Emtriva 200 mg hard capsules

Each hard capsule contains 200 mg emtricitabine.

For a full list of excipients, see section 6.1.

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.

Emtriva is indicated for the treatment of HIV1 infected adults and children in combination with other antiretroviral agents.

This indication is based on studies in treatmentnaïve patients and treatmentexperienced 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 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).

The table 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.

* 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 endstage 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.

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 coadministered with medicinal products that are eliminated by active tubular secretion as such coadministration may lead to an increase in serum concentrations of either emtricitabine or a coadministered 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), nonspecific 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 coinfected 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 longterm 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 coinfected 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 coinfected with HIV and HBV. The use of emtricitabine in patient 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 coinfected 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 reemergence 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.

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 carinii 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 HIVdisease and/or longterm 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.

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 coadministered 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 coadministration 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. Coadministration 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 coadministered medicinal product due to competition for this elimination pathway.

There is no clinical experience as yet on the coadministration 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 breastfeed 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.

Assessment of adverse reactions is based on data from three studies in adults (n=1,479) and three paediatric studies (n=169). In the adult studies, 1,039 treatmentnaïve and 440 treatmentexperienced patients received emtricitabine (n=814) or comparator medicinal product (n=665) for 48 weeks in combination with other antiretroviral medicinal products. In three paediatric studies, treatmentnaïve (n=123) and treatmentexperienced (n=46) paediatric patients aged 4 months to 18 years were treated with emtricitabine in combination with other antiretroviral agents.

The adverse reactions with suspected (at least possible) relationship to treatment in adults are listed below by body system organ class and absolute 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, < 1/10) or uncommon ( 1/1,000, < 1/100).

Blood and lymphatic system disorders:

Common: neutropenia

Uncommon: anaemia

Metabolism and nutrition disorders:

Common: hypertriglyceridaemia, hyperglycaemia

Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues (see section 4.4).

Psychiatric disorders:

Common: insomnia, abnormal dreams

Nervous system disorders:

Very common: headache

Common: dizziness

Gastrointestinal disorders:

Very common: diarrhoea, nausea

Common: vomiting, abdominal pain, elevated amylase including elevated pancreatic amylase, elevated serum lipase, dyspepsia

Hepatobiliary disorders:

Common: hyperbilirubinaemia, elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT)

Skin and subcutaneous tissue disorders:

Common: allergic reaction, urticaria, vesiculobullous rash, pustular rash, maculopapular rash, pruritus, rash, and skin discolouration (hyperpigmentation)

Musculoskeletal and connective tissue disorders:

Very common: elevated creatine kinase

General disorders and administration site conditions:

Common: asthenia, pain

In addition to the adverse reactions reported in adults, anaemia was common and skin discolouration (hyperpigmentation) was very common in paediatric patients.

The adverse reaction profile in patients coinfected with HBV is similar to that observed in patients infected with HIV without coinfection 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.

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 intraabdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).

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).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or longterm exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (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.

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 (HIV1 and HIV2) and hepatitis B virus (HBV).

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'triphosphate, which competitively inhibits HIV1 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 (IC₅₀) value for emtricitabine against laboratory and clinical isolates of HIV1 was in the range of 0.0013 to 0.5 µmol/l. In combination studies of emtricitabine with protease inhibitors, nucleoside, nucleotide and nonnucleoside 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 (IC₅₀) value for emtricitabine was in the range of 0.01 to 0.04 µmol/l.

Resistance: HIV1 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 HIV1 mutation was observed in vitro and in HIV1 infected patients.

Emtricitabine-resistant viruses were crossresistant to lamivudine, but retained sensitivity to other nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, stavudine, tenofovir, abacavir, didanosine and zalcitabine), all nonnucleoside reverse transcriptase inhibitors (NNRTIs) and all protease inhibitors (PIs). Viruses resistant to zidovudine, zalcitabine, didanosine and NNRTIs retained their sensitivity to emtricitabine (IC₅₀=0.002 µmol/l to 0.08 µmol/l).

Clinical experience: Emtricitabine in combination with other antiretroviral agents, including nucleoside analogues, nonnucleoside analogues and protease inhibitors, has been shown to be effective in the treatment of HIV infection in treatmentnaïve patients and treatmentexperienced 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 treatmentnaïve 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 noninferior to lamivudine with respect to the proportion of responders (< 400 copies/ml) through 48 weeks (77% emtricitabine, 82% lamivudine). Additionally, in a second study, treatmentexperienced 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 PIHAART regimen. At 48 weeks of treatment the emtricitabinecontaining 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 PIHAART regimen.

In infants and children older than 4 months, the majority of patients achieved or maintained complete suppression of plasma HIV1 RNA through 48 weeks (89% achieved 400 copies/ml and 77% achieved 50 copies/ml).

Absorption: Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours postdose. In 20 HIV infected subjects receiving 200 mg emtricitabine daily as hard capsules, steadystate plasma emtricitabine peak concentrations (C_max), trough concentrations (C_min) and area under the plasma concentration time curve over a 24hour 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. Steadystate trough plasma concentrations reached levels approximately 4fold above the in vitro IC₉₀ 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 (AUC₀) 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 0.02200 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'Oglucuronide (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 uridine5'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 halflife of emtricitabine is approximately 10 hours.

Linearity/nonlinearity: The pharmacokinetics of emtricitabine are proportional to dose over the dose range of 25200 mg following single or repeated administration.

Intracellular pharmacokinetics: In a clinical study, the intracellular halflife of emtricitabinetriphosphate 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 nonHIV infected subjects with varying degrees of renal insufficiency. Subjects were grouped according to baseline creatinine clearance (> 80 ml/min as normal function; 5080 ml/min as mild impairment; 3049 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 nonHBV 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 4day 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 3month 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.

Nonclinical 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.

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)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

White high-density polyethylene (HDPE) bottle fitted with a childresistant closure, containing 30 hard capsules.

Blisters made of polychlorotrifluorethylene (PCTFE) / polyethylene (PE) / polyvinylchloride (PVC) / aluminium. Each blister pack contains 30 hard capsules.

Pack size: 30 hard capsules.

Any unused product or waste material should be disposed of in accordance with local requirements.

Gilead Sciences International Limited

Cambridge

CB21 6GT

United Kingdom

EU/1/03/261/001

EU/1/03/261/002

Date of first authorisation: 24 October 2003

Date of last renewal: 22 September 2008

09/2008

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.