ↔ 
(CYP3A4 induction) 

Since decreased 
concentrations of 
artemether, 
dihydroartemisinin, or 
lumefantrine may result 
in a decrease of 
antimalarial efficacy, 
caution is recommended 
when Atripla and 
artemether/lumefantrine 
tablets are 
co-administered. 

Artemether/Lumefantrine/Emtricitabine Interaction not studied. 
Artemether/Lumefantrine/Tenofovir 
disoproxil 

Interaction not studied. 

Atovaquone and proguanil 
hydrochloride/Efavirenz 
(250/100 mg single dose/600 mg q.d.) 

Atovaquone: 
AUC: ↓ 75% (↓ 62 to ↓ 84) 
Cmax: ↓ 44% (↓ 20 to ↓ 61) 
 
Proguanil: 
AUC: ↓ 43% (↓ 7 to ↓ 65) 
Cmax: ↔ 

Concomitant 
administration of 
atovaquone/proguanil 
with Atripla should be 
avoided. 

Atovaquone and proguanil 
hydrochloride/Emtricitabine 

Interaction not studied. 

Atovaquone and proguanil 
hydrochloride/Tenofovir disoproxil 

Interaction not studied. 

ANTICONVULSANTS 
Carbamazepine/Efavirenz 
(400 mg q.d./600 mg q.d.) 

Carbamazepine: 
AUC: ↓ 27% (↓ 20 to ↓ 33) 
Cmax: ↓ 20% (↓ 15 to ↓ 24) 
Cmin: ↓ 35% (↓ 24 to ↓ 44) 
 
Efavirenz: 
AUC: ↓ 36% (↓ 32 to ↓ 40) 
Cmax: ↓ 21% (↓ 15 to ↓ 26) 
Cmin: ↓ 47% (↓ 41 to ↓ 53) 
(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. 

No dose recommendation 
can be made for the use 
of Atripla with 
carbamazepine.  An 
alternative anticonvulsant 
should be considered.  
Carbamazepine plasma 
levels should be 
monitored periodically. 

Carbamazepine/Emtricitabine Interaction not studied. 
Carbamazepine/Tenofovir disoproxil Interaction not studied. 



22 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Phenytoin, Phenobarbital, and other 
anticonvulsants that are substrates of CYP 
isozymes 

Interaction not studied with efavirenz, 
emtricitabine, or tenofovir disoproxil.  
There is a potential for reduction or 
increase in the plasma concentrations 
of phenytoin, phenobarbital and other 
anticonvulsants that are substrates of 
CYP isozymes with efavirenz. 

When Atripla is co-
administered with an 
anticonvulsant that is a 
substrate of CYP 
isozymes, periodic 
monitoring of 
anticonvulsant levels 
should be conducted. 

Valproic acid/Efavirenz 
(250 mg b.i.d./600 mg q.d.) 

No clinically significant effect on 
efavirenz pharmacokinetics.  Limited 
data suggest there is no clinically 
significant effect on valproic acid 
pharmacokinetics. 

Atripla and valproic acid 
can be co-administered 
without dose adjustment.  
Patients should be 
monitored for seizure 
control. Valproic acid/Emtricitabine Interaction not studied. 

Valproic acid/Tenofovir disoproxil Interaction not studied. 
Vigabatrin/Efavirenz 
Gabapentin/Efavirenz 

Interaction not studied.  Clinically 
significant interactions are not 
expected 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. 

Atripla and vigabatrin or 
gabapentin can be co-
administered without 
dose adjustment. 

Vigabatrin/Emtricitabine 
Gabapentin/Emtricitabine 

Interaction not studied. 

Vigabatrin/Tenofovir disoproxil 
Gabapentin/Tenofovir disoproxil 

Interaction not studied. 

ANTICOAGULANTS 
Warfarin/Efavirenz 
Acenocoumarol/Efavirenz 

Interaction not studied.  Plasma 
concentrations and effects of warfarin 
or acenocoumarol are potentially 
increased or decreased by efavirenz. 

Dose adjustment of 
warfarin or 
acenocoumarol may be 
required when 
co-administered with 
Atripla. 

ANTIDEPRESSANTS 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
Sertraline/Efavirenz 
(50 mg q.d./600 mg q.d.) 

Sertraline: 
AUC: ↓ 39% (↓ 27 to ↓ 50) 
Cmax: ↓ 29% (↓ 15 to ↓ 40) 
Cmin: ↓ 46% (↓ 31 to ↓ 58) 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↑ 11% (↑ 6 to ↑ 16) 
Cmin: ↔ 
(CYP3A4 induction) 

When co-administered 
with Atripla, sertraline 
dose increases should be 
guided by clinical 
response. 

Sertraline/Emtricitabine Interaction not studied. 
Sertraline/Tenofovir disoproxil Interaction not studied. 



23 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Paroxetine/Efavirenz 
(20 mg q.d./600 mg q.d.) 

Paroxetine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Efavirenz: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

Atripla and paroxetine 
can be co-administered 
without dose adjustment. 

Paroxetine/Emtricitabine Interaction not studied. 
Paroxetine/Tenofovir disoproxil Interaction not studied. 
Fluoxetine/Efavirenz Interaction not studied.  Since 

fluoxetine shares a similar metabolic 
profile with paroxetine, i.e. a strong 
CYP2D6 inhibitory effect, a similar 
lack of interaction would be expected 
for fluoxetine. 

Atripla and fluoxetine 
can be co-administered 
without dose adjustment. 

Fluoxetine/Emtricitabine Interaction not studied. 
Fluoxetine/Tenofovir disoproxil Interaction not studied. 
Norepinephrine and dopamine reuptake inhibitor 
Bupropion/Efavirenz 
[150 mg single dose (sustained 
release)/600 mg q.d.] 

Bupropion: 
AUC: ↓ 55% (↓ 48 to ↓ 62) 
Cmax: ↓ 34% (↓ 21 to ↓ 47) 
 
Hydroxybupropion: 
AUC: ↔ 
Cmax: ↑ 50% (↑ 20 to ↑ 80) 
(CYP2B6 induction) 

Increases in bupropion 
dosage should be guided 
by clinical response, but 
the maximum 
recommended dose of 
bupropion should not be 
exceeded.  No dose 
adjustment is necessary 
for efavirenz. Bupropion/Emtricitabine Interaction not studied. 

Bupropion/Tenofovir disoproxil Interaction not studied. 



24 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
CARDIOVASCULAR AGENTS 
Calcium Channel Blockers 
Diltiazem/Efavirenz 
(240 mg q.d./600 mg q.d.) 

Diltiazem: 
AUC: ↓ 69% (↓ 55 to ↓ 79)  
Cmax: ↓ 60% (↓ 50 to ↓ 68)  
Cmin: ↓ 63% (↓ 44 to ↓ 75) 
 
Desacetyl diltiazem: 
AUC: ↓ 75% (↓ 59 to ↓ 84)  
Cmax: ↓ 64% (↓ 57 to ↓ 69)  
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. 

Dose adjustments of 
diltiazem when co-
administered with Atripla 
should be guided by 
clinical response (refer to 
the Summary of Product 
Characteristics for 
diltiazem). 

Diltiazem/Emtricitabine Interaction not studied. 
Diltiazem/Tenofovir disoproxil Interaction not studied. 
Verapamil, Felodipine, Nifedipine and 
Nicardipine 

Interaction not studied with efavirenz, 
emtricitabine, or tenofovir disoproxil.  
When efavirenz is co-administered 
with a calcium channel blocker that is 
a substrate of the CYP3A4 enzyme, 
there is a potential for reduction in the 
plasma concentrations of the calcium 
channel blocker. 

Dose adjustments of 
calcium channel blockers 
when co-administered 
with Atripla should be 
guided by clinical 
response (refer to the 
Summary of Product 
Characteristics for the 
calcium channel blocker). 



25 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
LIPID LOWERING MEDICINAL PRODUCTS 
HMG Co-A Reductase Inhibitors 
Atorvastatin/Efavirenz 
(10 mg q.d./600 mg q.d.) 

Atorvastatin: 
AUC: ↓ 43% (↓ 34 to ↓ 50) 
Cmax: ↓ 12% (↓ 1 to ↓ 26) 
 
2-hydroxy atorvastatin: 
AUC: ↓ 35% (↓ 13 to ↓ 40) 
Cmax: ↓ 13% (↓ 0 to ↓ 23) 
 
4-hydroxy atorvastatin: 
AUC: ↓ 4% (↓ 0 to ↓ 31) 
Cmax: ↓ 47% (↓ 9 to ↓ 51) 
 
Total active HMG Co-A reductase 
inhibitors:  
AUC: ↓ 34% (↓ 21 to ↓ 41) 
Cmax: ↓ 20% (↓ 2 to ↓ 26) 

Cholesterol levels should 
be periodically 
monitored.  Dosage 
adjustments of 
atorvastatin may be 
required when 
co-administered with 
Atripla (refer to the 
Summary of Product 
Characteristics for 
atorvastatin). 

Atorvastatin/Emtricitabine Interaction not studied. 
Atorvastatin/Tenofovir disoproxil Interaction not studied. 
Pravastatin/Efavirenz 
(40 mg q.d./600 mg q.d.) 

Pravastatin: 
AUC: ↓ 40% (↓ 26 to ↓ 57) 
Cmax: ↓ 18% (↓ 59 to ↑ 12) 

Cholesterol levels should 
be periodically 
monitored.  Dosage 
adjustments of 
pravastatin may be 
required when 
co-administered with 
Atripla (refer to the 
Summary of Product 
Characteristics for 
pravastatin). 

Pravastatin/Emtricitabine Interaction not studied. 
Pravastatin/Tenofovir disoproxil  Interaction not studied. 

Simvastatin/Efavirenz 
(40 mg q.d./600 mg q.d.) 

Simvastatin: 
AUC: ↓ 69% (↓ 62 to ↓ 73) 
Cmax: ↓ 76% (↓ 63 to ↓ 79) 
 
Simvastatin acid: 
AUC: ↓ 58% (↓ 39 to ↓ 68) 
Cmax: ↓ 51% (↓ 32 to ↓ 58) 
 
Total active HMG Co-A reductase 
inhibitors: 
AUC: ↓ 60% (↓ 52 to ↓ 68) 
Cmax: ↓ 62% (↓ 55 to ↓ 78) 
(CYP3A4 induction) 
 
Co-administration of efavirenz with 
atorvastatin, pravastatin, or 
simvastatin did not affect efavirenz 
AUC or Cmax values. 

Cholesterol levels should 
be periodically 
monitored.  Dosage 
adjustments of 
simvastatin may be 
required when 
co-administered with 
Atripla (refer to the 
Summary of Product 
Characteristics for 
simvastatin). 

Simvastatin/Emtricitabine Interaction not studied. 
Simvastatin/Tenofovir disoproxil Interaction not studied. 



26 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Rosuvastatin/Efavirenz Interaction not studied.  Rosuvastatin 

is largely excreted unchanged via the 
faeces, therefore interaction with 
efavirenz is not expected. 

Atripla and rosuvastatin 
can be co-administered 
without dose adjustment. 

Rosuvastatin/Emtricitabine Interaction not studied. 
Rosuvastatin/Tenofovir disoproxil Interaction not studied. 
HORMONAL CONTRACEPTIVES 
Oral: 
Ethinyloestradiol+Norgestimate/Efavirenz 
(0.035 mg+0.25 mg q.d./600 mg q.d.) 

Ethinyloestradiol: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↓ 8% (↑ 14 to ↓ 25) 
 
Norelgestromin (active metabolite): 
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. 

A reliable method of 
barrier contraception 
must be used in addition 
to hormonal 
contraceptives 
(see section 4.6). 

Ethinyloestradiol/Tenofovir disoproxil 
(-/245 mg q.d.) 

Ethinyloestradiol: 
AUC: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 

Norgestimate/Ethinyloestradiol/ 
Emtricitabine 

Interaction not studied. 

Injection: 
Depomedroxyprogesterone acetate 
(DMPA)/Efavirenz 
(150 mg IM single dose DMPA) 

In a 3-month drug interaction study, 
no significant differences in MPA 
pharmacokinetic parameters were 
found between subjects receiving 
efavirenz-containing antiretroviral 
therapy and subjects receiving 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. 

Because of the limited 
information available, a 
reliable method of barrier 
contraception must be 
used in addition to 
hormonal contraceptives 
(see section 4.6). 

DMPA/Tenofovir disoproxil Interaction not studied. 
DMPA/Emtricitabine Interaction not studied. 



27 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Implant: 
Etonogestrel/Efavirenz 

Decreased exposure of etonogestrel 
may be expected (CYP3A4 
induction).  There have been 
occasional post-marketing reports of 
contraceptive failure with etonogestrel 
in efavirenz-exposed patients. 

A reliable method of 
barrier contraception 
must be used in addition 
to hormonal 
contraceptives 
(see section 4.6). 

Etonogestrel/Tenofovir disoproxil Interaction not studied. 
Etonogestrel/Emtricitabine Interaction not studied. 
IMMUNOSUPPRESSANTS 
Immunosuppressants metabolised by 
CYP3A4 (e.g. cyclosporine, tacrolimus, 
sirolimus)/Efavirenz 

Interaction not studied. 
↓ exposure of the immunosuppressant 
may be expected (CYP3A4 
induction). 
These immunosuppressants are not 
anticipated to impact exposure of 
efavirenz. 

Dose adjustments of the 
immunosuppressant may 
be required.  Close 
monitoring of 
immunosuppressant 
concentrations for at least 
two weeks (until stable 
concentrations are 
reached) is recommended 
when starting or stopping 
treatment with Atripla. 

Tacrolimus/Emtricitabine/Tenofovir 
disoproxil 
(0.1 mg/kg q.d./200 mg/245 mg q.d.) 

Tacrolimus: 
AUC: ↔ 
Cmax: ↔ 
C24h: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
C24h: ↔ 
 
Tenofovir disoproxil: 
AUC: ↔ 
Cmax: ↔ 
C24h: ↔ 

OPIOIDS 
Methadone/Efavirenz 
(35-100 mg q.d./600 mg q.d.) 

Methadone: 
AUC: ↓ 52% (↓ 33 to ↓ 66) 
Cmax: ↓ 45% (↓ 25 to ↓ 59) 
(CYP3A4 induction) 
 
In a study of HIV infected intravenous 
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. 

Concomitant 
administration with 
Atripla should be avoided 
due to the risk for QTc 
prolongation (see section 
4.3). 

Methadone/Tenofovir disoproxil 
(40-110 mg q.d./245 mg q.d.) 

Methadone: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

Methadone/Emtricitabine Interaction not studied. 



28 

Medicinal product by therapeutic areas Effects on drug levels 
Mean percent change in AUC, Cmax, 
Cmin with 90% confidence intervals 

if available 
(mechanism) 

Recommendation 
concerning 

co-administration with 
Atripla 

(efavirenz 600 mg, 
emtricitabine 200 mg, 
tenofovir disoproxil 

245 mg) 
Buprenorphine/naloxone/Efavirenz Buprenorphine: 

AUC: ↓ 50% 
 
Norbuprenorphine: 
AUC: ↓ 71% 
 
Efavirenz: 
No clinically significant 
pharmacokinetic interaction. 

Despite the decrease in 
buprenorphine exposure, 
no patients exhibited 
withdrawal symptoms.  
Dose adjustment of 
buprenorphine may not 
be necessary when 
co-administered with 
Atripla. 

Buprenorphine/naloxone/Emtricitabine Interaction not studied. 
Buprenorphine/naloxone/Tenofovir 
disoproxil  

Interaction not studied. 

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. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential (see below and section 5.3) 
 
Pregnancy should be avoided in women receiving Atripla.  Women of childbearing potential should 
undergo pregnancy testing before initiation of Atripla. 
 
Contraception in males and females 
 
Barrier contraception should always be used in combination with other methods of contraception (for 
example, oral or other hormonal contraceptives, see section 4.5) while on therapy with Atripla.  
Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after 
discontinuation of Atripla is recommended.   
 
Pregnancy 
 
Efavirenz: There have been seven retrospective reports of findings consistent with neural tube defects, 
including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any 
efavirenz-containing fixed-dose combination tablets) in the first trimester.  Two additional cases 
(1 prospective and 1 retrospective) including events consistent with neural tube defects have been 
reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir 
disoproxil.  A causal relationship of these events to the use of efavirenz has not been established, and 
the denominator is unknown.  As neural tube defects occur within the first 4 weeks of foetal 
development (at which time neural tubes are sealed), this potential risk would concern women exposed 
to efavirenz during the first trimester of pregnancy.  
 



29 

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 
904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live 
births.  One child was reported to have a neural tube defect, and the frequency and pattern of other 
birth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as 
well as those in HIV negative controls.  The incidence of neural tube defects in the general population 
ranges from 0.5-1 case per 1,000 live births. 
 
Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3).  
 
Emtricitabine and tenofovir disoproxil: A large amount of data on pregnant women (more than 1000 
pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with 
emtricitabine and tenofovir disoproxil.  Animal studies on emtricitabine and tenofovir disoproxil do 
not indicate reproductive toxicity (see section 5.3). 
 
Atripla should not be used during pregnancy unless the clinical condition of the woman requires 
treatment with efavirenz/emtricitabine/tenofovir disoproxil. 
 
Breast-feeding 
 
Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk.  There is 
insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants.  A 
risk to the infants cannot be excluded.  Therefore Atripla should not be used during breast-feeding. 
 
As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order 
to avoid transmission of HIV to the infant. 
 
Fertility 
 
No human data on the effect of Atripla are available.  Animal studies do not indicate harmful effects of 
efavirenz, emtricitabine or tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
dizziness has been reported during treatment with efavirenz, emtricitabine and tenofovir disoproxil.  
Efavirenz may also cause impaired concentration and/or somnolence.  Patients should be instructed 
that if they experience these symptoms they should avoid potentially hazardous tasks such as driving 
and operating machinery. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients 
either as the fixed-dose combination tablet Atripla (study AI266073) or as the component products 
(study GS-01-934).  Adverse reactions were generally consistent with those seen in previous studies of 
the individual components.  The most frequently reported adverse reactions considered possibly or 
probably related to Atripla among patients treated up to 48 weeks in study AI266073 were psychiatric 
disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%). 
 
Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric 
adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); 
severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported. 
 
Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy 
(including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to 



30 

fractures) have also been reported.  Monitoring of renal function is recommended for patients 
receiving Atripla (see section 4.4). 
 
Discontinuation of Atripla therapy in patients co-infected with HIV and HBV may be associated with 
severe acute exacerbations of hepatitis (see section 4.4). 
 
The administration of Atripla with food may increase efavirenz exposure and may lead to an increase 
in the frequency of adverse reactions (see sections 4.4 and 5.2). 
 
Tabulated list of adverse reactions 
 
The adverse reactions from clinical study and post-marketing experience with Atripla and the 
individual components of Atripla in antiretroviral combination therapy are listed in Table 2 below by 
body system organ class, frequency and the component(s) of Atripla to which the adverse reactions are 
attributable.  Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness.  Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), 
uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Adverse reactions associated with the use of Atripla: Treatment-emergent adverse reactions 
considered possibly or probably related to Atripla reported in study AI266073 (over 48 weeks; 
n = 203), which have not been associated with one of the individual components of Atripla, include: 
 
Common: - anorexia 
 
Uncommon: - dry mouth 
 - incoherent speech 
 - increased appetite 
 - libido decreased 
 - myalgia 
 
Table 2: Adverse reactions associated with Atripla listed by the component(s) of Atripla to which 
the adverse reactions are attributable 
 

 Atripla 
Efavirenz Emtricitabine Tenofovir disoproxil 

Blood and lymphatic system disorders: 
Common  neutropenia  
Uncommon  anaemia1  
Immune system disorders: 
Common  allergic reaction  
Uncommon hypersensitivity   
Metabolism and nutrition disorders: 
Very common   hypophosphataemia2 
Common hypertriglyceridaemia3 hyperglycaemia, 

hypertriglyceridaemia 
 

Uncommon hypercholesterolaemia3  hypokalaemia2 
Rare   lactic acidosis 



31 

 Atripla 
Efavirenz Emtricitabine Tenofovir disoproxil 

Psychiatric disorders: 
Common depression (severe in 

1.6%)3, anxiety3, 
abnormal dreams3, 
insomnia3 

abnormal dreams, 
insomnia 

 

Uncommon suicide attempt3, suicide 
ideation3, psychosis3, 
mania3, paranoia3, 
hallucination3, euphoric 
mood3, affect lability3, 
confusional state3, 
aggression3, catatonia3 

  

Rare completed suicide3,4, 
delusion3,4, neurosis3,4 

  

Nervous system disorders: 
Very common  headache dizziness 
Common cerebellar coordination 

and balance 
disturbances3, 
somnolence (2.0%)3, 
headache (5.7%)3, 
disturbance in attention 
(3.6%)3, dizziness 
(8.5%)3 

dizziness headache 

Uncommon convulsions3, amnesia3, 
thinking abnormal3, 
ataxia3, coordination 
abnormal3, agitation3, 
tremor 

  

Eye disorders: 
Uncommon vision blurred   
Ear and labyrinth disorders: 
Uncommon tinnitus, vertigo   
Vascular disorders: 
Uncommon flushing   
Gastrointestinal disorders: 
Very common  diarrhoea, nausea diarrhoea, vomiting, 

nausea 
Common diarrhoea, vomiting, 

abdominal pain, nausea 
elevated amylase 
including elevated 
pancreatic amylase, 
elevated serum lipase, 
vomiting, abdominal 
pain, dyspepsia 

abdominal pain, 
abdominal distension, 
flatulence 

Uncommon pancreatitis  pancreatitis 
Hepatobiliary disorders: 
Common elevated aspartate 

aminotransferase (AST), 
elevated alanine 
aminotransferase (ALT), 
elevated gamma-
glutamyltransferase 
(GGT) 

elevated serum AST 
and/or elevated serum 
ALT, 
hyperbilirubinaemia 

increased transaminases 

Uncommon hepatitis acute   
Rare hepatic failure3,4  hepatic steatosis, 

hepatitis 



32 

 Atripla 
Efavirenz Emtricitabine Tenofovir disoproxil 

Skin and subcutaneous tissue disorders: 
Very common rash (moderate-severe, 

11.6%, all grades, 18%)3 
 rash 

Common pruritus vesiculobullous rash, 
pustular rash, 
maculopapular rash, 
rash, pruritus, urticaria, 
skin discolouration 
(increased 
pigmentation)1 

 

Uncommon Stevens-Johnson 
syndrome, erythema 
multiforme3, severe rash 
(< 1%) 

angioedema4  

Rare photoallergic dermatitis  angioedema 
Musculoskeletal and connective tissue disorders: 
Very common  elevated creatine kinase  
Uncommon   rhabdomyolysis2, 

muscular weakness2 
Rare   osteomalacia (manifested 

as bone pain and 
infrequently contributing 
to fractures)2,4, 
myopathy2 

Renal and urinary disorders: 
Uncommon   increased creatinine, 

proteinuria, proximal 
renal tubulopathy 
including Fanconi 
syndrome 

Rare   renal failure (acute and 
chronic), acute tubular 
necrosis, nephritis 
(including acute 
interstitial nephritis)4, 
nephrogenic diabetes 
insipidus 

Reproductive system and breast disorders: 
Uncommon gynaecomastia   
General disorders and administration site conditions: 
Very common   asthenia 
Common fatigue pain, asthenia  

1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was 
administered to paediatric patients. 
2 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 
associated with tenofovir disoproxil in the absence of this condition. 
3 See section 4.8 Description of selected adverse reactions for more details. 
4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovir 
disoproxil.  The frequency category was estimated from a statistical calculation based on the total number of patients treated 
with efavirenz in clinical trials (n = 3,969) or exposed to emtricitabine in randomised controlled clinical trials (n = 1,563) or 
exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access programme (n = 7,319). 
 
Description of selected adverse reactions 
 
Rash: In clinical trials of efavirenz, rashes were usually mild-to-moderate maculopapular skin 
eruptions that occurred within the first two weeks of initiating therapy with efavirenz.  In most patients 
rash resolved with continuing therapy with efavirenz within one month.  Atripla can be reinitiated in 
patients interrupting therapy because of rash.  Use of appropriate antihistamines and/or corticosteroids 
is recommended when Atripla is restarted. 
 



33 

Psychiatric symptoms: Patients with a history of psychiatric disorders appear to be at greater risk of 
serious psychiatric adverse reactions listed in the efavirenz column of Table 2. 
 
Nervous system symptoms: Nervous system symptoms are common with efavirenz, one of the 
components of Atripla.  In clinical controlled studies of efavirenz, nervous system symptoms of 
moderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2% of patients 
discontinued therapy due to such symptoms.  They usually begin during the first one or two days of 
efavirenz therapy and generally resolve after the first two to four weeks.  They may occur more 
frequently when Atripla is taken concomitantly with meals possibly due to increased efavirenz plasma 
levels (see section 5.2).  Dosing at bedtime seems to improve the tolerability of these symptoms 
(see section 4.2). 
 
Hepatic failure with efavirenz: Hepatic failure, including cases in patients with no pre-existing hepatic 
disease or other identifiable risk factors, as reported post-marketing, were sometimes characterised by 
a fulminant course, progressing in some cases to transplantation or death. 
 
Renal impairment: As Atripla may cause renal damage, monitoring of renal function is recommended 
(see sections 4.4 and 4.8 Summary of the safety profile).  Proximal renal tubulopathy generally 
resolved or improved after tenofovir disoproxil discontinuation.  However, in some patients, declines 
in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation.  
Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV 
disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of 
experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see 
section 4.4). 
 
Lactic acidosis: Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in 
combination with other antiretrovirals.  Patients with predisposing factors such as severe hepatic 
impairment (CPT, Class C) (see section 4.3), or patients receiving concomitant medications known to 
induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir 
disoproxil treatment, including fatal outcomes. 
 
Metabolic parameters: Weight and levels of blood lipids and glucose may increase during 
antiretroviral therapy (see section 4.4). 
 
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time 
of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections 
may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been 
reported; however, the reported time to onset is more variable and these events can occur many 
months after initiation of treatment (see section 4.4). 
 
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally 
acknowledged risk factors, advanced HIV disease or long-term exposure to CART.  The frequency of 
this is unknown (see section 4.4). 
 
Paediatric population 
 
Insufficient safety data are available for children below 18 years of age.  Atripla is not recommended 
in this population (see section 4.2). 
 
Other special populations 
 
Elderly: Atripla has not been studied in patients over the age of 65.  Elderly patients are more likely to 
have decreased hepatic or renal function, therefore caution should be exercised when treating elderly 
patients with Atripla (see section 4.2). 
 



34 

Patients with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoring 
of renal function is recommended in any patient with mild renal impairment treated with Atripla 
(see sections 4.2, 4.4 and 5.2). 
 
HIV/HBV or HCV co-infected patients: Only a limited number of patients were co-infected with HBV 
(n = 13) or HCV (n = 26) in study GS-01-934.  The adverse reaction profile of efavirenz, emtricitabine 
and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV was similar to that 
observed in patients infected with HIV without co-infection.  However, as would be expected in this 
patient population, elevations in AST and ALT occurred more frequently than in the general 
HIV infected population. 
 
Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infected with 
HBV, clinical and laboratory evidence of hepatitis may occur after discontinuation of treatment 
(see section 4.4). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Some patients accidentally taking 600 mg efavirenz twice daily have reported increased nervous 
system symptoms.  One patient experienced involuntary muscle contractions. 
 
If overdose occurs, the patient must be monitored for evidence of toxicity (see section 4.8), and 
standard supportive treatment applied as necessary. 
 
Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz.  There is no 
specific antidote for overdose with efavirenz.  Since efavirenz is highly protein bound, dialysis is 
unlikely to remove significant quantities of it from blood. 
 
Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by 
haemodialysis.  It is not known whether emtricitabine or tenofovir can be removed by peritoneal 
dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use, antivirals for treatment of HIV infections, 
combinations, ATC code: J05AR06 
 
Mechanism of action and pharmacodynamic effects 
 
Efavirenz is an NNRTI of HIV-1.  Efavirenz non-competitively inhibits HIV-1 reverse transcriptase 
(RT) and does not significantly inhibit human immunodeficiency virus-2 (HIV-2) RT or cellular 
deoxyribonucleic acid (DNA) polymerases (α, β, γ, and δ).  Emtricitabine is a nucleoside analogue of 
cytidine.  Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate 
(nucleotide) analogue of adenosine monophosphate. 
 
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate 
and tenofovir diphosphate, respectively.  In vitro studies have shown that both emtricitabine and 
tenofovir can be fully phosphorylated when combined together in cells.  Emtricitabine triphosphate 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


35 

and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain 
termination. 
 
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA 
polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.  
 
Cardiac Electrophysiology 
 
The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo 
controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects 
enriched for CYP2B6 polymorphisms.  The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 
genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax 
observed in subjects with CYP2B6 *1/*1 genotype.  A positive relationship between efavirenz 
concentration and QTc prolongation was observed.  Based on the concentration-QTc relationship, the 
mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in 
subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days 
(see section 4.5).           
 
Antiviral activity in vitro 
 
Efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C, 
D, F, G, J, and N) but had reduced antiviral activity against group O viruses.  Emtricitabine displayed 
antiviral activity against HIV-1 clades A, B, C, D, E, F, and G.  Tenofovir displayed antiviral activity 
against HIV-1 clades A, B, C, D, E, F, G, and O.  Both emtricitabine and tenofovir showed strain 
specific activity against HIV-2 and antiviral activity against HBV. 
 
In combination studies evaluating the in vitro antiviral activity of efavirenz and emtricitabine together, 
efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic 
antiviral effects were observed. 
 
Resistance 
 
Resistance to efavirenz can be selected in vitro and resulted in single or multiple amino acid 
substitutions in HIV-1 RT, including L100I, V108I, V179D, and Y181C.  K103N was the most 
frequently observed RT substitution in viral isolates from patients who experienced rebound in viral 
load during clinical studies of efavirenz.  Substitutions at RT positions 98, 100, 101, 108, 138, 188, 
190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N.  
Cross-resistance profiles for efavirenz, nevirapine and delavirdine in vitro demonstrated that the 
K103N substitution confers loss of susceptibility to all three NNRTIs. 
 
The potential for cross-resistance between efavirenz and NRTIs is low because of the different binding 
sites on the target and mechanism of action.  The potential for cross-resistance between efavirenz and 
PIs is low because of the different enzyme targets involved. 
 
Resistance to emtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients due 
to the development of an M184V or M184I substitution in RT with emtricitabine or a K65R 
substitution in RT with tenofovir.  Emtricitabine-resistant viruses with the M184V/I mutation were 
cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and 
zidovudine.  The K65R mutation can also be selected by abacavir or didanosine and results in reduced 
susceptibility to these agents plus lamivudine, emtricitabine and tenofovir.  Tenofovir disoproxil 
should be avoided in patients with HIV-1 harbouring the K65R mutation.  Both the K65R and 
M184V/I mutation remain fully susceptible to efavirenz.  In addition, a K70E substitution in HIV-1 
RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, 
emtricitabine, lamivudine and tenofovir. 
 



36 

Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that 
included either an M41L or an L210W substitution in RT showed reduced susceptibility to tenofovir 
disoproxil. 
 
In vivo resistance (antiretroviral-naïve patients): In a 144-week open-label randomised clinical study 
(GS-01-934) in antiretroviral-naïve patients, where efavirenz, emtricitabine and tenofovir disoproxil 
were used as individual formulations (or as efavirenz and the fixed combination of emtricitabine and 
tenofovir disoproxil (Truvada) from week 96 to 144), genotyping was performed on plasma 
HIV-1 isolates from all patients with confirmed HIV RNA > 400 copies/ml at week 144 or early study 
drug discontinuation (see section on Clinical experience).  As of week 144: 
 
• The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in the 

efavirenz + emtricitabine + tenofovir disoproxil group and in 10/29 (34.5%) isolates analysed 
from the efavirenz + lamivudine/zidovudine group (p-value < 0.05, Fisher’s Exact test 
comparing the emtricitabine + tenofovir disoproxil group to the lamivudine/zidovudine group 
among all subjects). 

• No virus analysed contained the K65R or K70E mutation. 
• Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from 

13/19 (68%) patients in the efavirenz + emtricitabine + tenofovir disoproxil group and in virus 
from 21/29 (72%) patients in the efavirenz + lamivudine/zidovudine group.  A summary of 
resistance mutation development is shown in Table 3. 

 
Table 3: Development of resistance in study GS-01-934 through week 144 
 

 

Efavirenz+ 
emtricitabine+ 

tenofovir disoproxil  
(N=244) 

Efavirenz+lamivudine/zid
ovudine 
(N=243) 

Resistance analysis by week 144  19  31 
On-therapy genotypes 19 (100%) 29 (100%) 
Efavirenz resistance1 13 (68%) 21 (72%) 

K103N 8 (42%) 18* (62%) 
K101E 3 (16%) 3 (10%) 
G190A/S 2 (10.5%) 4 (14%) 
Y188C/H 1 (5%) 2 (7%) 
V108I 1 (5%) 1 (3%) 
P225H 0  2 (7%) 

M184V/I 2 (10.5%) 10* (34.5%) 
K65R 0  0  
K70E 0  0  
TAMs2 0  2 (7%) 
* p-value < 0.05, Fisher’s Exact test comparing efavirenz + emtricitabine + tenofovir disoproxil group to efavirenz 

+ lamivudine/zidovudine group among all patients. 
1 Other efavirenz resistance mutations included A98G (n=1), K103E (n=1), V179D (n=1), and M230L (n=1). 
2 Thymidine analogue associated mutations included D67N (n=1) and K70R (n=1). 

 
In the open-label extended phase of study GS-01-934, where patients received Atripla on an empty 
stomach, 3 additional cases of resistance were seen.  All 3 subjects had received a fixed dose 
combination of lamivudine and zidovudine (Combivir) and efavirenz for 144 weeks and then switched 
to Atripla. Two subjects with confirmed virologic rebound developed NNRTI resistance-associated 
substitutions to efavirenz including K103N, V106V/I/M and Y188Y/C reverse transcriptase 
substitutions at week 240 (96 weeks on Atripla) and week 204 (60 weeks on Atripla).  A third subject 
had pre-existing NNRTI resistance-associated substitutions to efavirenz and the M184V reverse 
transcriptase resistance-associated substitution to emtricitabine at entry into the Atripla extension 
phase and experienced a suboptimal virologic response, and developed K65K/R, S68N and K70K/E 
NRTI resistance-associated substitutions at week 180 (36 weeks on Atripla). 
 



37 

Please refer to the Summary of Product Characteristics for the individual components for additional 
information regarding in vivo resistance with these medicinal products. 
 
Clinical efficacy and safety 
 
In a 144-week open-label randomised clinical study (GS-01-934) antiretroviral treatment-naïve 
HIV-1 infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovir 
disoproxil or a fixed combination of lamivudine and zidovudine (Combivir) administered twice daily 
and efavirenz once daily (please refer to the Summary of Product Characteristics for Truvada).  
Patients who completed 144 weeks of treatment with either treatment arm in study GS-01-934 were 
given the option to continue in an open-label extended phase of the study with Atripla on an empty 
stomach.  Data are available from 286 patients who switched to Atripla: 160 had previously received 
efavirenz, emtricitabine and tenofovir disoproxil, and 126 had previously received Combivir and 
efavirenz.  High rates of virologic suppression were maintained by subjects from both initial treatment 
groups who then received Atripla in the open-label extended phase of the study.  After 96 weeks of 
Atripla treatment, HIV-1 RNA plasma concentrations remained < 50 copies/ml in 82% of patients and 
< 400 copies/ml in 85% of patients (intention to treat analysis (ITT), missing=failure). 
 
Study AI266073 was a 48-week open-label randomised clinical study in HIV infected patients 
comparing the efficacy of Atripla to antiretroviral therapy consisting of at least two nucleoside or 
nucleotide reverse transcriptase inhibitors (NRTIs) with a protease inhibitor or non-nucleoside reverse 
transcriptase inhibitor; however not a regimen containing all Atripla components (efavirenz, 
emtricitabine and tenofovir disoproxil).  Atripla was administered on an empty stomach 
(see section 4.2).  Patients had never experienced virological failure on a previous antiretroviral 
therapy, had no known HIV-1 mutations that confer resistance to any of the three components within 
Atripla, and had been virologically suppressed for at least three months at baseline.  Patients either 
changed to Atripla (N=203) or continued on their original antiretroviral treatment regimen (N=97).  
Forty-eight week data showed that high levels of virologic suppression, comparable to the original 
treatment regimen, were maintained in patients who were randomised to change to Atripla 
(see Table 4). 
 
Table 4: 48-week efficacy data from study AI266073 in which Atripla was administered to 
virologically suppressed patients on combination antiretroviral therapy 
 
 Treatment group  

Endpoint Atripla (N=203) 
n/N (%) 

Stayed on original 
treatment regimen 

(N=97) 
n/N (%) 

Difference between Atripla and 
original treatment regimen 

(95%CI) 

 patients with HIV-1 RNA < 50 copies/ml 
PVR (KM) 94.5% 85.5% 8.9% (-7.7% to 25.6%) 
M=Excluded 179/181 (98.9%) 85/87 (97.7%) 1.2% (-2.3% to 6.7%) 
M=Failure 179/203 (88.2%) 85/97 (87.6%) 0.5% (-7.0% to 9.3%) 
Modified LOCF 190/203 (93.6%) 94/97 (96.9%) -3.3 (-8.3% to 2.7%) 
 patients with HIV-1 RNA < 200 copies/ml 
PVR (KM) 98.4% 98.9% -0.5% (-3.2% to 2.2%) 
M=Excluded 181/181 (100%) 87/87 (100%) 0% (-2.4% to 4.2%) 
M=Failure 181/203 (89.2%) 87/97 (89.7%) -0.5% (-7.6% to 7.9%) 
PVR (KM): Pure virologic response assessed using the Kaplan Meier (KM) method 
M: Missing 
Modified LOCF: Post-hoc analysis where patients who failed virologically or discontinued for adverse events were treated as 
failures; for other drop-outs, the LOCF (last observation carried forward) method was applied 
 
When the two strata were analysed separately, response rates in the stratum with prior PI-treatment 
were numerically lower for patients switched to Atripla [92.4% versus 94.0% for the PVR (sensitivity 
analysis) for Atripla and SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%).  In 
the prior-NNRTI stratum, response rates were 98.9% vs 97.4% for Atripla and SBR patients 
respectively; a difference (95%CI) of 1.4% (-4.0%, 6.9%)]. 



38 

 
A similar trend was observed in a sub-group analysis of treatment-experienced patients with baseline 
HIV-1 RNA < 75 copies/ml from a retrospective cohort study (data collected over 20 months, see 
Table 5). 
 
Table 5: Maintenance of pure virologic response (Kaplan Meier % (Standard Error) [95%CI]) 
at week 48 for treatment-experienced patients with baseline HIV-1 RNA < 75 copies/ml who had 
therapy switched to Atripla according to the type of prior antiretroviral regimen (Kaiser 
Permanente patient database) 
 

Prior Atripla components 
(N=299) 

Prior NNRTI-based regimen 
(N=104) 

Prior PI-based regimen 
(N=34) 

98.9% (0.6%) 
[96.8%, 99.7%] 

98.0% (1.4%) 
[92.3%, 99.5%] 

93.4% (4.5%) 
[76.2%, 98.3%] 

 
No data are currently available from clinical studies with Atripla in treatment-naïve patients or in 
heavily pretreated patients.  There is no clinical experience with Atripla in patients who are 
experiencing virological failure in a first-line antiretroviral treatment regimen or in combination with 
other antiretroviral agents. 
 
Patients coinfected with HIV and HBV 
 
Limited clinical experience in patients co-infected with HIV and HBV suggests that treatment with 
emtricitabine or tenofovir disoproxil in antiretroviral combination therapy to control HIV infection 
also results in a reduction in HBV DNA (3 log10 reduction or 4 to 5 log10 reduction, respectively) 
(see section 4.4). 
 
Paediatric population 
 
The safety and efficacy of Atripla in children under the age of 18 years have not been established. 
 
5.2 Pharmacokinetic properties 
 
The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil were used to 
determine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil, administered 
separately in HIV infected patients.  The bioequivalence of one Atripla film-coated tablet with one 
efavirenz 600 mg film-coated tablet plus one emtricitabine 200 mg hard capsule plus one tenofovir 
disoproxil 245 mg film-coated tablet (equivalent to 300 mg tenofovir disoproxil fumarate) 
administered together, was established following single dose administration to fasting healthy subjects 
in study GS-US-177-0105 (see Table 6). 
 
Table 6: Summary of pharmacokinetic data from study GS-US-177-0105 
 

 
Efavirenz 

(n=45) 
Emtricitabine 

(n=45) 
Tenofovir disoproxil 

(n=45) 

Parameters Test Reference 
GMR (%) 
(90%CI) Test Reference 

GMR (%) 
(90%CI) Test Reference 

GMR (%) 
(90%CI) 

Cmax (ng/ml) 2,264.3 (26.8) 
2,308.6 
(30.3) 

98.79 
(92.28, 
105.76) 

2,130.6 
(25.3) 

2,384.4 
(20.4) 

88.84 
(84.02, 
93.94) 

325.1 
(34.2) 

352.9 
(29.6) 

91.46 
(84.64, 
98.83) 

AUC0-last 
(ng∙h/ml) 

125,623.6 
(25.7) 

132,795.7 
(27.0) 

95.84 
(90.73, 
101.23) 

10,682.6 
(18.1) 

10,874.4 
(14.9) 

97.98 
(94.90, 
101.16) 

1,948.8 
(32.9) 

1,969.0 
(32.8) 

99.29 
(91.02, 
108.32) 

AUCinf 
(ng∙h/ml) 

146,074.9 
(33.1) 

155,518.6 
(34.6) 

95.87 
(89.63, 
102.55) 

10,854.9 
(17.9) 

11,054.3 
(14.9) 

97.96 
(94.86, 
101.16) 

2,314.0 
(29.2) 

2,319.4 
(30.3) 

100.45 
(93.22, 
108.23) 

T1/2 
(h) 

180.6 
(45.3) 

182.5 
(38.3)  

14.5 
(53.8) 

14.6 
(47.8)  

18.9 
(20.8) 

17.8 
(22.6)  



39 

Test: single fixed-dose combination tablet taken under fasted conditions. 
Reference: single dose of a 600 mg efavirenz tablet, 200 mg emtricitabine capsule and 300 mg tenofovir disoproxil tablet 
taken under fasted conditions. 
Values for Test and Reference are mean (% coefficient of variation). 
GMR=geometric least-squares mean ratio, CI=confidence interval 
 
Absorption 
 
In HIV infected patients, peak efavirenz plasma concentrations were attained by 5 hours and 
steady-state concentrations reached in 6 to 7 days.  In 35 patients receiving efavirenz 600 mg once 
daily, steady-state peak concentration (Cmax) was 12.9 ± 3.7 µM (29%) [mean ± standard deviation 
(S.D.) (coefficient of variation (%CV))], steady-state Cmin was 5.6 ± 3.2 µM (57%), and AUC was 
184 ± 73 µM•h (40%). 
 
Emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours post-dose.  
Following multiple dose oral administration of emtricitabine to 20 HIV infected patients, steady-state 
Cmax was 1.8 ± 0.7 µg/ml (mean ± S.D.) (39%CV), steady-state Cmin was 0.09 ± 0.07 µg/ml (80%) and 
the AUC was 10.0 ± 3.1 µg•h/ml (31%) over a 24 hour dosing interval. 
 
Following oral administration of a single 300 mg dose of tenofovir disoproxil to HIV-1 infected 
patients in the fasted state, maximum tenofovir concentrations were achieved within one hour and the 
Cmax and AUC (mean ± S.D.) (%CV) values were 296 ± 90 ng/ml (30%) and 2,287 ± 685 ng•h/ml 
(30%), respectively.  The oral bioavailability of tenofovir from tenofovir disoproxil in fasted patients 
was approximately 25%. 
 
Effect of food 
 
Atripla has not been evaluated in the presence of food. 
 
Administration of efavirenz capsules with a high fat meal increased the mean AUC and Cmax of 
efavirenz by 28% and 79%, respectively, compared to administration in a fasted state.  Compared to 
fasted administration, dosing of tenofovir disoproxil and emtricitabine in combination with either a 
high fat meal or a light meal increased the mean AUC of tenofovir by 43.6% and 40.5%, and Cmax by 
16% and 13.5%, respectively without affecting emtricitabine exposures. 
 
Atripla is recommended for administration on an empty stomach since food may increase efavirenz 
exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8).  
It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower following 
administration of Atripla on an empty stomach as compared to the individual component tenofovir 
disoproxil when taken with food (see section 5.1). 
 
Distribution 
 
Efavirenz is highly bound (> 99%) to human plasma proteins, predominantly albumin. 
 
In vitro binding of emtricitabine to human plasma proteins is < 4% and independent of concentrations 
over the range of 0.02 to 200 µg/ml.  Following intravenous administration the volume of distribution 
of emtricitabine was approximately 1.4 l/kg.  After oral administration, emtricitabine is widely 
distributed throughout the body.  The mean plasma to blood concentration ratio was approximately 1.0 
and the mean semen to plasma concentration ratio was approximately 4.0. 
 
In vitro binding of tenofovir to human plasma or serum protein is < 0.7% and 7.2%, respectively over 
the tenofovir concentration range 0.01 to 25 µg/ml.  Following intravenous administration the volume 
of distribution of tenofovir was approximately 800 ml/kg.  After oral administration, tenofovir is 
widely distributed throughout the body. 
 



40 

Biotransformation 
 
Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz 
is principally metabolised by the CYP system to hydroxylated metabolites with subsequent 
glucuronidation of these hydroxylated metabolites.  These metabolites are essentially inactive against 
HIV-1.  The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible 
for efavirenz metabolism and that it inhibits CYP isozymes 2C9, 2C19, and 3A4.  In in vitro studies 
efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well 
above those achieved clinically. 
 
Efavirenz plasma exposure may be increased in patients with homozygous G516T genetic variant of 
the CYP2B6 isozyme.  The clinical implications of such an association are unknown; however, the 
potential for an increased frequency and severity of efavirenz-associated adverse events cannot be 
excluded. 
 
Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own 
metabolism, which may be clinically relevant in some patients.  In uninfected volunteers, multiple 
doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation 
(22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 
76 hours).  Efavirenz has also been shown to induce UGT1A1.  Exposures of raltegravir (a UGT1A1 
substrate) are reduced in the presence of efavirenz (see section 4.5, Table 1).  Although in vitro data 
suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports of both 
increased and decreased exposures to substrates of these enzymes when co-administered with 
efavirenz in vivo.  The net effect of co-administration is not clear. 
 
There is limited metabolism of emtricitabine.  The biotransformation of emtricitabine includes 
oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and 
conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose).  In vitro 
studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the 
CYP enzymes.  Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by 
any of the major human CYP isoforms involved in drug biotransformation.  Also, emtricitabine did not 
inhibit uridine 5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation. 
 
Elimination 
 
Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses (see also data 
from bioequivalence study described above) and 40 to 55 hours after multiple doses.  Approximately 
14 to 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose 
was excreted in urine as unchanged efavirenz. 
 
Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.  
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in 
urine (approximately 86%) and faeces (approximately 14%).  Thirteen percent of the emtricitabine 
dose was recovered in urine as three metabolites.  The systemic clearance of emtricitabine averaged 
307 ml/min. 
 
Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.  
Tenofovir is primarily excreted by the kidneys by both filtration and an active tubular transport system 
with approximately 70 to 80% of the dose excreted unchanged in urine following intravenous 
administration.  The apparent clearance of tenofovir averaged approximately 307 ml/min.  Renal 
clearance has been estimated to be approximately 210 ml/min, which is in excess of the glomerular 
filtration rate.  This indicates that active tubular secretion is an important part of the elimination of 
tenofovir. 
 



41 

Pharmacokinetics in special populations 
 
Age 
Pharmacokinetic studies have not been performed with efavirenz, emtricitabine or tenofovir in elderly 
patients (over 65 years of age). 
 
Gender 
The pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.  Limited 
data suggest that females may have higher exposure to efavirenz but they do not appear to be less 
tolerant of efavirenz. 
 
Ethnicity 
Limited data suggest that Asian and Pacific Island patients may have higher exposure to efavirenz but 
they do not appear to be less tolerant of efavirenz. 
 
Paediatric population 
Pharmacokinetic studies have not been performed with Atripla in infants and children under 18 years 
of age (see section 4.2). 
 
Renal impairment 
The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration of 
the separate pharmaceutical forms or as Atripla have not been studied in HIV infected patients with 
renal impairment. 
 
Pharmacokinetic parameters were determined following administration of single doses of the 
individual preparations of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected 
patients with varying degrees of renal impairment.  The degree of renal impairment was defined 
according to baseline creatinine clearance (normal renal function when creatinine 
clearance > 80 ml/min; mild impairment with creatinine clearance=50 to 79 ml/min; moderate 
impairment with creatinine clearance=30 to 49 ml/min and severe impairment with creatinine 
clearance=10 to 29 ml/min). 
 
The mean (%CV) emtricitabine exposure increased from 12 µg•h/ml (25%) in subjects with normal 
renal function to 20 µg•h/ml (6%), 25 µg•h/ml (23%) and 34 µg•h/ml (6%) in patients with mild, 
moderate and severe renal impairment, respectively. 
 
The mean (%CV) tenofovir exposure increased from 2,185 ng•h/ml (12%) in patients with normal 
renal function, to 3,064 ng•h/ml (30%), 6,009 ng•h/ml (42%) and 15,985 ng•h/ml (45%) in patients 
with mild, moderate and severe renal impairment, respectively. 
 
In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug 
exposures substantially increased over 72 hours to 53 µg•h/ml (19%) of emtricitabine, and over 
48 hours to 42,857 ng•h/ml (29%) of tenofovir. 
 
The pharmacokinetics of efavirenz have not been studied in patients with renal impairment.  However, 
less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal 
impairment on exposure to efavirenz is likely to be minimal. 
 
Atripla is not recommended for patients with moderate or severe renal impairment 
(creatinine clearance < 50 ml/min).  Patients with moderate or severe renal impairment require dose 
interval adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with the 
combination tablet (see sections 4.2 and 4.4). 
 
Hepatic impairment 
The pharmacokinetics of Atripla have not been studied in HIV infected patients with hepatic 
impairment.  Atripla should be administered with caution to patients with mild hepatic impairment 
(see sections 4.3 and 4.4). 



42 

 
Atripla must not be used in patients with severe hepatic impairment (see section 4.3) and is not 
recommended for patients with moderate hepatic impairment.  In a single-dose study of efavirenz, 
half-life was doubled in the single patient with severe hepatic impairment (Child-Pugh-Turcotte 
Class C), indicating a potential for a much greater degree of accumulation.  A multiple-dose study of 
efavirenz showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic 
impairment (Child-Pugh-Turcotte Class A) compared with controls.  There were insufficient data to 
determine whether moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C) affects 
efavirenz pharmacokinetics. 
 
The pharmacokinetics of emtricitabine have not been studied in non-HBV infected patients with 
varying degrees of hepatic insufficiency.  In general, emtricitabine pharmacokinetics in HBV infected 
patients were similar to those in healthy subjects and in HIV infected patients. 
 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients with 
varying degrees of hepatic impairment defined according to CPT classification.  Tenofovir 
pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no 
dose adjustment of tenofovir disoproxil is required in these subjects. 
 
5.3 Preclinical safety data 
 
Efavirenz: Non-clinical safety pharmacology studies on efavirenz reveal no special hazard for humans.  
In repeated-dose toxicity studies, biliary hyperplasia was observed in cynomolgus monkeys given 
efavirenz for ≥ 1 year at a dose resulting in mean AUC values approximately 2-fold greater than those 
in humans given the recommended dose.  The biliary hyperplasia regressed upon cessation of dosing.  
Biliary fibrosis has been observed in rats.  Non-sustained convulsions were observed in some monkeys 
receiving efavirenz for ≥ 1 year, at doses yielding plasma AUC values 4- to 13-fold greater than those 
in humans given the recommended dose. 
 
Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays.  Carcinogenicity 
studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in 
male mice.  The mechanism of tumour formation and the potential relevance for humans are not 
known.  Carcinogenicity studies in male mice, male and female rats were negative. 
 
Reproductive toxicity studies showed increased foetal resorptions in rats.  No malformations were 
observed in foetuses from efavirenz-treated rats and rabbits.  However, malformations were observed 
in 3 of 20 foetuses/newborns from efavirenz-treated cynomolgus monkeys given doses resulting in 
plasma efavirenz concentrations similar to those seen in humans.  Anencephaly and unilateral 
anophthalmia with secondary enlargement of the tongue were observed in one foetus, 
microophthalmia was observed in another foetus and cleft palate was observed in a third foetus.   
 
Emtricitabine: Non-clinical data on emtricitabine reveal no special hazard for humans based on 
conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic 
potential, and toxicity to reproduction and development.  
 
Tenofovir disoproxil: Non-clinical safety pharmacology studies on tenofovir disoproxil reveal no 
special hazard for humans.  Findings in repeated-dose toxicity studies in rats, dogs and monkeys at 
exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical 
use include renal and bone toxicity and a decrease in serum phosphate concentration.  Bone toxicity 
was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs).  
The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in 
paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures 
following subcutaneous dosing (≥ 40-fold the exposure in patients).  Findings in the rat and monkey 
studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with 
potential secondary reduction in BMD.   
 



43 

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results 
in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat 
hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay. 
 
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an 
extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 
 
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or 
foetal parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in 
peri-postnatal toxicity studies at maternally toxic doses. 
 
Combination of emtricitabine and tenofovir disoproxil: Genotoxicity and repeated-dose toxicity 
studies of one month or less with the combination of these two components found no exacerbation of 
toxicological effects compared to studies with the separate components.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Croscarmellose sodium 
Hyprolose 
Magnesium stearate (E572) 
Microcrystalline cellulose (E460) 
Sodium laurilsulfate 
 
Film-coating 
Iron oxide black 
Iron oxide red 
Macrogol 3350 
Poly(vinyl alcohol) 
Talc 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
90 (3 bottles of 30) film-coated tablets. 
 
Not all pack sizes may be marketed. 
 



44 

6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/430/001 
EU/1/07/430/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 December 2007 
 
Date of latest renewal: 17 September 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



46 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
 



47 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



49 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Atripla 600 mg/200 mg/245 mg film-coated tablets 
efavirenz/emtricitabine/tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of 
tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 (3 bottles of 30) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
 



50 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/430/001 30 film-coated tablets 
EU/1/07/430/002 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Atripla [outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC {number} 
SN {number} 
NN {number} 
[outer packaging only]



51 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



52 

Package leaflet: Information for the patient 
 

Atripla 600 mg/200 mg/245 mg film-coated tablets 
Efavirenz/emtricitabine/tenofovir disoproxil 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet: 
1. What Atripla is and what it is used for 
2. What you need to know before you take Atripla 
3. How to take Atripla 
4. Possible side effects 
5. How to store Atripla 
6. Contents of the pack and other information 
 
 
1. What Atripla is and what it is used for 
 
Atripla contains three active substances that are used to treat human immunodeficiency virus 
(HIV) infection: 
 
- Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) 
- Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) 
- Tenofovir is a nucleotide reverse transcriptase inhibitor (NtRTI) 
 
Each of these active substances, also known as antiretroviral medicines, work by interfering with an 
enzyme (reverse transcriptase) that is essential for the virus to multiply. 
 
Atripla is a treatment for Human Immunodeficiency Virus (HIV) infection in adults aged 18 years 
and over who have previously been treated with other antiretroviral medicines and have their HIV-1 
infection under control for at least three months.  Patients must not have experienced failure of a 
previous HIV therapy. 
 
 
2. What you need to know before you take Atripla 
 
Do not take Atripla 
 
- if you are allergic to efavirenz, emtricitabine, tenofovir, tenofovir disoproxil or any of the other 

ingredients of this medicine (listed in section 6). 
 
- if you have severe liver disease. 
 
- if you have a heart condition, such as an abnormal electrical signal called prolongation of 

the QT interval that puts you at high risk for severe heart rhythm problems (Torsade de 
Pointes). 

 
- if any member of your family (parents, grandparents, brothers or sisters) has died suddenly due 

to a heart problem or was born with heart problems. 
 



53 

- if your doctor has told you that you have high or low levels of electrolytes such as potassium or 
magnesium in your blood. 

 
- if you are currently taking any of the following medicines (see also “Other Medicines and 

Atripla”): 
- astemizole or terfenadine (used to treat hay fever or other allergies) 
- bepridil (used to treat heart disease) 
- cisapride (used to treat heartburn) 
- elbasvir/grazoprevir (used to treat hepatitis C) 
- ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and 

methylergonovine) (used to treat migraines and cluster headaches) 
- midazolam or triazolam (used to help you sleep) 
- pimozide, imipramine, amitriptyline or clomipramine (used to treat certain mental 

conditions) 
- St. John’s wort (Hypericum perforatum) (a herbal preparation used for depression and 

anxiety) 
- voriconazole (used to treat fungal infections) 
- flecainide, metoprolol (used to treat irregular heart beat) 
- certain antibiotics (macrolides, fluoroquinolones, imidazole) 
- triazole antifungal agents 
- certain antimalarial agents 
- methadone (used to treat opiate addiction) 
 

If you are taking any of these medicines, tell your doctor immediately.  Taking these medicines 
with Atripla could cause serious or life-threatening side effects or stop these medicines from working 
properly. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Atripla. 
 
- You can still pass on HIV when taking this medicine, although the risk is lowered by effective 

antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid infecting other 
people.  This medicine is not a cure for HIV infection.  While taking Atripla you may still 
develop infections or other illnesses associated with HIV infection. 

 
- You must remain under the care of your doctor while taking Atripla. 
 
- Tell your doctor: 
 

- if you are taking other medicines that contain efavirenz, emtricitabine, tenofovir 
disoproxil, tenofovir alafenamide, or lamivudine or adefovir dipivoxil.  Atripla should not 
be taken with any of these medicines. 

 
- if you have or have had kidney disease, or if tests have shown problems with your 

kidneys.  Atripla is not recommended if you have moderate to severe kidney disease. 
 
Atripla may affect your kidneys.  Before starting treatment, your doctor may order blood 
tests to assess kidney function.  Your doctor may also order blood tests during treatment 
to monitor your kidneys. 
 
Atripla is not usually taken with other medicines that can damage your kidneys (see Other 
medicines and Atripla).  If this is unavoidable, your doctor will monitor your kidney 
function once a week. 
 

- if you have a heart disorder, such as abnormal electrical signal called prolongation 
of the QT interval. 



54 

 
- if you have a history of mental illness, including depression, or of substance or alcohol 

abuse.  Tell your doctor immediately if you feel depressed, have suicidal thoughts or have 
strange thoughts (see section 4, Possible side effects). 
 

- if you have a history of convulsions (fits or seizures) or if you are being treated with 
anticonvulsant therapy such as carbamazepine, phenobarbital and phenytoin.  If you are 
taking any of these medicines, your doctor may need to check the level of anticonvulsant 
medicine in your blood to ensure that it is not affected while taking Atripla.  Your doctor 
may give you a different anticonvulsant. 

 
- if you have a history of liver disease, including chronic active hepatitis.  Patients with 

liver disease including chronic hepatitis B or C, who are treated with combination 
antiretrovirals, have a higher risk of severe and potentially life-threatening liver problems.  
Your doctor may conduct blood tests in order to check how well your liver is working or 
may switch you to another medicine.  If you have severe liver disease, do not take 
Atripla (see earlier in section 2, Do not take Atripla). 

 
If you have hepatitis B infection, your doctor will carefully consider the best treatment 
regimen for you.  Tenofovir disoproxil and emtricitabine, two of the active substances in 
Atripla, show some activity against hepatitis B virus although emtricitabine is not 
approved for the treatment of hepatitis B infection.  Symptoms of your hepatitis may 
become worse after discontinuation of Atripla.  Your doctor may then conduct blood tests 
at regular intervals in order to check how well your liver is working (see section 3, If you 
stop taking Atripla). 

 
- Independent of a history of liver disease, your doctor will consider regular blood tests to 

check how your liver is working. 
 
- if you are over 65.  Insufficient numbers of patients over 65 years of age have been 

studied.  If you are over 65 years of age and are prescribed Atripla, your doctor will 
monitor you carefully. 

 
- Once you start taking Atripla, look out for: 
 

- signs of dizziness, difficulty sleeping, drowsiness, difficulty concentrating or 
abnormal dreaming.  These side effects may start in the first 1 or 2 days of treatment 
and usually go away after the first 2 to 4 weeks. 

 
- any signs of skin rash.  Rashes may be caused by Atripla.  If you see any signs of a 

severe rash with blistering or fever, stop taking Atripla and tell your doctor at once.  If 
you had a rash while taking another NNRTI, you may be at higher risk of getting a rash 
with Atripla. 

 
- any signs of inflammation or infection.  In some patients with advanced HIV infection 

(AIDS) and a history of opportunistic infection, signs and symptoms of inflammation 
from previous infections may occur soon after anti-HIV treatment is started.  It is believed 
that these symptoms are due to improvement in the body’s immune response, enabling the 
body to fight infections that may have been present with no obvious symptoms.  If you 
notice any symptoms of infection, please tell your doctor at once. 

 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs 
when the immune system attacks healthy body tissue) may also occur after you start 
taking medicines for the treatment of your HIV infection.  Autoimmune disorders may 
occur many months after the start of treatment.  If you notice any symptoms of infection 
or other symptoms such as muscle weakness, weakness beginning in the hands and feet 



55 

and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please 
inform your doctor immediately to seek necessary treatment. 

 
- bone problems.  Some patients taking combination antiretroviral therapy may develop a 

bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to 
the bone).  The length of combination antiretroviral therapy, corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index, among others, may be 
some of the many risk factors for developing this disease.  Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement.  If you notice any of these symptoms please inform your doctor.  

 
Bone problems (sometimes resulting in fractures) may also occur due to damage to 
kidney tubule cells (see section 4, Possible side effects). 

 
Children and adolescents 
 
- Do not give Atripla to children and adolescents under 18 years of age.  The use of Atripla in 

children and adolescents has not been studied. 
 
Other medicines and Atripla 
 
You must not take Atripla with certain medicines.  These are listed under Do not take Atripla, at 
the start of section 2.  They include some common medicines and some herbal preparations (including 
St. John’s wort) which can cause serious interactions. 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Also, Atripla should not be taken with any other medicines that contain efavirenz (unless 
recommended by your doctor), emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or 
lamivudine or adefovir dipivoxil. 
 
Tell your doctor if you are taking other medicines which may damage your kidneys.  Some examples 
include: 
- aminoglycosides, vancomycin (medicines for bacterial infections) 
- foscarnet, ganciclovir, cidofovir (medicines for viral infections) 
- amphotericin B, pentamidine (medicines for fungal infections) 
- interleukin-2 (to treat cancer) 
- non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains) 
 
Atripla may interact with other medicines, including herbal preparations such as Ginkgo biloba 
extracts.  As a result, the amounts of Atripla or other medicines in your blood may be affected.  This 
may stop your medicines from working properly, or may make any side effects worse.  In some cases, 
your doctor may need to adjust your dose or check your blood levels.  It is important to tell your 
doctor or pharmacist if you are taking any of the following: 
 
- Medicines containing didanosine (for HIV infection): Taking Atripla with other antiviral 

medicines that contain didanosine can raise the levels of didanosine in your blood and may 
reduce CD4 cell counts.  Inflammation of the pancreas and lactic acidosis (excess lactic acid in 
the blood), which sometimes caused death, have been reported rarely when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your doctor will carefully 
consider whether to treat you with medicines containing tenofovir and didanosine. 

- Other medicines used for HIV infection: The following protease inhibitors: darunavir, 
indinavir, lopinavir/ritonavir, ritonavir, or ritonavir boosted atazanavir or saquinavir.  Your 
doctor may consider giving you an alternative medicine or changing the dose of the protease 
inhibitors.  Also, tell your doctor if you are taking maraviroc. 



56 

- Medicines used to treat infection with the hepatitis C virus: elbasvir/grazoprevir, 
glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir. 

- Medicines used to lower blood fats (also called statins): Atorvastatin, pravastatin, 
simvastatin.  Atripla can reduce the amount of statins in your blood.  Your doctor will check 
your cholesterol levels and will consider changing the dose of your statin, if needed. 

- Medicines used to treat convulsions/seizures (anticonvulsants): Carbamazepine, phenytoin, 
phenobarbital.  Atripla can reduce the amount of the anticonvulsant in your blood.  
Carbamazepine can reduce the amount of efavirenz, one of the components of Atripla, in your 
blood.  Your doctor may need to consider giving you a different anticonvulsant. 

- Medicines used to treat bacterial infections, including tuberculosis and AIDS-related 
mycobacterium avium complex: Clarithromycin, rifabutin, rifampicin.  Your doctor may need to 
consider changing your dose or giving you an alternative antibiotic.  In addition, your doctor 
may consider giving you an additional dose of efavirenz to treat your HIV infection. 

- Medicines used to treat fungal infections (antifungals): Itraconazole or posaconazole.  
Atripla can reduce the amount of itraconazole or posaconazole in your blood.  Your doctor may 
need to consider giving you a different antifungal. 

- Medicines used to treat malaria: Atovaquone/proguanil or artemether/lumefantrine.  Atripla 
may reduce the amount of atovaquone/proguanil or artemether/lumefantrine in your blood. 

- Hormonal contraceptive, such as birth control pills, an injected contraceptive (for 
example, Depo-Provera), or a contraceptive implant (for example, Implanon): You must 
also use a reliable barrier method of contraception (see Pregnancy and breast-feeding).  Atripla 
may make hormonal contraceptives less likely to work.  Pregnancies have occurred in women 
taking efavirenz, a component of Atripla, while using a contraceptive implant, although it has 
not been established that the efavirenz therapy caused the contraceptive to fail. 

- Sertraline, a medicine used to treat depression, as your doctor may need to change your dose of 
sertraline. 

- Bupropion, a medicine used to treat depression or to help you stop smoking, as your doctor 
may need to change your dose of bupropion. 

- Diltiazem or similar medicines (called calcium channel blockers): When you start taking 
Atripla, your doctor may need to adjust your dose of the calcium channel blocker. 

- Medicines used to prevent organ transplant rejection (also called immunosuppressants), 
such as cyclosporine, sirolimus or tacrolimus.  When you start or stop taking Atripla your doctor 
will closely monitor your plasma levels of the immunosuppressant and may need to adjust its 
dose. 

- Warfarin or acenocoumarol (medicines used to reduce clotting of the blood): Your doctor 
may need to adjust your dose of warfarin or acenocoumarol. 

- Ginkgo biloba extracts (herbal preparation). 
 

Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Women should not get pregnant during treatment with Atripla and for 12 weeks thereafter.  
Your doctor may require you to take a pregnancy test to ensure you are not pregnant before starting 
treatment with Atripla. 
 
If you could get pregnant while receiving Atripla, you need to use a reliable form of barrier 
contraception (for example, a condom) with other methods of contraception including oral (pill) or 
other hormonal contraceptives (for example, implants, injection).  Efavirenz, one of the active 
components of Atripla, may remain in your blood for a time after therapy is stopped.  Therefore, you 
should continue to use contraceptive measures, as above, for 12 weeks after you stop taking Atripla. 
 
Tell your doctor immediately if you are pregnant or intend to become pregnant.  If you are 
pregnant, you should take Atripla only if you and your doctor decide it is clearly needed. 
 



57 

Serious birth defects have been seen in unborn animals and in the babies of women treated with 
efavirenz during pregnancy.   
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
If you have taken Atripla during your pregnancy, your doctor may request regular blood tests and other 
diagnostic tests to monitor the development of your child. In children whose mothers took NRTIs 
during pregnancy, the benefit from the protection against HIV outweighed the risk of side effects. 
 
Do not breast-feed during treatment with Atripla.  Both HIV and the ingredients of Atripla may 
pass through breast milk and cause serious harm to your baby. 
 
Driving and using machines 
 
Atripla may cause dizziness, impaired concentration and drowsiness.  If you are affected, do not 
drive and do not use any tools or machines. 
 
Atripla contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Atripla 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is: 
One tablet taken each day by mouth.  Atripla should be taken on an empty stomach (commonly 
defined as 1 hour before or 2 hours after a meal) preferably at bedtime.  This may make some side 
effects (for example, dizziness, drowsiness) less troublesome.  Swallow Atripla whole with water. 
 
Atripla must be taken every day. 
 
If your doctor decides to stop one of the components of Atripla, you may be given efavirenz, 
emtricitabine and/or tenofovir disoproxil separately or with other medicines for the treatment of your 
HIV infection. 
 
If you take more Atripla than you should 
 
If you accidentally take too many Atripla tablets you may be at increased risk of experiencing possible 
side effects with this medicine (see section 4, Possible side effects).  Contact your doctor or nearest 
emergency department for advice.  Keep the tablet bottle with you so that you can easily describe what 
you have taken. 
 
If you forget to take Atripla 
 
It is important not to miss a dose of Atripla. 
 
If you do miss a dose of Atripla within 12 hours of when it is usually taken, take it as soon as you 
can, and then take your next dose at its regular time. 
 
If it is almost time (less than 12 hours) for your next dose anyway, do not take the missed dose.  
Wait and take the next dose at the regular time.  Do not take a double dose to make up for a forgotten 
tablet. 
 



58 

If you throw up the tablet (within 1 hour after taking Atripla), you should take another tablet.  Do 
not wait until your next dose is due.  You do not need to take another tablet if you were sick more than 
1 hour after taking Atripla. 
 
If you stop taking Atripla 
 
Don’t stop taking Atripla without talking to your doctor.  Stopping Atripla can seriously affect 
your response to future treatment.  If Atripla is stopped, speak to your doctor before you restart taking 
Atripla tablets.  Your doctor may consider giving you the components of Atripla separately if you are 
having problems or need your dose adjusted. 
 
When your supply of Atripla starts to run low, get more from your doctor or pharmacist.  This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time.  The virus may then become harder to treat. 
 
If you have both HIV infection and hepatitis B, it is especially important not to stop your Atripla 
treatment without talking to your doctor first.  Some patients have had blood tests or symptoms 
indicating that their hepatitis has got worse after stopping emtricitabine or tenofovir disoproxil (two of 
the three components of Atripla).  If Atripla is stopped your doctor may recommend that you resume 
hepatitis B treatment.  You may require blood tests to check how your liver is working for 4 months 
after stopping treatment.  In some patients with advanced liver disease or cirrhosis, stopping treatment 
is not recommended as this may lead to worsening of your hepatitis, which may be life-threatening. 
 
Tell your doctor immediately about new or unusual symptoms after you stop treatment, particularly 
symptoms you associate with hepatitis B infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible serious side effects: tell your doctor immediately 
 
- Lactic acidosis (excess lactic acid in the blood) is a rare (may affect up to 1 in every 

1,000 patients) but serious side effect that can be fatal.  The following side effects may be signs 
of lactic acidosis: 
- deep rapid breathing 
- drowsiness 
- feeling sick (nausea), being sick (vomiting) and stomach pain. 

 
If you think you may have lactic acidosis, contact your doctor immediately. 
 
Other possible serious side effects 
 
The following side effects are uncommon (these may affect up to 1 in every 100 patients): 
 
• allergic reaction (hypersensitivity) that may cause severe skin reactions (Stevens-Johnson 

syndrome, erythema multiforme, see section 2)  
• swelling of the face, lips, tongue or throat 
• angry behaviour, suicidal thoughts, strange thoughts, paranoia, unable to think clearly, mood 

being affected, seeing or hearing things that are not really there (hallucinations), suicide 



59 

attempts, personality change (psychosis), catatonia (a condition in which the patient is rendered 
motionless and speechless for a period). 

• pain in the abdomen (stomach), caused by inflammation of the pancreas 
• forgetfulness, confusion, fitting (seizures), incoherent speech, tremor (shaking) 
• yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the 

liver 
• damage to kidney tubules 
 
Psychiatric side effects in addition to those listed above include delusions (false beliefs), neurosis.  
Some patients have committed suicide.  These problems tend to occur more often in those who have a 
history of mental illness.  Always notify your doctor immediately if you have these symptoms. 
 
Side effects to the liver: If you are also infected with hepatitis B virus, you may experience a 
worsening of hepatitis after discontinuation of treatment (see section 3). 
 
The following side effects are rare (these may affect up to 1 in every 1,000 patients): 
 
• liver failure, in some cases leading to death or liver transplant.  Most cases occurred in patients 

who already had liver disease, but there have been a few reports in patients without any existing 
liver disease 

• inflammation of the kidney, passing a lot of urine and feeling thirsty 
• back pain caused by kidney problems, including kidney failure.  Your doctor may do blood tests 

to see if your kidneys are working properly 
• softening of the bones (with bone pain and sometimes resulting in fractures) which may occur 

due to damage to the kidney tubule cells 
• fatty liver 
 
If you think that you may have any of these serious side effects, talk to your doctor. 
 
Most frequent side effects 
 
The following side effects are very common (these may affect more than 1 in 10 patients) 
 
• dizziness, headache, diarrhoea, feeling sick (nausea), being sick (vomiting) 
• rashes (including red spots or blotches sometimes with blistering and swelling of the skin), 

which may be allergic reactions 
• feeling weak 
 
Tests may also show: 
• decreases in phosphate levels in the blood 
• increased levels of creatine kinase in the blood that may result in muscle pain and weakness 
 
Other possible side effects 
 
The following side effects are common (these may affect up to 1 in 10 patients) 
 
• allergic reactions 
• disturbances of coordination and balance 
• feeling worried or depressed 
• difficulty sleeping, abnormal dreams, difficulty concentrating, drowsiness 
• pain, stomach pain 
• problems with digestion resulting in discomfort after meals, feeling bloated, wind (flatulence) 
• loss of appetite 
• tiredness 
• itching 



60 

• changes in skin colour including darkening of the skin in patches often starting on hands and 
soles of feet 

 
Tests may also show: 
• low white blood cell count (a reduced white blood cell count can make you more prone to 

infection) 
• liver and pancreas problems 
• increased fatty acids (triglycerides), bilirubin or sugar levels in the blood 
 
The following side effects are uncommon (these may affect up to 1 in every 100 patients): 
 
• breakdown of muscle, muscle pain or weakness 
• anaemia (low red blood cell count) 
• a feeling of spinning or tilting (vertigo), whistling, ringing or other persistent noise in the ears 
• blurred vision 
• chills 
• breast enlargement in males 
• decreased sexual drive 
• flushing 
• dry mouth 
• increased appetite 
 
Tests may also show: 
• decreases in potassium in the blood 
• increases in creatinine in the blood 
• proteins in urine 
• increased cholesterol in the blood 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
The following side effects are rare (these may affect up to 1 in every 1,000 patients) 
 
• itchy rash to the skin caused by a reaction to sunlight 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Atripla 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


61 

6. Contents of the pack and other information 
 
What Atripla contains 
 
- The active substances are efavirenz, emtricitabine and tenofovir disoproxil.  Each Atripla 

film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of 
tenofovir disoproxil (as fumarate). 

- The other ingredients in the tablet are croscarmellose sodium, hyprolose, magnesium stearate, 
microcrystalline cellulose, sodium laurilsulfate.  Refer to section 2 “Atripla contains sodium”. 

- The other ingredients in the tablet film coating are iron oxide black, iron oxide red, 
macrogol 3350, poly(vinyl alcohol), talc, titanium dioxide. 

 
What Atripla looks like and contents of the pack 
 
Atripla film-coated tablets are pink, capsule shaped tablets, engraved on one side with the number 
“123” and plain on the other side.  Atripla comes in bottles of 30 tablets (with a silica gel sachet that 
must be kept in the bottle to help protect your tablets).  The silica gel desiccant is contained in a 
separate sachet and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer: 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 (0) 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 (0) 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 



62 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel.: +48 (0) 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 (0) 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 (0) 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 

 
This leaflet was last revised in . 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET