ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
STOCRIN 50 mg hard capsules
2.
Each hard capsule contains 50 mg of efavirenz.
Excipient: each hard capsule contains 28.5 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
Dark yellow and white, printed with “3805”.
4.
STOCRIN is indicated in antiviral combination treatment of human immunodeficiency virus-1
(HIV-1) infected adults, adolescents and children 3 years of age and older.
STOCRIN has not been adequately studied in patients with advanced HIV disease, namely in patients
with CD4 counts < 50 cells/mm
3
,
or after failure of protease inhibitor (PI) containing regimens.
Although cross-resistance of efavirenz with PIs has not been documented, there are at present
insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of
regimens containing STOCRIN.
For a summary of clinical and pharmacodynamic information, see section 5.1.
Posology
Therapy should be initiated by a physician experienced in the management of HIV infection.
Concomitant antiretroviral therapy:
STOCRIN must be given in combination with other antiretroviral
medicines (see section 4.5).
It is recommended that STOCRIN be taken on an empty stomach. The increased efavirenz
concentrations observed following administration of STOCRIN with food may lead to an increase in
frequency of adverse reactions (see sections 4.4 and 5.2).
In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is
recommended (see
section
4.8).
Adults:
the recommended dose of STOCRIN in combination with nucleoside analogue reverse
transcriptase inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily.
Dose adjustment:
If STOCRIN is coadministered with voriconazole, the voriconazole maintenance
dose must be increased to 400 mg every 12 hours and the STOCRIN dose must be reduced by 50 %,
2
i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz
should be restored (see section 4.5).
If STOCRIN is coadministered with rifampicin, an increase in the dose of STOCRIN to 800 mg/day
may be considered (see section 4.5).
Special populations
Renal impairment:
the pharmacokinetics of efavirenz have not been studied in patients with renal
insufficiency; however, less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the
impact of renal impairment on efavirenz elimination should be minimal (see section 4.4).
Hepatic impairment:
patients with mild liver disease may be treated with their normally recommended
dose of efavirenz. Patients should be monitored carefully for dose-related adverse reactions,
especially nervous system symptoms (see sections 4.3 and 4.4).
Paediatric population (3 to 17 years):
the recommended dose of STOCRIN in combination with a PI
and/or NRTIs for patients between 3 and 17 years of age is described in Table 1. STOCRIN hard
capsules must only be administered to children who are able to reliably swallow hard capsules. The
safety and efficacy of STOCRIN in children below the age of 3 years or weighing less than 13 kg have
not yet been established (see sections 5.1 and 5.2).
Table 1
Paediatric dose to be administered once daily
Body Weight
STOCRIN
13 to < 15
200
15 to < 20
250
20 to < 25
300
25 to < 32.5
350
32.5 to < 40
400
≥ 40
600
Hypersensitivity to the active substance or to any of the excipients.
Efavirenz must not be used in patients with severe hepatic impairment (Child Pugh Class C)
(see section 5.2).
Efavirenz 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 CYP3A4 by efavirenz could result in
inhibition of metabolism and create the potential for serious and/or 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
efavirenz due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz
(see
section
4.5).
Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing
regimen. As with all other non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistant virus
emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral
3
kg
Dose (mg)
agent(s) to be used in combination with efavirenz should take into consideration the potential for viral
cross-resistance (see section 5.1).
Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine,
and tenofovir disoproxil fumarate, is not recommended.
When prescribing medicinal products concomitantly with STOCRIN, physicians should refer to the
corresponding Summary of Product Characteristics.
Patients should be advised that current antiretroviral therapy, including efavirenz, has not been proven
to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.
Appropriate precautions should continue to be employed.
If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected
intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral
medicinal products. The antiretroviral medicinal products should be restarted at the same time upon
resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of
antiretroviral agents is not advisable because of the increased potential for selection of resistant virus.
Rash:
mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves
with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the
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. The
incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1 %. Efavirenz
must be discontinued in patients developing severe rash associated with blistering, desquamation,
mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be
given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus
(see
section
4.8).
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class
is limited (see section 4.8). Efavirenz is not recommended for patients who have had a life-threatening
cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.
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 risks of continued therapy outweigh 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 (see section 4.8). Nervous system symptoms
usually begin during the first one or two days of therapy and generally resolve after the first
2 - 4 weeks. Patients should be informed that if they do occur, these common symptoms are likely to
improve with continued therapy and are not predictive of subsequent onset of any of the less frequent
psychiatric symptoms.
Seizures:
convulsions have been observed in patients receiving efavirenz, generally in the presence of
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.
4
Hepatic events:
a few of the postmarketing reports of hepatic failure 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 patients without pre-existing hepatic dysfunction or other risk factors.
Effect of food:
the administration of STOCRIN with food may increase efavirenz exposure
(see section 5.2) and may lead to an increase in the frequency of adverse reactions (see section 4.8). It
is recommended that STOCRIN be taken on an empty stomach, preferably at bedtime.
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.
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 PIs and lipoatrophy and 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 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).
.
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.
Special populations:
Liver disease: efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3
and 5.2) and not recommended in patients with moderate hepatic impairment because of insufficient
data to determine whether dose adjustment is necessary. Because of the extensive cytochrome
P450-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver
disease, caution must be exercised in administering efavirenz to patients with mild hepatic
impairment. Patients should be monitored carefully for dose-related adverse reactions, especially
nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at
periodic intervals (see section 4.2).
The safety and efficacy of efavirenz has not been established in patients with significant underlying
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. 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 efavirenz 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. In case of concomitant antiviral therapy for hepatitis B or C, please
refer also to the relevant product information for these medicinal products.
5
Renal insufficiency
: the pharmacokinetics of efavirenz have not been studied in patients with renal
insufficiency; however, less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the
impact of renal impairment on efavirenz elimination should be minimal (see section 4.2). There is no
experience in patients with severe renal failure and close safety monitoring is recommended in this
population.
Elderly patients
: insufficient numbers of elderly patients have been evaluated in clinical studies to
determine whether they respond differently than younger patients.
Paediatric population
: efavirenz has not been evaluated in children below 3 years of age or who weigh
less than 13 kg. Therefore, efavirenz should not be given to children less than 3 years of age.
Rash was reported in 26 of 57 children (46 %) treated with efavirenz during a 48-week period and was
severe in three patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with
efavirenz in children may be considered.
Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicinal product. Individuals with these
conditions may take efavirenz oral solution, which is free from lactose.
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.
Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam,
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine,
ergonovine, and methylergonovine) since inhibition of their metabolism may lead to serious,
life-threatening events (see section 4.3).
St. John’s wort (Hypericum perforatum):
co-administration of efavirenz and St. John’s wort or herbal
preparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can be reduced
by concomitant use of St. John's wort due to induction of drug metabolising enzymes and/or transport
proteins by St. John's wort. If a patient is already taking St. John’s wort, stop St. John’s wort, check
viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John’s wort
and the dose of efavirenz may need adjusting. The inducing effect of St. John’s wort may persist for
at least 2 weeks after cessation of treatment (see section 4.3).
Other interactions
Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease
inhibitors and other non-antiretroviral medicinal products are listed in Table 2 below (increase is
indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or
“q12h”). If available, 90% or 95% confidence intervals are shown in parentheses. Studies were
conducted in healthy subjects unless otherwise noted.
6
Table 2: Interactions between efavirenz and other medicinal products
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors (PI)
Atazanavir/ritonavir/Efavirenz
(400 mg once daily/100 mg once
daily/600 mg once daily, all
administered with food)
Atazanavir (pm):
AUC: ↔* (↓ 9 to ↑ 10)
C
max
: ↑ 17 %* (↑ 8 to ↑ 27)
C
min
: ↓ 42 %* (↓ 31 to ↓ 51)
Co-administration of efavirenz
with atazanavir/ritonavir is not
recommended. If the
co-administration of atazanavir
with an NNRTI is required, an
increase in the dose of both
atazanavir and ritonavir to
400 mg and 200 mg,
respectively, in combination
with efavirenz could be
considered with close clinical
monitoring.
Atazanavir/ritonavir/Efavirenz
(400 mg once daily/200 mg once
daily/600 mg once daily, 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 once
daily in the evening without
efavirenz. This decrease in
atazanavir C
min
might negatively
impact the efficacy of atazanavir.
** based on historical comparison
Darunavir/ritonavir/Efavirenz
(300 mg twice daily*/100 mg twice
daily/600 mg once daily)
Darunavir:
AUC : ↓ 13 %
C
min
: ↓ 31 %
(CYP3A4 induction)
Efavirenz:
AUC : ↑ 21 %
C
min
: ↑ 17 %
(CYP3A4 inhibition)
The clinical significance of the
changes has not been
established. Similar findings are
expected with the approved
darunavir/ritonavir 600/100 mg
twice daily dose. This
combination should be used with
caution.
See ritonavir row below.
*lower than recommended dose
Fosamprenavir/ritonavir/Efavirenz
(700 mg twice daily/100 mg twice
daily/600 mg once daily)
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for any of these medicinal
products.
See also ritonavir row below.
Fosamprenavir/Nelfinavir/Efavirenz
Interaction not studied
No dose adjustment is necessary
for any of these medicinal
products.
Fosamprenavir/Saquinavir/Efavirenz
Interaction not studied
Not recommended, as the
exposure to both PIs is expected
to be significantly decreased.
Indinavir/Efavirenz
(800 mg q8h/200 mg once daily)
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 daily.
(CYP3A4 induction)
Efavirenz:
No clinically significant
pharmacokinetic interaction
While the clinical significance of
decreased indinavir
concentrations has not been
established, the magnitude of the
observed pharmacokinetic
interaction should be taken into
consideration when choosing a
regimen containing both
efavirenz and indinavir.
No dose adjustment is necessary
for efavirenz when given with
7
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Indinavir/ritonavir/Efavirenz
(800 mg twice daily/100 mg twice
daily/600 mg once daily)
Indinavir:
AUC: ↓ 25 % (↓ 16 to ↓ 32)
b
C
max
: ↓ 17 % (↓ 6 to ↓ 26)
b
C
min
: ↓ 50 % (↓ 40 to ↓ 59)
b
Efavirenz:
No clinically significant
pharmacokinetic interaction
The geometric mean C
min
for
indinavir (0.33 mg/l) when given
with ritonavir and efavirenz was
higher than the mean historical
C
min
(0.15 mg/l) when indinavir
was given alone at 800 mg q8h. In
HIV-1 infected patients (n = 6), the
pharmacokinetics of indinavir and
efavirenz were generally
comparable to these uninfected
volunteer data.
indinavir or indinavir/ritonavir.
See also ritonavir row below.
Lopinavir/ritonavir soft capsules or
oral solution/Efavirenz
Substantial decrease in lopinavir
exposure.
With efavirenz, an increase of
the lopinavir/ritonavir soft
capsule or oral solution doses by
33 % should be considered
(4 capsules/~6.5 ml twice daily
instead of 3 capsules/5 ml twice
daily). Caution is warranted
since this dose adjustment might
be insufficient in some patients.
The dose of lopinavir/ritonavir
tablets should be increased to
500/125 mg twice daily when
co-administered with efavirenz
600 mg once daily.
See also ritonavir row below.
Lopinavir/ritonavir tablets/ Efavirenz
(400/100 mg twice daily/600 mg once
daily)
Lopinavir concentrations:
↓ 30-40 %
(500/125 mg twice daily/600 mg once
daily)
Lopinavir concentrations: similar
to lopinavir/ritonavir 400/100 mg
twice daily without efavirenz
Nelfinavir/Efavirenz
(750 mg q8h/600 mg once daily)
Nelfinavir:
AUC: ↑ 20 % (↑ 8 to ↑ 34)
C
max
: ↑ 21 % (↑ 10 to ↑ 33)
The combination was generally
well tolerated.
No dose adjustment is necessary
for either medicinal product.
8
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Ritonavir/Efavirenz
(500 mg twice daily/600 mg once
daily)
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)
b
Evening C
min
: ↑ 24 % (↑ 3 to ↑ 50)
b
Efavirenz:
AUC: ↑ 21 % (↑ 10 to ↑ 34)
C
max
: ↑ 14 % (↑ 4 to ↑ 26)
C
min
: ↑ 25 % (↑ 7 to ↑ 46)
b
(inhibition of CYP-mediated
oxidative metabolism)
When efavirenz was given with
ritonavir 500 mg or 600 mg twice
daily, the combination was not well
tolerated (for example, dizziness,
nausea, paraesthesia and elevated
liver enzymes occurred).
Sufficient data on the tolerability
of efavirenz with low-dose
ritonavir (100 mg, once or twice
daily) are not available.
When using efavirenz 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.
Saquinavir/ritonavir/Efavirenz
Interaction not studied.
No data are available to make a
dose recommendation. See also
ritonavir row above. Use of
efavirenz in combination with
saquinavir as the sole protease
inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz
(100 mg twice daily/600 mg once
daily)
Maraviroc:
AUC
12
: ↓ 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.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz
(400 mg single dose/ - )
Raltegravir:
AUC: ↓ 36 %
C
12
: ↓ 21 %
C
max
: ↓ 36 %
(UGT1A1 induction)
No dose adjustment is necessary
for raltegravir.
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 are not
expected since the NRTIs are
metabolised via a different route
than efavirenz and would be
unlikely to compete for the same
metabolic enzymes and elimination
pathways.
No dose adjustment is necessary
for either medicinal product.
9
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
NNRTIs/Efavirenz
Interaction not studied.
Since use of two NNRTIs proved
not beneficial in terms of
efficacy and safety,
co-administration of efavirenz
and another NNRTI is not
recommended.
Antibiotics
Azithromycin/Efavirenz
(600 mg single dose/400 mg once
daily)
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for either medicinal product.
Clarithromycin/Efavirenz
(500 mg q12h/400 mg once daily)
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. No dose adjustment
is necessary for efavirenz.
Other macrolide antibiotics (e.g.,
erythromycin)/Efavirenz
Interaction not studied.
No data are available to make a
dose recommendation.
Antimycobacterials
Rifabutin/Efavirenz
(300 mg once daily/600 mg once
daily)
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 administered with
efavirenz. Consider doubling the
rifabutin dose in regimens where
rifabutin is given 2 or 3 times a
week in combination with
efavirenz.
Rifampicin/Efavirenz
(600 mg once daily/600 mg once
daily)
Efavirenz:
AUC: ↓ 26 % (↓ 15 to ↓ 36)
C
max
:
↓ 20 % (↓ 11 to ↓ 28)
C
min
: ↓ 32 % (↓ 15 to ↓ 46)
(CYP3A4 and CYP2B6 induction)
When taken with rifampicin,
increasing efavirenz daily dose
to 800 mg may provide exposure
similar to a daily dose of
600 mg, when taken without
rifampicin. The clinical effect of
this dose adjustment has not
been adequately evaluated.
Individual tolerability and
virological response should be
considered when making the
dose adjustment (see
section 5.2). No dose adjustment
is necessary for rifampicin.
10
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Antifungals
Itraconazole/Efavirenz
(200 mg q12h/600 mg once daily)
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:
No clinically significant
pharmacokinetic change.
Since no dose recommendation
for itraconazole can be made,
alternative antifungal treatment
should be considered.
Posaconazole/Efavirenz
--/400 mg once daily
Posaconazole:
AUC: ↓ 50 %
C
max
: ↓ 45 %
(UDP-G induction)
Concomitant use of
posaconazole and efavirenz
should be avoided unless the
benefit to the patient outweighs
the risk.
Voriconazole/Efavirenz
(200 mg twice daily/400 mg once
daily)
Voriconazole:
AUC: ↓ 77 %
C
max
:
↓ 61 %
Efavirenz:
AUC: ↑ 44 %
C
max
:
↑ 38 %
Voriconazole:
AUC: ↓ 7 % (↓ 23 to ↑ 13) *
C
max
:
↑ 23 % (↓ 1 to ↑ 53) *
Efavirenz:
AUC: ↑ 17 % (↑ 6 to ↑ 29) **
C
max
:
↔**
*compared to 200 mg twice daily
alone
** compared to 600 mg once daily
alone
(competitive inhibition of oxidative
metabolism)
When efavirenz is
co-administered with
voriconazole, the voriconazole
maintenance dose must be
increased to 400 mg twice daily
and the efavirenz dose must be
reduced by 50 %, i.e., to 300 mg
once daily. When treatment with
voriconazole is stopped, the
initial dose of efavirenz should
be restored.
Voriconazole/Efavirenz
(400 mg twice daily/300 mg once
daily)
Fluconazole/Efavirenz
(200 mg once daily/400 mg once
daily)
No clinically significant
pharmacokinetic interaction
No dose adjustment is necessary
for either medicinal product.
Ketoconazole and other imidazole
antifungals
Interaction not studied
No data are available to make a
dose recommendation.
11
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
ACID REDUCING AGENTS
Aluminium hydroxide-magnesium
hydroxide-simethicone
antacid/Efavirenz
(30 mL single dose/400 mg single
dose)
Famotidine/Efavirenz
(40 mg single dose/400 mg single
dose)
Neither aluminium/magnesium
hydroxide antacids nor famotidine
altered the absorption of efavirenz.
Co-administration of efavirenz
with medicinal products that
alter gastric pH would not be
expected to affect efavirenz
absorption.
ANTIANXIETY AGENTS
Lorazepam/Efavirenz
(2 mg single dose/600 mg once daily)
Lorazepam:
AUC: ↑ 7 % (↑ 1 to ↑ 14)
C
max
:
↑ 16 % (↑ 2 to ↑ 32)
These changes are not considered
clinically significant.
No dose adjustment is necessary
for either medicinal product.
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.
ANTICONVULSANTS
Carbamazepine/Efavirenz
(400 mg once daily/600 mg once
daily)
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)
The steady-state AUC, C
max
and
C
min
of the active carbamazepine
epoxide metabolite remained
unchanged. Co-administration of
higher doses of either efavirenz or
carbamazepine has not been
studied.
No dose recommendation can be
made. An alternative
anticonvulsant should be
considered. Carbamazepine
plasma levels should be
monitored periodically.
Phenytoin, Phenobarbital, and other
anticonvulsants that are substrates of
CYP450 isoenzymes
Interaction not studied. There is a
potential for reduction or increase
in the plasma concentrations of
phenytoin, phenobarbital and other
anticonvulsants that are substrates
of CYP450 isoenzymes when
co-administered with efavirenz.
When efavirenz 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 twice daily/600 mg once
daily)
No clinically significant effect on
efavirenz pharmacokinetics.
Limited data suggest there is no
clinically significant effect on
valproic acid pharmacokinetics.
No dose adjustment is necessary
for efavirenz. Patients should be
monitored for seizure control.
12
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
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.
No dose adjustment is necessary
for any of these medicinal
products.
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz
(50 mg once daily/600 mg once daily)
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)
Sertraline dose increases should
be guided by clinical response.
No dose adjustment is necessary
for efavirenz.
Paroxetine/Efavirenz
(20 mg once daily/600 mg once daily)
No clinically significant
pharmacokinetic interaction
No dose adjustment is necessary
for either medicinal product.
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.
No dose adjustment is necessary
for either medicinal product.
ANTIHISTAMINES
Cetirizine/Efavirenz
(10 mg single dose/600 mg once
daily)
Cetirizine:
AUC: ↔
C
max
: ↓ 24 % (↓ 18 to ↓ 30)
These changes are not considered
clinically significant.
Efavirenz:
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for either medicinal product.
13
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz
(240 mg once daily/600 mg once
daily)
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
should be guided by clinical
response (refer to the Summary
of Product Characteristics for
diltiazem). No dose adjustment
is necessary for efavirenz.
Verapamil, Felodipine, Nifedipine and
Nicardipine
Interaction not studied. 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 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 once daily/600 mg once daily)
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. Dose
adjustments of atorvastatin may
be required (refer to the
Summary of Product
Characteristics for the
atorvastatin). No dose
adjustment is necessary for
efavirenz.
Pravastatin/Efavirenz
(40 mg once daily/600 mg once daily)
Pravastatin:
AUC: ↓ 40 % (↓ 26 to ↓ 57)
C
max
: ↓ 18 % (↓ 59 to ↑ 12)
Cholesterol levels should be
periodically monitored. Dose
adjustments of pravastatin may
be required (refer to the
Summary of Product
Characteristics for pravastatin).
No dose adjustment is necessary
for efavirenz.
14
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Simvastatin/Efavirenz
(40 mg once daily/600 mg once daily)
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. Dose
adjustments of simvastatin may
be required (refer to the
Summary of Product
Characteristics for simvastatin).
No dose adjustment is necessary
for efavirenz.
Rosuvastatin/Efavirenz
Interaction not studied.
Rosuvastatin is largely excreted
unchanged via the faeces, therefore
interaction with efavirenz is not
expected.
No dose adjustment is necessary
for either medicinal product.
HORMONAL CONTRACEPTIVES
Oral:
Ethinyloestradiol+Norgestimate/
Efavirenz
(0.035 mg+0.25 mg once
daily/600 mg once daily)
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)
Injection: Depo-
medroxyprogesterone 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).
15
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Implant: Etonogestrel/Efavirenz
Interaction not studied. Decreased
exposure of etonogestrel may be
expected (CYP3A4 induction).
There have been occasional
postmarketing 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).
IMMUNOSUPPRESSANTS
Immunosuppressants metabolized by
CYP3A4 (e.g., cyclosporine,
tacrolimus, sirolimus)/Efavirenz
Interaction not studied. Decreased
exposure of the
immunosuppressant may be
expected (CYP3A4 induction).
These immunosuppressants are not
anticipated to affect exposure of
efavirenz.
Dose adjustments of the
immunosuppressant may be
required. Close monitoring of
immunosuppressant
concentrations for at least
2 weeks (until stable
concentrations are reached) is
recommended when starting or
stopping treatment with
efavirenz.
OPIOIDS
Methadone/Efavirenz
(stable maintenance, 35-100 mg once
daily/600 mg once daily)
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 should be monitored for
signs of withdrawal and their
methadone dose increased as
required to alleviate withdrawal
symptoms.
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 or efavirenz may
not be necessary when
co-administered.
a
90 % confidence intervals unless otherwise noted.
b
95 % confidence intervals.
Paediatric population
Interaction studies have only been performed in adults.
Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.
16
Women of childbearing potential:
pregnancy should be avoided in women treated with efavirenz.
Barrier contraception should always be used in combination with other methods of contraception (for
example, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of
adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.
Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz.
Pregnancy:
there are limited amount of data from the use of efavirenz in pregnant women. In
postmarketing 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 in animals have shown reproductive toxicity including
marked teratogenic effects (see
section 5.3).
Breastfeeding:
studies in rats have demonstrated that efavirenz is excreted in milk reaching
concentrations much higher than those in maternal plasma. It is not known whether efavirenz is
excreted in human milk. Since animal data suggest that the substance may be passed into breast milk,
it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended
that HIV infected women do not breast feed their infants under any circumstances in order to avoid
transmission of HIV.
Fertility:
the effect of efavirenz on male and female fertility in rats has only been evaluated at doses
that achieved systemic drug exposures equivalent to or below those achieved in humans given
recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of male
or female rats (doses up to 100 mg/kg/bid), and did not affect sperm or offspring of treated male rats
(doses up to 200 mg/bid). The reproductive performance of offspring born to female rats given
efavirenz was not affected.
Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be
instructed that if they experience these symptoms they should avoid potentially hazardous tasks such
as driving or operating machinery.
a. Summary of the safety profile
Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received
600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most
frequently reported adverse reactions of at least moderate severity reported in at least 5 % of patients
were rash (11.6 %), dizziness (8.5 %), nausea (8.0 %), headache (5.7 %) and fatigue (5.5 %). The
most notable adverse reactions associated with efavirenz are rash and nervous system symptoms.
Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first
2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme;
psychiatric adverse reactions including severe depression, death by suicide, and psychosis like
behaviour; and seizures have been reported in patients treated with efavirenz. The administration of
STOCRIN with food may increase efavirenz exposure and may lead to an increase in the frequency of
adverse reactions (see section 4.4).
The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006)
in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration
180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine +
lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not
associated with any new safety concerns.
17
b. Tabulated list of adverse reactions
Adverse reactions of moderate or greater severity with at least possible relationship to treatment
regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended
dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions
observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens.
Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,
< 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); or very rare (< 1/10,000).
Immune system disorders
uncommon
hypersensitivity
Psychiatric disorders
common
abnormal dreams, anxiety, depression, insomnia*
uncommon
affect lability, aggression, confusional state,
euphoric mood, hallucination, mania, paranoia,
psychosis
‡
, suicide attempt, suicide ideation
rare
delusion
‡‡
, neurosis
‡‡
, completed suicide
‡‡
*
Nervous system disorders
common
cerebellar coordination and balance
disturbances
‡
,
disturbance in attention (3.6 %),
dizziness (8.5 %), headache (5.7 %), somnolence
(2.0 %)*
uncommon
agitation, amnesia, ataxia, coordination abnormal,
convulsions, thinking abnormal,
tremor
‡
Eye disorders
uncommon
vision blurred
Ear and labyrinth disorders
uncommon
tinnitus
‡
,
vertigo
Vascular disorders
uncommon
flushing
‡
Gastrointestinal disorders
common
abdominal pain, diarrhoea, nausea, vomiting
uncommon
pancreatitis
Hepatobiliary disorders
uncommon
hepatitis acute
rare
hepatic failure
‡‡
*
Skin and subcutaneous tissue disorders
very common
rash (11.6 %)*
common
pruritus
18
uncommon
erythema multiforme, Stevens-Johnson
syndrome*
rare
photoallergic dermatitis
‡
Reproductive system and breast disorders
uncommon
gynaecomastia
General disorders and administration site conditions
common
fatigue
*
See section
c. Description of selected adverse reactions
for more details.
‡
These adverse reactions were identified through post-marketing surveillance;
however the
frequencies were determined using data from 16 clinical trials (n=3,969).
‡‡
These adverse reactions were identified through post-marketing surveillance but not reported as
drug-related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare"
was defined per A Guideline on Summary of Product Characteristics (SmPC) guidance (rev. 2,
Sept 2009) on the basis of an estimated upper bound of the 95 % confidence interval for 0 events
given the number of subjects treated with efavirenz in these clinical trials (n=3,969).
c. Description of selected adverse reactions
Rash:
in clinical studies, 26 % of patients treated with 600 mg of efavirenz experienced skin rash
compared with 17 % of patients treated in control groups. Skin rash was considered treatment related
in 18 % of patients treated with efavirenz. Severe rash occurred in less than 1 % of patients treated
with efavirenz, and 1.7 % discontinued therapy because of rash. The incidence of erythema
multiforme or Stevens-Johnson syndrome was approximately 0.1 %.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two
weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with
efavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because of
rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is
restarted.
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class
is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy,
primarily based on retrospective cohort data from published literature, range from 13 to 18 %,
comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.)
Psychiatric symptoms:
serious psychiatric adverse reactions have been reported in patients treated with
efavirenz. In controlled trials the frequency of specific serious psychiatric events were:
- severe depression
Efavirenz regimen
(n=1,008)
Control regimen
(n=635)
- suicidal ideation
0.6 %
0.3 %
- non-fatal suicide attempts
0.4 %
0 %
- aggressive behaviour
0.4 %
0.3 %
- paranoid reactions
0.4 %
0.3 %
- manic reactions
0.1 %
0 %
Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric
adverse reactions with frequencies of each of the above events ranging from 0.3 % for manic reactions
to 2.0 % for both severe depression and suicidal ideation. There have also been post-marketing reports
of death by suicide, delusions and psychosis-like behaviour.
19
1.6 %
0.6 %
Nervous system symptoms:
in clinical controlled
trials, frequently reported adverse reactions included,
but were not limited to: dizziness, insomnia, somnolence, impaired concentration and abnormal
dreaming. Nervous system symptoms of moderate-to-severe intensity were experienced by 19 %
(severe 2.0 %) of patients compared to 9 % (severe 1 %) of patients receiving control regimens. In
clinical studies 2 % of patients treated with efavirenz discontinued therapy due to such symptoms.
Nervous system symptoms usually begin during the first one or two days of therapy and generally
resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system
symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous
system symptoms may occur more frequently when efavirenz 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 and can be recommended during the first weeks of therapy
and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or
splitting the daily dose has not been shown to provide benefit.
Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset
nervous system symptoms among efavirenz-treated patients were generally similar to those in the
control arm.
Hepatic failure:
A few of the postmarketing reports of hepatic failure, including cases in patients with
no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant
course, progressing in some cases to transplantation or death.
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).
Lipodystrophy and metabolic abnormalities:
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).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (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).
Laboratory test abnormalities:
Liver enzymes
: elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to
greater than five times the upper limit of the normal range (ULN) were seen in 3 % of 1,008 patients
treated with 600 mg of efavirenz (5-8 % after long-term treatment in study 006). Similar elevations
were seen in patients treated with control regimens (5 % after long-term treatment). Elevations of
gamma-glutamyltransferase (GGT) to greater than five times ULN were observed in 4 % of all
patients treated with 600 mg of efavirenz and 1.5 - 2 % of patients treated with control regimens (7 %
of efavirenz-treated patients and 3 % of control-treated patients after long-term treatment). Isolated
elevations of GGT in patients receiving efavirenz may reflect enzyme induction. In the long-term
study (006), 1 % of patients in each treatment arm discontinued because of liver or biliary system
disorders.
Amylase
: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels
greater than 1.5 times the upper limit of normal were seen in 10 % of patients treated with efavirenz
20
and 6 % of patients treated with control regimens. The clinical significance of asymptomatic increases
in serum amylase is unknown.
Lipids
: increases in total cholesterol of 10 - 20 % have been observed in some uninfected volunteers
receiving efavirenz. In clinical trials of various efavirenz-containing regimens in treatment naive
patients, total cholesterol, HDL-cholesterol, and triglycerides increased over 48 weeks of treatment
(21 – 31 %, 23 – 34 %, and 23 – 49 %, respectively). The proportion of patients with a total
cholesterol/HDL-cholesterol ratio greater than 5 was unchanged. The magnitude of changes in lipid
levels may be influenced by factors such as duration of therapy and other components of the
antiretroviral regimen.
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.
d. Paediatric population:
Undesirable effects in children were generally similar to those of adult patients. Rash was reported
more frequently in children (in a clinical study including 57 children who received efavirenz during a
48-week period, rash was reported in 46 %) and was more often of higher grade than in adults (severe
rash was reported in 5.3 % of children). Prophylaxis with appropriate antihistamines prior to initiating
therapy with efavirenz in children may be considered. Although nervous system symptoms are
difficult for young children to report, they appear to be less frequent in children and were generally
mild. In the study of 57 children, 3.5 % of patients experienced nervous system symptoms of moderate
intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of
nervous system symptoms.
e. Other special populations
Liver enzymes in hepatitis B or C co-infected patients
: in the long-term data set from study 006,
137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and
84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for
hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected
patients in study 006, elevations in AST to greater than five times ULN developed in 13 % of
efavirenz treated patients and in 7 % of controls, and elevations in ALT to greater than five times ULN
developed in 20 % and 7 % respectively. Among co-infected patients, 3 % of those treated with
efavirenz and 2 % in the control arm discontinued because of liver disorders (see section 4.4).
Some patients accidentally taking 600 mg twice daily have reported increased nervous system
symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with efavirenz should consist of general supportive measures, including
monitoring of vital signs and observation of the patient’s clinical status. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Non-nucleoside reverse transcriptase inhibitors.
21
ATC code: J05A G03
Mechanism of action:
efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of
HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA
polymerases (α, β, γ or δ).
Antiviral activity:
the free concentration of efavirenz required for 90 to 95 % inhibition of wild type or
zidovudine-resistant laboratory and clinical isolates
in vitro
ranged from 0.46 to 6.8 nM in
lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte
cultures.
Resistance:
the potency of efavirenz in cell culture against viral variants with amino acid substitutions
at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease
was similar to that observed against wild type viral strains. The single substitutions which led to the
highest resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position
100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold
resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing
K103N in addition to other amino acid substitutions in RT.
K103N was the most frequently observed RT substitution in viral isolates from patients who
experienced a significant rebound in viral load during clinical studies of efavirenz in combination with
indinavir or zidovudine + lamivudine. This mutation was observed in 90 % of patients receiving
efavirenz with virological failure. 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. The
pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of
the other antiviral medications used in combination with efavirenz.
Cross resistance:
cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture
demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of
three delavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained
the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not
cross-resistant to efavirenz.
Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed
evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs.
Thirteen isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and
delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a
valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment
failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to
nevirapine and delavirdine.
The potential for cross resistance between efavirenz and PIs is low because of the different enzyme
targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of
the different binding sites on the target and mechanism of action.
Clinical efficacy:
Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely
with CD4 counts < 50 cells/mm
3
, or in PI or NNRTI experienced patients. Clinical experience in
controlled studies with combinations including didanosine or zalcitabine is limited.
Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in
combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of
quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and
NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced
patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of
indinavir was 1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used
22
without efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of
NRTIs given every 12 hours were used in each of these studies.
Study 006,
a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or
efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to
be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count
was 341 cells/mm
3
and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for
study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 3.
In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who
terminated the study early for any reason, or who had a missing HIV-RNA measurement that was
either preceded or followed by a measurement above the limit of assay quantification were considered
to have HIV-RNA above 50 or above 400 copies/ml at the missing time points.
Table 3: Efficacy results for study 006
Responder rates (NC = F
a
)
Plasma HIV-RNA
Mean change
from
baseline-CD4
cell count
< 400 copies/ml
(95 % C.I.
b
)
< 50 copies/ml
(95 % C.I.
b
)
cells/mm
3
(S.E.M.
c
)
Treatment
Regimen
d
n
48 weeks
48 weeks
48 weeks
EFV +
ZDV + 3TC
202
67 %
(60 %, 73 %)
62 %
(55 %, 69 %)
187
(11.8)
EFV + IDV 206
54 %
(47 %, 61 %)
48 %
(41 %, 55 %)
177
(11.3)
IDV +
ZDV + 3TC
206
45 %
(38 %, 52 %)
40 %
(34 %, 47 %)
153
(12.3)
a
NC
=
F, noncompleter
=
failure.
b
C.I., confidence interval.
c
S.E.M., standard error of the mean.
d
EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.
Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with
EFV +IDV, 196 patients with EFV + ZDV + 3TC and 127 patients with IDV + ZDV + 3TC,
respectively), suggest durability of response in terms of proportions of patients with HIV RNA
< 400 copies/ml, HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell
count.
Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled
196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled
327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed
to change their patient’s NRTI regimen upon entry into the study. Responder rates were highest in
patients who switched NRTIs.
Table 4: Efficacy results for studies ACTG
364 and 020
Responder rates (NC = F
a
)
Plasma HIV-RNA
Mean change from
baseline-CD4 cell count
Study Number/
Treatment Regimens
b
n
%
(95 % C.I.
c
)
% (95 % C.I.) cells/mm
3
(S.E.M.
d
)
Study ACTG 364
48 weeks
< 500 copies/ml
< 50 copies/ml
EFV + NFV + NRTIs
65 70
(59, 82)
---
---
107
(17.9)
EFV + NRTIs
65 58
(46, 70)
---
---
114
(21.0)
NFV + NRTIs
66 30
(19, 42)
---
---
94
(13.6)
23
Responder rates (NC = F
a
)
Plasma HIV-RNA
Mean change from
baseline-CD4 cell count
Study Number/
Treatment Regimens
b
n
%
(95 % C.I.
c
)
% (95 % C.I.) cells/mm
3
(S.E.M.
d
)
Study 020
24 weeks
< 400 copies/ml
< 50 copies/ml
EFV + IDV + NRTIs
157 60
(52, 68)
49
(41, 58)
104
(9.1)
IDV + NRTIs
170 51
(43, 59)
38
(30, 45)
77
(9.9)
a
NC = F, noncompleter = failure.
b
EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor;
NFV, nelfinavir.
c
C.I., confidence interval for proportion of patients in response.
d
S.E.M., standard error of the mean.
---, not performed.
Paediatric population:
ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced
paediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safety
of efavirenz in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more
NRTIs. The starting dose of efavirenz
was the equivalent of a 600 mg dose (adjusted from calculated
body size based on weight). The response rate, based on the NC = F analysis of the percentage of
patients with plasma HIV-RNA < 400 copies/ml at 48 weeks was 60 % (95 %, C.I. 47, 72), and 53 %
(C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/ml. The mean CD4
cell counts were increased by 63 ± 34.5 cells/mm
3
from baseline. The durability of the response was
similar to that seen in adult patients.
5.2 Pharmacokinetic properties
Absorption:
peak efavirenz plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following
single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases
in C
max
and AUC were seen for doses up to 1,600 mg; the increases were less than proportional
suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours)
did not change following multiple dosing and steady-state plasma concentrations were reached in
6 - 7 days.
In HIV infected patients at steady state, mean C
max
, mean C
min
, and mean AUC were linear with
200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily,
steady state C
max
was 12.9 ± 3.7 μM (29 %) [mean ± S.D. (% C.V.)], steady state C
min
was
5.6 ± 3.2 μM (57 %), and AUC was 184 ± 73 μM·h (40 %).
Effect of food:
the bioavailability of a single
600 mg dose of efavirenz hard capsules in uninfected
volunteers was increased 22 % and 17 %, respectively, when given with a meal of high fat or normal
composition, relative to the bioavailability of a 600 mg dose given under fasted conditions
(see section 4.4).
Distribution:
efavirenz is highly bound (approximately 99.5 - 99.75 %) to human plasma proteins,
predominantly albumin. In HIV-1 infected patients (n = 9) who received efavirenz 200 to 600 mg
once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19 %
(mean 0.69 %) of the corresponding plasma concentration. This proportion is approximately 3-fold
higher than the non-protein-bound (free) fraction of efavirenz in plasma.
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 isozymes responsible for efavirenz metabolism and that it inhibited
24
P450 isozymes 2C9, 2C19, and 3A4. In
in vitro
studies efavirenz did not inhibit CYP2E1 and
inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the 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 - 400 mg per day for 10 days resulted in a lower than
predicted extent of accumulation (22 - 42 % lower) and a shorter terminal half-life compared with
single dose administration (see below).
Elimination:
efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and
40 – 55 hours after multiple doses. Approximately 14 - 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.
Hepatic impairment:
In a single-dose study, half life was doubled in the single patient with severe
hepatic impairment (Child-Pugh Class C), indicating a potential for a much greater degree of
accumulation. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in
patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were
insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or
C) affects efavirenz pharmacokinetics.
Gender, race, elderly:
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 in the elderly.
Paediatric population:
In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from
calculated body size based on weight), steady state C
max
was 14.1 μM, steady state C
min
was 5.6 μM,
and AUC was 216 μM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to
adults.
5.3 Preclinical safety data
Efavirenz was not mutagenic or clastogenic in conventional
genotoxicity assays.
Efavirenz induced foetal resorptions in rats. Malformations were observed in
3 of 20 foetuses/newborns from efavirenz-treated cynomolgus monkeys given doses resulting in
plasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral
anophthalmia with secondary enlargement of the tongue were observed in one foetus,
microophthalmia was observed in another foetus, and cleft palate was observed in a third foetus. No
malformations were observed in foetuses from efavirenz-treated rats and rabbits.
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).
Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female
mice, but not in male mice. The mechanism of tumour formation and the potential relevance for
humans are not known.
25
Carcinogenicity studies in male mice, 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.
6.
6.1 List of excipients
Capsule core
Sodium laurilsulfate
Lactose monohydrate
Magnesium stearate
Sodium starch glycolate
Capsule shell
Gelatine
Sodium laurilsulfate
Yellow iron oxide (E172)
Titanium dioxide (E171)
Silicon dioxide (E551)
Printing ink
Cochineal carminic acid (E120)
Indigo carmine (E132)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and content of container
HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 30 hard
capsules.
6.6 Special precautions for disposal
No special requirements.
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
26
8.
EU/1/99/111/001 - bottle
9.
Date of first authorisation: 28 May 1999.
Date of latest renewal: 28 May 2009.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
27
1.
STOCRIN 100 mg hard capsules
2.
Each hard capsule contains 100 mg of efavirenz.
Excipient: each hard capsule contains 57.0 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White, printed with “3807”.
4.
STOCRIN is indicated in antiviral combination treatment of human immunodeficiency virus-1
(HIV-1) infected adults, adolescents and children 3 years of age and older.
STOCRIN has not been adequately studied in patients with advanced HIV disease, namely in patients
with CD4 counts < 50 cells/mm
3
,
or after failure of protease inhibitor (PI) containing regimens.
Although cross-resistance of efavirenz with PIs has not been documented, there are at present
insufficient data on the efficacy of subsequent use of PI based combination therapy after failure of
regimens containing STOCRIN.
For a summary of clinical and pharmacodynamic information, see section 5.1.
Posology
Therapy should be initiated by a physician experienced in the management of HIV infection.
Concomitant antiretroviral therapy:
STOCRIN must be given in combination with other antiretroviral
medicines (see section
4.5).
It is recommended that STOCRIN be taken on an empty stomach. The increased efavirenz
concentrations observed following administration of STOCRIN with food may lead to an increase in
frequency of adverse reactions (see sections 4.4 and 5.2).
In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is
recommended (see section 4.8).
Adults:
the recommended dose of STOCRIN in combination with nucleoside analogue reverse
transcriptase inhibitors (NRTIs) with or without a PI (see section 4.5) is 600 mg orally, once daily.
Dose adjustment:
If STOCRIN is coadministered with voriconazole, the voriconazole maintenance
dose must be increased to 400 mg every 12 hours and the STOCRIN dose must be reduced by 50 %,
28
i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz
should be restored (see section 4.5).
If STOCRIN is coadministered with rifampicin, an increase in the dose of STOCRIN to 800 mg/day
may be considered (see section 4.5).
Special populations
Renal impairment:
the pharmacokinetics of efavirenz have not been studied in patients with renal
insufficiency; however, less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the
impact of renal impairment on efavirenz elimination should be minimal (see section 4.4).
Hepatic impairment:
patients with mild liver disease may be treated with their normally recommended
dose of efavirenz. Patients should be monitored carefully for dose-related adverse reactions,
especially nervous system symptoms (see sections 4.3 and 4.4).
Paediatric population (3 to 17 years):
the recommended dose of STOCRIN in combination with a PI
and/or NRTIs for patients between 3 and 17 years of age is described in Table 1. STOCRIN hard
capsules must only be administered to children who are able to reliably swallow hard capsules. The
safety and efficacy of STOCRIN in children below the age of 3 years or weighing less than 13 kg have
not yet been established (see sections 5.1 and 5.2).
Table 1
Paediatric dose to be administered once daily
Body Weight
STOCRIN
13 to < 15
200
15 to < 20
250
20 to < 25
300
25 to < 32.5
350
32.5 to < 40
400
≥ 40
600
Hypersensitivity to the active substance or to any of the excipients.
Efavirenz must not be used in patients with severe hepatic impairment (Child Pugh Class C)
(see section 5.2).
Efavirenz 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 CYP3A4 by efavirenz could result in
inhibition of metabolism and create the potential for serious and/or 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
efavirenz due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz
(see section
4.5).
Efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing
regimen. As with all other non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistant virus
emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral
29
kg
Dose (mg)
agent(s) to be used in combination with efavirenz should take into consideration the potential for viral
cross-resistance (see section 5.1).
Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine,
and tenofovir disoproxil fumarate, is not recommended.
When prescribing medicinal products concomitantly with STOCRIN, physicians should refer to the
corresponding Summary of Product Characteristics.
Patients should be advised that current antiretroviral therapy, including efavirenz, has not been proven
to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.
Appropriate precautions should continue to be employed.
If any antiretroviral medicinal product in a combination regimen is interrupted because of suspected
intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral
medicinal products. The antiretroviral medicinal products should be restarted at the same time upon
resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of
antiretroviral agents is not advisable because of the increased potential for selection of resistant virus.
Rash:
mild-to-moderate rash has been reported in clinical studies with efavirenz and usually resolves
with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the
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. The
incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1 %. Efavirenz
must be discontinued in patients developing severe rash associated with blistering, desquamation,
mucosal involvement or fever. If therapy with efavirenz is discontinued, consideration should also be
given to interrupting therapy with other antiretroviral agents to avoid development of resistant virus
(see section 4.8).
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class
is limited (see section 4.8). Efavirenz is not recommended for patients who have had a life-threatening
cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.
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 risks of continued therapy outweigh 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 (see section 4.8). Nervous system symptoms
usually begin during the first one or two days of therapy and generally resolve after the first 2 - 4
weeks. Patients should be informed that if they do occur, these common symptoms are likely to
improve with continued therapy and are not predictive of subsequent onset of any of the less frequent
psychiatric symptoms.
Seizures:
convulsions have been observed in patients receiving efavirenz, generally in the presence of
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.
30
Hepatic events:
a few of the postmarketing reports of hepatic failure 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 patients without pre-existing hepatic dysfunction or other risk factors.
Effect of food:
the administration of STOCRIN with food may increase efavirenz exposure
(see section 5.2) and may lead to an increase in the frequency of adverse reactions (see section 4.8). It
is recommended that STOCRIN be taken on an empty stomach, preferably at bedtime.
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.
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 PIs and lipoatrophy and 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 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).
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.
Special populations:
Liver disease: efavirenz is contraindicated in patients with severe hepatic impairment (see sections 4.3
and 5.2) and not recommended in patients with moderate hepatic impairment because of insufficient
data to determine whether dose adjustment is necessary. Because of the extensive cytochrome
P450-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver
disease, caution must be exercised in administering efavirenz to patients with mild hepatic
impairment. Patients should be monitored carefully for dose-related adverse reactions, especially
nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at
periodic intervals (see section 4.2).
The safety and efficacy of efavirenz has not been established in patients with significant underlying
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at increased risk for severe and potentially fatal hepatic adverse reactions. 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 efavirenz 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. In case of concomitant antiviral therapy for hepatitis B or C, please
refer also to the relevant product information for these medicinal products.
31
Renal insufficiency
: the pharmacokinetics of efavirenz have not been studied in patients with renal
insufficiency; however, less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the
impact of renal impairment on efavirenz elimination should be minimal (see section 4.2). There is no
experience in patients with severe renal failure and close safety monitoring is recommended in this
population.
Elderly patients
: insufficient numbers of elderly patients have been evaluated in clinical studies to
determine whether they respond differently than younger patients.
Paediatric population
: efavirenz has not been evaluated in children below 3 years of age or who weigh
less than 13 kg. Therefore, efavirenz should not be given to children less than 3 years of age.
Rash was reported in 26 of 57 children (46 %) treated with efavirenz during a 48-week period and was
severe in three patients. Prophylaxis with appropriate antihistamines prior to initiating therapy with
efavirenz in children may be considered.
Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicinal product. Individuals with these
conditions may take efavirenz oral solution, which is free from lactose.
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.
Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam,
triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine,
ergonovine, and methylergonovine) since inhibition of their metabolism may lead to serious,
life-threatening events (see section 4.3).
St. John’s wort (Hypericum perforatum):
co-administration of efavirenz and St. John’s wort or herbal
preparations containing St. John’s wort is contraindicated. Plasma levels of efavirenz can be reduced
by concomitant use of St. John's wort due to induction of drug metabolising enzymes and/or transport
proteins by St. John's wort. If a patient is already taking St. John’s wort, stop St. John’s wort, check
viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John’s wort
and the dose of efavirenz may need adjusting. The inducing effect of St. John’s wort may persist for
at least 2 weeks after cessation of treatment (see section 4.3).
Other interactions
Interactions between efavirenz and protease inhibitors, antiretroviral agents other than protease
inhibitors and other non-antiretroviral medicinal products are listed in Table 2 below (increase is
indicated as “↑”, decrease as “↓”, no change as “↔”, and once every 8 or 12 hours as “q8h” or
“q12h”). If available, 90 % or 95 % confidence intervals are shown in parentheses. Studies were
conducted in healthy subjects unless otherwise noted.
32
Table 2: Interactions between efavirenz and other medicinal products
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors (PI)
Atazanavir/ritonavir/Efavirenz
(400 mg once daily/100 mg once
daily/600 mg once daily, all
administered with food)
Atazanavir (pm):
AUC: ↔* (↓ 9 to ↑ 10)
C
max
: ↑ 17 %* (↑ 8 to ↑ 27)
C
min
: ↓ 42 %* (↓ 31 to ↓ 51)
Co-administration of efavirenz
with atazanavir/ritonavir is not
recommended. If the
co-administration of atazanavir
with an NNRTI is required, an
increase in the dose of both
atazanavir and ritonavir to
400 mg and 200 mg,
respectively, in combination
with efavirenz could be
considered with close clinical
monitoring.
Atazanavir/ritonavir/Efavirenz
(400 mg once daily/200 mg once
daily/600 mg once daily, 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 once
daily in the evening without
efavirenz. This decrease in
atazanavir C
min
might negatively
impact the efficacy of atazanavir.
** based on historical comparison
Darunavir/ritonavir/Efavirenz
(300 mg twice daily*/100 mg twice
daily/600 mg once daily)
Darunavir:
AUC : ↓ 13 %
C
min
: ↓ 31 %
(CYP3A4 induction)
Efavirenz:
AUC : ↑ 21 %
C
min
: ↑ 17 %
(CYP3A4 inhibition)
The clinical significance of the
changes has not been
established. Similar findings are
expected with the approved
darunavir/ritonavir 600/100 mg
twice daily dose. This
combination should be used with
caution.
See ritonavir row below.
*lower than recommended dose
Fosamprenavir/ritonavir/Efavirenz
(700 mg twice daily/100 mg twice
daily/600 mg once daily)
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for any of these medicinal
products.
See also ritonavir row below.
Fosamprenavir/Nelfinavir/Efavirenz
Interaction not studied
No dose adjustment is necessary
for any of these medicinal
products.
Fosamprenavir/Saquinavir/Efavirenz
Interaction not studied
Not recommended, as the
exposure to both PIs is expected
to be significantly decreased.
Indinavir/Efavirenz
(800 mg q8h/200 mg once daily)
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 daily.
(CYP3A4 induction)
Efavirenz:
No clinically significant
pharmacokinetic interaction
While the clinical significance of
decreased indinavir
concentrations has not been
established, the magnitude of the
observed pharmacokinetic
interaction should be taken into
consideration when choosing a
regimen containing both
efavirenz and indinavir.
No dose adjustment is necessary
for efavirenz when given with
33
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Indinavir/ritonavir/Efavirenz
(800 mg twice daily/100 mg twice
daily/600 mg once daily)
Indinavir:
AUC: ↓ 25 % (↓ 16 to ↓ 32)
b
C
max
: ↓ 17 % (↓ 6 to ↓ 26)
b
C
min
: ↓ 50 % (↓ 40 to ↓ 59)
b
Efavirenz:
No clinically significant
pharmacokinetic interaction
The geometric mean C
min
for
indinavir (0.33 mg/l) when given
with ritonavir and efavirenz was
higher than the mean historical
C
min
(0.15 mg/l) when indinavir
was given alone at 800 mg q8h. In
HIV-1 infected patients (n = 6), the
pharmacokinetics of indinavir and
efavirenz were generally
comparable to these uninfected
volunteer data.
indinavir or indinavir/ritonavir.
See also ritonavir row below.
Lopinavir/ritonavir soft capsules or
oral solution/Efavirenz
Substantial decrease in lopinavir
exposure.
With efavirenz, an increase of
the lopinavir/ritonavir soft
capsule or oral solution doses by
33 % should be considered
(4 capsules/~6.5 ml twice daily
instead of 3 capsules/5 ml twice
daily). Caution is warranted
since this dose adjustment might
be insufficient in some patients.
The dose of lopinavir/ritonavir
tablets should be increased to
500/125 mg twice daily when
co-administered with efavirenz
600 mg once daily.
See also ritonavir row below.
Lopinavir/ritonavir tablets/ Efavirenz
(400/100 mg twice daily/600 mg once
daily)
Lopinavir concentrations:
↓ 30-40 %
(500/125 mg twice daily/600 mg once
daily)
Lopinavir concentrations: similar
to lopinavir/ritonavir 400/100 mg
twice daily without efavirenz
Nelfinavir/Efavirenz
(750 mg q8h/600 mg once daily)
Nelfinavir:
AUC: ↑ 20 % (↑ 8 to ↑ 34)
C
max
: ↑ 21 % (↑ 10 to ↑ 33)
The combination was generally
well tolerated.
No dose adjustment is necessary
for either medicinal product.
34
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Ritonavir/Efavirenz
(500 mg twice daily/600 mg once
daily)
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)
b
Evening C
min
: ↑ 24 % (↑ 3 to ↑ 50)
b
Efavirenz:
AUC: ↑ 21 % (↑ 10 to ↑ 34)
C
max
: ↑ 14 % (↑ 4 to ↑ 26)
C
min
: ↑ 25 % (↑ 7 to ↑ 46)
b
(inhibition of CYP-mediated
oxidative metabolism)
When efavirenz was given with
ritonavir 500 mg or 600 mg twice
daily, the combination was not well
tolerated (for example, dizziness,
nausea, paraesthesia and elevated
liver enzymes occurred).
Sufficient data on the tolerability
of efavirenz with low-dose
ritonavir (100 mg, once or twice
daily) are not available.
When using efavirenz 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.
Saquinavir/ritonavir/Efavirenz
Interaction not studied.
No data are available to make a
dose recommendation. See also
ritonavir row above. Use of
efavirenz in combination with
saquinavir as the sole protease
inhibitor is not recommended.
CCR5 antagonist
Maraviroc/Efavirenz
(100 mg twice daily/600 mg once
daily)
Maraviroc:
AUC
12
: ↓ 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.
Integrase strand transfer inhibitor
Raltegravir/Efavirenz
(400 mg single dose/ - )
Raltegravir:
AUC: ↓ 36 %
C
12
: ↓ 21 %
C
max
: ↓ 36 %
(UGT1A1 induction)
No dose adjustment is necessary
for raltegravir.
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 are not
expected since the NRTIs are
metabolised via a different route
than efavirenz and would be
unlikely to compete for the same
metabolic enzymes and elimination
pathways.
No dose adjustment is necessary
for either medicinal product.
35
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
NNRTIs/Efavirenz
Interaction not studied.
Since use of two NNRTIs proved
not beneficial in terms of
efficacy and safety,
co-administration of efavirenz
and another NNRTI is not
recommended.
Antibiotics
Azithromycin/Efavirenz
(600 mg single dose/400 mg once
daily)
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for either medicinal product.
Clarithromycin/Efavirenz
(500 mg q12h/400 mg once daily)
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. No dose adjustment
is necessary for efavirenz.
Other macrolide antibiotics (e.g.,
erythromycin)/Efavirenz
Interaction not studied.
No data are available to make a
dose recommendation.
Antimycobacterials
Rifabutin/Efavirenz
(300 mg once daily/600 mg once
daily)
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 administered with
efavirenz. Consider doubling the
rifabutin dose in regimens where
rifabutin is given 2 or 3 times a
week in combination with
efavirenz.
Rifampicin/Efavirenz
(600 mg once daily/600 mg once
daily)
Efavirenz:
AUC: ↓ 26 % (↓ 15 to ↓ 36)
C
max
:
↓ 20 % (↓ 11 to ↓ 28)
C
min
: ↓ 32 % (↓ 15 to ↓ 46)
(CYP3A4 and CYP2B6 induction)
When taken with rifampicin,
increasing efavirenz daily dose
to 800 mg may provide exposure
similar to a daily dose of
600 mg, when taken without
rifampicin. The clinical effect of
this dose adjustment has not
been adequately evaluated.
Individual tolerability and
virological response should be
considered when making the
dose adjustment (see
section 5.2). No dose adjustment
is necessary for rifampicin.
36
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Antifungals
Itraconazole/Efavirenz
(200 mg q12h/600 mg once daily)
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:
No clinically significant
pharmacokinetic change.
Since no dose recommendation
for itraconazole can be made,
alternative antifungal treatment
should be considered.
Posaconazole/Efavirenz
--/400 mg once daily
Posaconazole:
AUC: ↓ 50 %
C
max
: ↓ 45 %
(UDP-G induction)
Concomitant use of
posaconazole and efavirenz
should be avoided unless the
benefit to the patient outweighs
the risk.
Voriconazole/Efavirenz
(200 mg twice daily/400 mg once
daily)
Voriconazole:
AUC: ↓ 77 %
C
max
:
↓ 61 %
Efavirenz:
AUC: ↑ 44 %
C
max
:
↑ 38 %
Voriconazole:
AUC: ↓ 7 % (↓ 23 to ↑ 13) *
C
max
:
↑ 23 % (↓ 1 to ↑ 53) *
Efavirenz:
AUC: ↑ 17 % (↑ 6 to ↑ 29) **
C
max
:
↔**
*compared to 200 mg twice daily
alone
** compared to 600 mg once daily
alone
(competitive inhibition of oxidative
metabolism)
When efavirenz is
co-administered with
voriconazole, the voriconazole
maintenance dose must be
increased to 400 mg twice daily
and the efavirenz dose must be
reduced by 50 %, i.e., to 300 mg
once daily. When treatment with
voriconazole is stopped, the
initial dose of efavirenz should
be restored.
Voriconazole/Efavirenz
(400 mg twice daily/300 mg once
daily)
Fluconazole/Efavirenz
(200 mg once daily/400 mg once
daily)
No clinically significant
pharmacokinetic interaction
No dose adjustment is necessary
for either medicinal product.
Ketoconazole and other imidazole
antifungals
Interaction not studied
No data are available to make a
dose recommendation.
37
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
ACID REDUCING AGENTS
Aluminium hydroxide-magnesium
hydroxide-simethicone
antacid/Efavirenz
(30 mL single dose/400 mg single
dose)
Famotidine/Efavirenz
(40 mg single dose/400 mg single
dose)
Neither aluminium/magnesium
hydroxide antacids nor famotidine
altered the absorption of efavirenz.
Co-administration of efavirenz
with medicinal products that
alter gastric pH would not be
expected to affect efavirenz
absorption.
ANTIANXIETY AGENTS
Lorazepam/Efavirenz
(2 mg single dose/600 mg once daily)
Lorazepam:
AUC: ↑ 7 % (↑ 1 to ↑ 14)
C
max
:
↑ 16 % (↑ 2 to ↑ 32)
These changes are not considered
clinically significant.
No dose adjustment is necessary
for either medicinal product.
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.
ANTICONVULSANTS
Carbamazepine/Efavirenz
(400 mg once daily/600 mg once
daily)
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)
The steady-state AUC, C
max
and
C
min
of the active carbamazepine
epoxide metabolite remained
unchanged. Co-administration of
higher doses of either efavirenz or
carbamazepine has not been
studied.
No dose recommendation can be
made. An alternative
anticonvulsant should be
considered. Carbamazepine
plasma levels should be
monitored periodically.
Phenytoin, Phenobarbital, and other
anticonvulsants that are substrates of
CYP450 isoenzymes
Interaction not studied. There is a
potential for reduction or increase
in the plasma concentrations of
phenytoin, phenobarbital and other
anticonvulsants that are substrates
of CYP450 isoenzymes when
co-administered with efavirenz.
When efavirenz 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 twice daily/600 mg once
daily)
No clinically significant effect on
efavirenz pharmacokinetics.
Limited data suggest there is no
clinically significant effect on
valproic acid pharmacokinetics.
No dose adjustment is necessary
for efavirenz. Patients should be
monitored for seizure control.
38
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
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.
No dose adjustment is necessary
for any of these medicinal
products.
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Sertraline/Efavirenz
(50 mg once daily/600 mg once daily)
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)
Sertraline dose increases should
be guided by clinical response.
No dose adjustment is necessary
for efavirenz.
Paroxetine/Efavirenz
(20 mg once daily/600 mg once daily)
No clinically significant
pharmacokinetic interaction
No dose adjustment is necessary
for either medicinal product.
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.
No dose adjustment is necessary
for either medicinal product.
ANTIHISTAMINES
Cetirizine/Efavirenz
(10 mg single dose/600 mg once
daily)
Cetirizine:
AUC: ↔
C
max
: ↓ 24 % (↓ 18 to ↓ 30)
These changes are not considered
clinically significant.
Efavirenz:
No clinically significant
pharmacokinetic interaction.
No dose adjustment is necessary
for either medicinal product.
39
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
CARDIOVASCULAR AGENTS
Calcium Channel Blockers
Diltiazem/Efavirenz
(240 mg once daily/600 mg once
daily)
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
should be guided by clinical
response (refer to the Summary
of Product Characteristics for
diltiazem). No dose adjustment
is necessary for efavirenz.
Verapamil, Felodipine, Nifedipine and
Nicardipine
Interaction not studied. 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 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 once daily/600 mg once daily)
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. Dose
adjustments of atorvastatin may
be required (refer to the
Summary of Product
Characteristics for the
atorvastatin). No dose
adjustment is necessary for
efavirenz.
Pravastatin/Efavirenz
(40 mg once daily/600 mg once daily)
Pravastatin:
AUC: ↓ 40 % (↓ 26 to ↓ 57)
C
max
: ↓ 18 % (↓ 59 to ↑ 12)
Cholesterol levels should be
periodically monitored. Dose
adjustments of pravastatin may
be required (refer to the
Summary of Product
Characteristics for pravastatin).
No dose adjustment is necessary
for efavirenz.
40
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Simvastatin/Efavirenz
(40 mg once daily/600 mg once daily)
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. Dose
adjustments of simvastatin may
be required (refer to the
Summary of Product
Characteristics for simvastatin).
No dose adjustment is necessary
for efavirenz.
Rosuvastatin/Efavirenz
Interaction not studied.
Rosuvastatin is largely excreted
unchanged via the faeces, therefore
interaction with efavirenz is not
expected.
No dose adjustment is necessary
for either medicinal product.
HORMONAL CONTRACEPTIVES
Oral:
Ethinyloestradiol+Norgestimate/
Efavirenz
(0.035 mg+0.25 mg once
daily/600 mg once daily)
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).
Injection: Depo-
medroxyprogesterone 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).
41
Medicinal product by therapeutic
areas
(dose)
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with confidence
intervals if available
a
(mechanism)
Recommendation concerning
co-administration with
efavirenz
Implant: Etonogestrel/Efavirenz
Interaction not studied. Decreased
exposure of etonogestrel may be
expected (CYP3A4 induction).
There have been occasional
postmarketing 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).
IMMUNOSUPPRESSANTS
Immunosuppressants metabolized by
CYP3A4 (e.g., cyclosporine,
tacrolimus, sirolimus)/Efavirenz
Interaction not studied. Decreased
exposure of the
immunosuppressant may be
expected (CYP3A4 induction).
These immunosuppressants are not
anticipated to affect exposure of
efavirenz.
Dose adjustments of the
immunosuppressant may be
required. Close monitoring of
immunosuppressant
concentrations for at least
2 weeks (until stable
concentrations are reached) is
recommended when starting or
stopping treatment with
efavirenz.
OPIOIDS
Methadone/Efavirenz
(stable maintenance, 35-100 mg once
daily/600 mg once daily)
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 should be monitored for
signs of withdrawal and their
methadone dose increased as
required to alleviate withdrawal
symptoms.
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 or efavirenz may
not be necessary when
co-administered.
a
90 % confidence intervals unless otherwise noted.
b
95 % confidence intervals.
Paediatric population
Interaction studies have only been performed in adults.
Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options.
42
Women of childbearing potential:
pregnancy should be avoided in women treated with efavirenz.
Barrier contraception should always be used in combination with other methods of contraception (for
example, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of
adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.
Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz.
Pregnancy:
there are limited amount of data from the use of efavirenz in pregnant women. In
postmarketing 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 in animals have shown reproductive toxicity including
marked teratogenic effects (see
section 5.3).
Breastfeeding:
studies in rats have demonstrated that efavirenz is excreted in milk reaching
concentrations much higher than those in maternal plasma. It is not known whether efavirenz is
excreted in human milk. Since animal data suggest that the substance may be passed into breast milk,
it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended
that HIV infected women do not breast feed their infants under any circumstances in order to avoid
transmission of HIV.
Fertility:
the effect of efavirenz on male and female fertility in rats has only been evaluated at doses
that achieved systemic drug exposures equivalent to or below those achieved in humans given
recommended doses of efavirenz. In these studies, efavirenz did not impair mating or fertility of male
or female rats (doses up to 100 mg/kg/bid), and did not affect sperm or offspring of treated male rats
(doses up to 200 mg/bid). The reproductive performance of offspring born to female rats given
efavirenz was not affected.
Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be
instructed that if they experience these symptoms they should avoid potentially hazardous tasks such
as driving or operating machinery.
a. Summary of the safety profile
Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received
600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most
frequently reported adverse reactions of at least moderate severity reported in at least 5 % of patients
were rash (11.6 %), dizziness (8.5 %), nausea (8.0 %), headache (5.7 %) and fatigue (5.5 %). The
most notable adverse reactions associated with efavirenz are rash and nervous system symptoms.
Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first
2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme;
psychiatric adverse reactions including severe depression, death by suicide, and psychosis like
behaviour; and seizures have been reported in patients treated with efavirenz. The administration of
STOCRIN with food may increase efavirenz exposure and may lead to an increase in the frequency of
adverse reactions (see section 4.4).
The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006)
in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration
180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine +
lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not
associated with any new safety concerns.
43
b. Tabulated list of adverse reactions
Adverse reactions of moderate or greater severity with at least possible relationship to treatment
regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended
dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions
observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens.
Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,
< 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); or very rare (< 1/10,000).
Immune system disorders
uncommon
hypersensitivity
Psychiatric disorders
common
abnormal dreams, anxiety, depression, insomnia*
uncommon
affect lability, aggression, confusional state,
euphoric mood, hallucination, mania, paranoia,
psychosis
‡
, suicide attempt, suicide ideation
rare
delusion
‡‡
, neurosis
‡‡
, completed suicide
‡‡
*
Nervous system disorders
common
cerebellar coordination and balance
disturbances
‡
,
disturbance in attention (3.6 %),
dizziness (8.5 %), headache (5.7 %), somnolence
(2.0 %)*
uncommon
agitation, amnesia, ataxia, coordination abnormal,
convulsions, thinking abnormal,
tremor
‡
Eye disorders
uncommon
vision blurred
Ear and labyrinth disorders
uncommon
tinnitus
‡
,
vertigo
Vascular disorders
uncommon
flushing
‡
Gastrointestinal disorders
common
abdominal pain, diarrhoea, nausea, vomiting
uncommon
pancreatitis
Hepatobiliary disorders
uncommon
hepatitis acute
rare
hepatic failure
‡‡
*
Skin and subcutaneous tissue disorders
very common
rash (11.6 %)*
common
pruritus
44
uncommon
erythema multiforme, Stevens-Johnson
syndrome*
rare
photoallergic dermatitis
‡
Reproductive system and breast disorders
uncommon
gynaecomastia
General disorders and administration site conditions
common
fatigue
*
See section
c. Description of selected adverse reactions
for more details.
‡
These adverse reactions were identified through post-marketing surveillance;
however the
frequencies were determined using data from 16 clinical trials (n=3,969).
‡‡
These adverse reactions were identified through post-marketing surveillance but not reported as
drug-related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare"
was defined per A Guideline on Summary of Product Characteristics (SmPC) guidance (rev. 2,
Sept 2009) on the basis of an estimated upper bound of the 95 % confidence interval for 0 events
given the number of subjects treated with efavirenz in these clinical trials (n=3,969).
c. Description of selected adverse reactions
Rash:
in clinical studies, 26 % of patients treated with 600 mg of efavirenz experienced skin rash
compared with 17 % of patients treated in control groups. Skin rash was considered treatment related
in 18 % of patients treated with efavirenz. Severe rash occurred in less than 1 % of patients treated
with efavirenz, and 1.7 % discontinued therapy because of rash. The incidence of erythema
multiforme or Stevens-Johnson syndrome was approximately 0.1 %.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two
weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with
efavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because of
rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is
restarted.
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class
is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy,
primarily based on retrospective cohort data from published literature, range from 13 to 18 %,
comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.)
Psychiatric symptoms:
serious psychiatric adverse reactions have been reported in patients treated with
efavirenz. In controlled trials the frequency of specific serious psychiatric eventswere:
Efavirenz regimen
(n=1,008)
Control regimen
(n=635)
- severe depression
1.6 %
0.6 %
- suicidal ideation
0.6 %
0.3 %
- non-fatal suicide attempts
0.4 %
0 %
- aggressive behaviour
0.4 %
0.3 %
- paranoid reactions
0.4 %
0.3 %
- manic reactions
0.1 %
0 %
Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric
adverse reactions with frequencies of each of the above events ranging from 0.3 % for manic reactions
45
to 2.0 % for both severe depression and suicidal ideation. There have also been post-marketing reports
of death by suicide, delusions and psychosis-like behaviour.
Nervous system symptoms:
in clinical controlled
trials, frequently reported adverse reactions included,
but were not limited to: dizziness, insomnia, somnolence, impaired concentration and abnormal
dreaming. Nervous system symptoms of moderate-to-severe intensity were experienced by 19 %
(severe 2.0 %) of patients compared to 9 % (severe 1 %) of patients receiving control regimens. In
clinical studies 2 % of patients treated with efavirenz discontinued therapy due to such symptoms.
Nervous system symptoms usually begin during the first one or two days of therapy and generally
resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system
symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous
system symptoms may occur more frequently when efavirenz 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 and can be recommended during the first weeks of therapy
and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or
splitting the daily dose has not been shown to provide benefit.
Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset
nervous system symptoms among efavirenz-treated patients were generally similar to those in the
control arm.
Hepatic failure:
A few of the postmarketing reports of hepatic failure, including cases in patients with
no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant
course, progressing in some cases to transplantation or death.
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).
Lipodystrophy and metabolic abnormalities:
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).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (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).
Laboratory test abnormalities:
Liver enzymes: elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to
greater than five times the upper limit of the normal range (ULN) were seen in 3 % of 1,008 patients
treated with 600 mg of efavirenz (5-8 % after long-term treatment in study 006). Similar elevations
were seen in patients treated with control regimens (5 % after long-term treatment). Elevations of
gamma-glutamyltransferase (GGT) to greater than five times ULN were observed in 4 % of all
patients treated with 600 mg of efavirenz and 1.5 - 2 % of patients treated with control regimens (7 %
of efavirenz-treated patients and 3 % of control-treated patients after long-term treatment). Isolated
elevations of GGT in patients receiving efavirenz may reflect enzyme induction. In the long-term
study (006), 1 % of patients in each treatment arm discontinued because of liver or biliary system
disorders.
46
Amylase
: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels
greater than 1.5 times the upper limit of normal were seen in 10 % of patients treated with efavirenz
and 6 % of patients treated with control regimens. The clinical significance of asymptomatic increases
in serum amylase is unknown.
Lipids
: increases in total cholesterol of 10 - 20 % have been observed in some uninfected volunteers
receiving efavirenz. In clinical trials of various efavirenz-containing regimens in treatment naive
patients, total cholesterol, HDL-cholesterol, and triglycerides increased over 48 weeks of treatment
(21 – 31 %, 23 – 34 %, and 23 – 49 %, respectively). The proportion of patients with a total
cholesterol/HDL-cholesterol ratio greater than 5 was unchanged. The magnitude of changes in lipid
levels may be influenced by factors such as duration of therapy and other components of the
antiretroviral regimen.
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.
d. Paediatric population:
Undesirable effects in children were generally similar to those of adult patients. Rash was reported
more frequently in children (in a clinical study including 57 children who received efavirenz during a
48-week period, rash was reported in 46 %) and was more often of higher grade than in adults (severe
rash was reported in 5.3 % of children). Prophylaxis with appropriate antihistamines prior to initiating
therapy with efavirenz in children may be considered. Although nervous system symptoms are
difficult for young children to report, they appear to be less frequent in children and were generally
mild. In the study of 57 children, 3.5 % of patients experienced nervous system symptoms of moderate
intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of
nervous system symptoms.
e. Other special populations
Liver enzymes in hepatitis B or C co-infected patients
: in the long-term data set from study 006,
137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and
84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for
hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected
patients in study 006, elevations in AST to greater than five times ULN developed in 13 % of
efavirenz treated patients and in 7 % of controls, and elevations in ALT to greater than five times ULN
developed in 20 % and 7 % respectively. Among co-infected patients, 3 % of those treated with
efavirenz and 2 % in the control arm discontinued because of liver disorders (see section 4.4).
Some patients accidentally taking 600 mg twice daily have reported increased nervous system
symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with efavirenz should consist of general supportive measures, including
monitoring of vital signs and observation of the patient’s clinical status. 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.
47
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Non-nucleoside reverse transcriptase inhibitors.
ATC code: J05A G03
Mechanism of action:
efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of
HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA
polymerases (α, β, γ or δ).
Antiviral activity:
the free concentration of efavirenz required for 90 to 95 % inhibition of wild type or
zidovudine-resistant laboratory and clinical isolates
in vitro
ranged from 0.46 to 6.8 nM in
lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte
cultures.
Resistance:
the potency of efavirenz in cell culture against viral variants with amino acid substitutions
at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease
was similar to that observed against wild type viral strains. The single substitutions which led to the
highest resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position
100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold
resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing
K103N in addition to other amino acid substitutions in RT.
K103N was the most frequently observed RT substitution in viral isolates from patients who
experienced a significant rebound in viral load during clinical studies of efavirenz in combination with
indinavir or zidovudine + lamivudine. This mutation was observed in 90 % of patients receiving
efavirenz with virological failure. 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. The
pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of
the other antiviral medications used in combination with efavirenz.
Cross resistance:
cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture
demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of
three delavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained
the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not
cross-resistant to efavirenz.
Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed
evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs.
Thirteen isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and
delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a
valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment
failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to
nevirapine and delavirdine.
The potential for cross resistance between efavirenz and PIs is low because of the different enzyme
targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of
the different binding sites on the target and mechanism of action.
Clinical efficacy:
Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely
with CD4 counts < 50 cells/mm
3
, or in PI or NNRTI experienced patients. Clinical experience in
controlled studies with combinations including didanosine or zalcitabine is limited.
Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in
combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of
48
quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and
NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced
patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of
indinavir was 1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used
without efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of
NRTIs given every 12 hours were used in each of these studies.
Study 006,
a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or
efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required
to be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell
count was 341 cells/mm
3
and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy
results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found
in Table 3. In the analysis of responder rates (the non-completer equals failure analysis [NC = F]),
patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement
that was either preceded or followed by a measurement above the limit of assay quantification were
considered to have HIV-RNA above 50 or above 400 copies/ml at the missing time points.
Table 3: Efficacy results for study
006
Responder rates (NC = F
a
)
Plasma HIV-RNA
Mean change
from
baseline-CD4
cell count
< 400 copies/ml
(95 % C.I.
b
)
< 50 copies/ml
(95 % C.I.
b
)
cells/mm
3
(S.E.M.
c
)
Treatment
Regimen
d
n
48 weeks
48 weeks
48 weeks
EFV +
ZDV + 3TC
202
67 %
(60 %, 73 %)
62 %
(55 %, 69 %)
187
(11.8)
EFV + IDV 206
54 %
(47 %, 61 %)
48 %
(41 %, 55 %)
177
(11.3)
IDV +
ZDV + 3TC
206
45 %
(38 %, 52 %)
40 %
(34 %, 47 %)
153
(12.3)
a
NC
=
F, noncompleter
=
failure.
b
C.I., confidence interval.
c
S.E.M., standard error of the mean.
d
EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.
Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with
EFV +IDV, 196 patients with EFV + ZDV + 3TC and 127 patients with IDV + ZDV + 3TC,
respectively), suggest durability of response in terms of proportions of patients with HIV RNA
< 400 copies/ml, HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell
count.
Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled
196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled
327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed
to change their patient’s NRTI regimen upon entry into the study. Responder rates were highest in
patients who switched NRTIs.
49
Table
4: Efficacy results for studies ACTG
364 and 020
Responder rates (NC = F
a
)
Plasma HIV-RNA
Mean change from
baseline-CD4 cell count
Study Number/
Treatment Regimens
b
n
%
(95 % C.I.
c
)
% (95 % C.I.) cells/mm
3
(S.E.M.
d
)
Study ACTG 364
48 weeks
< 500 copies/ml
< 50 copies/ml
EFV + NFV + NRTIs
65 70
(59, 82)
---
---
107
(17.9)
EFV + NRTIs
65 58
(46, 70)
---
---
114
(21.0)
NFV + NRTIs
66 30
(19, 42)
---
---
94
(13.6)
Study 020
24 weeks
< 400 copies/ml
< 50 copies/ml
EFV + IDV + NRTIs
157 60
(52, 68)
49
(41, 58)
104
(9.1)
IDV + NRTIs
170 51
(43, 59)
38
(30, 45)
77
(9.9)
a
NC = F, noncompleter = failure.
b
EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor;
NFV, nelfinavir.
c
C.I., confidence interval for proportion of patients in response.
d
S.E.M., standard error of the mean.
---, not performed.
Paediatric population:
ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced
paediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safety
of efavirenz in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more
NRTIs. The starting dose of efavirenz
was the equivalent of a 600 mg dose (adjusted from calculated
body size based on weight). The response rate, based on the NC = F analysis of the percentage of
patients with plasma HIV-RNA < 400 copies/ml at 48 weeks was 60 % (95 %, C.I. 47, 72), and 53 %
(C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/ml. The mean CD4
cell counts were increased by 63 ± 34.5 cells/mm
3
from baseline. The durability of the response was
similar to that seen in adult patients.
5.2 Pharmacokinetic properties
Absorption:
peak efavirenz plasma concentrations of 1.6 - 9.1 μM were attained by 5 hours following
single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose related increases
in C
max
and AUC were seen for doses up to 1,600 mg; the increases were less than proportional
suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3 - 5 hours)
did not change following multiple dosing and steady-state plasma concentrations were reached in
6 - 7 days.
In HIV infected patients at steady state, mean C
max
, mean C
min
, and mean AUC were linear with
200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily,
steady state C
max
was 12.9 ± 3.7 μM (29 %) [mean ± S.D. (% C.V.)], steady state C
min
was
5.6 ± 3.2 μM (57 %), and AUC was 184 ± 73 μM·h (40 %).
Effect of food:
the bioavailability of a single
600 mg dose of efavirenz hard capsules in uninfected
volunteers was increased 22 % and 17 %, respectively, when given with a meal of high fat or normal
composition, relative to the bioavailability of a 600 mg dose given under fasted conditions
(see section 4.4).
Distribution:
efavirenz is highly bound (approximately 99.5 - 99.75 %) to human plasma proteins,
predominantly albumin. In HIV-1 infected patients (n = 9) who received efavirenz 200 to 600 mg
once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19 %
(mean 0.69 %) of the corresponding plasma concentration. This proportion is approximately 3-fold
higher than the non-protein-bound (free) fraction of efavirenz in plasma.
50
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 isozymes responsible for efavirenz metabolism and that it inhibited
P450 isozymes 2C9, 2C19, and 3A4. In
in vitro
studies efavirenz did not inhibit CYP2E1 and
inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the 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 - 400 mg per day for 10 days resulted in a lower than
predicted extent of accumulation (22 - 42 % lower) and a shorter terminal half-life compared with
single dose administration (see below).
Elimination:
efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and
40 – 55 hours after multiple doses. Approximately 14 - 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.
Hepatic impairment:
In a single-dose study, half life was doubled in the single patient with severe
hepatic impairment (Child-Pugh Class C), indicating a potential for a much greater degree of
accumulation. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in
patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were
insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or
C) affects efavirenz pharmacokinetics.
Gender, race, elderly:
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 in the elderly.
Paediatric population:
In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from
calculated body size based on weight), steady state C
max
was 14.1 μM, steady state C
min
was 5.6 μM,
and AUC was 216 μM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to
adults.
5.3 Preclinical safety data
Efavirenz was not mutagenic or clastogenic in conventional
genotoxicity assays.
Efavirenz induced foetal resorptions in rats. Malformations were observed in 3 of
20 foetuses/newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma
efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia
with secondary enlargement of the tongue were observed in one foetus, microophthalmia was
observed in another foetus, and cleft palate was observed in a third foetus. No malformations were
observed in foetuses from efavirenz-treated rats and rabbits.
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).
51
Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female
mice, but not in male mice. The mechanism of tumour formation and the potential relevance for
humans are not known.
Carcinogenicity studies in male mice, male and female rats were negative. While the carcinogenic
potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the
potential carcinogenic risk to humans.
6.
6.1 List of excipients
Capsule core
Sodium laurilsulfate
Lactose monohydrate
Magnesium stearate
Sodium starch glycolate
Capsule shell
Gelatine
Sodium laurilsulfate
Titanium dioxide (E171)
Silicon dioxide (E551)
Printing ink
Cochineal carminic acid (E120)
Iindigo carmine (E132)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and content of container
HDPE bottles with a child-resistant polypropylene closure. Each carton contains 1 bottle of 30 hard
capsules.
6.6 Special precautions for disposal
No special requirements.
52
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/99/111/002 - bottle
9.
Date of first authorisation: 28 May 1999.
Date of latest renewal: 28 May 2009.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
53
1.
Marketing Authorisation Holder
Manufacturer
Merck Sharp & Dohme Limited
Merck Sharp & Dohme B.V.
Hertfordshire EN11 9BU
Postbus 581
United Kingdom
2003 PC Haarlem
The Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
267
Hertford Road, Hoddesdon
Waarderweg 39
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
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Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
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Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800-9999000
medicalinfo.nl@merck.com
Deutschland
Bristol-Myers Squibb GmbH &
C
O
.
KGaA
Tel: +49 89 121 42-0
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +30 210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Bristol-Myers Squibb, S.A.
Tel: +34 91 456 53 00
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
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Bristol-Myers Squibb Sarl.
Tél: +33 (0) 810 410 500
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Bristol-Myers Squibb Pharmaceuticals Ltd.
Tel: +353 (1 800) 749 749
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
268
Ísland
Icepharma hf.
Simí: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Bristol-Myers Squibb S.r.l.
Tel: +39 06 50 39 61
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus
_
info
@
merck
.
com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Bristol-Myers Squibb Pharmaceuticals Ltd.
Tel: +44 (0800) 731 1736
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
269
Source: European Medicines Agency
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