ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Emtriva 200 mg hard capsules
2.
Each hard capsule contains 200 mg emtricitabine.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
Each capsule has a white opaque body with a light blue opaque cap. Each capsule is printed with
“200 mg” on the cap and “GILEAD” and [Gilead logo] on the body in black ink.
4.
Emtriva is indicated for the treatment of HIV-1 infected adults and children in combination with other
antiretroviral agents.
This indication is based on studies in treatment-naïve patients and treatment-experienced patients with
stable virological control. There is no experience of the use of Emtriva in patients who are failing
their current regimen or who have failed multiple regimens (see section 5.1).
When deciding on a new regimen for patients who have failed an antiretroviral regimen, careful
consideration should be given to the patterns of mutations associated with different medicinal products
and the treatment history of the individual patient. Where available, resistance testing may be
appropriate.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Emtriva 200 mg hard capsules may be taken with or without food.
Adults:
The recommended dose of Emtriva is one 200 mg hard capsule, taken orally, once daily.
Children and adolescents up to 18 years of age:
The recommended dose of Emtriva for children and
adolescents weighing at least 33 kg who are able to swallow hard capsules is one 200 mg hard capsule,
taken orally, once daily.
There are no data regarding the efficacy and only very limited data regarding the safety of
emtricitabine in infants below 4 months of age. Therefore Emtriva is not recommended for use in
those aged less than 4 months. (For pharmacokinetic data in this age group, see section 5.2).
Emtriva is also available as a 10 mg/ml oral solution for use in infants older than 4 months of age,
children and patients who are unable to swallow hard capsules and patients with renal insufficiency.
Please refer to the Summary of Product Characteristics for Emtriva 10 mg/ml oral solution. Due to a
difference in the bioavailability of emtricitabine between the hard capsule and oral solution
presentations, 240 mg emtricitabine administered as the oral solution should provide similar plasma
2
levels to those observed after administration of one 200 mg emtricitabine hard capsule (see
section 5.2).
Elderly:
There are no safety and efficacy data available in patients over the age of 65 years. However,
no adjustment in the recommended daily dose for adults should be required unless there is evidence of
renal insufficiency.
Renal insufficiency:
Emtricitabine is eliminated by renal excretion and exposure to emtricitabine was
significantly increased in patients with renal insufficiency (see section 5.2). Dose or dose interval
adjustment is required in all patients with creatinine clearance < 50 ml/min (see section 4.4).
Table 1 below provides dose interval adjustment guidelines for the 200 mg hard capsules according to
the degree of renal insufficiency. The safety and efficacy of these dose interval adjustment guidelines
have not been clinically evaluated. Therefore, clinical response to treatment and renal function should
be closely monitored in these patients (see section 4.4).
Patients with renal insufficiency can also be managed by administration of Emtriva 10 mg/ml oral
solution to provide a reduced daily dose of emtricitabine. Please refer to the Summary of Product
Characteristics for Emtriva 10 mg/ml oral solution.
Table 1: Dose interval guidelines for 200 mg hard capsules adjusted according to creatinine
clearance
Creatinine Clearance (CL
cr
) (ml/min)
≥ 50
30-49
15-29
<
15
(functionally
anephric,
requiring
intermittent
haemodialysis)
*
Recommended
dose interval for
200 mg hard
capsules
One 200 mg hard
capsule every
24 hours
One 200 mg hard
capsule every
48 hours
One 200 mg hard
capsule every
72 hours
One 200 mg hard
capsule every
96 hours
* Assumes a 3 h haemodialysis session three times a week commencing at least 12 h after
administration of the last dose of emtricitabine.
Patients with end-stage renal disease (ESRD) managed with other forms of dialysis such as
ambulatory peritoneal dialysis have not been studied and no dose recommendations can be made.
No data are available on which to make a dosage recommendation in paediatric patients with renal
insufficiency.
Hepatic insufficiency:
No data are available on which to make a dose recommendation for patients
with hepatic insufficiency. However, based on the minimal metabolism of emtricitabine and the renal
route of elimination it is unlikely that a dose adjustment would be required in patients with hepatic
insufficiency (see section 5.2).
If Emtriva is discontinued in patients co-infected with HIV and HBV, these patients should be closely
monitored for evidence of exacerbation of hepatitis (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
3
Emtriva should not be taken with any other medicinal products containing emtricitabine or medicinal
products containing lamivudine.
General:
Emtricitabine is not recommended as monotherapy for the treatment of HIV infection. It
must be used in combination with other antiretrovirals. Please also refer to the Summaries of Product
Characteristics of the other antiretroviral medicinal products used in the combination regimen.
Patients receiving emtricitabine or any other antiretroviral therapy may continue to develop
opportunistic infections and other complications of HIV infection, and therefore should remain under
close clinical observation by physicians experienced in the treatment of patients with HIV associated
diseases.
Patients should be advised that antiretroviral therapies, including emtricitabine, have 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 used. Patients should also be informed that
emtricitabine is not a cure for HIV infection.
Renal function:
Emtricitabine is principally eliminated by the kidney via glomerular filtration and
active tubular secretion. Emtricitabine exposure may be markedly increased in patients with moderate
or severe renal insufficiency (creatinine clearance < 50 ml/min) receiving daily doses of 200 mg
emtricitabine as hard capsules or 240 mg as the oral solution. Consequently, either a dose interval
adjustment (using Emtriva 200 mg hard capsules) or a reduction in the daily dose of emtricitabine
(using Emtriva 10 mg/ml oral solution) is required in all patients with creatinine clearance
< 50 ml/min. The safety and efficacy of the dose interval adjustment guidelines provided in
section 4.2 are based on single dose pharmacokinetic data and modelling and have not been clinically
evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in
patients treated with emtricitabine at prolonged dosing intervals (see sections 4.2 and 5.2).
Caution should be exercised when emtricitabine is co-administered with medicinal products that are
eliminated by active tubular secretion as such co-administration may lead to an increase in serum
concentrations of either emtricitabine or a co-administered medicinal product, due to competition for
this elimination pathway (see section 4.5).
Lactic acidosis:
Lactic acidosis, usually associated with hepatic steatosis, has been reported with the
use of nucleoside analogues. Early symptoms (symptomatic hyperlactataemia) include benign
digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite,
weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including
motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver
failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral
lipomatosis and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors has
4
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.
Liver function:
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. Patients with chronic hepatitis B or C infection
treated with combination antiretroviral therapy are at increased risk of experiencing severe, and
potentially fatal, hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C,
please also refer to the relevant Summary of Product Characteristics for these medicinal products.
If there is evidence of exacerbations of liver disease in such patients, interruption or discontinuation of
treatment must be considered.
Patients co-infected with hepatitis B virus (HBV):
Emtricitabine is active
in vitro
against HBV.
However, limited data are available on the efficacy and safety of emtricitabine (as a 200 mg hard
capsule once daily) in patients who are co-infected with HIV and HBV. The use of emtricitabine in
patients with chronic HBV induces the same mutation pattern in the YMDD motif observed with
lamivudine therapy. The YMDD mutation confers resistance to both emtricitabine and lamivudine.
Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory
follow-up for at least several months after stopping treatment with emtricitabine for evidence of
exacerbations of hepatitis. Such exacerbations have been seen following discontinuation of
emtricitabine treatment in HBV infected patients without concomitant HIV infection and have been
detected primarily by serum alanine aminotransferase (ALT) elevations in addition to re-emergence of
HBV DNA. In some of these patients, HBV reactivation was associated with more severe liver
disease, including decompensation and liver failure. There is insufficient evidence to determine
whether re-initiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis. In
patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since
post-treatment exacerbations of hepatitis may lead to hepatic decompensation.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV negative infants exposed
in utero
and/or postnatally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders
(hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological
disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological
disorders are transient or permanent is currently unknown. Any child exposed
in utero
to nucleoside
and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up
and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or
symptoms. These findings do not affect current national recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome:
In HIV infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterium infections, and
Pneumocystis jirovecii
pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
5
experience joint aches and pain, joint stiffness or difficulty in movement.
In vitro
, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450
isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme
responsible for glucuronidation. Based on the results of these
in vitro
experiments and the known
elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving
emtricitabine with other medicinal products is low.
There are no clinically significant interactions when emtricitabine is co-administered with indinavir,
zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.
Emtricitabine is primarily excreted via glomerular filtration and active tubular secretion. With the
exception of famciclovir and tenofovir disoproxil fumarate, the effect of co-administration of
emtricitabine with medicinal products that are excreted by the renal route, or other medicinal products
known to affect renal function, has not been evaluated. Co-administration of emtricitabine with
medicinal products that are eliminated by active tubular secretion may lead to an increase in serum
concentrations of either emtricitabine or a co-administered medicinal product due to competition for
this elimination pathway.
There is no clinical experience as yet on the co-administration of cytidine analogues. Consequently,
the use of emtricitabine in combination with lamivudine or zalcitabine for the treatment of HIV
infection cannot be recommended at this time.
The safety of emtricitabine in human pregnancy has not been established.
Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to
pregnancy, foetal development, parturition or postnatal development (see section 5.3).
Emtricitabine should be used during pregnancy only if necessary.
Given that the potential risks to developing human foetuses are unknown, the use of emtricitabine in
women of childbearing potential must be accompanied by the use of effective contraception.
It is not known if emtricitabine is excreted in human milk.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV.
No studies on the effects on the ability to drive and use machines have been performed. However,
patients should be informed that dizziness has been reported during treatment with emtricitabine.
a. Summary of the safety profile
In clinical trials of HIV infected adults, the most frequently occurring adverse reactions to
emtricitabine were diarrhoea (14.0%), headache (10.2%), elevated creatine kinase (10.2%) and nausea
(10.0%). In addition to the adverse reactions reported in adults, anaemia (9.5%) and skin
discolouration (31.8%) occurred more frequently in clinical trials involving HIV infected paediatric
patients.
Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with
6
emtricitabine (see sections 4.4 and 4.8c).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see
section 4.4).
Discontinuation of Emtriva therapy in patients co-infected with HIV and HBV may be associated with
severe acute exacerbations of hepatitis (see section 4.4).
b. Tabulated summary of adverse reactions
Assessment of adverse reactions from clinical study data is based on experience in three studies in
adults (n=1,479) and three paediatric studies (n=169). In the adult studies, 1,039 treatment-naïve and
440 treatment-experienced patients received emtricitabine (n=814) or comparator medicinal product
(n=665) for 48 weeks in combination with other antiretroviral medicinal products.
The adverse reactions with suspected (at least possible) relationship to treatment in adults from clinical
trial and post-marketing experience are listed in Table 2 below by body system organ class and
frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) or
uncommon (≥ 1/1,000 to < 1/100).
Table 2: Tabulated summary of adverse reactions associated with emtricitabine based on clinical
study and post-marketing experience
Frequency Emtricitabine
Blood and lymphatic system disorders:
Common: neutropenia
Uncommon: anaemia
2
Immune system disorders:
Common: allergic reaction
Metabolism and nutrition disorders:
Common: hypertriglyceridaemia, hyperglycaemia
Psychiatric disorders:
Common: insomnia, abnormal dreams
Nervous system disorders:
Very common: headache
Common: dizziness
Gastrointestinal disorders:
Very common: diarrhoea, nausea
Common: elevated amylase including elevated pancreatic amylase, elevated serum lipase,
vomiting, abdominal pain, dyspepsia
Hepatobiliary disorders:
Common: elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine
aminotransferase (ALT), hyperbilirubinaemia
Skin and subcutaneous tissue disorders:
Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria,
skin discolouration (increased pigmentation)
1,2
Uncommon: angioedema
3
Musculoskeletal and connective tissue disorders:
Very common:
7
elevated creatine kinase
General disorders and administration site conditions:
Common:
asthenia, pain
1
See section
c.
Description of selected adverse reactions
for more details.
2
Anaemia was common and skin discolouration (increased pigmentation) was very common when
emtricitabine was administered to paediatric patients (see section d.).
3
This adverse reaction, which was identified through post-marketing surveillance, was not observed in
randomised, controlled clinical trials in adults or paediatric HIV clinical trials of emtricitabine. The
frequency category of uncommon was estimated from a statistical calculation based on the total
number of patients exposed to emtricitabine in these clinical studies (n=1,563).
c. Description of selected adverse reactions
Skin discolouration (increased pigmentation):
Skin discolouration, manifested by hyperpigmentation
mainly on the palms and/or soles, was generally mild, asymptomatic and of little clinical significance.
The mechanism is unknown.
Lipids, lipodystrophy and metabolic abnormalities:
Combination antiretroviral therapy has been
associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin
resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see
section 4.4).
Immune Reactivation Syndrome:
In HIV infected patients with severe immune deficiency at the time
of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic
or residual opportunistic infections may arise (see section 4.4).
Osteonecrosis:
Cases of osteonecrosis have been reported, particularly in patients with generally
acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral
therapy (CART). The frequency of this is unknown (see section 4.4).
Lactic acidosis and severe hepatomegaly with steatosis:
Lactic acidosis, usually associated with
hepatic steatosis, has been reported with the use of nucleoside analogues (see section 4.4).
d. Paediatric population
Assessment of adverse reactions in paediatric patients from clinical study data is based on experience
in three paediatric studies (n=169) where treatment-naïve (n=123) and treatment-experienced (n=46)
paediatric HIV infected patients aged 4 months to 18 years were treated with emtricitabine in
combination with other antiretroviral agents.
In addition to the adverse reactions reported in adults (see section b.), the following adverse reactions
were observed more frequently in paediatric patients: anaemia was common (9.5%) and skin
discolouration (increased pigmentation) was very common (31.8%) in paediatric patients.
e. Other special population(s)
Elderly:
Emtriva has not been studied in patients over the age of 65. Elderly patients are more likely
to have decreased renal function, therefore caution should be exercised when treating elderly patients
with Emtriva (see section 4.2).
Patients with renal impairment:
Emtricitabine is eliminated by renal excretion and exposure to
emtricitabine was significantly increased in patients with renal insufficiency. Dose or dose interval
adjustment is required in all patients with creatinine clearance < 50 ml/min (see sections 4.2, 4.4 and
5.2).
HIV/HBV co-infected patients:
The adverse reaction profile in patients co-infected with HBV is
similar to that observed in patients infected with HIV without co-infection with HBV. However, as
8
would be expected in this patient population, elevations in AST and ALT occurred more frequently
than in the general HIV infected population.
Exacerbations of hepatitis after discontinuation of treatment:
In HIV infected patients co-infected
with HBV, exacerbations of hepatitis may occur after discontinuation of treatment (see section 4.4).
Administration of up to 1,200 mg emtricitabine has been associated with the adverse reactions listed
above (see section 4.8).
If overdose occurs, the patient should be monitored for signs of toxicity and standard supportive
treatment applied as necessary.
Up to 30% of the emtricitabine dose can be removed by haemodialysis. It is not known whether
emtricitabine can be removed by peritoneal dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code:
J05AF09.
Mechanism of action:
Emtricitabine is a synthetic nucleoside analogue of cytidine with activity that is
specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus (HBV).
Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which
competitively inhibits HIV-1 reverse transcriptase, resulting in DNA chain termination. Emtricitabine
is a weak inhibitor of mammalian DNA polymerase α, β and ε and mitochondrial DNA polymerase γ.
Emtricitabine did not exhibit cytotoxicity to peripheral blood mononuclear cells (PBMCs), established
lymphocyte and monocyte-macrophage cell lines or bone marrow progenitor cells
in vitro
. There was
no evidence of toxicity to mitochondria
in vitro
or
in vivo
.
Antiviral activity in vitro:
The 50% inhibitory concentration (IC
50
) value for emtricitabine against
laboratory and clinical isolates of HIV-1 was in the range of 0.0013 to 0.5 µmol/l. In combination
studies of emtricitabine with protease inhibitors, nucleoside, nucleotide and non-nucleoside analogue
inhibitors of HIV reverse transcriptase, additive to synergistic effects were observed. Most of these
combinations have not been studied in humans.
When tested for activity against laboratory strains of HBV, the 50% inhibitory concentration (IC
50
)
value for emtricitabine was in the range of 0.01 to 0.04 µmol/l.
Resistance:
HIV-1 resistance to emtricitabine develops as the result of changes at codon 184 causing
the methionine to be changed to a valine (an isoleucine intermediate has also been observed) of the
HIV reverse transcriptase. This HIV-1 mutation was observed
in vitro
and in HIV-1 infected patients.
Emtricitabine-resistant viruses were cross-resistant to lamivudine, but retained sensitivity to other
nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, stavudine, tenofovir, abacavir,
didanosine and zalcitabine), all non-nucleoside reverse transcriptase inhibitors (NNRTIs) and all
protease inhibitors (PIs). Viruses resistant to zidovudine, zalcitabine, didanosine and NNRTIs
retained their sensitivity to emtricitabine (IC
50
=0.002 µmol/l to 0.08 µmol/l).
Clinical experience:
Emtricitabine in combination with other antiretroviral agents, including
nucleoside analogues, non-nucleoside analogues and protease inhibitors, has been shown to be
9
effective in the treatment of HIV infection in treatment-naïve patients and treatment-experienced
patients with stable virological control. There is no experience of the use of emtricitabine in patients
who are failing their current regimen or who have failed multiple regimens. There is no clinical
experience of the use of emtricitabine in infants less than 4 months of age.
In antiretroviral treatment-naïve adults, emtricitabine was significantly superior to stavudine when
both medicinal products were taken in combination with didanosine and efavirenz through 48 weeks
of treatment. Phenotypic analysis showed no significant changes in emtricitabine susceptibility unless
the M184V/I mutation had developed.
In virologically stable treatment-experienced adults, emtricitabine, in combination with an NRTI
(either stavudine or zidovudine) and a protease inhibitor (PI) or an NNRTI was shown to be
non-inferior to lamivudine with respect to the proportion of responders (< 400 copies/ml) through
48 weeks (77% emtricitabine, 82% lamivudine). Additionally, in a second study,
treatment-experienced adults on a stable PI based highly active antiretroviral therapy (HAART)
regimen were randomised to a once daily regimen containing emtricitabine or to continue with their
PI-HAART regimen. At 48 weeks of treatment the emtricitabine-containing regimen demonstrated an
equivalent proportion of patients with HIV RNA < 400 copies/ml (94% emtricitabine
versus
92%) and
a greater proportion of patients with HIV RNA < 50 copies/ml (95% emtricitabine
versus
87%)
compared with the patients continuing with their PI-HAART regimen.
In infants and children older than 4 months, the majority of patients achieved or maintained complete
suppression of plasma HIV-1 RNA through 48 weeks (89% achieved ≤ 400 copies/ml and 77%
achieved ≤ 50 copies/ml).
5.2 Pharmacokinetic properties
Absorption:
Emtricitabine is rapidly and extensively absorbed following oral administration with peak
plasma concentrations occurring at 1 to 2 hours post-dose. In 20 HIV infected subjects receiving
200 mg emtricitabine daily as hard capsules, steady-state plasma emtricitabine peak concentrations
(C
max
), trough concentrations (C
min
) and area under the plasma concentration time curve over a 24-hour
dosing interval (AUC) were 1.8±0.7 µg/ml, 0.09±0.07 µg/ml and 10.0±3.1 µg·h/ml, respectively.
Steady-state trough plasma concentrations reached levels approximately 4-fold above the
in vitro
IC
90
values for anti-HIV activity.
The absolute bioavailability of emtricitabine from Emtriva 200 mg hard capsules was estimated to be
93% and the absolute bioavailability from Emtriva 10 mg/ml oral solution was estimated to be 75%.
In a pilot study in children and a definitive bioequivalence study in adults, the Emtriva 10 mg/ml oral
solution was shown to have approximately 80% of the bioavailability of the Emtriva 200 mg hard
capsules. The reason for this difference is unknown. Due to this difference in bioavailability, 240 mg
emtricitabine administered as the oral solution should provide similar plasma levels to those observed
after administration of one 200 mg emtricitabine hard capsule. Therefore, children who weigh at least
33 kg may take either one 200 mg hard capsule daily or the oral solution up to a maximum dose of
240 mg (24 ml), once daily.
Administration of Emtriva 200 mg hard capsules with a high-fat meal or administration of Emtriva
10 mg/ml oral solution with a low-fat or high-fat meal did not affect systemic exposure (AUC
0-∞
) of
emtricitabine; therefore Emtriva 200 mg hard capsules and Emtriva 10 mg/ml oral solution may be
administered with or without food.
Distribution: In vitro
binding of emtricitabine to human plasma proteins was < 4% and independent of
concentration over the range of 0.02-200 µg/ml. The mean plasma to blood concentration ratio was
approximately 1.0 and the mean semen to plasma concentration ratio was approximately 4.0.
The apparent volume of distribution after intravenous administration of emtricitabine was
1.4±0.3 l/kg, indicating that emtricitabine is widely distributed throughout the body to both
10
intracellular and extracellular fluid spaces.
Biotransformation:
There is limited metabolism of emtricitabine. The biotransformation of
emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers
(approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide
(approximately 4% of dose).
Emtricitabine did not inhibit
in vitro
drug metabolism mediated by the following human CYP450
isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4.
Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible
for glucuronidation.
Elimination:
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose
achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the
emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of
emtricitabine averaged 307 ml/min (4.03 ml/min/kg). Following oral administration, the elimination
half-life of emtricitabine is approximately 10 hours.
Linearity/non-linearity:
The pharmacokinetics of emtricitabine are proportional to dose over the dose
range of 25-200 mg following single or repeated administration.
Intracellular pharmacokinetics:
In a clinical study, the intracellular half-life of
emtricitabine-triphosphate in peripheral blood mononuclear cells was 39 hours. Intracellular
triphosphate levels increased with dose, but reached a plateau at doses of 200 mg or greater.
Adults with renal insufficiency:
Pharmacokinetic parameters were determined following administration
of a single dose of 200 mg emtricitabine hard capsules to 30 non-HIV infected subjects with varying
degrees of renal insufficiency. Subjects were grouped according to baseline creatinine clearance
(> 80 ml/min as normal function; 50-80 ml/min as mild impairment; 30-49 ml/min as moderate
impairment; < 30 ml/min as severe impairment; < 15 ml/min as functionally anephric requiring
haemodialysis).
The systemic emtricitabine exposure (mean ± standard deviation) increased from 11.8±2.9 µg·h/ml in
subjects with normal renal function to 19.9±1.1, 25.0±5.7 and 34.0±2.1 µg·h/ml, in patients with mild,
moderate and severe renal impairment, respectively.
In patients with ESRD on haemodialysis, approximately 30% of the emtricitabine dose was recovered
in dialysate over a 3 hour dialysis period which had been started within 1.5 hours of emtricitabine
dosing (blood flow rate of 400 ml/min and dialysate flow rate of approximately 600 ml/min).
Hepatic insufficiency:
The pharmacokinetics of emtricitabine have not been studied in non-HBV
infected subjects with varying degrees of hepatic insufficiency. In general, emtricitabine
pharmacokinetics in HBV infected subjects were similar to those in healthy subjects and in
HIV infected subjects.
Age, gender and ethnicity:
In general, the pharmacokinetics of emtricitabine in infants, children and
adolescents (aged 4 months up to 18 years) are similar to those seen in adults.
The mean AUC in 77 infants, children and adolescents receiving 6 mg/kg emtricitabine once daily as
oral solution or 200 mg emtricitabine as hard capsules once daily was similar to the mean AUC of
10.0 µg·h/ml in 20 adults receiving 200 mg hard capsules once daily.
In an open-label, non-comparative study, pharmacokinetic data were obtained from 20 neonates of
HIV infected mothers who received two 4-day courses of emtricitabine oral solution between the first
week of life and 3 months of age at a dose level of 3 mg/kg once daily. This dose is half of that
approved for infants aged 4 months and over (6 mg/kg). The apparent total body clearance at steady
11
state (CL/F) increased with age over the 3-month period with a corresponding decrease in AUC.
Plasma emtricitabine exposure (AUC) in infants up to 3 months of age who received 3 mg/kg
emtricitabine once daily was similar to that observed using 6 mg/kg daily doses in HIV infected adults
and children aged 4 months and over.
Pharmacokinetic data are not available in the elderly.
Although the mean C
max
and C
min
were approximately 20% higher and mean AUC was 16% higher in
females compared to males, this difference was not considered clinically significant. No clinically
important pharmacokinetic difference due to race has been identified.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and reproductive/developmental toxicity.
Emtricitabine did not show any carcinogenic potential in long-term oral carcinogenicity studies in
mice and rats.
6.
6.1 List of excipients
Capsule contents:
Cellulose, microcrystalline (E460)
Crospovidone
Magnesium stearate (E572)
Povidone (E1201)
Capsule shell:
Gelatin
Indigotine (E132)
Titanium dioxide (E171)
Printing ink containing:
Black iron oxide (E172)
Shellac (E904)
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 contents of container
White high-density polyethylene (HDPE) bottle fitted with a child-resistant closure, containing
30 hard capsules.
Blisters made of polychlorotrifluorethylene (PCTFE) / polyethylene (PE) / polyvinylchloride (PVC) /
aluminium. Each blister pack contains 30 hard capsules.
12
Pack size: 30 hard capsules.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
8.
EU/1/03/261/001
EU/1/03/261/002
9.
Date of first authorisation: 24 October 2003
Date of last renewal: 22 September 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
13
1.
Emtriva 10 mg/ml oral solution
2.
Each ml of Emtriva oral solution contains 10 mg emtricitabine.
Excipient(s):
Each dose (24 ml) contains 36 mg methyl parahydroxybenzoate (E218), 3.6 mg propyl
parahydroxybenzoate (E216), 1.2 mg Sunset Yellow (E110) and has a sodium content of 254 mg. For
a full list of excipients, see section 6.1.
3.
Oral solution.
The clear solution is orange to dark orange in colour.
4.
Emtriva is indicated for the treatment of HIV-1 infected adults and children in combination with other
antiretroviral agents.
This indication is based on studies in treatment-naïve patients and treatment-experienced patients with
stable virological control. There is no experience of the use of Emtriva in patients who are failing
their current regimen or who have failed multiple regimens (see section 5.1).
When deciding on a new regimen for patients who have failed an antiretroviral regimen, careful
consideration should be given to the patterns of mutations associated with different medicinal products
and the treatment history of the individual patient. Where available, resistance testing may be
appropriate.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Emtriva 10 mg/ml oral solution may be taken with or without food. A measuring cup is provided (see
section 6.5).
Adults:
The recommended dose of Emtriva 10 mg/ml oral solution is 240 mg (24 ml) once daily.
Infants, children and adolescents up to 18 years of age:
The recommended dose of Emtriva 10 mg/ml
oral solution is 6 mg/kg up to a maximum of 240 mg (24 ml) once daily.
Children who weigh at least 33 kg may either take one 200 mg hard capsule daily or may take
emtricitabine as the oral solution up to a maximum of 240 mg once daily.
There are no data regarding the efficacy and only very limited data regarding the safety of
emtricitabine in infants below 4 months of age. Therefore Emtriva is not recommended for use in
those aged less than 4 months. (For pharmacokinetic data in this age group, see section 5.2).
14
Emtriva 200 mg hard capsules are available for adults, adolescents and children who weigh at least
33 kg and can swallow hard capsules. Please refer to the Summary of Product Characteristics for
Emtriva 200 mg hard capsules. Due to a difference in the bioavailability of emtricitabine between the
hard capsule and oral solution presentations, 240 mg emtricitabine administered as the oral solution
(24 ml) should provide similar plasma levels to those observed after administration of one 200 mg
emtricitabine hard capsule (see section 5.2).
Elderly:
There are no safety and efficacy data available in patients over the age of 65 years. However,
no adjustment in the recommended daily dose for adults should be required unless there is evidence of
renal insufficiency.
Renal insufficiency:
Emtricitabine is eliminated by renal excretion and exposure to emtricitabine was
significantly increased in patients with renal insufficiency (see section 5.2). Dose or dose interval
adjustment is required in all patients with creatinine clearance < 50 ml/min (see section 4.4).
Table 1 below provides daily doses of Emtriva 10 mg/ml oral solution according to the degree of renal
insufficiency. The safety and efficacy of these doses have not been clinically evaluated. Therefore,
clinical response to treatment and renal function should be closely monitored in these patients (see
section 4.4).
Patients with renal insufficiency can also be managed by administration of Emtriva 200 mg hard
capsules at modified dose intervals. Please refer to the Summary of Product Characteristics for
Emtriva 200 mg hard capsules.
Table 1: Daily doses of Emtriva 10 mg/ml oral solution adjusted according to creatinine
clearance
Creatinine Clearance (CL
cr
) (ml/min)
≥
50
30-49
15-29
<
15
(functionally
anephric,
requiring
intermittent
haemodialysis)*
Recommended
dose of Emtriva
10 mg/ml oral
solution every
24 hours
240 mg
(24 ml)
120 mg
(12 ml)
80 mg
(8 ml)
60 mg
(6 ml)
* Assumes a 3 h haemodialysis session three times a week commencing at least 12 h after
administration of the last dose of emtricitabine.
Patients with end-stage renal disease (ESRD) managed with other forms of dialysis such as
ambulatory peritoneal dialysis have not been studied and no dose recommendations can be made.
No data are available on which to make a dosage recommendation in paediatric patients with renal
insufficiency.
Hepatic insufficiency:
No data are available on which to make a dose recommendation for patients
with hepatic insufficiency. However, based on the minimal metabolism of emtricitabine and the renal
route of elimination it is unlikely that a dose adjustment would be required in patients with hepatic
insufficiency (see section 5.2).
If Emtriva is discontinued in patients co-infected with HIV and HBV, these patients should be closely
15
monitored for evidence of exacerbation of hepatitis (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Emtriva should not be taken with any other medicinal products containing emtricitabine or medicinal
products containing lamivudine.
General:
Emtricitabine is not recommended as monotherapy for the treatment of HIV infection. It
must be used in combination with other antiretrovirals. Please also refer to the Summaries of Product
Characteristics of the other antiretroviral medicinal products used in the combination regimen.
Patients receiving emtricitabine or any other antiretroviral therapy may continue to develop
opportunistic infections and other complications of HIV infection, and therefore should remain under
close clinical observation by physicians experienced in the treatment of patients with HIV associated
diseases.
Patients should be advised that antiretroviral therapies, including emtricitabine, have 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 used. Patients should also be informed that
emtricitabine is not a cure for HIV infection.
Renal function:
Emtricitabine is principally eliminated by the kidney via glomerular filtration and
active tubular secretion. Emtricitabine exposure may be markedly increased in patients with moderate
or severe renal insufficiency (creatinine clearance < 50 ml/min) receiving daily doses of 200 mg
emtricitabine as hard capsules or 240 mg as the oral solution. Consequently, either a dose interval
adjustment (using Emtriva 200 mg hard capsules) or a reduction in the daily dose of emtricitabine
(using Emtriva 10 mg/ml oral solution) is required in all patients with creatinine clearance
< 50 ml/min. The safety and efficacy of the reduced doses provided in section 4.2 are based on single
dose pharmacokinetic data and modelling and have not been clinically evaluated. Therefore, clinical
response to treatment and renal function should be closely monitored in patients treated with a reduced
dose of emtricitabine (see sections 4.2 and 5.2).
Caution should be exercised when emtricitabine is co-administered with medicinal products that are
eliminated by active tubular secretion as such co-administration may lead to an increase in serum
concentrations of either emtricitabine or a co-administered medicinal product, due to competition for
this elimination pathway (see section 4.5).
Lactic acidosis:
Lactic acidosis, usually associated with hepatic steatosis, has been reported with the
use of nucleoside analogues. Early symptoms (symptomatic hyperlactataemia) include benign
digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite,
weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including
motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver
failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
16
Patients at increased risk should be followed closely.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral
lipomatosis and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors 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.
Liver function:
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. Patients with chronic hepatitis B or C infection
treated with combination antiretroviral therapy are at increased risk of experiencing severe, and
potentially fatal, hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C,
please also refer to the relevant Summary of Product Characteristics for these medicinal products.
If there is evidence of exacerbations of liver disease in such patients, interruption or discontinuation of
treatment must be considered.
Patients co-infected with hepatitis B virus (HBV):
Emtricitabine is active
in vitro
against HBV.
However, limited data are available on the efficacy and safety of emtricitabine (as a 200 mg hard
capsule once daily) in patients who are co-infected with HIV and HBV. The use of emtricitabine in
patients with chronic HBV induces the same mutation pattern in the YMDD motif observed with
lamivudine therapy. The YMDD mutation confers resistance to both emtricitabine and lamivudine.
Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory
follow-up for at least several months after stopping treatment with emtricitabine for evidence of
exacerbations of hepatitis. Such exacerbations have been seen following discontinuation of
emtricitabine treatment in HBV infected patients without concomitant HIV infection and have been
detected primarily by serum alanine aminotransferase (ALT) elevations in addition to re-emergence of
HBV DNA. In some of these patients, HBV reactivation was associated with more severe liver
disease, including decompensation and liver failure. There is insufficient evidence to determine
whether re-initiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis. In
patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since
post-treatment exacerbations of hepatitis may lead to hepatic decompensation.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV negative infants exposed
in utero
and/or postnatally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders
(hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological
disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological
disorders are transient or permanent is currently unknown. Any child exposed
in utero
to nucleoside
and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up
and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or
symptoms. These findings do not affect current national recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome:
In HIV infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterium infections, and
Pneumocystis jirovecii
pneumonia. Any inflammatory symptoms
17
should be evaluated and treatment instituted when necessary.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Emtriva oral solution contains Sunset Yellow (E110) which may cause allergic reactions, methyl
parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic
reactions (possibly delayed). This medicinal product contains 254 mg of sodium per dose which
should be taken into consideration by patients on a controlled sodium diet.
In vitro
, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450
isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme
responsible for glucuronidation. Based on the results of these
in vitro
experiments and the known
elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving
emtricitabine with other medicinal products is low.
There are no clinically significant interactions when emtricitabine is co-administered with indinavir,
zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.
Emtricitabine is primarily excreted via glomerular filtration and active tubular secretion. With the
exception of famciclovir and tenofovir disoproxil fumarate, the effect of co-administration of
emtricitabine with medicinal products that are excreted by the renal route, or other medicinal products
known to affect renal function, has not been evaluated. Co-administration of emtricitabine with
medicinal products that are eliminated by active tubular secretion may lead to an increase in serum
concentrations of either emtricitabine or a co-administered medicinal product due to competition for
this elimination pathway.
There is no clinical experience as yet on the co-administration of cytidine analogues. Consequently,
the use of emtricitabine in combination with lamivudine or zalcitabine for the treatment of HIV
infection cannot be recommended at this time.
The safety of emtricitabine in human pregnancy has not been established.
Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to
pregnancy, foetal development, parturition or postnatal development (see section 5.3).
Emtricitabine should be used during pregnancy only if necessary.
Given that the potential risks to developing human foetuses are unknown, the use of emtricitabine in
women of childbearing potential must be accompanied by the use of effective contraception.
It is not known if emtricitabine is excreted in human milk.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV.
No studies on the effects on the ability to drive and use machines have been performed. However,
patients should be informed that dizziness has been reported during treatment with emtricitabine.
18
a. Summary of the safety profile
In clinical trials of HIV infected adults, the most frequently occurring adverse reactions to
emtricitabine were diarrhoea (14.0%), headache (10.2%), elevated creatine kinase (10.2%) and nausea
(10.0%). In addition to the adverse reactions reported in adults, anaemia (9.5%) and skin
discolouration (31.8%) occurred more frequently in clinical trials involving HIV infected paediatric
patients.
Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with
emtricitabine (see sections 4.4 and 4.8c).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see
section 4.4).
Discontinuation of Emtriva therapy in patients co-infected with HIV and HBV may be associated with
severe acute exacerbations of hepatitis (see section 4.4).
b. Tabulated summary of adverse reactions
Assessment of adverse reactions from clinical study data is based on experience in three studies in
adults (n=1,479) and three paediatric studies (n=169). In the adult studies, 1,039 treatment-naïve and
440 treatment-experienced patients received emtricitabine (n=814) or comparator medicinal product
(n=665) for 48 weeks in combination with other antiretroviral medicinal products.
The adverse reactions with suspected (at least possible) relationship to treatment in adults from clinical
trial and post-marketing experience are listed in Table 2 below by body system organ class and
frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) or
uncommon (≥ 1/1,000 to < 1/100).
Table 2: Tabulated summary of adverse reactions associated with emtricitabine based on clinical
study and post-marketing experience
Frequency Emtricitabine
Blood and lymphatic system disorders:
Common: neutropenia
Uncommon: anaemia
2
Immune system disorders:
Common: allergic reaction
Metabolism and nutrition disorders:
Common: hypertriglyceridaemia, hyperglycaemia
Psychiatric disorders:
Common: insomnia, abnormal dreams
Nervous system disorders:
Very common: headache
Common: dizziness
Gastrointestinal disorders:
Very common: diarrhoea, nausea
Common: elevated amylase including elevated pancreatic amylase, elevated serum lipase,
vomiting, abdominal pain, dyspepsia
Hepatobiliary disorders:
Common:
19
elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine
aminotransferase (ALT), hyperbilirubinaemia
Skin and subcutaneous tissue disorders:
Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria,
skin discolouration (increased pigmentation)
1,2
Uncommon: angioedema
3
Musculoskeletal and connective tissue disorders:
Very common: elevated creatine kinase
General disorders and administration site conditions:
Common:
asthenia, pain
1
See section
c. Description of selected adverse reactions
for more details.
2
Anaemia was common and skin discolouration (increased pigmentation) was very common when
emtricitabine was administered to paediatric patients (see section d.).
3
This adverse reaction, which was identified through post-marketing surveillance, was not observed in
randomised controlled clinical trials in adults or paediatric HIV clinical trials of emtricitabine. The
frequency category of uncommon was estimated from a statistical calculation based on the total
number of patients exposed to emtricitabine in these clinical studies (n=1,563).
c. Description of selected adverse reactions
Skin discolouration (increased pigmentation):
Skin discolouration, manifested by hyperpigmentation
mainly on the palms and/or soles, was generally mild, asymptomatic and of little clinical significance.
The mechanism is unknown.
Lipids, lipodystrophy and metabolic abnormalities:
Combination antiretroviral therapy has been
associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin
resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see
section 4.4).
Immune Reactivation Syndrome:
In HIV infected patients with severe immune deficiency at the time
of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic
or residual opportunistic infections may arise (see section 4.4).
Osteonecrosis:
Cases of osteonecrosis have been reported, particularly in patients with generally
acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral
therapy (CART). The frequency of this is unknown (see section 4.4).
Lactic acidosis and severe hepatomegaly with steatosis:
Lactic acidosis, usually associated with
hepatic steatosis, has been reported with the use of nucleoside analogues (see section 4.4).
d. Paediatric population
Assessment of adverse reactions in paediatric patients from clinical study data is based on experience
in three paediatric studies (n=169) where treatment-naïve (n=123) and treatment-experienced (n=46)
paediatric HIV infected patients aged 4 months to 18 years were treated with emtricitabine in
combination with other antiretroviral agents.
In addition to the adverse reactions reported in adults (see section b.), the following adverse reactions
were observed more frequently in paediatric patients: anaemia was common (9.5%) and skin
discolouration (increased pigmentation) was very common (31.8%) in paediatric patients.
e. Other special population(s)
Elderly:
Emtriva has not been studied in patients over the age of 65. Elderly patients are more likely
to have decreased renal function, therefore caution should be exercised when treating elderly patients
with Emtriva (see section 4.2).
20
Patients with renal impairment:
Emtricitabine is eliminated by renal excretion and exposure to
emtricitabine was significantly increased in patients with renal insufficiency. Dose or dose interval
adjustment is required in all patients with creatinine clearance < 50 ml/min (see sections 4.2, 4.4 and
5.2).
HIV/HBV co-infected patients:
The adverse reaction profile in patients co-infected with HBV is
similar to that observed in patients infected with HIV without co-infection with HBV. However, as
would be expected in this patient population, elevations in AST and ALT occurred more frequently
than in the general HIV infected population.
Exacerbations of hepatitis after discontinuation of treatment:
In HIV infected patients co-infected
with HBV, exacerbations of hepatitis may occur after discontinuation of treatment (see section 4.4).
Administration of up to 1,200 mg emtricitabine has been associated with the adverse reactions listed
above (see section 4.8).
If overdose occurs, the patient should be monitored for signs of toxicity and standard supportive
treatment applied as necessary.
Up to 30% of the emtricitabine dose can be removed by haemodialysis. It is not known whether
emtricitabine can be removed by peritoneal dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code:
J05AF09.
Mechanism of action:
Emtricitabine is a synthetic nucleoside analogue of cytidine with activity that is
specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus (HBV).
Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which
competitively inhibits HIV-1 reverse transcriptase, resulting in DNA chain termination. Emtricitabine
is a weak inhibitor of mammalian DNA polymerase α, β and ε and mitochondrial DNA polymerase γ.
Emtricitabine did not exhibit cytotoxicity to peripheral blood mononuclear cells (PBMCs), established
lymphocyte and monocyte-macrophage cell lines or bone marrow progenitor cells
in vitro
. There was
no evidence of toxicity to mitochondria
in vitro
or
in vivo
.
Antiviral activity in vitro:
The 50% inhibitory concentration (IC
50
) value for emtricitabine against
laboratory and clinical isolates of HIV-1 was in the range of 0.0013 to 0.5 µmol/l. In combination
studies of emtricitabine with protease inhibitors, nucleoside, nucleotide and non-nucleoside analogue
inhibitors of HIV reverse transcriptase, additive to synergistic effects were observed. Most of these
combinations have not been studied in humans.
When tested for activity against laboratory strains of HBV, the 50% inhibitory concentration (IC
50
)
value for emtricitabine was in the range of 0.01 to 0.04 µmol/l.
Resistance:
HIV-1 resistance to emtricitabine develops as the result of changes at codon 184 causing
the methionine to be changed to a valine (an isoleucine intermediate has also been observed) of the
HIV reverse transcriptase. This HIV-1 mutation was observed
in vitro
and in HIV-1 infected patients.
Emtricitabine-resistant viruses were cross-resistant to lamivudine, but retained sensitivity to other
21
nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, stavudine, tenofovir, abacavir,
didanosine and zalcitabine), all non-nucleoside reverse transcriptase inhibitors (NNRTIs) and all
protease inhibitors (PIs). Viruses resistant to zidovudine, zalcitabine, didanosine and NNRTIs
retained their sensitivity to emtricitabine (IC
50
=0.002 µmol/l to 0.08 µmol/l).
Clinical experience:
Emtricitabine in combination with other antiretroviral agents, including
nucleoside analogues, non-nucleoside analogues and protease inhibitors, has been shown to be
effective in the treatment of HIV infection in treatment-naïve patients and treatment-experienced
patients with stable virological control. There is no experience of the use of emtricitabine in patients
who are failing their current regimen or who have failed multiple regimens. There is no clinical
experience of the use of emtricitabine in infants less than 4 months of age.
In antiretroviral treatment-naïve adults, emtricitabine was significantly superior to stavudine when
both medicinal products were taken in combination with didanosine and efavirenz through 48 weeks
of treatment. Phenotypic analysis showed no significant changes in emtricitabine susceptibility unless
the M184V/I mutation had developed.
In virologically stable treatment-experienced adults, emtricitabine, in combination with an NRTI
(either stavudine or zidovudine) and a protease inhibitor (PI) or an NNRTI was shown to be
non-inferior to lamivudine with respect to the proportion of responders (< 400 copies/ml) through
48 weeks (77% emtricitabine, 82% lamivudine). Additionally, in a second study,
treatment-experienced adults on a stable PI based highly active antiretroviral therapy (HAART)
regimen were randomised to a once daily regimen containing emtricitabine or to continue with their
PI-HAART regimen. At 48 weeks of treatment the emtricitabine-containing regimen demonstrated an
equivalent proportion of patients with HIV RNA < 400 copies/ml (94% emtricitabine
versus
92%) and
a greater proportion of patients with HIV RNA < 50 copies/ml (95% emtricitabine
versus
87%)
compared with the patients continuing with their PI-HAART regimen.
In infants and children older than 4 months, the majority of patients achieved or maintained complete
suppression of plasma HIV-1 RNA through 48 weeks (89% achieved ≤ 400 copies/ml and 77%
achieved ≤ 50 copies/ml).
5.2 Pharmacokinetic properties
Absorption:
Emtricitabine is rapidly and extensively absorbed following oral administration with peak
plasma concentrations occurring at 1 to 2 hours post-dose. In 20 HIV infected subjects receiving
200 mg emtricitabine daily as hard capsules, steady-state plasma emtricitabine peak concentrations
(C
max
), trough concentrations (C
min
) and area under the plasma concentration time curve over a 24-hour
dosing interval (AUC) were 1.8±0.7 µg/ml, 0.09±0.07 µg/ml and 10.0±3.1 µg·h/ml, respectively.
Steady-state trough plasma concentrations reached levels approximately 4-fold above the
in vitro
IC
90
values for anti-HIV activity.
The absolute bioavailability of emtricitabine from Emtriva 200 mg hard capsules was estimated to be
93% and the absolute bioavailability from Emtriva 10 mg/ml oral solution was estimated to be 75%.
In a pilot study in children and a definitive bioequivalence study in adults, the Emtriva 10 mg/ml oral
solution was shown to have approximately 80% of the bioavailability of the Emtriva 200 mg hard
capsules. The reason for this difference is unknown. Due to this difference in bioavailability, 240 mg
emtricitabine administered as the oral solution should provide similar plasma levels to those observed
after administration of one 200 mg emtricitabine hard capsule. Therefore, children who weigh at least
33 kg may take either one 200 mg hard capsule daily or the oral solution up to a maximum dose of
240 mg (24 ml), once daily.
Administration of Emtriva 200 mg hard capsules with a high-fat meal or administration of Emtriva
10 mg/ml oral solution with a low-fat or high-fat meal did not affect systemic exposure (AUC
0-∞
) of
emtricitabine; therefore Emtriva 200 mg hard capsules and Emtriva 10 mg/ml oral solution may be
administered with or without food.
22
Distribution: In vitro
binding of emtricitabine to human plasma proteins was < 4% and independent of
concentration over the range of 0.02-200 µg/ml. The mean plasma to blood concentration ratio was
approximately 1.0 and the mean semen to plasma concentration ratio was approximately 4.0.
The apparent volume of distribution after intravenous administration of emtricitabine was
1.4±0.3 l/kg, indicating that emtricitabine is widely distributed throughout the body to both
intracellular and extracellular fluid spaces.
Biotransformation:
There is limited metabolism of emtricitabine. The biotransformation of
emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers
(approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide
(approximately 4% of dose).
Emtricitabine did not inhibit
in vitro
drug metabolism mediated by the following human CYP450
isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4.
Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible
for glucuronidation.
Elimination:
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose
achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the
emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of
emtricitabine averaged 307 ml/min (4.03 ml/min/kg). Following oral administration, the elimination
half-life of emtricitabine is approximately 10 hours.
Linearity/non-linearity:
The pharmacokinetics of emtricitabine are proportional to dose over the dose
range of 25-200 mg following single or repeated administration.
Intracellular pharmacokinetics:
In a clinical study, the intracellular half-life of
emtricitabine-triphosphate in peripheral blood mononuclear cells was 39 hours. Intracellular
triphosphate levels increased with dose, but reached a plateau at doses of 200 mg or greater.
Adults with renal insufficiency:
Pharmacokinetic parameters were determined following administration
of a single dose of 200 mg emtricitabine hard capsules to 30 non-HIV infected subjects with varying
degrees of renal insufficiency. Subjects were grouped according to baseline creatinine clearance
(> 80 ml/min as normal function; 50-80 ml/min as mild impairment; 30-49 ml/min as moderate
impairment; < 30 ml/min as severe impairment; < 15 ml/min as functionally anephric requiring
haemodialysis).
The systemic emtricitabine exposure (mean ± standard deviation) increased from 11.8±2.9 µg·h/ml in
subjects with normal renal function to 19.9±1.1, 25.0±5.7 and 34.0±2.1 µg·h/ml, in patients with mild,
moderate and severe renal impairment, respectively.
In patients with ESRD on haemodialysis, approximately 30% of the emtricitabine dose was recovered
in dialysate over a 3 hour dialysis period which had been started within 1.5 hours of emtricitabine
dosing (blood flow rate of 400 ml/min and dialysate flow rate of approximately 600 ml/min).
Hepatic insufficiency:
The pharmacokinetics of emtricitabine have not been studied in non-HBV
infected subjects with varying degrees of hepatic insufficiency. In general, emtricitabine
pharmacokinetics in HBV infected subjects were similar to those in healthy subjects and in
HIV infected subjects.
Age, gender and ethnicity:
In general, the pharmacokinetics of emtricitabine in infants, children and
adolescents (aged 4 months up to 18 years) are similar to those seen in adults.
The mean AUC in 77 infants, children and adolescents receiving 6 mg/kg emtricitabine once daily as
23
oral solution or 200 mg emtricitabine as hard capsules once daily was similar to the mean AUC of
10.0 µg·h/ml in 20 adults receiving 200 mg hard capsules once daily.
In an open-label, non-comparative study, pharmacokinetic data were obtained from 20 neonates of
HIV infected mothers who received two 4-day courses of emtricitabine oral solution between the first
week of life and 3 months of age at a dose level of 3 mg/kg once daily. This dose is half of that
approved for infants aged 4 months and over (6 mg/kg). The apparent total body clearance at steady
state (CL/F) increased with age over the 3-month period with a corresponding decrease in AUC.
Plasma emtricitabine exposure (AUC) in infants up to 3 months of age who received 3 mg/kg
emtricitabine once daily was similar to that observed using 6 mg/kg daily doses in HIV infected adults
and children aged 4 months and over.
Pharmacokinetic data are not available in the elderly.
Although the mean C
max
and C
min
were approximately 20% higher and mean AUC was 16% higher in
females compared to males, this difference was not considered clinically significant. No clinically
important pharmacokinetic difference due to race has been identified.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and reproductive/developmental toxicity.
Emtricitabine did not show any carcinogenic potential in long-term oral carcinogenicity studies in
mice and rats.
6.
6.1 List of excipients
Cotton candy flavouring
Disodium edetate
Hydrochloric acid
Methyl parahydroxybenzoate (E218)
Propylene glycol
Propyl parahydroxybenzoate (E216)
Sodium hydroxide
Sodium phosphate monobasic hydrate
Sunset yellow (E110)
Purified water
Xylitol (E967)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
After first opening: 45 days.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
After opening: Do not store above 25°C.
24
6.5 Nature and contents of container
Amber-coloured polyethylene terephthalate (PET) bottle with a child-resistant closure. The pack also
contains a 30 ml polypropylene measuring cup with 1.0 ml graduations. The bottle contains 170 ml of
solution.
6.6 Special precautions for disposal
Patients should be instructed that any solution left in the bottle 45 days after opening should be
discarded according to local requirements or returned to the pharmacy.
7.
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
8.
EU/1/03/261/003
9.
Date of first authorisation: 24 October 2003
Date of last renewal: 22 September 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
25
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Gilead Sciences Limited
Unit 13 Stillorgan Industrial Park
Blackrock County Dublin
Ireland
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill Co. Cork
Ireland
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The holder of this marketing authorisation must inform the European Commission about the marketing
plans for the medicinal product authorised by this decision.
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 6.0
presented in Module 1.8.1 of the Marketing Authorisation, is in place and functioning before
and whilst the product is on the market.
Risk Management Plan
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
27
PSURs:
The Marketing Authorisation Holder will submit PSUR’s on an annual basis.
28
ANNEX III
LABELLING AND PACKAGE LEAFLET
29
A. LABELLING
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE AND CARTON LABELLING
1.
Emtriva 200 mg hard capsules
Emtricitabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains 200 mg emtricitabine.
3.
LIST OF EXCIPIENTS
4.
30 hard capsules.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
31
Gilead Sciences Intl Ltd
Cambridge
CB21 6GT
United Kingdom
EU/1/03/261/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Emtriva [outer packaging only]
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BLISTER CARTON LABELLING
1.
Emtriva 200 mg hard capsules
Emtricitabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains 200 mg emtricitabine.
3.
LIST OF EXCIPIENTS
4.
30 hard capsules.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
33
Gilead Sciences Intl Ltd
Cambridge
CB21 6GT
United Kingdom
EU/1/03/261/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Emtriva [outer packaging only]
34
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Emtriva 200 mg hard capsules
Emtricitabine
2.
Gilead Sciences Intl Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE AND CARTON LABELLING
1.
Emtriva 10 mg/ml oral solution
Emtricitabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 10 mg emtricitabine.
3.
LIST OF EXCIPIENTS
Contains E110, E216, E218, and sodium. See leaflet for further information.
4.
170 ml oral solution.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After opening: the solution should be used within 45 days. It is advised to write the date of removal
from the refrigerator on the package.
Opened:
36
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
After opening: do not store above 25ºC.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Gilead Sciences Intl Ltd
Cambridge
CB21 6GT
United Kingdom
EU/1/03/261/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Emtriva [outer packaging only]
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
Emtriva 200 mg hard capsules
Emtricitabine
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Emtriva is and what it is used for
3.
How to take Emtriva
4.
Possible side effects
5.
How to store Emtriva
6.
Further information
1.
WHAT EMTRIVA IS AND WHAT IT IS USED FOR
Emtriva is a treatment for Human Immunodeficiency Virus
(HIV) infection in adults, children and
infants above 4 months of age. Emtriva 200 mg hard capsules are
only suitable for patients who
weigh at least 33 kg.
Emtriva oral solution is available for people who have difficulty in swallowing
Emtriva hard capsules.
Emtriva contains the active substance
emtricitabine.
This active substance is an
antiretroviral
medicine which is used to treat HIV infection. Emtricitabine is a
nucleoside reverse transcriptase
inhibitor
(NRTI) which works by interfering with the normal working of an enzyme (reverse
transcriptase) that is essential for the HIV virus to reproduce itself. Emtriva may lower the amount of
HIV in the blood (viral load). It may also help to increase the number of T cells called CD4 cells.
Emtriva should always be combined with other medicines to treat HIV infection.
You can still pass on HIV to others
while you’re taking this drug, so it is important to take
precautions to avoid infecting other people.
This medicine is not a cure for HIV infection.
While taking Emtriva you may still develop
infections or other illnesses associated with HIV infection.
2.
BEFORE YOU TAKE EMTRIVA
Do not take Emtriva
•
If you are allergic
(hypersensitive)
to emtricitabine or any of the other ingredients of Emtriva
200 mg hard capsules listed at the end of this leaflet.
If this applies to you, tell your doctor immediately.
Take special care with Emtriva
•
Tell your doctor if you have had kidney disease,
or if tests have shown problems with your
kidneys. Before starting treatment, your doctor may order blood tests to assess kidney function
39
2.
Before you take Emtriva
and may advise you to take the capsules less often or prescribe Emtriva oral solution. Your
doctor may also order blood tests during treatment to monitor your kidneys.
•
Talk to your doctor if you are over 65.
Emtriva has not been studied in patients over 65 years
of age. If you are older than this and are prescribed Emtriva, your doctor will monitor you
carefully.
•
Do not give Emtriva to infants
under 4 months of age.
•
Talk to your doctor if you have a history of liver disease, including hepatitis.
Patients with
liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a
higher risk of severe and potentially fatal liver complications. If you have hepatitis B infection,
your doctor will carefully consider the best treatment regimen for you. If you have a history of
liver disease or chronic hepatitis B infection your doctor may conduct blood tests in order to
carefully monitor liver function.
•
If you are diabetic, overweight or have high cholesterol, talk to your doctor.
Combination
antiretroviral therapies may raise blood sugar, increase blood fats (hyperlipaemia), cause
changes to body fat, and resistance to insulin (see section 4,
Possible side effects
).
•
Once you start taking Emtriva, look out for possible signs of lactic acidosis.
Medicines
containing nucleoside analogues, including Emtriva, can cause
lactic acidosis
(excess of lactic
acid in your blood), together with an enlarged liver. This is a rare but serious side effect; it has
occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are
very overweight. If you have liver disease you may also be more at risk of getting this
condition. While you are being treated with Emtriva, your doctor will monitor you closely for
any signs that you may be developing lactic acidosis. Signs are:
•
Deep, rapid breathing
•
Drowsiness
•
Nausea (feeling sick), vomiting and stomach pain
If you notice any of these symptoms,
tell your doctor immediately.
•
Look out for infections.
If you have advanced HIV disease (AIDS) and another infection, you
may develop inflammation or worsening of the symptoms of infection when you start treatment
with Emtriva. These may be signs that your body’s improved immune system is fighting
infection. If you notice signs of inflammation or infection soon after you start taking Emtriva,
tell your doctor at once.
•
Bone problems.
Some patients taking combination antiretroviral therapy may develop a bone
disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).
The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption,
severe immunosuppression, higher body mass index, among others, may be some of the many
risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and
pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any
of these symptoms please inform your doctor.
Taking other medicines
You should not take Emtriva
if you are already taking other medicines that contain emtricitabine,
lamivudine or zalcitabine, which are also used to treat HIV infection, unless otherwise directed by
your doctor.
Please tell your doctor or pharmacist
if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. They will advise if Emtriva can be taken with
your other medicines.
Do not stop your treatment without contacting your doctor.
40
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
•
You must not take Emtriva during pregnancy
unless specifically directed by your doctor.
There are no clinical data on the use of Emtriva in pregnant women and it is not usually used
unless absolutely necessary.
•
If you could get pregnant
during treatment with Emtriva, you must use an effective method of
contraception to stop you getting pregnant.
•
If you become pregnant, or plan to become pregnant,
ask your doctor about the potential
benefits and risks of your antiretroviral therapy to you and your child.
If you have taken Emtriva during your pregnancy, your doctor may request regular blood tests and
other diagnostic tests to monitor the development of your child. In children whose mothers took
NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk of side
effects.
•
Do not breast-feed if you are taking Emtriva.
It is not yet known whether the active
substance in this medicine passes into human breast milk. It is known that the virus can be
passed to the baby in breast milk.
Driving and using machines
Emtriva may cause dizziness. If you experience dizziness while taking Emtriva,
do not drive
and do
not use any tools or machines.
3.
HOW TO TAKE EMTRIVA
•
Always take Emtriva exactly as your doctor has told you.
You should check with your
doctor or pharmacist if you are not sure.
The usual dose:
•
Adults: one 200 mg hard capsule each day with or without food.
Swallow the hard capsule
with a glass of water.
•
Children and adolescents up to 18 years of age
who weigh at least 33 kg and who are able to
swallow hard capsules: one 200 mg hard capsule, each day with or without food.
For infants from 4 months, children, and patients who are unable to swallow hard capsules and
patients with kidney problems, Emtriva is available as a liquid (an oral solution). If you have
difficulty in swallowing the capsules, tell your doctor.
•
Always take the dose recommended by your doctor.
This is to make sure that your medicine
is fully effective, and to reduce the risk of developing resistance to the treatment. Do not
change the dose unless your doctor tells you to.
•
If you have problems with your kidneys,
your doctor may advise you to take Emtriva less
frequently.
•
Your doctor will prescribe Emtriva with other antiretroviral medicines.
Please refer to the
patient information leaflets of the other antiretrovirals for guidance on how to take those
medicines.
41
If you take more Emtriva than you should
If you accidentally take too many Emtriva hard capsules, contact your doctor or nearest emergency
department for advice. Keep the carton with you so that you can easily describe what you have taken.
If you forget to take Emtriva
It is important not to miss a dose of Emtriva.
If you do miss a dose
of Emtriva, take it as soon as you can, and then take your next dose at its
regular time.
If it is almost time for your next dose
anyway, forget about the missed dose. Wait and take the next
dose at the regular time. Do not take a double dose to make up for a forgotten hard capsule.
If you are sick
(vomit)
If it’s less than an hour since you took Emtriva,
take another capsule. You do not need to take
another capsule if you were sick more than an hour after taking Emtriva.
If you stop taking Emtriva
•
Don’t stop taking Emtriva without talking to your doctor.
Stopping treatment with Emtriva
may reduce the effectiveness of the anti-HIV therapy recommended by your doctor. Speak with
your doctor before you stop, particularly if you are experiencing any side effects or you have
another illness. Contact your doctor again before you restart taking Emtriva capsules.
•
If you have both HIV infection and hepatitis B,
it is especially important not to stop your
Emtriva treatment without talking to your doctor first. Some patients have had blood tests or
symptoms indicating that their hepatitis has got worse after stopping Emtriva. You may require
blood tests for several months after stopping treatment. In some patients with advanced liver
disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of
hepatitis.
Tell your doctor immediately about new or unusual symptoms after you stop treatment,
particularly symptoms you associate with hepatitis B infection.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Emtriva can cause side effects, although not everybody gets them.
Tell your doctor about any of the following side effects:
Very common side effects
(These can affect more than 1 user in 10)
•
headache, diarrhoea, feeling sick (nausea)
•
muscle pain and weakness (if creatine kinase levels in the blood are increased)
Common side effects
(These can affect 1 to 10 users in 100)
•
dizziness, weakness, difficulty sleeping, abnormal dreams
42
•
being sick (vomiting), problems with digestion resulting in discomfort after meals, stomach pain
•
rashes (including red spots or blotches sometimes with blistering and swelling of the skin),
which may be allergic reactions, itching, changes in skin colour including darkening of the skin
in patches
•
pain
Tests may also show:
•
low white blood cell count (a reduced white blood cell count can make you more prone to
infection)
•
increased triglycerides (fatty acids), bile or sugar in the blood
•
liver and pancreas problems
Uncommon side effects
(These can affect 1 to 10 users in 1,000)
•
anaemia (low red blood cell count)
•
swelling of the face, lips, tongue or throat
Children given emtricitabine experienced
changes in skin colour
including darkening of the skin in
patches (very common) and
anaemia
(common). Anaemia means the production of red blood cells is
reduced, and a child may have symptoms of tiredness or breathlessness.
Medicines like Emtriva can cause lactic acidosis (excess lactic acid in the blood). The following may
be signs of lactic acidosis:
•
Deep, rapid breathing
•
Drowsiness
•
Nausea (feeling sick), vomiting and stomach pain
If you notice any of these symptoms,
tell your doctor immediately.
Combination antiretroviral therapy (including Emtriva) may
change your body shape,
by changing
the way body fat is distributed. You may lose fat from your legs, arms and face; gain fat around the
abdomen (tummy) and internal organs; get larger breasts or fatty lumps on the back of the neck
(‘buffalo hump’). The cause and the long-term effects of these changes are not yet known.
Combination antiretroviral therapy may also cause
hyperlipaemia
(increased fats in the blood) and
resistance to insulin. Your doctor will test for these changes.
If you get any of the side effects listed,
or if you notice any side effects not listed in this leaflet,
tell
your doctor.
5.
HOW TO STORE EMTRIVA
Keep out of the reach and sight of children.
Do not use Emtriva after the expiry date which is stated on the bottle, blister pack and outer carton
after {EXP}. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
43
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Emtriva contains
•
The active substance is
emtricitabine.
Each hard capsule contains 200 mg emtricitabine.
•
The other ingredients are:
Capsule contents:
microcrystalline cellulose (E460), crospovidone, magnesium stearate (E572),
povidone (E1201)
Capsule shell:
gelatin, indigotine (E132), titanium dioxide (E171)
Printing ink containing:
black iron oxide (E172), shellac (E904)
What Emtriva looks like and contents of the pack
Emtriva hard capsules have a white opaque body with a light blue opaque cap. Each capsule is printed
with “200 mg” on the cap and “GILEAD” and [Gilead logo] on the body in black ink. Emtriva comes
in bottles or blister packs containing 30 capsules.
Emtriva is also available as an oral solution for use in children and infants older than 4 months,
patients who have difficulty in swallowing and patients with kidney problems. There is a separate
Package Leaflet for Emtriva 10 mg/ml oral solution.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
Manufacturer:
Gilead Sciences Limited
Unit 13, Stillorgan Industrial Park
Blackrock
County Dublin
Ireland
or
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill Co. Cork
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
44
België/Belgique/Belgien
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
Luxembourg/Luxemburg
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
България
Gilead Sciences International Ltd
Teл: + 44 (0) 20 7136 8820
Magyarország
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Česká republika
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Malta
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Danmark
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Nederland
Gilead Sciences Netherlands B.V.
Tel: + 31 (0) 20 718 3698
Deutschland
Gilead Sciences GmbH
Tel: + 49 (0) 89 899890-0
Norge
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Eesti
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Österreich
Gilead Sciences GesmbH
Tel: + 43 1 260 830
Ελλάδα
Gilead Sciences Ελλάς Μ.ΕΠΕ.
Τηλ: + 30 210 8930 100
Polska
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
España
Gilead Sciences, S.L.
Tel: + 34 91 378 98 30
Portugal
Gilead Sciences, Lda.
Tel: + 351 21 7928790
France
Gilead Sciences
Tél: + 33 (0) 1 42 73 70 70
România
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Ireland
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
Slovenija
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Ísland
Gilead Sciences Sweden AB
Sími: + 46 (0) 8 5057 1849
Slovenská republika
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Italia
Gilead Sciences S.r.l.
Tel: + 39 02 439201
Suomi/Finland
Gilead Sciences Sweden AB
Puh/Tel: + 46 (0) 8 5057 1849
Κύπρος
Gilead Sciences Ελλάς Μ.ΕΠΕ.
Τηλ: + 30 210 8930 100
Sverige
Gilead Sciences Sweden AB
Tel: + 46 (0) 8 5057 1849
Latvija
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
United Kingdom
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
45
Lietuva
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
Emtriva 10 mg/ml oral solution
Emtricitabine
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Emtriva is and what it is used for
3.
How to take Emtriva
4.
Possible side effects
5.
How to store Emtriva
6.
Further information
1.
WHAT EMTRIVA IS AND WHAT IT IS USED FOR
Emtriva is a treatment for Human Immunodeficiency Virus
(HIV) infection in adults, children and
infants above 4 months of age. Emtriva oral solution is particularly suitable for people who have
difficulty in swallowing Emtriva hard capsules.
Emtriva contains the active substance
emtricitabine.
This active substance is an
antiretroviral
medicine which is used to treat HIV infection. Emtricitabine is a
nucleoside reverse transcriptase
inhibitor
(NRTI) which works by interfering with the normal working of an enzyme (reverse
transcriptase) that is essential for the HIV virus to reproduce itself. Emtriva may lower the amount of
HIV in the blood (viral load). It may also help to increase the number of T cells called CD4 cells.
Emtriva should always be combined with other medicines to treat HIV infection.
You can still pass on HIV to others
while you’re taking this drug, so it is important to take
precautions to avoid infecting other people.
This medicine is not a cure for HIV infection.
While taking Emtriva you may still develop
infections or other illnesses associated with HIV infection.
2.
BEFORE YOU TAKE EMTRIVA
Do not take Emtriva
•
If you are allergic
(hypersensitive)
to emtricitabine or any of the other ingredients of
Emtriva 10 mg/ml oral solution listed at the end of this leaflet.
If this applies to you, tell your doctor immediately.
Take special care with Emtriva
•
Tell your doctor if you have had kidney disease,
or if tests have shown problems with your
kidneys. Before starting treatment, your doctor may order blood tests to assess kidney function
47
2.
Before you take Emtriva
and may advise you to take a reduced dose of the oral solution or prescribe Emtriva hard
capsules. Your doctor may also order blood tests during treatment to monitor your kidneys.
•
Talk to your doctor if you are over 65.
Emtriva has not been studied in patients over 65 years
of age. If you are older than this and are prescribed Emtriva, your doctor will monitor you
carefully.
•
Do not give Emtriva to infants
under 4 months of age.
•
Talk to your doctor if you have a history of liver disease, including hepatitis.
Patients with
liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a
higher risk of severe and potentially fatal liver complications. If you have hepatitis B infection,
your doctor will carefully consider the best treatment regimen for you. If you have a history of
liver disease or chronic hepatitis B infection your doctor may conduct blood tests in order to
carefully monitor liver function.
•
If you are diabetic, overweight or have high cholesterol, talk to your doctor.
Combination
antiretroviral therapies may raise blood sugar, increase blood fats (hyperlipaemia), cause
changes to body fat, and resistance to insulin (see section 4,
Possible side effects
).
•
Once you start taking Emtriva, look out for possible signs of lactic acidosis.
Medicines
containing nucleoside analogues, including Emtriva, can cause
lactic acidosis
(excess of lactic
acid in your blood), together with an enlarged liver. This is a rare but serious side effect; it has
occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are
very overweight. If you have liver disease you may also be more at risk of getting this
condition. While you are being treated with Emtriva, your doctor will monitor you closely for
any signs that you may be developing lactic acidosis. Signs are:
•
Deep, rapid breathing
•
Drowsiness
•
Nausea (feeling sick), vomiting and stomach pain
If you notice any of these symptoms,
tell your doctor immediately.
•
Look out for infections.
If you have advanced HIV disease (AIDS) and another infection, you
may develop inflammation or worsening of the symptoms of infection when you start treatment
with Emtriva. These may be signs that your body’s improved immune system is fighting
infection. If you notice signs of inflammation or infection soon after you start taking Emtriva,
tell your doctor at once.
•
Bone problems.
Some patients taking combination antiretroviral therapy may develop a bone
disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).
The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption,
severe immunosuppression, higher body mass index, among others, may be some of the many
risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and
pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any
of these symptoms please inform your doctor.
Taking other medicines
You should not take Emtriva
if you are already taking other medicines that contain emtricitabine,
lamivudine or zalcitabine, which are also used to treat HIV infection, unless otherwise directed by
your doctor.
Please tell your doctor or pharmacist
if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. They will advise if Emtriva can be taken with
your other medicines.
Do not stop your treatment without contacting your doctor.
48
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
•
You must not take Emtriva during pregnancy
unless specifically directed by your doctor.
There are no clinical data on the use of Emtriva in pregnant women and it is not usually used
unless absolutely necessary.
•
If you could get pregnant
during treatment with Emtriva, you must use an effective method of
contraception to stop you getting pregnant.
•
If you become pregnant, or plan to become pregnant,
ask your doctor about the potential
benefits and risks of your antiretroviral therapy to you and your child.
If you have taken Emtriva during your pregnancy, your doctor may request regular blood tests and
other diagnostic tests to monitor the development of your child. In children whose mothers took
NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk of side
effects.
•
Do not breast-feed if you are taking Emtriva.
It is not yet known whether the active
substance in this medicine passes into human breast milk. It is known that the virus can be
passed to the baby in breast milk.
Driving and using machines
Emtriva may cause dizziness. If you experience dizziness while taking Emtriva,
do not drive
and do
not use any tools or machines.
Important information about some of the ingredients of Emtriva oral solution
Sunset yellow (E110) may cause allergic reactions. The methyl parahydroxybenzoate (E218) and
propyl parahydroxybenzoate (E216) may cause allergic reactions (possibly delayed). This medicine
contains 254 mg of sodium per dose which should be taken into consideration by patients on a
controlled sodium diet.
3.
HOW TO TAKE EMTRIVA
•
Always take Emtriva exactly as your doctor has told you.
You should check with your
doctor or pharmacist if you are not sure.
The usual dose:
•
Adults:
Your doctor will advise the correct amount of Emtriva oral solution to be taken.
Emtriva oral solution can be taken with or without food.
•
Infants, children and adolescents weighing 40 kg or less:
the dose of Emtriva 10 mg/ml oral
solution is calculated according to your body weight. Examples of body weight and the
corresponding doses and volumes of the oral solution to be taken each day are given in the table
below:
49
Per day
Body weight (kg)
Emtricitabine dose (mg)
How much 10 mg/ml solution to take
(ml)
5 kg
30 mg
3 ml
10 kg
60 mg
6 ml
15 kg
90 mg
9 ml
20 kg
120 mg
12 ml
25 kg
150 mg
15 ml
30 kg
180 mg
18 ml
35 kg
210 mg
21 ml
40 kg
240 mg
24 ml
Make sure that you understand how to measure and give the right amount of oral solution according to
the weight of the person being treated. Use the measuring cup provided in the carton to measure the
correct dose. The cup has lines to indicate each ml of solution.
If you are unsure how much Emtriva you should take ask your doctor or pharmacist.
•
Always take the dose recommended by your doctor.
This is to make sure that your medicine
is fully effective, and to reduce the risk of developing resistance to the treatment. Do not
change the dose unless your doctor tells you to.
•
If you have problems with your kidneys,
your doctor may advise you to take Emtriva less
frequently.
•
Your doctor will prescribe Emtriva with other antiretroviral medicines.
Please refer to the
patient information leaflets of the other antiretrovirals for guidance on how to take those
medicines.
Emtriva is also available as hard capsules. These are only suitable for patients who weigh at least
33 kg and can swallow hard capsules. The blood levels obtained after taking one Emtriva 200 mg
hard capsule are similar to those obtained after taking 24 ml of the oral solution. If you would like to
switch from taking Emtriva oral solution to Emtriva hard capsules, please talk to your doctor.
If you take more Emtriva than you should
If you accidentally take too much Emtriva oral solution, contact your doctor or nearest emergency
department for advice. Keep the oral solution bottle with you so that you can easily describe what you
have taken.
If you forget to take Emtriva
It is important not to miss a dose of Emtriva.
If you do miss a dose
of Emtriva, take it as soon as you can, and then take your next dose at its
regular time.
If it is almost time for your next dose
anyway, forget about the missed dose. Wait and take the next
dose at the regular time. Do not take a double dose to make up for a forgotten dose.
50
If you are sick
(vomit)
If it’s less than an hour since you took Emtriva,
take another dose. You do not need to take another
dose if you were sick more than an hour after taking Emtriva.
If you stop taking Emtriva
•
Don’t stop taking Emtriva without talking to your doctor.
Stopping treatment with Emtriva
may reduce the effectiveness of the anti-HIV therapy recommended by your doctor. Speak with
your doctor before you stop, particularly if you are experiencing any side effects or you have
another illness. Contact your doctor again before you restart taking Emtriva oral solution.
•
If you have both HIV infection and hepatitis B,
it is especially important not to stop your
Emtriva treatment without talking to your doctor first. Some patients have had blood tests or
symptoms indicating that their hepatitis has got worse after stopping Emtriva. You may require
blood tests for several months after stopping treatment. In some patients with advanced liver
disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of
hepatitis.
Tell your doctor immediately about new or unusual symptoms after you stop treatment,
particularly symptoms you associate with hepatitis B infection.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Emtriva can cause side effects, although not everybody gets them.
Tell your doctor about any of the following side effects:
Very common side effects
(
These can affect more than 1 user in 10
)
•
headache, diarrhoea, feeling sick (nausea)
•
muscle pain and weakness (if creatine kinase levels in the blood are increased)
Common side effects
(
These can affect 1 to 10 users in 100
)
•
dizziness, weakness, difficulty sleeping, abnormal dreams
•
being sick (vomiting), problems with digestion resulting in discomfort after meals, stomach pain
•
rashes (including red spots or blotches sometimes with blistering and swelling of the skin),
which may be allergic reactions, itching, changes in skin colour including darkening of the skin
in patches
•
pain
Tests may also show:
•
low white blood cell count (a reduced white blood cell count can make you more prone to
infection)
•
increased triglycerides (fatty acids), bile or sugar in the blood
51
•
liver and pancreas problems
Uncommon side effects
(
These can affect 1 to 10 users in 1,000
)
•
anaemia (low red blood cell count)
•
swelling of the face, lips, tongue or throat
Children given emtricitabine experienced
changes in skin colour
including darkening of the skin in
patches (very common) and
anaemia
(common). Anaemia means the production of red blood cells is
reduced, and a child may have symptoms of tiredness or breathlessness.
Medicines like Emtriva can cause lactic acidosis (excess lactic acid in the blood). The following may
be signs of lactic acidosis:
•
Deep, rapid breathing
•
Drowsiness
•
Nausea (feeling sick), vomiting and stomach pain
If you notice any of these symptoms,
tell your doctor immediately.
Combination antiretroviral therapy (including Emtriva) may
change your body shape,
by changing
the way body fat is distributed. You may lose fat from your legs, arms and face; gain fat around the
abdomen (tummy) and internal organs; get larger breasts or fatty lumps on the back of the neck
(‘buffalo hump’). The cause and the long-term effects of these changes are not yet known.
Combination antiretroviral therapy may also cause
hyperlipaemia
(increased fats in the blood) and
resistance to insulin. Your doctor will test for these changes.
If you get any of the side effects listed,
or if you notice any side effects not listed in this leaflet,
tell
your doctor.
5.
HOW TO STORE EMTRIVA
Keep out of the reach and sight of children.
Do not use Emtriva after the expiry date which is stated on the bottle and outer carton after {EXP}.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C) until opened.
After opening the bottle, do not store above 25ºC. The content of the bottle should be used up within
45 days of opening. It is advised to write the date of removal from the refrigerator on the package.
If there is any solution left in the bottle after 45 days, this should be discarded according to local
requirements or returned to the pharmacy.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Emtriva contains
•
The active substance is
emtricitabine.
One ml of Emtriva oral solution contains 10 mg
emtricitabine (10 mg/ml).
52
•
The other ingredients are:
cotton candy flavouring, disodium edetate, hydrochloric acid,
methyl parahydroxybenzoate (E218), propylene glycol, propyl parahydroxybenzoate (E216),
sodium hydroxide, sodium phosphate monobasic hydrate, sunset yellow (E110), purified water,
xylitol (E967).
What Emtriva looks like and contents of the pack
Emtriva oral solution is a clear, orange to dark orange solution that comes in bottles containing 170 ml
with a measuring cup.
Emtriva is also available as hard capsules. These are only suitable for patients who weigh at least
33 kg and can swallow hard capsules. There is a separate Package Leaflet for Emtriva 200 mg hard
capsules.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
Manufacturer:
Gilead Sciences Limited
Unit 13, Stillorgan Industrial Park
Blackrock
County Dublin
Ireland
or
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill Co. Cork
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
Luxembourg/Luxemburg
Gilead Sciences Belgium BVBA
Tél/Tel: + 32 (0) 24 01 35 79
България
Gilead Sciences International Ltd
Teл: + 44 (0) 20 7136 8820
Magyarország
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Česká republika
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Malta
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Danmark
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Nederland
Gilead Sciences Netherlands B.V.
Tel: + 31 (0) 20 718 3698
53
Deutschland
Gilead Sciences GmbH
Tel: + 49 (0) 89 899890-0
Norge
Gilead Sciences Sweden AB
Tlf: + 46 (0) 8 5057 1849
Eesti
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Österreich
Gilead Sciences GesmbH
Tel: + 43 1 260 830
Ελλάδα
Gilead Sciences Ελλάς Μ.ΕΠΕ.
Τηλ: + 30 210 8930 100
Polska
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
España
Gilead Sciences, S.L.
Tel: + 34 91 378 98 30
Portugal
Gilead Sciences, Lda.
Tel: + 351 21 7928790
France
Gilead Sciences
Tél: + 33 (0) 1 42 73 70 70
România
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Ireland
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
Slovenija
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Ísland
Gilead Sciences Sweden AB
Sími: + 46 (0) 8 5057 1849
Slovenská republika
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
Italia
Gilead Sciences S.r.l.
Tel: + 39 02 439201
Suomi/Finland
Gilead Sciences Sweden AB
Puh/Tel: + 46 (0) 8 5057 1849
Κύπρος
Gilead Sciences Ελλάς Μ.ΕΠΕ.
Τηλ: + 30 210 8930 100
Sverige
Gilead Sciences Sweden AB
Tel: + 46 (0) 8 5057 1849
Latvija
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
United Kingdom
Gilead Sciences Ltd
Tel: + 44 (0) 1223 897555
Lietuva
Gilead Sciences International Ltd
Tel: + 44 (0) 20 7136 8820
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
54
Source: European Medicines Agency
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