EMTRIVA 200mg capsules medication leaflet

Emtriva 200 mg hard capsules

Each hard capsule contains 200 mg of emtricitabine.

For the full list of excipients, see section 6.1.

Hard capsule.

Each capsule has a white opaque body with a light blue opaque cap, of dimensions 19.4 mm x 6.9 mm.

Each capsule is printed with “200 mg” on the cap and “GILEAD” and [Gilead logo] on the body inblack ink.

Emtriva is indicated in combination with other antiretroviral medicinal products for the treatment ofhuman immunodeficiency virus-1 (HIV-1) infected adults and children aged 4 months and over.

This indication is based on studies in treatment-naïve patients and treatment-experienced patients withstable virological control. There is no experience of the use of Emtriva in patients who are failingtheir 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, carefulconsideration should be given to the patterns of mutations associated with different medicinal productsand the treatment history of the individual patient. Where available, resistance testing may beappropriate.

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.

If a patient misses a dose of Emtriva within 12 hours of the time it is usually taken, the patient shouldtake Emtriva with or without food as soon as possible and resume their normal dosing schedule. If apatient misses a dose of Emtriva by more than 12 hours and it is almost time for their next dose, thepatient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Emtriva, another dose should be taken. If the patientvomits more than 1 hour after taking Emtriva they do not need to take another dose.

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 ofrenal insufficiency.

Renal insufficiency: Emtricitabine is eliminated by renal excretion and exposure to emtricitabine wassignificantly increased in patients with renal insufficiency (see section 5.2). Dose or dose intervaladjustment is required in all patients with creatinine clearance < 30 mL/min (see section 4.4).

Table 1 below provides dose interval adjustment guidelines for the 200 mg hard capsules according tothe degree of renal insufficiency. The safety and efficacy of the dose interval adjustments to every 72or 96 hours in patients with creatinine clearance < 30 mL/min have not been clinically evaluated.

Therefore, clinical response to treatment and renal function should be closely monitored in thesepatients (see section 4.4).

Patients with renal insufficiency can also be managed by administration of Emtriva 10 mg/mL oralsolution to provide a reduced daily dose of emtricitabine. Please refer to the Summary of Product

Characteristics for Emtriva 10 mg/mL oral solution.

Table 1: Dose interval guidelines for 200 mg hard capsules adjusted according to creatinineclearance

Creatinine clearance (mL/min)≥ 30 15-29 < 15 (functionallyanephric, requiringintermittenthaemodialysis)*

Recommended dose One 200 mg hard capsule One 200 mg hard capsule One 200 mg hard capsuleinterval for 200 mg every 24 hours every 72 hours every 96 hourshard capsules

* Assumes a 3-hour haemodialysis session three times a week commencing at least 12 h after administration of the last doseof emtricitabine.

Patients with end-stage renal disease (ESRD) managed with other forms of dialysis such asambulatory peritoneal dialysis have not been studied and no dose recommendations can be made.

Hepatic insufficiency: No data are available on which to make a dose recommendation for patientswith hepatic insufficiency. However, based on the minimal metabolism of emtricitabine and the renalroute of elimination it is unlikely that a dose adjustment would be required in patients with hepaticinsufficiency (see section 5.2).

If Emtriva is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patientsshould be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Paediatric population: The recommended dose of Emtriva for children aged 4 months and over andadolescents up to 18 years of age weighing at least 33 kg who are able to swallow hard capsules is one200 mg hard capsule, taken orally, once daily.

There are no data regarding the efficacy and only very limited data regarding the safety ofemtricitabine in infants below 4 months of age. Therefore Emtriva is not recommended for use inthose aged less than 4 months (for pharmacokinetic data in this age group, see section 5.2).

No data are available on which to make a dose recommendation in paediatric patients with renalinsufficiency.

Emtriva 200 mg hard capsules should be taken once daily, orally with or without food.

Emtriva is also available as a 10 mg/mL oral solution for use in infants aged 4 months and over,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 adifference in the bioavailability of emtricitabine between the hard capsule and oral solutionpresentations, 240 mg emtricitabine administered as the oral solution should provide similar plasmalevels to those observed after administration of one 200 mg emtricitabine hard capsule (seesection 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Emtricitabine is not recommended as monotherapy for the treatment of HIV infection. It must be usedin combination with other antiretrovirals. Please also refer to the Summaries of Product

Characteristics of the other antiretroviral medicinal products used in the combination regimen.

Emtriva should not be taken with any other medicinal products containing emtricitabine or medicinalproducts containing lamivudine.

Patients receiving emtricitabine or any other antiretroviral therapy may continue to developopportunistic infections and other complications of HIV infection, and therefore should remain underclose clinical observation by physicians experienced in the treatment of patients with HIV associateddiseases.

Emtricitabine is principally eliminated by the kidney via glomerular filtration and active tubularsecretion. Emtricitabine exposure may be markedly increased in patients with severe renalinsufficiency (creatinine clearance < 30 mL/min) receiving daily doses of 200 mg emtricitabine ashard 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 Emtriva10 mg/mL oral solution) is required in all patients with creatinine clearance < 30 mL/min. The safetyand efficacy of the dose interval adjustment guidelines provided in section 4.2 are based on singledose pharmacokinetic data and modelling and have not been clinically evaluated. Therefore, clinicalresponse to treatment and renal function should be closely monitored in patients treated withemtricitabine at prolonged dosing intervals (see sections 4.2 and 5.2).

Caution should be exercised when emtricitabine is co-administered with medicinal products that areeliminated by active tubular secretion as such co-administration may lead to an increase in serumconcentrations of either emtricitabine or a co-administered medicinal product, due to competition forthis elimination pathway (see section 4.5).

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. Patients with chronic hepatitis B or C infectiontreated with CART are at increased risk of experiencing severe, and potentially fatal, hepatic adverseevents. 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 oftreatment must be considered.

Patients co-infected with HBV

Emtricitabine is active in vitro against HBV. However, limited data are available on the efficacy andsafety of emtricitabine (as a 200 mg hard capsule once daily) in patients who are co-infected with HIVand HBV. The use of emtricitabine in patients with chronic HBV induces the same mutation patternin the YMDD motif observed with lamivudine therapy. The YMDD mutation confers resistance toboth emtricitabine and lamivudine.

Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratoryfollow-up for at least several months after stopping treatment with emtricitabine for evidence ofexacerbations of hepatitis. Such exacerbations have been seen following discontinuation ofemtricitabine treatment in HBV infected patients without concomitant HIV infection and have beendetected primarily by serum alanine aminotransferase (ALT) elevations in addition to re-emergence of

HBV DNA. In some of these patients, HBV reactivation was associated with more severe liverdisease, including decompensation and liver failure. There is insufficient evidence to determinewhether re-initiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis. Inpatients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended sincepost-treatment exacerbations of hepatitis may lead to hepatic decompensation.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown etiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples includecytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystisjirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted whennecessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to CART.

Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

Emtriva has not been studied in patients over the age of 65. Elderly patients are more likely to havedecreased renal function; therefore caution should be exercised when treating elderly patients with

Emtriva.

In addition to the adverse reactions experienced by adults, anaemia and skin discolouration occurredmore frequently in clinical trials involving HIV infected paediatric patients (see section 4.8).

Interaction studies have only been performed in adults.

In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzymeresponsible for glucuronidation. Based on the results of these in vitro experiments and the knownelimination pathways of emtricitabine, the potential for CYP450 mediated interactions involvingemtricitabine with other medicinal products is low.

There are no clinically significant interactions when emtricitabine is co-administered with indinavir,zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.

Emtricitabine is primarily excreted via glomerular filtration and active tubular secretion. With theexception of famciclovir and tenofovir disoproxil fumarate, the effect of co-administration ofemtricitabine with medicinal products that are excreted by the renal route, or other medicinal productsknown to affect renal function, has not been evaluated. Co-administration of emtricitabine withmedicinal products that are eliminated by active tubular secretion may lead to an increase in serumconcentrations of either emtricitabine or a co-administered medicinal product due to competition forthis elimination pathway.

There is no clinical experience as yet on the co-administration of cytidine analogues. Consequently,the use of emtricitabine in combination with lamivudine for the treatment of HIV infection cannot berecommended at this time.

A moderate amount of data on pregnant women (between 300 and1,000 pregnancy outcomes) indicateno malformations or foetal/neonatal toxicity associated with emtricitabine. Animal studies do notindicate reproductive toxicity. The use of emtricitabine may be considered during pregnancy, ifnecessary.

Emtricitabine has been shown to be excreted in human milk. There is insufficient information on theeffects of emtricitabine in newborns/infants. Therefore Emtriva should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

No human data on the effect of emtricitabine are available. Animal studies do not indicate harmfuleffects of emtricitabine on fertility.

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.

In clinical trials of HIV infected adults, the most frequently occurring adverse reactions toemtricitabine were diarrhoea (14.0%), headache (10.2%), elevated creatine kinase (10.2%) and nausea(10.0%). In addition to the adverse reactions reported in adults, anaemia (9.5%) and skindiscolouration (31.8%) occurred more frequently in clinical trials involving HIV infected paediatricpatients.

Discontinuation of Emtriva therapy in patients co-infected with HIV and HBV may be associated withsevere acute exacerbations of hepatitis (see section 4.4).

Assessment of adverse reactions from clinical study data is based on experience in three studies inadults (n = 1,479) and three paediatric studies (n = 169). In the adult studies, 1,039 treatment-naïveand 440 treatment-experienced patients received emtricitabine (n = 814) or comparator medicinalproduct (n = 665) for 48 weeks in combination with other antiretroviral medicinal products.

The adverse reactions with suspected (at least possible) relationship to treatment in adults from clinicaltrial and post-marketing experience are listed in Table 2 below by body system organ class andfrequency. Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) oruncommon (≥ 1/1,000 to < 1/100).

Table 2: Tabulated summary of adverse reactions associated with emtricitabine based on clinicalstudy and post-marketing experience

Frequency Emtricitabine

Common: neutropenia

Uncommon: anaemia2

Common: allergic reaction

Common: hypertriglyceridaemia, hyperglycaemia

Common: insomnia, abnormal dreams

Very common: headache

Common: dizziness

Very common: diarrhoea, nausea

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

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

Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skindiscolouration (increased pigmentation)1,2

Uncommon: angioedema3

Very common: elevated creatine kinase

Frequency Emtricitabine

Common: pain, asthenia1 See section 4.8, Description of selected adverse reactions for more details.2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine wasadministered to paediatric patients (see section 4.8, Paediatric population).3 This adverse reaction, which was identified through post-marketing surveillance, was not observed in randomisedcontrolled clinical trials in adults or paediatric HIV clinical trials of emtricitabine. The frequency category of uncommonwas estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in these clinicalstudies (n = 1,563).

Skin discolouration (increased pigmentation): Skin discolouration, manifested by hyperpigmentationmainly on the palms and/or soles, was generally mild, asymptomatic and of little clinical significance.

The mechanism is unknown.

Metabolic parameters: Weight and levels of blood lipids and glucose may increase duringantiretroviral therapy (see section 4.4).

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the timeof initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infectionsmay arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also beenreported; however, the reported time to onset is more variable and these events can occur manymonths after initiation of treatment (see section 4.4).

Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generallyacknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency ofthis is unknown (see section 4.4).

Assessment of adverse reactions in paediatric patients from clinical study data is based on experiencein three paediatric studies (n = 169) where treatment-naïve (n = 123) and treatment-experienced(n = 46) paediatric HIV infected patients aged 4 months to 18 years were treated with emtricitabine incombination with other antiretroviral agents.

In addition to the adverse reactions reported in adults (see section 4.8, Tabulated summary of adversereactions), the following adverse reactions were observed more frequently in paediatric patients:anaemia was common (9.5%) and skin discolouration (increased pigmentation) was very common(31.8%) in paediatric patients.

Other special population(s)

Elderly: Emtriva has not been studied in patients over the age of 65. Elderly patients are more likelyto have decreased renal function, therefore caution should be exercised when treating elderly patientswith Emtriva (see section 4.2).

Patients with renal impairment: Emtricitabine is eliminated by renal excretion and exposure toemtricitabine was significantly increased in patients with renal insufficiency. Dose or dose intervaladjustment is required in all patients with creatinine clearance < 30 mL/min (see sections 4.2, pct. 4.4 and5.2).

HIV/HBV co-infected patients: The adverse reaction profile in patients co-infected with HBV issimilar to that observed in patients infected with HIV without co-infection with HBV. However, aswould be expected in this patient population, elevations in AST and ALT occurred more frequentlythan in the general HIV infected population.

Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infectedwith HBV, exacerbations of hepatitis may occur after discontinuation of treatment (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Administration of up to 1,200 mg emtricitabine has been associated with the adverse reactions listedabove (see section 4.8).

If overdose occurs, the patient should be monitored for signs of toxicity and standard supportivetreatment applied as necessary.

Up to 30% of the emtricitabine dose can be removed by haemodialysis. It is not known whetheremtricitabine can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code:

J05AF09

Mechanism of action and pharmacodynamic effects

Emtricitabine is a synthetic nucleoside analogue of cytidine with activity that is specific to HIV-1,

HIV-2 and HBV.

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5’-triphosphate, whichcompetitively inhibits HIV-1 reverse transcriptase, resulting in DNA chain termination. Emtricitabineis 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), establishedlymphocyte and monocyte-macrophage cell lines or bone marrow progenitor cells in vitro. There wasno evidence of toxicity to mitochondria in vitro or in vivo.

Antiviral activity in vitro: The 50% inhibitory concentration (IC50) value for emtricitabine againstlaboratory and clinical isolates of HIV-1 was in the range of 0.0013 to 0.5 µmol/l. In combinationstudies of emtricitabine with protease inhibitors (PIs), nucleoside, nucleotide and non-nucleosideanalogue inhibitors of HIV reverse transcriptase, additive to synergistic effects were observed. Mostof these combinations have not been studied in humans.

When tested for activity against laboratory strains of HBV, the IC50 value for emtricitabine was in therange of 0.01 to 0.04 µmol/l.

Resistance: HIV-1 resistance to emtricitabine develops as the result of changes at codon 184 causingthe methionine to be changed to a valine (an isoleucine intermediate has also been observed) of the

HIV reverse transcriptase. This HIV-1 mutation was observed in vitro and in HIV-1 infected patients.

Emtricitabine-resistant viruses were cross-resistant to lamivudine, but retained sensitivity to othernucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, stavudine, tenofovir, abacavir anddidanosine), all non-nucleoside reverse transcriptase inhibitors (NNRTIs) and all PIs. Virusesresistant to zidovudine, didanosine and NNRTIs retained their sensitivity to emtricitabine(IC50 = 0.002 µmol/l to 0.08 µmol/l).

Emtricitabine in combination with other antiretroviral agents, including nucleoside analogues,non-nucleoside analogues and PIs, has been shown to be effective in the treatment of HIV infection intreatment-naïve patients and treatment-experienced patients with stable virological control. There isno experience of the use of emtricitabine in patients who are failing their current regimen or who havefailed multiple regimens.

In antiretroviral treatment-naïve adults, emtricitabine was significantly superior to stavudine whenboth medicinal products were taken in combination with didanosine and efavirenz through 48 weeksof treatment. Phenotypic analysis showed no significant changes in emtricitabine susceptibility unlessthe M184V/I mutation had developed.

In virologically stable treatment-experienced adults, emtricitabine, in combination with an NRTI(either stavudine or zidovudine) and a PI or an NNRTI was shown to be non-inferior to lamivudinewith respect to the proportion of responders (< 400 copies/mL) through 48 weeks (77% emtricitabine,82% lamivudine). Additionally, in a second study, treatment-experienced adults on a stable PI-basedhighly active antiretroviral therapy (HAART) regimen were randomised to a once daily regimencontaining emtricitabine or to continue with their PI-HAART regimen. At 48 weeks of treatment theemtricitabine-containing regimen demonstrated an equivalent proportion of patients with HIV RNA< 400 copies/mL (94% emtricitabine versus 92%) and a greater proportion of patients with HIV RNA< 50 copies/mL (95% emtricitabine versus 87%) compared with the patients continuing with their

PI-HAART regimen.

In infants and children older than 4 months, the majority of patients achieved or maintained completesuppression of plasma HIV-1 RNA through 48 weeks (89% achieved ≤ 400 copies/mL and 77%achieved ≤ 50 copies/mL).

There is no clinical experience of the use of emtricitabine in infants less than 4 months of age.

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasmaconcentrations occurring at 1 to 2 hours post-dose. In 20 HIV infected subjects receiving 200 mgemtricitabine daily as hard capsules, steady-state plasma emtricitabine peak concentrations (Cmax),trough concentrations (Cmin) and area under the plasma concentration time curve over a 24-hour dosinginterval (AUC) were 1.8 ± 0.7 µg/mL, 0.09 ± 0.07 µg/mL and 10.0 ± 3.1 µg·h/mL, respectively.

Steady-state trough plasma concentrations reached levels approximately 4-fold above the in vitro IC90values for anti-HIV activity.

The absolute bioavailability of emtricitabine from Emtriva 200 mg hard capsules was estimated to be93% 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 oralsolution was shown to have approximately 80% of the bioavailability of the Emtriva 200 mg hardcapsules. The reason for this difference is unknown. Due to this difference in bioavailability, 240 mgemtricitabine administered as the oral solution should provide similar plasma levels to those observedafter administration of one 200 mg emtricitabine hard capsule. Therefore, children who weigh at least33 kg may take either one 200 mg hard capsule daily or the oral solution up to a maximum dose of240 mg (24 mL), once daily.

Administration of Emtriva 200 mg hard capsules with a high-fat meal or administration of Emtriva10 mg/mL oral solution with a low-fat or high-fat meal did not affect systemic exposure (AUC0-∞) ofemtricitabine; therefore Emtriva 200 mg hard capsules and Emtriva 10 mg/mL oral solution may beadministered with or without food.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent ofconcentration over the range of 0.02-200 µg/mL. The mean plasma to blood concentration ratio wasapproximately 1.0 and the mean semen to plasma concentration ratio was approximately 4.0.

The apparent volume of distribution after intravenous administration of emtricitabine was1.4 ± 0.3 L/kg, indicating that emtricitabine is widely distributed throughout the body to bothintracellular and extracellular fluid spaces.

There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3’-sulphoxide diastereomers (approximately 9% of dose) andconjugation with glucuronic acid to form 2’-O-glucuronide (approximately 4% of dose).

Emtricitabine did not inhibit in vitro drug metabolism mediated by the following human CYP450isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4.

Also, emtricitabine did not inhibit uridine-5’-diphosphoglucuronyl transferase, the enzyme responsiblefor glucuronidation.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 mL/min (4.03 mL/min/kg). Following oral administration, the elimination half-life ofemtricitabine is approximately 10 hours.

The pharmacokinetics of emtricitabine are proportional to dose over the dose range of 25-200 mgfollowing single or repeated administration.

Intracellular pharmacokinetics: In a clinical study, the intracellular half-life ofemtricitabine-triphosphate in PBMCs was 39 hours. Intracellular triphosphate levels increased withdose, 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 mgemtricitabine hard capsules to 30 non-HIV infected subjects with varying degrees of renalinsufficiency. Subjects were grouped according to baseline creatinine clearance (> 80 mL/min asnormal function; 50-80 mL/min as mild impairment; 30-49 mL/min as moderate impairment;< 30 mL/min as severe impairment; < 15 mL/min as functionally anephric requiring haemodialysis).

The systemic emtricitabine exposure (mean ± standard deviation) increased from 11.8 ± 2.9 µg·h/mLin subjects with normal renal function to 19.9 ± 1.1, 25.0 ± 5.7 and 34.0 ± 2.1 µg·h/mL, in patientswith mild, moderate and severe renal impairment, respectively.

In patients with ESRD on haemodialysis, approximately 30% of the emtricitabine dose was recoveredin dialysate over a 3-hour dialysis period which had been started within 1.5 hours of emtricitabinedosing (blood flow rate of 400 mL/min and dialysate flow rate of approximately 600 mL/min).

The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects withvarying degrees of hepatic insufficiency. In general, emtricitabine pharmacokinetics in HBV infectedsubjects were similar to those in healthy subjects and in HIV infected subjects.

Pharmacokinetic data are not available in the elderly (over 65 years of age).

Although the mean Cmax and Cmin were approximately 20% higher and mean AUC was 16% higher infemales compared to males, this difference was not considered clinically significant.

No clinically important pharmacokinetic difference due to ethnicity has been identified.

In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 monthsup 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 asoral solution or 200 mg emtricitabine as hard capsules once daily was similar to the mean AUC of10.0 µg·h/mL in 20 adults receiving 200 mg hard capsules once daily.

In an open-label, non-comparative study, pharmacokinetic data were obtained from 20 neonates of

HIV infected mothers who received two 4-day courses of emtricitabine oral solution between the firstweek of life and 3 months of age at a dose level of 3 mg/kg once daily. This dose is half of thatapproved for infants aged 4 months and over (6 mg/kg). The apparent total body clearance atsteady-state (CL/F) increased with age over the 3-month period with a corresponding decrease in

AUC. Plasma emtricitabine exposure (AUC) in infants up to 3 months of age who received 3 mg/kgemtricitabine once daily was similar to that observed using 6 mg/kg daily doses in HIV infected adultsand children aged 4 months and over.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction and development.

Crospovidone

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Povidone (E1201)

Gelatin

Indigotine (E132)

Titanium dioxide (E171)

Printing ink containing

Black iron oxide (E172)

Shellac (E904)

Not applicable.

Bottle4 years

Blister3 years

This medicinal product does not require any special storage conditions.

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure, containing30 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 medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/03/261/001

EU/1/03/261/002

Date of first authorisation: 24 October 2003

Date of latest renewal: 22 September 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.