US PDR version
FDA panel recommended Truvada for preventive use
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Truvada 200 mg/245 mg film-coated tablets
2.
Each film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil
(equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).
Excipient(s):
Each tablet contains 80 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Blue, capsule-shaped, film-coated tablet, debossed on one side with “GILEAD” and on the other side
with “701”.
4.
Truvada is a fixed dose combination of emtricitabine and tenofovir disoproxil fumarate. It is indicated
in antiretroviral combination therapy for the treatment of HIV-1 infected adults.
The demonstration of the benefit of the combination emtricitabine and tenofovir disoproxil fumarate in
antiretroviral therapy is based solely on studies performed in treatment-naïve patients (see section 5.1).
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
Adults:
The recommended dose of Truvada is one tablet, taken orally, once daily. In order to optimise
the absorption of tenofovir, it is recommended that Truvada should be taken with food. Even a light
meal improves absorption of tenofovir from the combination tablet (see section 5.2).
Where discontinuation of therapy with one of the components of Truvada is indicated or where dose
modification is necessary, separate preparations of emtricitabine and tenofovir disoproxil fumarate are
available. Please refer to the Summary of Product Characteristics for these medicinal products.
Children and adolescents:
Truvada is not recommended for use in children below the age of 18 years
due to insufficient data on safety and efficacy (see section 5.2).
Elderly:
No data are available on which to make a dose recommendation for 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 impairment:
Emtricitabine and tenofovir are eliminated by renal excretion and the exposure to
emtricitabine and tenofovir increases in patients with renal dysfunction. There are limited data on the
2
safety and efficacy of Truvada in patients with moderate and severe renal impairment (creatinine
clearance < 50 ml/min) and long term safety data has not been evaluated for mild renal impairment
(creatinine clearance 50-80 ml/min). Therefore, in patients with renal impairment Truvada should
only be used if the potential benefits of treatment are considered to outweigh the potential risks.
Patients with renal impairment may require close monitoring of renal function (see section 4.4). Dose
interval adjustments are recommended for patients with creatinine clearance between 30 and
49 ml/min. These dose adjustments have not been confirmed in clinical studies and the clinical
response to treatment should be closely monitored in these patients (see sections 4.4 and 5.2).
Mild renal impairment (creatinine clearance 50-80 ml/min):
Limited data from clinical studies support
once daily dosing of Truvada in patients with mild renal impairment (see section 4.4).
Moderate renal impairment (creatinine clearance 30-49 ml/min):
Administration of Truvada every
48 hours is recommended, based on modelling of single-dose pharmacokinetic data for emtricitabine
and tenofovir disoproxil fumarate in non-HIV infected subjects with varying degrees of renal
impairment (see section 4.4).
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients:
Truvada is
not recommended for patients with severe renal impairment (creatinine clearance < 30 ml/min) and in
patients who require haemodialysis because appropriate dose reductions cannot be achieved with the
combination tablet.
Hepatic impairment:
The pharmacokinetics of Truvada and emtricitabine have not been studied in
patients with hepatic impairment. The pharmacokinetics of tenofovir have been studied in patients
with hepatic impairment and no dose adjustment is required for tenofovir disoproxil fumarate in these
patients. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it
is unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment
(see sections 4.4 and 5.2).
If Truvada 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).
Method of administration
If patients have difficulty in swallowing, Truvada can be disintegrated in approximately 100 ml of
water, orange juice or grape juice and taken immediately.
Hypersensitivity to the active substances or to any of the excipients.
Elderly:
Truvada 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 Truvada.
Co-administration of other medicinal products:
Truvada should not be administered concomitantly
with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate) or other
cytidine analogues, such as lamivudine (see section 4.5). Truvada should not be administered
concomitantly with adefovir dipivoxil.
Triple nucleoside therapy:
There have been reports of a high rate of virological failure and of
emergence of resistance at an early stage when tenofovir disoproxil fumarate was combined with
lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. There is
close structural similarity between lamivudine and emtricitabine and similarities in the
pharmacokinetics and pharmacodynamics of these two agents. Therefore, the same problems may be
seen if Truvada is administered with a third nucleoside analogue.
3
Patients receiving Truvada 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 must be advised that antiretroviral therapies, including Truvada, have not been proven to
prevent the risk of transmission of HIV to others through sexual contact or contamination with blood.
Appropriate precautions must continue to be used.
Renal impairment:
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination
of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been
reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with
Truvada and renal function (creatinine clearance and serum phosphate) is also monitored every four
weeks during the first year and then every three months. In patients at risk for renal impairment,
including patients who have previously experienced renal events while receiving adefovir dipivoxil,
consideration should be given to more frequent monitoring of renal function.
Patients with renal impairment (creatinine clearance < 80 ml/min), including haemodialysis patients:
Renal safety with Truvada has only been studied to a very limited degree in patients with impaired
renal function (creatinine clearance < 80 ml/min). Dose interval adjustments are recommended for
patients with creatinine clearance 30-49 ml/min (see section 4.2). Limited clinical study data suggest
that the prolonged dose interval is not optimal and could result in increased toxicity and possibly
inadequate response. Furthermore, in a small clinical study, a subgroup of patients with creatinine
clearance between 50 and 60 ml/min who received tenofovir disoproxil fumarate in combination with
emtricitabine every 24 hours had a 2-4-fold higher exposure to tenofovir and worsening of renal
function (see section 5.2). Therefore, a careful benefit-risk assessment is needed when Truvada is
used in patients with creatinine clearance < 60 ml/min, and renal function should be closely
monitored. In addition, the clinical response to treatment should be closely monitored in patients
receiving Truvada at a prolonged dosing interval. The use of Truvada is not recommended in patients
with severe renal impairment (creatinine clearance < 30 ml/min)
and in patients who require
haemodialysis since appropriate dose reductions cannot be achieved with the combination tablet (see
sections 4.2 and 5.2).
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in
any patient receiving Truvada, renal function should be re-evaluated within one week, including
measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8,
proximal tubulopathy). Consideration should also be given to interrupting treatment with Truvada in
patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate
to < 1.0 mg/dl (0.32 mmol/l).
Use of Truvada should be avoided with concurrent or recent use of a nephrotoxic medicinal product
(see section 4.5).
Truvada should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R
mutation (see section 5.1).
Bone effects:
In a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with
stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small
decreases in bone mineral density of the hip and spine were observed in both treatment groups.
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were
significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in
bone mineral density of hip were significantly greater in this group until 96 weeks. However, there
was no increased risk of fractures or evidence for clinically relevant bone abnormalities over
144 weeks.
4
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal
tubulopathy (see section 4.8). If bone abnormalities are suspected then appropriate consultation
should be obtained.
Patients with HIV and hepatitis B or C virus co-infection:
Patients with chronic hepatitis B or C
treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic
adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of
HIV infection in patients co-infected with hepatitis B virus (HBV).
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary
of Product Characteristics for these medicinal products.
The safety and efficacy of Truvada have not been established for the treatment of chronic
HBV infection. Emtricitabine and tenofovir individually and in combination have shown activity
against HBV in pharmacodynamic studies (see section 5.1). Limited clinical experience suggests that
emtricitabine and tenofovir disoproxil fumarate have anti-HBV activity when used in antiretroviral
combination therapy to control HIV infection.
Discontinuation of Truvada therapy in patients co-infected with HIV and HBV may be associated with
severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue
Truvada should be closely monitored with both clinical and laboratory follow-up for at least several
months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted.
In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended
since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Liver disease:
The safety and efficacy of Truvada have not been established in patients with
significant underlying liver disorders. The pharmacokinetics of Truvada and emtricitabine have not
been studied in patients with hepatic impairment. The pharmacokinetics of tenofovir have been
studied in patients with hepatic impairment and no dose adjustment is required in these patients.
Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is
unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment
(see section 5.2).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
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.
5
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
been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as
older age, and with drug related factors such as longer duration of antiretroviral treatment and
associated metabolic disturbances. Clinical examination should include evaluation for physical signs
of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and
blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be
excluded. However, 144-week clinical data from antiretroviral-naïve patients indicate that the risk of
lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered
with lamivudine and efavirenz.
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 reactions reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset
neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the
neurological disorders are transient or permanent is currently unknown. Any child exposed
in utero
to
nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant
signs or symptoms. These findings do not affect current national recommendations to use
antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome:
In HIV infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterial infections, and
Pneumocystis jirovecii
pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
HIV infected patients co-infected with hepatitis B virus may experience acute exacerbations of
hepatitis associated with immune reactivation syndrome following the initiation of antiretroviral
therapy.
Osteonecrosis:
Although the aetiology 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.
Co-administration of tenofovir disoproxil fumarate and didanosine:
is not recommended.
Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in
systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see
section 4.5). Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported.
Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been
6
associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction
increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine
co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high
rates of virological failure within several tested combinations.
Truvada contains lactose monohydrate. Consequently, patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take
this medicine.
As Truvada contains emtricitabine and tenofovir disoproxil fumarate, any interactions that have been
identified with these agents individually may occur with Truvada. Interaction studies have only been
performed in adults.
The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine
and tenofovir disoproxil fumarate were administered together
versus
each medicinal product dosed
alone.
In vitro
and clinical pharmacokinetic interaction studies have shown the potential for CYP450
mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal
products is low.
Concomitant use not recommended:
Due to similarities with emtricitabine, Truvada should not be administered concomitantly with other
cytidine analogues, such as lamivudine (see section 4.4).
As a fixed combination, Truvada should not be administered concomitantly with other medicinal
products containing any of the components, emtricitabine or tenofovir disoproxil fumarate (Viread,
Emtriva or Atripla).
Truvada should not be administered concomitantly with adefovir dipivoxil.
Didanosine:
The co-administration of Truvada and didanosine is not recommended (see section 4.4
and Table 1).
Renally eliminated medicinal products:
Since emtricitabine and tenofovir are primarily eliminated by
the kidneys, co-administration of Truvada with medicinal products that reduce renal function or
compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of
emtricitabine, tenofovir and/or the co-administered medicinal products.
Use of Truvada should be avoided with concurrent or recent use of a nephrotoxic medicinal product.
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet,
ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2. If concomitant use of Truvada and
nephrotoxic agents is unavoidable, renal function should be monitored weekly (see section 4.4).
Other interactions:
Interactions between the components of Truvada and protease inhibitors and nucleoside reverse
transcriptase inhibitors, are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no
change as “↔”, twice daily as “b.i.d.” and once daily as “q.d.”). If available, 90% confidence
intervals are shown in parentheses.
7
Table 1: Interactions between the individual components of Truvada and other medicinal
products
Medicinal product by
therapeutic areas
Effects on drug levels
Mean percent change in AUC,
C
max
, C
min
with 90%
confidence intervals if
available
(mechanism)
Recommendation concerning
co-administration with
Truvada
(emtricitabine 200 mg,
tenofovir disoproxil fumarate
300 mg)
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir/Tenofovir
disoproxil fumarate
(300 mg q.d./100 mg q.d./300 mg
q.d.)
Atazanavir:
AUC: ↓ 25% (↓ 42 to ↓ 3)
C
max
: ↓ 28% (↓ 50 to ↑ 5)
C
min
: ↓ 26% (↓ 46 to ↑ 10)
No dose adjustment is
recommended. The increased
exposure of tenofovir could
potentiate tenofovir associated
adverse events, including renal
disorders. Renal function
should be closely monitored
(see section 4.4).
Tenofovir:
AUC: ↑ 37%
C
max
: ↑ 34%
C
min
: ↑ 29%
Atazanavir/Ritonavir/Emtricitabine Interactionnotstudied.
Darunavir/Ritonavir/Tenofovir
disoproxil fumarate
(300 mg q.d./100 mg q.d./300 mg
q.d.)
Darunavir:
AUC: ↔
C
min
: ↔
No dose adjustment is
recommended. The increased
exposure of tenofovir could
potentiate tenofovir associated
adverse events, including renal
disorders. Renal function
should be closely monitored
(see section 4.4).
Tenofovir:
AUC: ↑ 22%
C
min
: ↑ 37%
Darunavir/Ritonavir/Emtricitabine Interaction not studied.
Lopinavir/Ritonavir/Tenofovir
disoproxil fumarate
(400 mg b.i.d./100 mg
b.i.d/300 mg q.d.)
Lopinavir/Ritonavir:
AUC: ↔
C
max
: ↔
C
min
: ↔
No dose adjustment is
recommended. The increased
exposure of tenofovir could
potentiate tenofovir associated
adverse events, including renal
disorders. Renal function
should be closely monitored
(see section 4.4).
Tenofovir:
AUC: ↑ 32% (↑ 25 to ↑ 38)
C
max
: ↔
C
min
: ↑ 51% (↑ 37 to ↑ 66)
Lopinavir/Ritonavir/Emtricitabine
Interaction not studied.
8
NRTIs
Didanosine/Tenofovir disoproxil
fumarate
Co-administration of tenofovir
disoproxil fumarate and
didanosine results in a 40-60%
increase in systemic exposure to
didanosine that may increase the
risk for didanosine-related
adverse events. Rare cases of
pancreatitis and lactic acidosis,
sometimes fatal, have been
reported. Co-administration of
tenofovir disoproxil fumarate
and didanosine at a dose of
400 mg daily has been
associated with a significant
decrease in CD4 cell count,
possibly due to an intracellular
interaction increasing
phosphorylated (i.e. active)
didanosine. A decreased dosage
of 250 mg didanosine
co-administered with tenofovir
disoproxil fumarate therapy has
been associated with reports of
high rates of virological failure
within several tested
combinations for the treatment
of HIV-1 infection.
Co-administration of Truvada
and didanosine is not
recommended
(see section 4.4).
Didanosine/Emtricitabine
Interaction not studied.
Studies conducted with other medicinal products:
Emtricitabine:
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.
There are no clinically significant pharmacokinetic interactions when emtricitabine is co-administered
with indinavir, zidovudine, stavudine or famciclovir.
Tenofovir disoproxil fumarate:
Co-administration of lamivudine, indinavir, efavirenz, nelfinavir or
saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, adefovir dipivoxil or the hormonal
contraceptive norgestimate/ethinyl oestradiol with tenofovir disoproxil fumarate did not result in any
clinically significant pharmacokinetic interaction.
Truvada:
Co-administration of tacrolimus with Truvada did not result in any clinically significant
pharmacokinetic interaction.
Pregnancy:
For emtricitabine and tenofovir disoproxil fumarate, insufficient data on exposed pregnancies are
available.
Animal studies do not indicate direct or indirect harmful effects of emtricitabine or tenofovir
disoproxil fumarate with respect to pregnancy, embryonal/foetal development, parturition or postnatal
development (see section 5.3).
9
However, Truvada should not be used during pregnancy unless no other alternative is available.
The use of Truvada must be accompanied by the use of effective contraception.
Lactation:
It is not known whether emtricitabine or tenofovir are 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 to the infant.
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 both emtricitabine
and tenofovir disoproxil fumarate.
a. Summary of the safety profile
The most frequently reported adverse reactions considered possibly or probably related to
emtricitabine and/or tenofovir disoproxil fumarate were nausea (12%) and diarrhoea (7%) in an open-
label randomised clinical trial (GS-01-934, see section 5.1). The safety profile of emtricitabine and
tenofovir disoproxil fumarate in this study was consistent with the previous experience with these
agents when each was administered with other antiretroviral agents.
In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and
proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities
(infrequently contributing to fractures) have been reported. Monitoring of renal function is
recommended for patients receiving Truvada (see section 4.4).
Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir
disoproxil fumarate and emtricitabine (see sections 4.4 and 4.8c).
Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended as this may
result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic
acidosis, sometimes fatal, have been reported (see section 4.4).
Discontinuation of Truvada 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
The adverse reactions considered at least possibly related to treatment with the components of Truvada
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), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).
Table 2: Tabulated summary of adverse reactions associated with the individual components of
Truvada based on clinical study and post-marketing experience
Frequency
Emtricitabine
Tenofovir disoproxil fumarate
Blood and lymphatic system disorders:
Common:
neutropenia
Uncommon:
anaemia
3
Immune system disorders:
Common:
allergic reaction
10
Metabolism and nutrition disorders:
Very common:
hypophosphataemia
1
Common:
hyperglycaemia,
hypertriglyceridaemia
Uncommon:
hypokalaemia
1
Rare:
lactic acidosis
2
Psychiatric disorders:
Common:
insomnia, abnormal dreams
Nervous system disorders:
Very common:
headache
dizziness
Common:
dizziness
headache
Gastrointestinal disorders:
Very common:
diarrhoea, nausea
diarrhoea, vomiting, nausea
elevated amylase including
elevated pancreatic amylase,
elevated serum lipase, vomiting,
abdominal pain, dyspepsia
Common:
abdominal pain, abdominal
distension, flatulence
Uncommon:
pancreatitis
2
Hepatobiliary disorders:
elevated serum aspartate
aminotransferase (AST) and/or
elevated serum alanine
aminotransferase (ALT),
hyperbilirubinaemia
Common:
increased transaminases
Rare:
hepatic steatosis
2
, hepatitis
Skin and subcutaneous disorders:
Very common:
rash
vesiculobullous rash,
pustular rash, maculopapular rash,
rash, pruritus, urticaria, skin
discolouration (increased
pigmentation)
3
Common:
Uncommon:
angioedema
4
Rare:
angioedema
Musculoskeletal and connective tissue disorders:
Very common:
elevated creatine kinase
rhabdomyolysis
1
, muscular
weakness
1
Uncommon:
osteomalacia (manifested as bone
pain and infrequently contributing
to fractures)
1,4
, myopathy
1
Rare:
Renal and urinary disorders:
Uncommon:
increased creatinine, proteinuria
renal failure (acute and chronic),
acute tubular necrosis, proximal
renal tubulopathy including
Fanconi syndrome, nephritis
(including acute interstitial
nephritis)
4
, nephrogenic diabetes
insipidus
Rare:
11
General disorders and administration site conditions:
Very common:
asthenia
Common: pain, asthenia
1
This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally
associated with tenofovir disoproxil fumarate in the absence of this condition.
2
See section
c. Description of selected adverse reactions
for more details.
3
Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was
administered to paediatric patients.
4
This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical
trials in adults or paediatric HIV clinical trials for emtricitabine or in randomised controlled clinical trials or the tenofovir
disoproxil fumarate expanded access program for tenofovir disoproxil fumarate. The frequency category was estimated from
a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical trials
(n = 1,563) or tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program
(n = 7,319).
c. Description of selected adverse reactions
Renal impairment:
As Truvada may cause renal damage monitoring of renal function is recommended
(see sections 4.4 and 4.8a).
Interaction with didanosine:
Co-administration of tenofovir disoproxil fumarate and didanosine is not
recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase
the risk of didanosine-related adverse events (see section 4.5). Rare cases of pancreatitis and lactic
acidosis, sometimes fatal, have been reported.
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. Treatment with nucleoside
analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic
acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels (see section 4.4).
d. Paediatric population
Insufficient safety data are available for children below 18 years of age. Truvada is not recommended
in this population (see section 4.2).
e. Other special population(s)
Elderly:
Truvada 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 Truvada (see section 4.4).
Patients with renal impairment:
Since tenofovir disoproxil fumarate can cause renal toxicity, close
monitoring of renal function is recommended in any patient with renal impairment treated with
Truvada (see sections 4.2, 4.4 and 5.2).
12
HIV/HBV or HCV co-infected patients:
Only a limited number of patients were co-infected with HBV
(n=13) or HCV (n=26) in study GS-01-934. The adverse reaction profile of emtricitabine and
tenofovir disoproxil fumarate in patients co-infected with HIV/HBV or HIV/HCV was similar to that
observed in patients infected with HIV without co-infection. However, as would be expected in this
patient population, elevations in AST and ALT occurred more frequently than in the general
HIV infected population.
Exacerbations of hepatitis after discontinuation of treatment:
In HIV infected patients co-infected
with HBV, clinical and laboratory evidence of hepatitis have occurred after discontinuation of
treatment (see section 4.4).
If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and
standard supportive treatment applied as necessary.
Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by
haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal
dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Antiviral for systemic use; antivirals for treatment of HIV infections,
combinations. ATC code: J05AR03
Mechanism of action and pharmacodynamic effects:
Emtricitabine is a nucleoside analogue of
cytidine. Tenofovir disoproxil fumarate is converted
in vivo
to tenofovir, a nucleoside monophosphate
(nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir have activity
that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate
and tenofovir diphosphate, respectively.
In vitro
studies have shown that both emtricitabine and
tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate
and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain
termination.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA
polymerases and there was no evidence of toxicity to mitochondria
in vitro
and
in vivo
.
Antiviral activity in vitro:
Synergistic antiviral activity was observed with the combination of
emtricitabine and tenofovir
in vitro
. Additive to synergistic effects were observed in combination
studies with protease inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV
reverse transcriptase.
Resistance:
Resistance has been seen
in vitro
and in some HIV-1 infected patients due to the
development of the M184V/I mutation with emtricitabine or the K65R mutation with tenofovir. No
other pathways of resistance to emtricitabine or tenofovir have been identified. Emtricitabine-resistant
viruses with the M184V/I mutation were cross-resistant to lamivudine, but retained sensitivity to
didanosine, stavudine, tenofovir and zidovudine. The K65R mutation can also be selected by abacavir
or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and
tenofovir. Tenofovir disoproxil fumarate should be avoided in patients with HIV-1 harbouring the
K65R mutation.
13
Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that
included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to
tenofovir disoproxil fumarate.
In vivo resistance (antiretroviral-naïve patients):
In an open-label randomised clinical study
(GS-01-934) in antiretroviral-naïve patients, genotyping was performed on plasma HIV-1 isolates
from all patients with confirmed HIV RNA > 400 copies/ml at weeks 48, 96 or 144 or at the time of
early study drug discontinuation. As of week 144:
•
The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in the
emtricitabine/tenofovir disoproxil fumarate/efavirenz group and in 10/29 (34.5%) isolates
analysed from the lamivudine/zidovudine/efavirenz group (p-value < 0.05, Fisher’s Exact test
comparing the emtricitabine+tenofovir disoproxil fumarate group to the lamivudine/zidovudine
group among all subjects).
•
No virus analysed contained the K65R mutation.
•
Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from
13/19 (68%) patients in the emtricitabine/tenofovir disoproxil fumarate/efavirenz group and in
virus from 21/29 (72%) patients in the comparative group.
Clinical experience:
In an open-label randomised clinical study (GS-01-934), antiretroviral-naïve
HIV-1 infected patients received either a once daily regimen of emtricitabine, tenofovir disoproxil
fumarate and efavirenz (n=255) or a fixed combination of lamivudine and zidovudine (Combivir)
administered twice daily and efavirenz once daily (n=254). Patients in the emtricitabine and tenofovir
disoproxil fumarate group were given Truvada and efavirenz from week 96 to week 144. At baseline
the randomised groups had similar median plasma HIV-1 RNA (5.02 and 5.00 log
10
copies/ml) and
CD4 counts (233 and 241 cells/mm
3
). The primary efficacy endpoint for this study was the
achievement and maintenance of confirmed HIV-1 RNA concentrations < 400 copies/ml over
48 weeks. Secondary efficacy analyses over 144 weeks included the proportion of patients with
HIV-1 RNA concentrations < 400 or < 50 copies/ml, and change from baseline in CD4 cell count.
The 48-week primary endpoint data showed that the combination of emtricitabine, tenofovir disoproxil
fumarate and efavirenz provided superior antiviral efficacy as compared with the fixed combination of
lamivudine and zidovudine (Combivir) with efavirenz as shown in Table 3. The 144 week secondary
endpoint data are also presented in Table 3.
14
Table 3: 48- and 144-week efficacy data from study GS-01-934 in which emtricitabine, tenofovir
disoproxil fumarate and efavirenz were administered to antiretroviral-naïve patients with
HIV-1 infection
GS-01-934
Treatment for 48 weeks
GS-01-934
Treatment fo
r 144 weeks
Emtricitabine+
tenofovir disoproxil
fumarate+efavirenz
Lamivudine+
zidovudine+efavirenz
Emtricitabine+
tenofovir disoproxil
fumarate+efavirenz*
Lamivudine+
zidovudine+efavirenz
HIV-1 RNA
< 400 copies/ml
(TLOVR)
84% (206/244)
73% (177/243)
71% (161/227)
58% (133/229)
p-value
0.002**
0.004**
% difference
(95%CI)
11% (4% to 19%)
13% (4% to 22%)
HIV-1 RNA
< 50 copies/ml
(TLOVR)
80% (194/244)
70% (171/243)
64% (146/227)
56% (130/231)
p-value
0.021**
0.082**
% difference
(95%CI)
9% (2% to 17%)
8% (-1% to 17%)
Mean change from
baseline in CD4 cell
count (cells/mm
3
)
+190
+158
+312
+271
p-value 0.002
a
0.089
a
Difference (95%CI) 32 (9 to 55) 41 (4 to 79)
* Patients receiving emtricitabine, tenofovir disoproxil fumarate and efavirenz were given Truvada plus efavirenz from
week 96 to 144.
** The p-value based on the Cochran-Mantel-Haenszel Test stratified for baseline CD4 cell count
TLOVR=Time to Loss of Virologic Response
a: Van Elteren Test
In a separate randomised clinical study (M02-418), one hundred and ninety antiretroviral-naïve adults
were also treated once daily with emtricitabine and tenofovir disoproxil fumarate in combination with
lopinavir/ritonavir given once or twice daily. At 48 weeks, 70% and 64% of patients demonstrated
HIV-1 RNA < 50 copies/ml with the once and twice daily regimens of lopinavir/ritonavir,
respectively. The mean changes in CD4 cell count from baseline were +185 cells/mm
3
and
+196 cells/mm
3
with the once and twice daily regimens of lopinavir/ritonavir, respectively.
Limited clinical experience in patients co-infected with HIV and HBV suggests that treatment with
emtricitabine or tenofovir disoproxil fumarate in antiretroviral combination therapy to control
HIV infection also results in a reduction in HBV DNA (3 log
10
reduction or 4 to 5 log
10
reduction,
respectively) (see section 4.4).
5.2 Pharmacokinetic properties
Absorption:
The bioequivalence of one Truvada film-coated tablet with one emtricitabine 200 mg hard
capsule and one tenofovir disoproxil fumarate 245 mg film-coated tablet was established following
single dose administration to fasting healthy subjects. Following oral administration of Truvada to
healthy subjects, emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed and tenofovir
disoproxil fumarate is converted to tenofovir. Maximum emtricitabine and tenofovir concentrations
are observed in serum within 0.5 to 3.0 h of dosing in the fasted state. Administration of Truvada with
food resulted in a delay of approximately three quarters of an hour in reaching maximum tenofovir
concentrations and increases in tenofovir AUC and C
max
of approximately 35% and 15%, respectively,
when administered with a high fat or light meal, compared to administration in the fasted state. In
order to optimise the absorption of tenofovir, it is recommended that Truvada should be taken with
food.
Distribution:
Following intravenous administration the volume of distribution of emtricitabine and
tenofovir was approximately 1.4 l/kg and 800 ml/kg, respectively. After oral administration of
15
emtricitabine or tenofovir disoproxil fumarate, emtricitabine and tenofovir are widely distributed
throughout the body.
In vitro
binding of emtricitabine to human plasma proteins was < 4% and
independent of concentration over the range of 0.02 to 200 µg/ml.
In vitro
protein binding of
tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir
concentration range 0.01 to 25 µg/ml.
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).
In vitro
studies have determined that neither tenofovir disoproxil
fumarate nor tenofovir are substrates for the CYP450 enzymes. Neither emtricitabine nor tenofovir
inhibited
in vitro
drug metabolism mediated by any of the major human CYP450 isoforms involved in
drug biotransformation. Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl
transferase, the enzyme responsible for glucuronidation.
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. Following oral administration, the elimination half-life of
emtricitabine is approximately 10 hours.
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system
with approximately 70-80% of the dose excreted unchanged in urine following intravenous
administration. The apparent clearance of tenofovir averaged approximately 307 ml/min. Renal
clearance has been estimated to be approximately 210 ml/min, which is in excess of the glomerular
filtration rate. This indicates that active tubular secretion is an important part of the elimination of
tenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to
18 hours.
Age, gender and ethnicity:
Emtricitabine and tenofovir pharmacokinetics are similar in male and
female patients. 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. Pharmacokinetic studies have not
been performed with tenofovir in children and adolescents (under 18 years). Pharmacokinetic studies
have not been performed with emtricitabine or tenofovir in the elderly (over 65 years).
Renal impairment:
Limited pharmacokinetic data are available for emtricitabine and tenofovir after
co-administration of separate preparations or as Truvada in patients with renal impairment.
Pharmacokinetic parameters were mainly determined following administration of single doses of
emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying
degrees of renal impairment. The degree of renal impairment was defined according to baseline
creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild impairment with
CrCl = 50-79 ml/min; moderate impairment with CrCl = 30-49 ml/min and severe impairment with
CrCl = 10-29 ml/min).
The mean (%CV) emtricitabine drug exposure increased from 12 (25%) µg•h/ml in subjects with
normal renal function, to 20 (6%) µg•h/ml, 25 (23%) µg•h/ml and 34 (6%) µg•h/ml, in patients with
mild, moderate and severe renal impairment, respectively.
The mean (%CV) tenofovir drug exposure increased from 2,185 (12%) ng•h/ml in patients with
normal renal function, to 3,064 (30%) ng•h/ml, 6,009 (42%) ng•h/ml and 15,985 (45%) ng•h/ml, in
patients with mild, moderate and severe renal impairment, respectively.
The increased dose interval for Truvada in patients with moderate renal impairment is expected to
result in higher peak plasma concentrations and lower C
min
levels as compared to patients with normal
renal function. The clinical implications of this are unknown.
16
In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug
exposures substantially increased over 72 hours to 53 (19%) µg•h/ml of emtricitabine, and over
48 hours to 42,857 (29%) ng•h/ml of tenofovir.
It is recommended that the dosing interval for Truvada is modified in patients with creatinine
clearance between 30 and 49 ml/min. Truvada is not suitable for patients with CrCl < 30 ml/min or
for those on haemodialysis (see section 4.2).
A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of
tenofovir disoproxil fumarate in combination with emtricitabine in HIV infected patients with renal
impairment. A subgroup of patients with baseline creatinine clearance between 50 and 60 ml/min,
receiving once daily dosing, had a 2-4-fold increase in tenofovir exposure and worsening renal
function.
Hepatic impairment:
The pharmacokinetics of Truvada have not been studied in patients with hepatic
impairment. However, it is unlikely that a dose adjustment would be required for Truvada in patients
with hepatic impairment.
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.
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients with
varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification.
Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment
suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir C
max
and
AUC
0-∞
values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng•h/ml, respectively, in normal subjects
compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng•h/ml in subjects with moderate hepatic
impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng•h/ml in subjects with severe hepatic
impairment.
5.3 Preclinical safety data
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies
of safety pharmacology, repeated dose toxicity and genotoxicity. Emtricitabine did not show any
carcinogenic potential in long-term oral carcinogenicity studies in mice and rats.
Preclinical studies of tenofovir disoproxil fumarate conducted in rats, dogs and monkeys revealed
target organ effects in gastrointestinal tract, kidney, bone and a decrease in serum phosphate
concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral
density (rats and dogs). Findings in the rat and monkey studies indicated that there was a
substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in
bone mineral density. The mechanisms of these toxicities are not completely understood.
Conventional reproductive/developmental toxicity studies with emtricitabine and tenofovir disoproxil
fumarate reveal no special hazard for humans.
Tenofovir disoproxil fumarate was positive in two out of three
in vitro
genotoxicity studies but
negative in the
in vivo
micronucleus assay.
Tenofovir disoproxil fumarate did not show any carcinogenic potential in a long-term oral
carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence
of duodenal tumours, considered likely related to high local concentrations in the gastrointestinal tract
at a dose of 600 mg/kg/day. While the mechanism of tumour formation is uncertain, the findings are
unlikely to be of relevance to humans.
17
The combination of emtricitabine and tenofovir disoproxil fumarate was positive in the
in vitro
mouse
lymphoma assay, with comparable results to those obtained for tenofovir disoproxil fumarate alone.
The combination of emtricitabine and tenofovir disoproxil fumarate was negative in the bacterial
reverse mutation assay (Ames assay).
A one month dog study using the combination of emtricitabine and tenofovir disoproxil fumarate,
found no exacerbation of toxicological effects compared to the separate components.
6.
6.1 List of excipients
Tablet core:
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate (E572)
Microcrystalline cellulose (E460)
Pregelatinised starch (gluten free)
Film-coating:
Glycerol triacetate (E1518)
Hypromellose (E464)
Indigo carmine aluminium lake (E132)
Lactose monohydrate
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
6.5 Nature and contents of container
HDPE bottle with a child-resistant closure containing 30 film-coated tablets and a silica gel desiccant.
The following pack sizes are available: outer cartons containing 1 x 30 film-coated tablet and 3 x
30 film-coated tablet bottles. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
18
8.
EU/1/04/305/001
EU/1/04/305/002
9.
Date of first authorisation:
21 February 2005
Date of latest renewal:
20 January 2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
19
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
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, Co. Dublin, Ireland
Gilead Sciences Limited, IDA Business & Technology Park, Carrigtohill, Co. Cork, Ireland
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
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan as agreed in version 4.0 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
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
PSURs
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
21
ANNEX III
LABELLING AND PACKAGE LEAFLET
22
A. LABELLING
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE AND CARTON LABELLING
1.
Truvada 200 mg/245 mg film-coated tablets
Emtricitabine/tenofovir disoproxil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil
(equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate, see leaflet for further information.
4.
30 film-coated tablets.
3 x 30 film-coated tablets.
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
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
24
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/1/04/305/001 30 film-coated tablets
EU/1/04/305/002 3 x 30 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Truvada [outer packaging only]
25
B. PACKAGE LEAFLET
26
PACKAGE LEAFLET: INFORMATION FOR THE USER
Truvada 200 mg/245 mg film-coated tablets
Emtricitabine/tenofovir disoproxil
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Truvada is and what it is used for
2.
Before you take Truvada
4.
Possible side effects
5.
How to store Truvada
6.
Further information
1.
WHAT TRUVADA IS AND WHAT IT IS USED FOR
Truvada is a treatment for Human Immunodeficiency Virus (HIV) infection
in adults over
18 years of age.
Truvada contains two active substances,
emtricitabine
and
tenofovir disoproxil
. Both of these
active substances are
antiretroviral
medicines which are used to treat HIV infection. Emtricitabine is
a
nucleoside reverse transcriptase inhibitor
and tenofovir is a
nucleotide reverse transcriptase
inhibitor.
However, both are generally known as NRTIs and they work by interfering with the normal
working of an enzyme (reverse transcriptase) that is essential for the virus to reproduce itself. Truvada
should always be used combined with other medicines to treat HIV infection. Truvada can be
administered in place of emtricitabine and tenofovir disoproxil used separately at the same doses.
This medicine is not a cure for HIV infection.
While taking Truvada you may still develop
infections or other illnesses associated with HIV infection. You can also pass on the virus to others, so
it is important to take precautions to avoid infecting other people.
2.
BEFORE YOU TAKE TRUVADA
Do not take Truvada
•
If you are allergic
(hypersensitive)
to emtricitabine, tenofovir, tenofovir disoproxil fumarate, or
any of the other ingredients of Truvada listed at the end of this leaflet.
If this applies to you, tell your doctor immediately.
Take special care with Truvada
•
Tell your doctor if you have had kidney disease, or if tests have shown problems with your
kidneys.
Truvada may affect your kidneys. Before starting treatment, your doctor may order
blood tests to assess kidney function. Your doctor may also order blood tests during treatment
to monitor your kidneys and may advise you to take the tablets less often. Truvada is not
recommended if you have severe kidney disease or are receiving haemodialysis.
27
-
Keep this leaflet. You may need to read it again.
3.
How to take Truvada
Truvada is not usually taken with other medicines that can damage your kidneys (see
Taking
other medicines
). If this is unavoidable, your doctor will monitor your kidney function once a
week.
•
Talk to your doctor if you are over 65.
Truvada has not been studied in patients over 65 years
of age. If you are older than this and are prescribed Truvada, your doctor will monitor you
carefully.
•
Truvada is not for use in children and adolescents under 18 years 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. Both active substances
in Truvada show some activity against hepatitis B virus although emtricitabine is not approved
for the treatment of hepatitis B infection. 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.
•
Once you start taking Truvada, look out for possible signs of lactic acidosis.
Medicines
containing nucleoside analogues, including Truvada, can cause lactic acidosis (excess of lactic
acid in your blood), together with an enlarged liver. Deep, rapid breathing, drowsiness, and non
specific symptoms such as nausea, vomiting and stomach pain, might indicate the development
of lactic acidosis. This rare but serious side effect has occasionally been fatal. Lactic acidosis
occurs more often in women, particularly if they are very overweight. If you have liver disease
you may also be more at risk of getting this condition. While you are being treated with
Truvada, your doctor will monitor you closely for any signs that you may be developing lactic
acidosis.
Other precautions
Combination antiretroviral therapies (including Truvada) may raise blood sugar, increase blood fats
(hyperlipaemia), cause changes to body fat, and resistance to insulin (see section 4,
Possible side
effects
).
If you are diabetic, overweight or have high cholesterol, talk to your doctor.
Look out for infections.
If you have advanced HIV infection (AIDS) and have an infection, you may
develop symptoms of infection and inflammation or worsening of the symptoms of an existing
infection once treatment with Truvada is started. These symptoms may indicate that your body’s
improved immune system is fighting infection. Look out for signs of inflammation or infection soon
after you start taking Truvada. If you notice signs of inflammation or infection,
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 inform your
doctor.
Bone problems (sometimes resulting in fractures) may also occur due to damage to kidney tubule cells
(see section 4,
Possible side effects
).
28
Taking other medicines
You should not take Truvada
if you are already taking other medicines that contain the components
of Truvada, emtricitabine and tenofovir disoproxil fumarate, or any other antiviral medicines that
contain lamivudine or adefovir dipivoxil.
Please tell your doctor or pharmacist if you are taking, or have recently taken any other medicines,
including medicines obtained without a prescription.
•
It is especially important to tell your doctor if you are taking other medicines which may
damage your kidneys.
These include:
•
aminoglycosides (for bacterial infection)
•
amphotericin B (for fungal infection)
•
foscarnet (for viral infection)
•
ganciclovir (for viral infection)
•
pentamidine (for infections)
•
vancomycin (for bacterial infection)
•
interleukin-2 (to treat cancer)
•
cidofovir (for viral infection)
•
Other medicines containing didanosine (for HIV infection):
Taking Truvada with other
antiviral medicines that contain didanosine can raise the levels of didanosine in your blood and
may reduce CD4 cell counts. Rarely, inflammation of the pancreas and lactic acidosis (excess
lactic acid in the blood), which sometimes causes death, have been reported when medicines
containing tenofovir disoproxil fumarate and didanosine were taken together. Your doctor will
carefully consider whether to treat you with combinations of tenofovir and didanosine.
Do not stop your treatment without contacting your doctor.
Taking Truvada with food and drink
•
Truvada should be taken with food.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
•
You must not take Truvada during pregnancy
unless specifically discussed with your doctor.
There are no clinical data on the use of Truvada in pregnant women and it is not usually used
unless absolutely necessary.
•
If you are a woman who could get pregnant during treatment with Truvada, you must use an
effective method of contraception to avoid becoming pregnant.
•
If you become pregnant, or plan to become pregnant, ask your doctor about the potential
benefits and risks of therapy with Truvada to you and your child.
If you have taken Truvada during your pregnancy, your doctor may request regular blood tests and
other diagnostic tests to monitor the development of your child. In children whose mothers took
NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk of side
effects.
•
Do not breast-feed during treatment with Truvada.
It is not yet known whether the active
substances in this medicine pass into human breast milk.
29
•
If you are a woman with HIV it is recommended that you do not breast-feed, to avoid passing
the virus to the baby in breast milk.
Driving and using machines
Truvada
can cause dizziness. If you feel dizzy while taking Truvada,
do not drive
and do not use any
tools or machines.
Important information about some of the ingredients of Truvada
Tell your doctor if you are lactose-intolerant or intolerant to other sugars.
Truvada contains
lactose monohydrate. If you know you are lactose-intolerant, or if you have been told that you have an
intolerance to any other sugars, talk to your doctor before taking this medicine.
3.
HOW TO TAKE TRUVADA
•
Always take Truvada 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 tablet each day with food.
If you have difficulty swallowing, you can use the tip of a spoon to crush the tablet. Then mix the
powder with about 100 ml (half a glass) of water, orange juice or grape juice, and drink immediately.
•
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 Truvada less
frequently.
•
If your doctor decides to stop
one of the components of Truvada or change the dose of
Truvada, you may be given emtricitabine and/or tenofovir separately instead of the combined
medicine or other medicines for the treatment of HIV infection.
•
Your doctor will prescribe Truvada with other antiretroviral medicines.
Please refer to the
patient information leaflets of the other antiretrovirals for guidance on how to take those
medicines.
If you take more Truvada than you should
If you accidentally take more than the recommended dose of Truvada, contact your doctor or nearest
emergency department for advice. Keep the tablet bottle with you so that you can easily describe what
you have taken.
If you forget to take Truvada
It is important not to miss a dose of Truvada.
If you do miss a dose
of Truvada, take it as soon as you can, and then take your next dose at its
regular time.
30
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 tablet.
If you throw up less than 1 hour after taking Truvada,
take another tablet. You do not need to take
another tablet if you were sick more than 1 hour after taking Truvada.
If you stop taking Truvada
•
Stopping treatment
with Truvada
may reduce the effectiveness of the anti-HIV therapy
recommended by your doctor. Speak with your doctor before you stop taking Truvada for any
reason, particularly if you are experiencing any side effects or you have another illness. Contact
your doctor before you restart taking Truvada tablets.
•
If you have HIV infection and hepatitis B,
it is especially important not to stop your Truvada
treatment without talking to your doctor first. Some patients have had blood tests or symptoms
indicating that their hepatitis has got worse after stopping Truvada. 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 your
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, Truvada
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 at least 10 in every 100 patients treated)
•
diarrhoea, being sick (vomiting), feeling sick (nausea), dizziness, headache, rash
•
feeling weak, weakness (if creatine kinase levels in the blood are increased)
Tests may also show:
•
decreases in phosphate in the blood
Common side effects
(These can affect 1 to 10 in every 100 patients treated)
•
pain, stomach pain
•
difficulty sleeping, abnormal dreams
•
problems with digestion resulting in discomfort after meals, feeling bloated, flatulence
•
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
•
other allergic reactions, such as wheezing, swelling or feeling light-headed
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
31
•
liver and pancreas problems
Uncommon side effects
(These can affect at least 1 in every 1,000 patients treated, but less than 1 in every 100 patients treated)
•
anaemia (low red blood cell count)
•
pain in the abdomen (tummy) caused by inflammation of the pancreas
•
breakdown of muscle, muscle pain or weakness
•
swelling of the face, lips, tongue or throat
Tests may also show:
•
decreases in potassium in the blood
•
increased creatinine in your blood
•
changes to your urine
Rare side effects
(These can affect at least 1 in every 10,000 patients treated, but less than 1 in every 1,000 patients
treated)
•
lactic acidosis (excess lactic acid in the blood)
is a serious side effect that can be
life-threatening. The following side effects may be signs of lactic acidosis:
•
deep rapid breathing
•
drowsiness
•
feeling sick (nausea), being sick (vomiting) and stomach pain
If you think you may have lactic acidosis, contact your doctor immediately.
•
back pain caused by kidney problems, including kidney failure. Your doctor may do blood
tests to see if your kidneys are working properly.
•
fatty liver
•
yellow skin or eyes, itching, or pain in the abdomen (tummy) caused by inflammation of the
liver
•
inflammation of the kidney, passing a lot of urine and feeling thirsty
•
softening of the bones (with bone pain and sometimes resulting in fractures)
Tests may also show:
•
damage to kidney tubule cells
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may
occur due to damage to kidney tubule cells.
Other possible effects
Children who were administered emtricitabine, one of the components of Truvada, also experienced
anaemia (low red blood cell count), commonly and changes in skin colour including darkening of the
skin in patches, very commonly. If the production of red blood cells is reduced, a child may have
symptoms of tiredness or breathlessness.
Truvada 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.
Truvada may also cause hyperlipaemia (increased fats in the blood) and resistance to insulin. Your
doctor will test for these changes.
32
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE TRUVADA
Keep out of the reach and sight of children.
Do not use Truvada after the expiry date which is stated on the bottle and carton after {EXP}. The
expiry date refers to the last day of that month.
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
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 Truvada contains
•
The active substances are
emtricitabine
and
tenofovir disoproxil
. Each Truvada film-coated
tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to
300 mg of tenofovir disoproxil fumarate, or 136 mg of tenofovir).
•
The other ingredients are
croscarmellose sodium, glycerol triacetate (E1518), hypromellose
(E464), indigo carmine aluminium lake (E132), lactose monohydrate, magnesium stearate
(E572), microcrystalline cellulose (E460), pregelatinised starch (gluten free) and titanium
dioxide (E171).
What Truvada looks like and contents of the pack
Truvada film-coated tablets are blue, capsule-shaped tablets, engraved on one side with the word
“GILEAD” and on the other side with the number “701”. Truvada comes in bottles of 30 tablets.
The following pack sizes are available: outer cartons containing 1 x 30 film-coated tablet and 3 x
30 film-coated tablet bottles. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer:
Marketing Authorisation Holder:
Gilead Sciences International Limited
Cambridge
CB21 6GT
United Kingdom
Manufacturer:
Gilead Sciences Limited
Unit 13, Stillorgan Industrial Park
Blackrock
County Dublin
Ireland
or
33
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
County Cork
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Gilead Sciences Belgium 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
Тел.: + 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
34
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/.
35
Source: European Medicines Agency
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