ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Atripla 600 mg/200 mg/245 mg film-coated tablets
2.
Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of
tenofovir disoproxil (as fumarate).
Excipient(s):
Each film-coated tablet contains 1 mmol (23.6 mg) of sodium.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Pink, capsule shaped, film-coated tablet, debossed with “123” on one side, plain on the other side.
4.
4.1
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 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
Therapy should be initiated by a physician experienced in the management of human
immunodeficiency virus (HIV) infection.
Posology
Adults:
the recommended dose of Atripla is one tablet taken orally once daily.
Method of administration
It is recommended that Atripla be swallowed whole with water.
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).
2
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 will be approximately 35% lower following administration of
Atripla on an empty stomach as compared to the individual component tenofovir disoproxil fumarate
when taken with food (see section 5.2). In virologically suppressed patients, the clinical relevance of
this reduction can be expected to be limited (see section 5.1). Further data on the clinical translation
of the decrease in pharmacokinetic exposure is awaited.
Children and adolescents:
Atripla is not recommended for use in children below 18 years of age due
to lack of data on safety and efficacy.
Elderly:
Atripla should be administered with caution to elderly patients (see section 4.4).
Dose adjustment:
if Atripla is co-administered with rifampicin, an additional 200 mg/day (800 mg
total) of efavirenz may be considered (see section 4.5).
Renal insufficiency:
Atripla is not recommended for patients with moderate or severe renal impairment
(creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require
dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved
with the combination tablet (see sections 4.4 and 5.2).
Hepatic impairment:
the pharmacokinetics of Atripla have not been studied in patients with hepatic
impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated
with the normal recommended dose of Atripla (see sections 4.3, 4.4 and 5.2). Patients should be
monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz
(see sections 4.3 and 4.4).
If Atripla is discontinued in patients co-infected with HIV and HBV, these patients should be closely
monitored for evidence of exacerbation of hepatitis (see section 4.4).
It is important to take Atripla on a regular dosing schedule to avoid missing doses. Patients should be
told that if they forget to take Atripla, they should take the missed dose right away, unless it is less
than 12 hours until the next day’s dose. In this case, patients should be told not to take the missed
dose and to take their next dose at the usual time.
Where discontinuation of therapy with one of the components of Atripla is indicated or where dose
modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil
fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal
products.
If therapy with Atripla is discontinued, consideration should be given to the long half-life of efavirenz
(see section 5.2) and long intracellular half-lives of tenofovir and emtricitabine. 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.
4.3
Hypersensitivity to the active substances or to any of the excipients.
Atripla must not be used in patients with severe hepatic impairment (CPT Class C) (see section 5.2).
Atripla must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam,
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine,
ergonovine, and methylergonovine), because competition for cytochrome P450 (CYP) 3A4 by
efavirenz could result in inhibition of metabolism and create the potential for serious and/or
3
life-threatening undesirable effects (for example, cardiac arrhythmias, prolonged sedation or
respiratory depression) (see section 4.5).
Herbal preparations containing St. John’s wort (
Hypericum perforatum
) must not be used while taking
Atripla due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz
(see section 4.5).
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; therefore, voriconazole and Atripla must not be
co-administered (see section 4.5).
4.4
General:
as a fixed combination, Atripla should not be administered concomitantly with other
medicinal products containing any of the same active components, efavirenz, emtricitabine or
tenofovir disoproxil fumarate. 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.
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.
Lactic acidosis:
lactic acidosis, usually associated with hepatic steatosis, has been reported with the
use of nucleoside analogues. Early symptoms (symptomatic hyperlactataemia) include benign
digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite,
weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including
motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver
failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Co-infection with hepatitis C and
treatment with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk must be followed closely.
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:
patients must be advised that antiretroviral therapies, including Atripla, have not
been proven to prevent the risk of transmission of HIV to others through sexual contact or
contamination with blood. Appropriate precautions must continue to be used.
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 cytochrome P450
(CYP450) system, caution should be exercised in administering Atripla to patients with mild hepatic
4
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 and should be
monitored according to standard practice. If there is evidence of worsening liver disease or persistent
elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the
benefit of continued therapy with Atripla needs to be weighed against the potential risks of significant
liver toxicity. In such patients, interruption or discontinuation of treatment must be considered
(see section 4.8).
In patients treated with other medicinal products associated with liver toxicity, monitoring of liver
enzymes is also recommended.
Hepatic events:
post-marketing reports of hepatic failure also occurred in patients with no pre-existing
hepatic disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be
considered for all patients independent of pre-existing hepatic dysfunction or other risk factors.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection:
patients with chronic
hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe
and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of
HIV infection in patients co-infected with HBV.
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary
of Product Characteristics for these medicinal products.
The safety and efficacy of Atripla have not been studied for the treatment of chronic HBV infection.
Emtricitabine and tenofovir individually and in combination have shown activity against HBV in
pharmacodynamic studies (see section 5.1). Limited clinical experience suggests that emtricitabine
and tenofovir disoproxil fumarate have an anti-HBV activity when used in antiretroviral combination
therapy to control HIV infection. Discontinuation of Atripla therapy in patients co-infected with HIV
and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with
HIV and HBV who discontinue Atripla must be closely monitored with both clinical and laboratory
follow-up for at least four months after stopping treatment with Atripla. If appropriate, resumption of
anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis,
treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead
to hepatic decompensation.
Psychiatric symptoms:
psychiatric adverse reactions have been reported in patients treated with
efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these
serious psychiatric adverse reactions. In particular, severe depression was more common in those with
a history of depression. There have also been post-marketing reports of severe depression, death by
suicide, delusions and psychosis-like behaviour. Patients should be advised that if they experience
symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor
immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if
so, to determine whether the risk of continued therapy outweighs the benefits (see section 4.8).
Nervous system symptoms:
symptoms including, but not limited to, dizziness, insomnia, somnolence,
impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients
receiving efavirenz 600 mg daily in clinical studies. Dizziness was also seen in clinical studies with
emtricitabine and tenofovir disoproxil fumarate. Headache has been reported in clinical studies with
emtricitabine (see section 4.8). Nervous system symptoms associated with efavirenz usually begin
during the first one or two days of therapy and generally resolve after the first two to four weeks.
Patients should be informed that if they do occur, these common symptoms are likely to improve with
5
continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric
symptoms.
Seizures:
convulsions have been observed in patients receiving efavirenz, generally in the presence of
a known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal
products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may
require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma
concentrations were decreased when carbamazepine was co-administered with efavirenz
(see section 4.5). Caution must be taken in any patient with a history of seizures.
Renal impairment:
Atripla is not recommended for patients with moderate or severe renal impairment.
Patients with moderate or severe renal impairment require a dose adjustment of emtricitabine and
tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.2
and 5.2). Use of Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal
product. If concomitant use of Atripla and nephrotoxic agents (e.g. aminoglycosides, amphotericin B,
foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2) is unavoidable, renal
function must be monitored weekly (see section 4.5).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy
(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in
clinical practice (see section 4.8).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with
Atripla and renal function (creatinine clearance and serum phosphate) is also monitored every
four weeks during the first year and then every three months. In patients with a history of renal
dysfunction or in patients who are at risk for renal dysfunction, including patients who have previously
experienced renal events while receiving adefovir dipivoxil, consideration should be given to more
frequent monitoring of renal function.
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). Where discontinuation of therapy with one of the components of Atripla is indicated or
where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir
disoproxil fumarate are available.
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.
Lipodystrophy and metabolic abnormalities:
combination antiretroviral therapy has been associated
with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of
these events are currently unknown. Knowledge about the mechanism is incomplete. A connection
between visceral lipomatosis and protease inhibitors (PI) and lipoatrophy and nucleoside reverse
transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been
associated with individual factors such as older age, and with drug-related factors such as longer
duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination
6
should include evaluation for physical signs of fat redistribution. Consideration should be given to the
measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as
clinically appropriate (see section 4.8).
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.
Mitochondrial dysfunction:
nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV negative infants exposed
in utero
and/or postnatally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset
neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the
neurological disorders are transient or permanent is currently unknown. Any child exposed
in utero
to
nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant
signs or symptoms. 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 combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterial infections, and pneumonia caused by
Pneumocystis
jiroveci
(formerly known as
Pneumocystis carinii
). Any inflammatory symptoms should be evaluated and treatment instituted
when necessary.
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
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Bone:
in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with
stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small
decreases in bone mineral density of the hip and spine were observed in both treatment groups.
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were
significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in
bone mineral density of the hip were significantly greater in this group until 96 weeks. However,
there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over
144 weeks.
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.
Other antiretroviral agents:
no data are available on the safety and efficacy of Atripla in combination
with other antiretroviral agents.
Didanosine
: co-administration of Atripla and didanosine is not recommended since exposure to
didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate
(see section 4.5).
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).
7
Elderly:
insufficient numbers of elderly patients have been evaluated in clinical studies of the
components of Atripla to determine whether they respond differently than younger patients. Caution
should be exercised when prescribing Atripla to the elderly, keeping in mind the greater frequency of
decreased hepatic or renal function in these patients.
Excipients:
this medicinal product contains 1 mmol (23.6 mg) of sodium per dose which should be
taken into consideration by patients on a controlled sodium diet.
4.5
No drug interaction studies have been conducted using Atripla. As Atripla contains efavirenz,
emtricitabine and tenofovir disoproxil fumarate, any interactions that have been identified with these
agents individually may occur with Atripla. Interaction studies with these agents have only been
performed in adults.
As a fixed combination, Atripla should not be administered concomitantly with other medicinal
products containing any of the components, efavirenz, emtricitabine or tenofovir disoproxil as
fumarate. 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.
Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP450 isoenzymes including CYP3A4
(see section 5.2). Other compounds that are substrates of CYP3A4 may have decreased plasma
concentrations when co-administered with efavirenz. Efavirenz exposure may also be altered when
given with medicinal products or food (for example, grapefruit juice) which affect CYP3A4 activity.
In vitro
and clinical pharmacokinetic interaction studies have shown the potential for CYP450-
mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal
products is low.
Cannabinoid test interaction:
efavirenz does not bind to cannabinoid receptors. False positive urine
cannabinoid test results have been reported in uninfected volunteers who received efavirenz. False
positive test results have only been observed with the CEDIA DAU Multi-Level THC assay, which is
used for screening, and have not been observed with other cannabinoid assays tested including tests
used for confirmation of positive results.
Atripla must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam,
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine,
ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious,
life-threatening events (see section 4.3).
Voriconazole:
co-administration of standard doses of efavirenz and voriconazole is contraindicated.
Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore,
voriconazole and Atripla must not be co-administered (see section 4.3 and Table 1).
St. John’s wort (Hypericum perforatum):
co-administration of Atripla and St. John’s wort or herbal
preparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can be reduced
by concomitant use of St. John’s wort due to induction of drug metabolising enzymes and/or transport
proteins by St. John’s wort. If a patient is already taking St. John’s wort, stop St. John’s wort, check
viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John’s
wort. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of
treatment (see section 4.3).
8
Concomitant use not recommended
Atazanavir/ritonavir:
insufficient data are available to make a dosing recommendation for
atazanavir/ritonavir in combination with Atripla. Therefore co-administration of atazanavir/ritonavir
and Atripla is not recommended (see Table 1).
Didanosine:
co-administration of Atripla and didanosine is not recommended (see section 4.4 and
Table 1).
Renally eliminated medicinal products:
since emtricitabine and tenofovir are primarily eliminated by
the kidneys, co-administration of Atripla with medicinal products that reduce renal function or
compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of
emtricitabine, tenofovir and/or the co-administered medicinal products.
Use of Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal product.
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet,
ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).
Other interactions
Interactions between the components of Atripla and protease inhibitors, antiretroviral agents other than
protease inhibitors and other non-antiretroviral medicinal products are listed in Table 1 below
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, once daily as
“q.d.” and once every 8 hours as “q8h”). If available, 90% confidence intervals are shown in
parentheses.
Table 1: Interactions between the individual components of Atripla and other medicinal
products
Medicinal product by therapeutic areas
Effects on drug levels
Mean percent change in AUC, C
max
,
C
min
with 90% confidence intervals
if available
(mechanism)
Recommendation
concerning
co-administration with
Atripla
(efavirenz 600 mg,
emtricitabine 200 mg,
tenofovir disoproxil
fumarate 300 mg)
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/ritonavir/Tenofovir disoproxil
fumarate
(300 mg q.d./100 mg q.d./300 mg q.d.)
Atazanavir:
AUC: ↓ 25% (↓ 42 to ↓ 3)
C
max
: ↓ 28% (↓ 50 to ↑ 5)
C
min
:
↓ 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.
9
Atazanavir/ritonavir/Efavirenz
(400 mg q.d./100 mg q.d./600 mg q.d., all
administered with food)
Atazanavir (pm):
AUC: ↔* (↓ 9% to ↑ 10%)
C
max
: ↑ 17%* (↑ 8 to ↑ 27)
C
min
: ↓ 42%* (↓ 31 to ↓ 51)
Atazanavir/ritonavir/Efavirenz
(400 mg q.d./200 mg q.d./600 mg q.d., all
administered with food)
Atazanavir (pm):
AUC: ↔*/** (↓ 10% to ↑ 26%)
C
max
: ↔*/** (↓ 5% to ↑ 26%)
C
min
: ↑ 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 C
min
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.)
Darunavir:
AUC: ↓ 13%
C
min
: ↓ 31%
(CYP3A4 induction)
Efavirenz:
AUC: ↑ 21%
C
min
: ↑ 17%
(CYP3A4 inhibition)
The clinical significance
of the changes in
darunavir and efavirenz
concentrations has not
been established. Similar
findings are expected
with the approved
darunavir/ritonavir
600/100 mg b.i.d. dose.
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.
*lower than recommended dose
Darunavir/ritonavir/Tenofovir disoproxil
fumarate
(300 mg b.i.d.*/100 mg b.i.d./300 mg
q.d.)
Darunavir:
AUC: ↔
C
min
: ↔
Tenofovir:
AUC: ↑ 22%
C
min
: ↑ 37%
*lower than recommended dose
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 fumarate
Interaction not studied.
Indinavir/Efavirenz
(800 mg q8h/200 mg q.d.)
Efavirenz:
AUC: ↔
C
max
: ↔
C
min
:
↔
Indinavir:
AUC: ↓ 31% (↓ 8 to ↓ 47)
C
min
: ↓ 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
10
Indinavir/Emtricitabine
(800 mg q8h/200 mg q.d.)
Indinavir:
AUC: ↔
C
max
: ↔
Emtricitabine:
AUC: ↔
C
max
: ↔
efavirenz, a component
of Atripla, and indinavir.
Indinavir/Tenofovir disoproxil fumarate
(800 mg q8h/300 mg q.d.)
Indinavir:
AUC: ↔
C
max
: ↔
Tenofovir:
AUC: ↔
C
max
: ↔
Lopinavir/ritonavir/Tenofovir disoproxil
fumarate
(400 mg b.i.d./100 mg b.i.d./300 mg q.d.)
Lopinavir/Ritonavir:
AUC: ↔
C
max
: ↔
C
min
:
↔
Tenofovir:
AUC: ↑ 32% (↑ 25 to ↑ 38)
C
max
: ↔
C
min
:
↑ 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
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/ritonavir tablets/Efavirenz
(400/100 mg b.i.d./600 mg q.d.)
Lopinavir concentrations: ↓ 30-40%
(500/125 mg b.i.d./600 mg q.d.)
Lopinavir concentrations: similar to
lopinavir/ritonavir 400/100 mg twice
daily without efavirenz. Dosage
adjustment of lopinavir/ritonavir is
necessary when given with efavirenz.
For co-administration of efavirenz
with low-dose ritonavir in
combination with a protease inhibitor,
see section on ritonavir below.
Lopinavir/ritonavir/Emtricitabine
Interaction not studied.
11
Ritonavir/Efavirenz
(500 mg b.i.d./600 mg q.d.)
Ritonavir:
Morning AUC: ↑ 18% (↑ 6 to ↑ 33)
Evening AUC: ↔
Morning C
max
: ↑ 24% (↑ 12 to ↑ 38)
Evening C
max
: ↔
Morning C
min
: ↑ 42% (↑ 9 to ↑ 86)
Evening C
min
: ↑ 24% (↑ 3 to ↑ 50)
Efavirenz:
AUC: ↑ 21% (↑ 10 to ↑ 34)
C
max
: ↑ 14% (↑ 4 to ↑ 26)
C
min
: ↑ 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 fumarate
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
fumarate
There were no clinically significant
pharmacokinetic interactions when
tenofovir disoproxil fumarate 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:
AUC
12h
: ↓ 45% (↓ 38 to ↓ 51)
C
max
: ↓ 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 fumarate
(300 mg b.i.d./300 mg q.d.)
Maraviroc:
AUC
12h
: ↔
C
max
: ↔
Tenofovir concentrations not
measured, no effect is expected.
Maraviroc/Emtricitabine
Interaction not studied.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz
(400 mg single dose/-)
Raltegravir:
AUC: ↓ 36%
C
12h
: ↓ 21%
C
max
: ↓ 36%
(UGT1A1 induction)
Atripla and raltegravir
can be co-administered
without dose adjustment.
12
Raltegravir/Tenofovir disoproxil fumarate
(400 mg b.i.d./-)
Raltegravir:
AUC: ↑ 49%
C
12h
: ↑ 3%
C
max
: ↑ 64%
(mechanism of interaction unknown)
Tenofovir:
AUC: ↓ 10%
C
12h
: ↓ 13%
C
max
: ↓ 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
fumarate. 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 fumarate Co-administration of tenofovir
disoproxil fumarate and didanosine
results in a 40-60% increase in
systemic exposure to didanosine that
may increase the risk for
didanosine-related adverse events.
Rare cases of pancreatitis and lactic
acidosis, sometimes fatal, have been
reported. Co-administration of
tenofovir disoproxil fumarate 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 fumarate
therapy has been associated with
reports of high rates of virologic
failure within several tested
combinations.
Co-administration of
Atripla and didanosine is
not recommended
(see section 4.4).
Didanosine/Efavirenz
Interaction not studied.
Didanosine/Emtricitabine
Interaction not studied.
13
Antibiotics
Clarithromycin/Efavirenz
(500 mg b.i.d./400 mg q.d.)
Clarithromycin:
AUC: ↓ 39% (↓ 30 to ↓ 46)
C
max
: ↓ 26% (↓ 15 to ↓ 35)
Clarithromycin
14-hydroxymetabolite:
AUC: ↑ 34% (↑ 18 to ↑ 53)
C
max
: ↑ 49% (↑ 32 to ↑ 69)
Efavirenz:
AUC: ↔
C
max
: ↑ 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
fumarate
Interaction not studied.
Antimycobacterials
Rifabutin/Efavirenz
(300 mg q.d./600 mg q.d.)
Rifabutin:
AUC: ↓ 38% (↓ 28 to ↓ 47)
C
max
: ↓ 32% (↓ 15 to ↓ 46)
C
min
: ↓ 45% (↓ 31 to ↓ 56)
Efavirenz:
AUC: ↔
C
max
: ↔
C
min
: ↓ 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.
Rifabutin/Emtricitabine
Interaction not studied.
Rifabutin/Tenofovir disoproxil fumarate
Interaction not studied.
Rifampicin/Efavirenz
(600 mg q.d./600 mg q.d.)
Efavirenz:
AUC: ↓ 26% (↓ 15 to ↓ 36)
C
max
: ↓ 20% (↓ 11 to ↓ 28)
C
min
: ↓ 32% (↓ 15 to ↓ 46)
(CYP3A4 and CYP2B6 induction)
When Atripla is taken
with rifampicin, 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
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.
Rifampicin/Tenofovir disoproxil fumarate
(600 mg q.d./300 mg q.d.)
Rifampicin:
AUC: ↔
C
max
: ↔
Tenofovir:
AUC: ↔
C
max
: ↔
Rifampicin/Emtricitabine
Interaction not studied.
14
Antifungals
Itraconazole/Efavirenz
(200 mg b.i.d./600 mg q.d.)
Itraconazole:
AUC: ↓ 39% (↓ 21 to ↓ 53)
C
max
: ↓ 37% (↓ 20 to ↓ 51)
C
min
: ↓ 44% (↓ 27 to ↓ 58)
(decrease in itraconazole
concentrations: CYP3A4 induction)
Hydroxyitraconazole:
AUC: ↓ 37% (↓ 14 to ↓ 55)
C
max
: ↓ 35% (↓ 12 to ↓ 52)
C
min
: ↓ 43% (↓ 18 to ↓ 60)
Efavirenz:
AUC: ↔
C
max
: ↔
C
min
: ↔
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
fumarate
Interaction not studied.
Posaconazole/Efavirenz
(-/400 mg q.d.)
Posaconazole:
AUC: ↓ 50%
C
max
: ↓ 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
fumarate
Interaction not studied.
Voriconazole/Efavirenz
(200 mg b.i.d./400 mg q.d.)
Voriconazole:
AUC: ↓ 77%
C
max
: ↓ 61%
Efavirenz:
AUC: ↑ 44%
C
max
: ↑ 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
fumarate
Interaction not studied.
ANTICONVULSANTS
Carbamazepine/Efavirenz
(400 mg q.d./600 mg q.d.)
Carbamazepine:
AUC: ↓ 27% (↓ 20 to ↓ 33)
C
max
: ↓ 20% (↓ 15 to ↓ 24)
C
min
: ↓ 35% (↓ 24 to ↓ 44)
Efavirenz:
AUC: ↓ 36% (↓ 32 to ↓ 40)
C
max
: ↓ 21% (↓ 15 to ↓ 26)
C
min
: ↓ 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
fumarate
Interaction not studied.
15
Phenytoin, Phenobarbital, and other
anticonvulsants that are substrates of
CYP450 isoenzymes
Interaction not studied with efavirenz,
emtricitabine, or tenofovir disoproxil
fumarate. There is a potential for
reduction or increase in the plasma
concentrations of phenytoin,
phenobarbital and other
anticonvulsants that are substrates of
CYP450 isoenzymes with efavirenz.
When Atripla is co-
administered with an
anticonvulsant that is a
substrate of CYP450
isoenzymes, 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
fumarate
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 fumarate
Gabapentin/Tenofovir disoproxil fumarate
Interaction not studied.
ANTICOAGULANTS
Warfarin/Efavirenz
Interaction not studied. Plasma
concentrations and effects of warfarin
are potentially increased or decreased
by efavirenz.
Dose adjustment of
warfarin 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)
C
max
: ↓ 29% (↓ 15 to ↓ 40)
C
min
: ↓ 46% (↓ 31 to ↓ 58)
Efavirenz:
AUC: ↔
C
max
: ↑ 11% (↑ 6 to ↑ 16)
C
min
: ↔
(CYP3A4 induction)
When co-administered
with Atripla, sertraline
dose increases should be
guided by clinical
response.
Sertraline/Emtricitabine
Interaction not studied.
Sertraline/Tenofovir disoproxil fumarate
Interaction not studied.
Paroxetine:
AUC: ↔
C
max
: ↔
C
min
: ↔
Efavirenz:
AUC: ↔
C
max
: ↔
C
min
: ↔
Paroxetine/Emtricitabine Interaction not studied.
Paroxetine/Tenofovir disoproxil fumarate Interaction not studied.
Atripla and paroxetine
can be co-administered
without dose adjustment.
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.
16
Paroxetine/Efavirenz
(20 mg q.d./600 mg q.d.)
Fluoxetine/Emtricitabine Interaction not studied.
Fluoxetine/Tenofovir disoproxil fumarate Interaction not studied.
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz
(240 mg q.d./600 mg q.d.)
Diltiazem:
AUC: ↓ 69% (↓ 55 to ↓ 79)
C
max
: ↓ 60% (↓ 50 to ↓ 68)
C
min
: ↓ 63% (↓ 44 to ↓ 75)
Desacetyl diltiazem:
AUC: ↓ 75% (↓ 59 to ↓ 84)
C
max
: ↓ 64% (↓ 57 to ↓ 69)
C
min
: ↓ 62% (↓ 44 to ↓ 75)
N-monodesmethyl diltiazem:
AUC: ↓ 37% (↓ 17 to ↓ 52)
C
max
: ↓ 28% (↓ 7 to ↓ 44)
C
min
: ↓ 37% (↓ 17 to ↓ 52)
Efavirenz:
AUC: ↑ 11% (↑ 5 to ↑ 18)
C
max
: ↑ 16% (↑ 6 to ↑ 26)
C
min
: ↑ 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 fumarate
Interaction not studied.
Verapamil, Felodipine, Nifedipine and
Nicardipine
Interaction not studied with efavirenz,
emtricitabine, or tenofovir disoproxil
fumarate. 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).
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)
C
max
: ↓ 12% (↓ 1 to ↓ 26)
2-hydroxy atorvastatin:
AUC: ↓ 35% (↓ 13 to ↓ 40)
C
max
: ↓ 13% (↓ 0 to ↓ 23)
4-hydroxy atorvastatin:
AUC: ↓ 4% (↓ 0 to ↓ 31)
C
max
: ↓ 47% (↓ 9 to ↓ 51)
Total active HMG Co-A reductase
inhibitors:
AUC: ↓ 34% (↓ 21 to ↓ 41)
C
max
: ↓ 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
fumarate
Interaction not studied.
Pravastatin/Efavirenz
(40 mg q.d./600 mg q.d.)
Pravastatin:
AUC: ↓ 40% (↓ 26 to ↓ 57)
C
max
: ↓ 18% (↓ 59 to ↑ 12)
Cholesterol levels should
be periodically
monitored. Dosage
adjustments of
Pravastatin/Emtricitabine
Interaction not studied.
17
Pravastatin/Tenofovir disoproxil fumarate Interaction not studied.
pravastatin may be
required when
co-administered with
Atripla (refer to the
Summary of Product
Characteristics for
pravastatin).
Simvastatin/Efavirenz
(40 mg q.d./600 mg q.d.)
Simvastatin:
AUC: ↓ 69% (↓ 62 to ↓ 73)
C
max
: ↓ 76% (↓ 63 to ↓ 79)
Simvastatin acid:
AUC: ↓ 58% (↓ 39 to ↓ 68)
C
max
: ↓ 51% (↓ 32 to ↓ 58)
Total active HMG Co-A reductase
inhibitors:
AUC: ↓ 60% (↓ 52 to ↓ 68)
C
max
: ↓ 62% (↓ 55 to ↓ 78)
(CYP3A4 induction)
Co-administration of efavirenz with
atorvastatin, pravastatin, or
simvastatin did not affect efavirenz
AUC or C
max
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
fumarate
Interaction not studied.
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
fumarate
Interaction not studied.
HORMONAL CONTRACEPTIVES
Oral:
Ethinyloestradiol+Norgestimate/Efavirenz
(0.035 mg+0.25 mg q.d./600 mg q.d.)
Ethinyloestradiol:
AUC: ↔
C
max
: ↔
C
min
: ↓ 8% (↑ 14 to ↓ 25)
Norelgestromin (active metabolite):
AUC: ↓ 64% (↓ 62 to ↓ 67)
C
max
: ↓ 46% (↓ 39 to ↓ 52)
C
min
: ↓ 82% (↓ 79 to ↓ 85)
Levonorgestrel (active metabolite):
AUC: ↓ 83% (↓ 79 to ↓ 87)
C
max
: ↓ 80% (↓ 77 to ↓ 83)
C
min
: ↓ 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
fumarate
(-/300 mg q.d.)
Ethinyloestradiol:
AUC: ↔
C
max
: ↔
Tenofovir:
AUC: ↔
C
max
: ↔
Norgestimate/Ethinyloestradiol/
Emtricitabine
Interaction not studied.
18
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 fumarate
Interaction not studied.
DMPA/Emtricitabine
Interaction not studied.
Implant:
Etonogestrel/Efavirenz
Interaction not studied. 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
fumarate
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 fumarate
(0.1 mg/kg q.d./200 mg/300 mg q.d.)
Tacrolimus:
AUC: ↔
C
max
: ↔
C
24h
: ↔
Emtricitabine:
AUC: ↔
C
max
: ↔
C
24h
: ↔
Tenofovir disoproxil fumarate:
AUC: ↔
C
max
: ↔
C
24h
: ↔
OPIOIDS
Methadone/Efavirenz
(35-100 mg q.d./600 mg q.d.)
Methadone:
AUC: ↓ 52% (↓ 33 to ↓ 66)
C
max
: ↓ 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.
Patients receiving
methadone and Atripla
concomitantly should be
monitored for signs of
withdrawal and their
methadone dose
increased as required to
alleviate withdrawal
symptoms.
19
Methadone/Tenofovir disoproxil fumarate
(40-110 mg q.d./300 mg q.d.)
Methadone:
AUC: ↔
C
max
: ↔
C
min
: ↔
Tenofovir:
AUC: ↔
C
max
: ↔
C
min
: ↔
Methadone/Emtricitabine
Interaction not studied.
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 fumarate
Interaction not studied.
Studies conducted with other medicinal products:
there were no clinically significant pharmacokinetic
interactions when efavirenz was administered with azithromycin, cetirizine, fosamprenavir/ritonavir,
lorazepam, nelfinavir, 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 fumarate was co-administered with emtricitabine, nelfinavir or
ribavirin.
Atripla should not be used during pregnancy unless clearly necessary (there are no other appropriate
treatment options).
Women of child bearing potential:
pregnancy should be avoided in women receiving Atripla. Barrier
contraception should always be used in combination with other methods of contraception (for
example, oral or other hormonal contraceptives) 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. Women of childbearing potential should undergo pregnancy testing before
initiation of Atripla.
Pregnancy:
there are no adequate or well-controlled studies of Atripla or its components in pregnant
women. In post-marketing experience through an antiretroviral pregnancy registry, outcomes for more
than 400 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral
regimen have been prospectively reported with no specific malformation pattern observed. A small
number of cases of neural tube defects including meningomyelocele, have been reported via the
registry. Most neural tube defects were isolated retrospectively reported cases, and causality cannot be
ruled out but has not been established. Studies of efavirenz in animals have shown reproductive
toxicity including marked teratogenic effects (see section 5.3).
Lactation:
studies in rats have demonstrated that efavirenz and tenofovir are excreted in milk;
concentrations of efavirenz were much higher than those in maternal plasma. It is not known whether
efavirenz, emtricitabine or tenofovir are excreted in human milk. Because of the potential for both
HIV transmission and the potential for serious undesirable effects in breast-feeding infants, mothers
should be instructed not to breast-feed if they are receiving Atripla.
20
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
fumarate. 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.
a. Summary of the safety profile
The combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 proximal renal tubulopathy (including Fanconi
syndrome) sometimes leading to bone abnormalities (infrequently contributing to 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).
b. 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
- libido decreased
- myalgia
21
- increased appetite
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
fumarate
Blood and lymphatic system disorders:
Common
neutropenia
Uncommon
anaemia
1
Immune system disorders:
Common
allergic reaction
Uncommon
hypersensitivity
Metabolism and nutrition disorders:
Very common
hypophosphataemia
2
Common
hyperglycaemia,
hypertriglyceridaemia
Uncommon
hypokalaemia
2
Rare
lactic acidosis
3
Psychiatric disorders:
Common
depression (severe in
1.6%)
3
, anxiety
3
,
abnormal dreams
3
,
insomnia
3
abnormal dreams,
insomnia
Uncommon
suicide attempt
3
,
suicide ideation
3
,
psychosis
3
, mania
3
,
paranoia
3
,
hallucination
3
,
euphoric mood
3
,
affect lability
3
,
confusional state
3
,
aggression
3
Rare
completed suicide
3,4
,
delusion
3,4
, neurosis
3,4
Nervous system disorders:
Very common
headache
dizziness
Common
cerebellar
coordination and
balance disturbances
3
,
somnolence (2.0%)
3
,
headache (5.7%)
3
,
disturbance in
attention (3.6%)
3
,
dizziness (8.5%)
3
dizziness
headache
Uncommon
convulsions
3
,
amnesia
3
, thinking
abnormal
3
, ataxia
3
,
coordination
abnormal
3
, agitation
3
,
tremor
Eye disorders:
Uncommon
vision blurred
Ear and labyrinth disorders:
Uncommon
tinnitus, vertigo
Vascular disorders:
Uncommon
flushing
22
Atripla
Efavirenz
Emtricitabine
Tenofovir disoproxil
fumarate
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
3
Hepatobiliary disorders:
Common
elevated serum
aspartate
aminotransferase
(AST) and/or
elevated serum
alanine
aminotransferase
(ALT),
hyperbilirubinaemia
increased
transaminases
Uncommon
hepatitis acute
Rare
hepatic failure
3,4
hepatic steatosis
3
,
hepatitis
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
multiforme
3
, severe
rash (< 1%)
angioedema
4
Rare
photoallergic
dermatitis
angioedema
23
Atripla
Efavirenz
Emtricitabine
Tenofovir disoproxil
fumarate
Musculoskeletal and connective tissue disorders:
Very common
elevated creatine
kinase
Uncommon
rhabdomyolysis
2
,
muscular weakness
2
Rare
osteomalacia
(manifested as bone
pain and infrequently
contributing to
fractures)
2,4
,
myopathy
2
Renal and urinary disorders:
Uncommon
increased creatinine,
proteinuria
Rare
renal failure (acute and
chronic), acute tubular
necrosis, proximal
renal tubulopathy
including Fanconi
syndrome, 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 fumarate in the absence of this condition.
3
See section
c. 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 fumarate. 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 fumarate in randomised controlled clinical trials and the expanded access
programme (n = 7,319).
c. 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.
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
24
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 4.8a).
Interaction with didanosine:
co-administration of Atripla and didanosine is not recommended as it
results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of
didanosine-related adverse events (see section 4.5). Rare cases of pancreatitis and lactic acidosis,
sometimes fatal, have been reported.
Lactic acidosis and severe hepatomegaly with steatosis:
lactic acidosis, usually associated with
hepatic steatosis, has been reported with the use of nucleoside analogues. Treatment with nucleoside
analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic
acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels (see section 4.4).
Lipids, lipodystrophy and metabolic abnormalities:
combination antiretroviral therapy has been
associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia,
insulin-resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump)
(see section 4.4).
Immune Reactivation Syndrome:
in HIV infected patients with severe immune deficiency at the time
of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic
or residual opportunistic infections may arise (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 combination antiretroviral
therapy (CART). The frequency of this is unknown (see section 4.4).
d. 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).
e. 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).
Patients with renal impairment:
since tenofovir disoproxil fumarate 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 fumarate 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.
25
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).
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations,
ATC code: J05AR06
Mechanism of action:
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 fumarate 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
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
.
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
26
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. No other pathways of resistance to emtricitabine or tenofovir have
been identified. 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 fumarate should be avoided
in patients with HIV-1 harbouring the K65R mutation. Both the K65R and M184V/I mutation remain
fully susceptible to efavirenz.
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 fumarate.
In vivo resistance (antiretroviral-naïve patients):
extremely limited resistance data from patients
treated with Atripla are currently available. However, in a 144-week open-label randomised clinical
study (GS-01-934) in antiretroviral-naïve patients, where efavirenz, emtricitabine and tenofovir
disoproxil fumarate were used as individual formulations (or as efavirenz and the fixed combination of
emtricitabine and tenofovir disoproxil fumarate (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 fumarate 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 fumarate group to the
lamivudine/zidovudine group among all subjects).
•
No virus analysed contained the K65R mutation.
•
Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from
13/19 (68%) patients in the efavirenz + emtricitabine + tenofovir disoproxil fumarate 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.
27
Table 3: Development of resistance in study GS-01-934 through week 144
Efavirenz+
emtricitabine+
tenofovir disoproxil
fumarate
(N=244)
Efavirenz+lamivudine/
zidovudine
(N=243)
Resistance analysis by week 144 19 31
On-therapy genotypes 19 (100%) 29 (100%)
Efavirenz resistance
1
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
TAMs
2
0 2 (7%)
* p-value < 0.05, Fisher’s Exact test comparing efavirenz + emtricitabine + tenofovir
disoproxil fumarate 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).
Please refer to the Summary of Product Characteristics for the individual components for additional
information regarding
in vivo
resistance with these medicinal products.
Clinical experience
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 fumarate 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. Preliminary 24-week data are available from a total of 286 patients who
changed to Atripla: 160 had previously received efavirenz, emtricitabine and tenofovir disoproxil
fumarate, and 126 had previously received Combivir and efavirenz. The majority of patients from
both initial treatment groups maintained virologic suppression after changing to Atripla. In 91% of the
patients the HIV-1 RNA plasma concentrations remained < 50 copies/ml and in 97% < 400 copies/ml,
after 24 weeks of Atripla treatment (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 fumarate). 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
28
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%)].
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.
29
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 fumarate in antiretroviral
combination therapy to control HIV infection also results in a reduction in HBV DNA (3 log
10
reduction or 4 to 5 log
10
reduction, respectively) (see section 4.4).
5.2 Pharmacokinetic properties
The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil fumarate were
used to determine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil fumarate,
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
fumarate
(n=45)
Parameters
Test Reference
GMR (%)
(90%CI) Test Reference
GMR (%)
(90%CI) Test Reference
GMR (%)
(90%CI)
C
max
(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)
AUC
0-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)
AUC
inf
(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)
T
1/2
(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)
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 fumarate 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 (C
max
) was 12.9 ± 3.7 µM (29%) [mean ± standard deviation
(S.D.) (coefficient of variation (%CV))], steady-state C
min
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
C
max
was 1.8 ± 0.7 µg/ml (mean ± S.D.) (39%CV), steady-state C
min
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 fumarate to
HIV-1 infected patients in the fasted state, maximum tenofovir concentrations were achieved within
one hour and the C
max
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 fumarate in fasted patients was approximately 25%.
30
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 C
max
of
efavirenz by 28% and 79%, respectively, compared to administration in a fasted state. Compared to
fasted administration, dosing of tenofovir disoproxil fumarate and emtricitabine in combination with
either a high fat meal or a light meal increased the mean AUC and C
max
of tenofovir by 35% and 15%,
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 will be approximately 35% lower following administration of
Atripla on an empty stomach as compared to the individual component tenofovir disoproxil fumarate
when taken with food. Forty-eight week data from a clinical study (AI266073) showed maintenance
of virologic suppression for patients who had stable virologic suppression on combination
antiretroviral therapy and subsequently changed to Atripla with a recommendation for administration
of Atripla on an empty stomach.
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.
Biotransformation:
studies in humans and
in vitro
studies using human liver microsomes have
demonstrated that efavirenz is principally metabolised by the cytochrome P450 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 isoenzymes responsible for efavirenz metabolism and that it inhibits
P450 isoenzymes 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 isoenzyme. 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 P450 enzymes, resulting in the induction of its own metabolism.
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).
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 fumarate nor tenofovir are substrates for the
CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited
in vitro
drug metabolism mediated by
any of the major human CYP450 isoforms involved in drug biotransformation. Also, emtricitabine did
not inhibit uridine 5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.
31
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 kidney 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.
Age, gender and ethnicity:
the pharmacokinetics of emtricitabine and tenofovir are similar in male and
female patients. Although limited data suggest that females as well as Asian and Pacific Island
patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz.
Pharmacokinetic studies have not been performed with efavirenz, emtricitabine or tenofovir in the
elderly (over 65 years).
Pharmacokinetic studies with Atripla have not been performed in infants and children
(see section 4.2).
Renal impairment:
the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil fumarate
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.
32
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 fumarate 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).
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 300 mg dose of tenofovir disoproxil fumarate 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 fumarate is required in these subjects.
5.3 Preclinical safety data
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, micro-ophthalmia was observed in another foetus, and cleft palate was observed in a third
foetus. Efavirenz induced foetal resorptions in rats. No malformations were observed in foetuses
from efavirenz-treated rats and rabbits.
Conventional reproductive/developmental toxicity studies with emtricitabine and tenofovir disoproxil
fumarate revealed no special hazard for humans.
Carcinogenicity studies using efavirenz 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 using efavirenz in male mice and in
male and female rats were negative. While the carcinogenic potential in humans is unknown, these
data suggest that the clinical benefit of efavirenz outweighs the potential carcinogenic risk to humans.
Tenofovir disoproxil fumarate did not show any carcinogenic potential in a long-term oral
carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence
of duodenal tumours, considered likely related to high local concentrations in the gastrointestinal tract
at a dose of 600 mg/kg/day. While the mechanism of tumour formation is uncertain, the findings are
unlikely to be of relevance to humans.
Emtricitabine did not show any carcinogenic potential in long-term studies in rats and mice.
Efavirenz and emtricitabine were negative in conventional genotoxic assays. Tenofovir disoproxil
fumarate was positive in two out of three
in vitro
genotoxicity studies but negative in the
in vivo
micronucleus assay. The combination of emtricitabine and tenofovir disoproxil fumarate was positive
in the
in vitro
mouse lymphoma assay, with comparable results to those obtained for tenofovir
33
disoproxil fumarate alone. The combination of emtricitabine and tenofovir disoproxil fumarate was
negative in the bacterial reverse mutation assay (Ames assay).
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 (see sections 4.4 and 4.8).
Preclinical studies of tenofovir disoproxil fumarate conducted in rats, dogs and monkeys revealed
effects on bone and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as
osteomalacia (monkeys) and reduced bone mineral density (rats and dogs). 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 bone mineral density. The mechanisms of these
toxicities are not completely understood.
A one month dog study using the combination of emtricitabine and tenofovir disoproxil fumarate
found no exacerbation of toxicological effects compared to the separate components.
6.
6.1 List of excipients
Tablet core:
Croscarmellose sodium
Hydroxypropylcellulose
Magnesium stearate
Microcrystalline cellulose
Sodium laurilsulfate
Film-coating:
Iron oxide black
Iron oxide red
Macrogol 3350
Poly(vinyl alcohol)
Talc
Titanium dioxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 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.
34
The following pack sizes are available: outer cartons containing 1 x 30 film-coated tablet and 3 x
30 film-coated tablet bottles. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bristol-Myers Squibb and Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
Co. Cork
Ireland
8.
EU/1/07/430/001
EU/1/07/430/002
9.
13 December 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
35
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
36
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Gilead Sciences Limited
Unit 13 Stillorgan Industrial Park
Blackrock
Co. Dublin
Ireland
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
Co. Cork
Ireland
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall ensure that additional risk minimisation activities to address the renal safety concerns
related to tenofovir disoproxil fumarate, one of the active substances contained in Atripla, are being
implemented for this fixed combination like for all medicinal products containing tenofovir disoproxil
fumarate.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0 (28/02/2008)
and included in the Type II variation (EMEA/H/C/000797/II/0003) is in place and functioning before
and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3 (February 2008) of the Risk Management Plan
(RMP) presented with the first PSUR and any subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
37
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
38
ANNEX III
LABELLING AND PACKAGE LEAFLET
39
A. LABELLING
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE AND CARTON LABELLING
1.
Atripla 600 mg/200 mg/245 mg film-coated tablets
efavirenz, emtricitabine and 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
Contains sodium. See leaflet for further information.
4.
30 film-coated tablets
3 x 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
41
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bristol-Myers Squibb and Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
Co. Cork
Ireland
EU/1/07/430/001 30 film-coated tablets
EU/1/07/430/002 3 x 30 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Atripla
[outer packaging only]
42
B. PACKAGE LEAFLET
43
PACKAGE LEAFLET: INFORMATION FOR THE USER
Atripla 600 mg/200 mg/245 mg
film-coated tablets
efavirenz, emtricitabine and tenofovir disoproxil
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Atripla is and what it is used for
2.
Before you take Atripla
4.
Possible side effects
5.
How to store Atripla
6.
Further 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 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.
BEFORE YOU TAKE ATRIPLA
Do not take Atripla
-
if you are allergic
(hypersensitive) to efavirenz, emtricitabine, tenofovir, tenofovir disoproxil
fumarate, or any of the other ingredients of Atripla listed at the end of this leaflet.
-
if you have severe liver disease.
-
if you are currently taking
any of the following medicines:
-
astemizole or terfenadine
(used to treat hay fever or other allergies)
-
bepridil
(used to treat heart disease)
-
cisapride
(used to treat heartburn)
-
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
(used to treat certain mental conditions)
44
-
Keep this leaflet. You may need to read it again.
3.
How to take Atripla
-
St. John’s wort
(
Hypericum perforatum
) (a herbal remedy used for depression and
anxiety)
-
voriconazole
(used to treat fungal infections)
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.
Take special care with Atripla
-
Do not give Atripla to children
and adolescents under 18 years of age. The use of Atripla in
children and adolescents has not yet been studied.
-
You can still pass on HIV
when taking this medicine, so it is important to take precautions to
avoid infecting other people through sexual contact or blood transfer. 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, 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
Taking other medicines
). If this is unavoidable, your doctor will monitor your kidney
function once a week.
-
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
45
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 diabetic, overweight or have high cholesterol.
Combination antiretroviral
therapies (including Atripla) may raise blood sugar levels, increase blood fats
(hyperlipaemia), cause changes to body fat, and resistance to insulin (see Section 4,
Possible side effects
).
-
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:
-
possible signs of lactic acidosis.
Some HIV medicines, including Atripla, that contain
nucleoside analogues can cause lactic acidosis (excess of lactic acid in your blood),
together with an enlarged liver.
Deep, rapid breathing, drowsiness,
and symptoms such
as
feeling sick
(nausea),
vomiting
and
stomach pain
, might indicate the development of
lactic acidosis. This rare but serious side effect has occasionally been fatal. Lactic
acidosis occurs more often in women, particularly if they are very overweight, and people
with liver disease. While you are being treated with Atripla, your doctor will monitor
you closely for any signs that you may be developing lactic acidosis. If you notice any
symptoms of lactic acidosis, please tell your doctor immediately.
-
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.
-
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 in patients who develop
damage to kidney tubule cells (see Section 4,
Possible side effects
).
46
Taking other medicines
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 remedies (including
St. John’s wort) which can cause serious interactions.
Tell your doctor
or pharmacist if you are taking or have recently taken any other medicines. This
includes non-prescription medicines and herbal remedies.
Also, Atripla should not be taken with any other medicines that contain efavirenz, emtricitabine,
tenofovir disoproxil, 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)
Atripla may interact with other medicines. 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 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 fumarate 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.
-
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.
-
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.
-
Methadone,
a medicine used to treat opiate addiction, as your doctor may need to change your
methadone dose.
47
-
Sertraline,
a medicine used to treat depression, as your doctor may need to change your dose of
sertraline.
-
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
(a
medicine used to reduce clotting of the blood): your doctor may need to adjust
your dose of warfarin.
Pregnancy and breast-feeding
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.
Serious birth defects have been seen in unborn animals and in the babies of women treated with
efavirenz during pregnancy. 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.
Ask your doctor or pharmacist for advice before taking any medicine.
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.
Important information about some of the ingredients of Atripla
This medicine contains 1 mmol (23.6 mg) of sodium per tablet which should be taken into
consideration if you are on a controlled sodium diet.
3.
HOW TO TAKE ATRIPLA
Always take Atripla exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose for adults
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). Swallow Atripla whole
with water.
Atripla must be taken every day.
48
It can help to take Atripla at bedtime.
This may make some side effects (for example, dizziness,
drowsiness) less troublesome.
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, 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, 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.
If you throw up the tablet (just after taking Atripla)
, you should take another tablet. Do not wait
until your next dose is due.
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
fumarate (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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Atripla can cause side effects, although not everybody gets them. When treating
HIV infection, it is not always possible to tell whether some of the unwanted effects are caused by
49
Atripla or by other medicines that you are taking at the same time, or by the HIV disease itself.
Tell
your doctor if you notice any of the following side effects:
Very common side effects
(These can affect more than 1 user in 10)
-
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:
-
increased levels of creatine kinase in the blood that may result in muscle pain and weakness
Common side effects
(These can affect 1 to 10 users in 100)
-
changes in skin colour including darkening of the skin in patches often starting on hands and
soles of feet
-
difficulty sleeping, abnormal dreams, difficulty concentrating, drowsiness
-
feeling worried or depressed
-
problems with digestion resulting in discomfort after meals, feeling bloated, wind (flatulence)
-
loss of appetite
-
tiredness
-
itching
-
disturbances of coordination and balance
-
allergic reactions
Tests may also show:
-
low white blood cell count (a reduced white blood cell count can make you more prone to
infection)
-
increased fatty acids (triglycerides), bilirubin or sugar levels in the blood
-
liver and pancreas problems
Uncommon side effects
(These can affect 1 to 10 users in 1,000)
-
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
attempts, personality change (psychosis)
-
forgetfulness, confusion, fitting (seizures), incoherent speech, tremor (shaking)
-
a feeling of spinning or tilting (vertigo), whistling, ringing or other persistent noise in the ears
-
dry mouth
-
allergic reaction (hypersensitivity) that may cause severe skin reactions (Stevens-Johnson
syndrome, erythema multiforme, see section 2)
-
flushing
-
yellow skin or eyes, itching, or pain in the abdomen (stomach) caused by inflammation of the
liver
-
pain in the abdomen (stomach), caused by inflammation of the pancreas
-
breast enlargement in males
-
anaemia (low red blood cell count)
-
decreased sexual drive
-
chills
50
-
dizziness, headache, diarrhoea, feeling sick (nausea), vomiting
-
decreases in phosphate levels in the blood
-
pain, stomach pain
-
blurred vision
-
increased appetite
-
breakdown of muscle, muscle pain or weakness
Tests may also show:
-
decreases in potassium in the blood
-
increases in creatinine in the blood
-
proteins in urine
Rare side effects
(These can affect 1 to 10 users in 10,000)
-
Lactic acidosis (excess lactic acid in the blood)
is a serious side effect that can be
life-threatening. The following side effects may be signs of lactic acidosis:
-
deep rapid breathing
-
tiredness
If you think you may have lactic acidosis, contact your doctor immediately.
feeling sick (nausea), vomiting and stomach pain.
-
back pain caused by kidney problems, including kidney failure. Your doctor may do blood tests
to see if your kidneys are working properly.
-
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.
-
itchy rash to the skin caused by a reaction to sunlight
-
inflammation of the kidney, passing a lot of urine and feeling thirsty
-
softening of the bones (with bone pain and sometimes resulting in fractures)
Tests may also show:
-
damage to kidney tubule cells
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.
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.
Other possible effects
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).
Combination antiretroviral therapy (such as Atripla) may change your body shape, by changing the
way body fat is distributed. You may lose fat from your legs, arms and face; gain fat around the
abdomen (tummy) and internal organs; get larger breasts or fatty lumps on the back of the neck
(‘buffalo hump’). The cause and the long-term effects of these changes are not yet known.
Combination antiretroviral therapy may also cause increased fat levels in the blood (hyperlipaemia)
and resistance to insulin. Your doctor will test for these changes.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
51
-
swelling of the face, lips, tongue or throat
-
-
fatty liver
5.
HOW TO STORE ATRIPLA
Keep out of the reach and sight of children.
Do not use Atripla after the expiry date which is stated on the bottle label 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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER 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, hydroxypropylcellulose,
magnesium stearate, microcrystalline cellulose, sodium laurilsulfate.
-
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 x 30 film-coated tablet and 3 x
30 film-coated tablet bottles. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Bristol-Myers Squibb and Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
Co. Cork
Ireland
Manufacturer:
Gilead Sciences Limited
Unit 13, Stillorgan Industrial Park
Blackrock
Co. Dublin
Ireland
or
52
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
Co. Cork
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
Luxembourg/Luxemburg
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
България
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Тел.: + 359 800 12 400
Magyarország
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Tel.: + 36 1 301 9700
Česká republika
Bristol-Myers Squibb spol. s r.o.
Tel: + 420 221 016 111
Malta
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Danmark
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Nederland
Gilead Sciences Netherlands B.V.
Tel: + 31 (0) 20 718 3698
Deutschland
Gilead Sciences GmbH
Tel: + 49 (0) 89 899890-0
Norge
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Eesti
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Tel: + 372 640 1301
Österreich
Gilead Sciences GesmbH
Tel: + 43 1 260 830
Ελλάδα
Gilead Sciences Ελλάς Μ.ΕΠΕ.
Τηλ: + 30 210 8930 100
Polska
Bristol-Myers Squibb Polska Sp. z o.o.
Tel.: + 48 22 5796666
España
Gilead Sciences, S.L.
Tel: + 34 91 378 98 30
Portugal
Gilead Sciences, Lda.
Tel: + 351 21 7928790
France
Gilead Sciences
Tél: + 33 (0) 1 42 73 70 70
România
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Tel: + 40 (0) 21 272 16 00
Ireland
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
Slovenija
Bristol-Myers Squibb spol. s r.o.
Tel: + 386 1 236 47 00
Ísland
Gilead Sciences Sweden AB
Sími: + 46 (0) 8 5057 1849
Slovenská republika
Bristol-Myers Squibb spol. s r.o.
Tel: + 421 2 59298411
53
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
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Tel: + 371 67 50 21 85
United Kingdom
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
Lietuva
Bristol-Myers Squibb Gyógyszerkereskedelmi
Kft.
Tel: + 370 5 2790 762
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
54
Source: European Medicines Agency
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