Consumer medicine information

EMTRIVA CAPSULES

Emtricitabine

BRAND INFORMATION

Brand name

Emtriva Capsules

Active ingredient

Emtricitabine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using EMTRIVA CAPSULES.

What is in this leaflet

This leaflet answers some of the common questions about EMTRIVA capsules. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist about your medical condition or treatment. If you have further questions, please ask your doctor or your pharmacist.

Keep this leaflet with your EMTRIVA capsules. You may need to read it again.

This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

What EMTRIVA capsules are used for

EMTRIVA is used to treat Human Immunodeficiency Virus (HIV) infection in adults and paediatric patients 12 years of age or older who weigh more than 33 kg. This medicine must be taken in combination with other anti-HIV medicines.

EMTRIVA belongs to a group of antiviral medicines, called nucleoside reverse transcriptase inhibitors (NRTIs).

This medicine is not a cure for HIV infection. While taking EMTRIVA you may still develop infections or other illnesses associated with HIV infection.

How EMTRIVA works

HIV infection destroys CD4 T cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) may develop.

EMTRIVA helps block HIV-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. EMTRIVA lowers the amount of HIV in the blood (viral load). EMTRIVA may also help to increase the number of T cells (CD4+ cells), allowing your immune system to improve. Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Before you take EMTRIVA

Who must not take it

Do not take EMTRIVA if you are allergic to:

  • emtricitabine or
  • any of the other ingredients of EMTRIVA.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue or other parts of the body

These are very serious effects. If you have them, you may have a serious allergic reaction. You may need urgent medical attention or hospitalisation. All of these side effects are very rare.

Do not take EMTRIVA, if you are already taking any other medicines that contain the same active ingredients such as:

  • TRUVADA
  • ATRIPLA
  • EVIPLERA
  • STRIBILD
  • GENVOYA

Do not take EMTRIVA if you are taking other medicines that contain:

  • lamivudine (e.g. Combivir, 3TC, Zeffix, Kivexa, Trizivir)

Do not take EMTRIVA if you are over the age of 65 before discussing this with your doctor.

Do not take EMTRIVA after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking EMTRIVA, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant, trying to become pregnant or breast feeding.

The safe use of EMTRIVA in human pregnancy has not been demonstrated. For this reason, it is important that women of child-bearing age receiving treatment with EMTRIVA use an effective method of contraception to avoid becoming pregnant. The active substance in this medicine (emtricitabine) has been found in breast milk at low concentrations. Consequently, it is recommended that nursing mothers do not breast-feed during treatment with EMTRIVA. In general, women infected with HIV should not breast-feed their infants in order to avoid transmission of HIV to their newborn infant.

Tell your doctor if you have or have ever had liver problems including hepatitis B infection.

Tell your doctor if you have or have ever had kidney problems.

This medicine is only available from a pharmacist after it has been prescribed by a doctor who specialises in the treatment of HIV infection. If you wish to continue receiving treatment with EMTRIVA it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV infection.

EMTRIVA does not reduce the risk of passing HIV to others through sexual contact or blood contamination. Therefore, it is important to continue to take appropriate precautions to prevent passing HIV to others.

If you have a long standing viral infection of your liver (hepatitis B) it may flare up when you stop taking EMTRIVA. This can cause serious illness particularly if your liver is already not working very well. If you have both HIV and hepatitis B, when you start taking your EMTRIVA capsules and even after you stop, your doctor is likely to arrange tests from time to time to check how well your liver is working.

Your doctor can discuss with you the benefits and risks of taking EMTRIVA.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking EMTRIVA.

Taking other medicines

Your doctor will generally prescribe EMTRIVA in combination with a number of other anti-HIV medicines.

Tell your doctor or pharmacist if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when taking EMTRIVA with other medicines.

How to take EMTRIVA

Always take the dose recommended by your doctor to ensure that your medicine is fully effective and to reduce the development of drug resistance.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Take one EMTRIVA 200 mg capsule once daily with or without food or as advised by your doctor.

If you are not sure how much EMTRIVA you should take, check with your doctor or pharmacist. Do not change the amount of EMTRIVA you take unless told to do so by your doctor.

Your doctor will tell you how much EMTRIVA to take and how often to take them. You will also find this information on the label of your medicine container.

EMTRIVA is absorbed rapidly. Do not take another EMTRIVA 200 mg capsule if vomiting has occurred unless it occurs within 1 hour after taking EMTRIVA.

How long to take it

Because your medicine helps to control your condition, but does not cure it, you will need to take EMTRIVA every day. Do not stop taking EMTRIVA without first talking to your doctor.

If you forget to take it

It is important to take the prescribed daily dose in order to get the maximum benefit of treatment.

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.

Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you have missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, pharmacist or Poisons Information Centre 13 11 26 (Australia) and 0800 764 766 (New Zealand) or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much EMTRIVA. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking EMTRIVA

Things you must do

Tell your doctor or pharmacist that you are taking EMTRIVA if you are about to be started on any other medicines.

If you feel that EMTRIVA is not helping your condition, tell your doctor or pharmacist.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if for any reason you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor as soon as possible if there is any worsening of your condition.

Things you must not do

Do not give EMTRIVA to anyone else, even if they have the same condition as you.

Do not stop taking EMTRIVA capsules or change the dose without first checking with your doctor.

It is important not to suddenly stop taking your EMTRIVA capsules, unless advised to do so by your doctor, since your condition may worsen.

Do not use EMTRIVA to treat any other complaints unless you doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how EMTRIVA affects you.

Side effects

Like all medicines, EMTRIVA can have side effects. Some may be serious and need medical attention.

Check with your doctor as soon as possible if you have any problems while taking EMTRIVA, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Headache
  • Nausea
  • Diarrhoea
  • Muscle pain and weakness
  • Dizziness
  • Skin rash
  • Changes in skin colour on the palms of the hands or soles of the feet
  • Fatigue/Tiredness
  • Difficulty sleeping
  • Abnormal dreams
  • Pain
  • Vomiting
  • Problems with digestion

Redistribution, accumulation or loss of body fat may occur in people receiving combination antiretroviral therapy. Contact your doctor if you notice changes in body fat.

Ask your doctor or pharmacist to answer any question you may have about these or other effects.

Serious Liver Problems (hepatotoxicity)
If you have any of the following symptoms after starting taking your medication DO NOT TAKE ANY MORE EMTRIVA OR OTHER ANTI-HIV MEDICINES and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital.

  • Your skin or the white part of your eyes turn yellow (jaundice)
  • Your urine turns dark
  • Your bowel movements (stools) turn light in colour
  • Nausea
  • Stomach pains

These side effects may be due to a condition called hepatotoxicity with liver enlargement and fat deposits in the liver (steatosis) which sometimes occurs in patients taking anti-HIV medicines.

Lactic Acidosis
If you have any of the following symptoms after taking your medication DO NOT TAKE ANY MORE EMTRIVA OR OTHER ANTI-HIV MEDICINES and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital.

  • You feel very weak or tired.
  • You have unusual (not normal) muscle pain.
  • You have trouble breathing.
  • You have stomach pain with nausea and vomiting
  • You feel cold, especially in your arms and legs.
  • You feel dizzy or lightheaded.
  • You have a fast or irregular heartbeat.

These side effects may be due to a condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis can be a medical emergency and may need to be treated in the hospital.

Hepatic Flares
If you have HIV infection and chronic hepatitis B infection you should not stop your EMTRIVA treatment without first discussing this with your doctor, as some patients have had blood tests or symptoms indicating a worsening of their hepatitis (“hepatic flare”) after stopping EMTRIVA. You may require blood tests for several months after stopping treatment.

Other side effects
This list of side effects is not complete. There have been other side effects in patients taking EMTRIVA. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Some people may get other side effects while taking EMTRIVA. If you are concerned, talk to your doctor or pharmacist.

Ask your doctor or pharmacist if you don’t understand anything in this list.

Do not be alarmed by this list of possible side-effects. Most of them are very rare and you may not experience any of them.

After taking EMTRIVA

Storage

Keep your EMTRIVA capsules in the bottle with the cap tightly closed until you take them.

Keep EMTRIVA capsules in a cool, dry place where it stays below 30°C.

Do not store EMTRIVA or any other medicine in a bathroom or near a sink. Do not leave them in the car or on a window sill – heat and dampness can destroy some medicines.

Keep EMTRIVA capsules where children cannot reach them.

A locked cupboard at least one-and-a half metres above the ground is a good place to store them.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

EMTRIVA is the brand name of your medicine.

EMTRIVA 200 mg hard capsules have a white opaque body with a light blue opaque cap. Each capsule is printed with “200 mg” on the white cap and “GILEAD” and the Gilead shield logo on the white body in black ink. EMTRIVA capsules are supplied in bottles containing 30 capsules.

Ingredients

Each EMTRIVA capsule contains 200 mg emtricitabine.

Each EMTRIVA capsule also contains the following ingredients:

  • Cellulose, microcrystalline
  • Crospovidone
  • Magnesium stearate
  • Povidone
  • Purified water
  • Capsule shell
  • Printing ink

Sponsor

Australia
Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne, Victoria 3004

New Zealand
Gilead Sciences (NZ)
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

AUST R 96426, 96427

Date of preparation: 4 July 2016

VIREAD, EMTRIVA, TRUVADA, EVIPLERA, STRIBILD, GENVOYA and HEPSERA are registered trademarks of Gilead Sciences, Inc. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. Other brands listed are trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, or Bristol-Myers Squibb & Gilead Sciences, LLC.

BRAND INFORMATION

Brand name

Emtriva Capsules

Active ingredient

Emtricitabine

Schedule

S4

 

1 Name of Medicine

Emtricitabine.

6.7 Physicochemical Properties

Emtricitabine is a synthetic nucleoside analogue, designated chemically as 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan 5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analogue of cytidine, which differs from other cytidine analogues in that it has a fluorine in the 5-position. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24.
Emtricitabine is a white to off white powder with a solubility of approximately 112 mg/mL in water at 25°C. The log P for emtricitabine is -0.43 and the pKa is 2.65.

Chemical structure.


CAS number.

143491-57-0.

2 Qualitative and Quantitative Composition

Emtriva is available as 200 mg hard capsules.
The active substance in Emtriva hard capsules is emtricitabine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Emtriva capsule has a white opaque body with 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Emtricitabine belongs to the nucleoside and nucleotide reverse transcriptase inhibitors pharmacotherapeutic group (ATC code: J05AF09).

Mechanism of action.

Emtricitabine is a synthetic nucleoside analogue of cytidine with activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus (HBV).
Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate is a competitive inhibitor of the HIV-1 reverse transcriptase, which results in DNA chain termination. Emtricitabine is a weak inhibitor of mammalian DNA polymerase α, β and ε and mitochondrial DNA polymerase γ in vitro.

Antiviral activity in vitro.

The in vitro antiviral activity of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% inhibitory concentration (IC50) value for emtricitabine was in the range of 0.0013 to 0.64 micromolar. In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine (3TC), stavudine (d4T), tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Emtricitabine displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F and G (IC50 values ranged from 0.007 to 0.075 micromolar) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 micromolar).
When tested for activity against laboratory strains of HBV, the 50% inhibitory concentration (EC50) value for emtricitabine was in the range of 0.01 to 0.04 micromol/L.

Clinical virology.

HIV resistance to emtricitabine develops as the result of changes at codon 184 causing the methionine to be changed to a valine (an isoleucine intermediate has also been observed) of the HIV reverse transcriptase. This HIV mutation was observed in vitro and in HIV infected patients.
Genotypic resistance analysis was performed in study 301A (see Section 5.1 Pharmacodynamic Properties, Clinical trials). This study was a double blind, active controlled multicentre study comparing emtricitabine administered in combination with didanosine and efavirenz versus d4T, didanosine and efavirenz in 571 antiretroviral naïve adult patients. Genotypic resistance analysis was performed in 48 of the 50 patients with virological failure (greater than 400 copies/mL) identified during the course of the study (13 in the emtricitabine group and 35 of the 37 patients with failure in the d4T group). Virological failure with at least 1 new genotypic mutation developed in 12/286 (4%) patients in the emtricitabine group and 31/285 (11%) in the d4T group (p = 0.005). Of these patients, 11 and 31 patients, respectively developed a NNRTI associated mutation. Five of the 11 emtricitabine group patients developed the M184/I mutation in addition to the NNRTI mutation and 1 developed a mutation at position K65N (possibly associated with didanosine).

Cross resistance.

Cross resistance among certain nucleoside analog reverse transcriptase inhibitors has been recognised (see Section 4.4 Special Warnings and Precautions for Use). Emtricitabine resistant viruses with the M184V mutation are cross resistant with lamivudine and zalcitabine. Viruses with the K65R mutation selected for in vivo by use of abacavir, didanosine, tenofovir and zalcitabine demonstrate reduced susceptibility to inhibition by emtricitabine. Viruses which harbour mutations which confer reduced susceptibility to other NRTIs i.e. d4T and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) or the NNRTI group (K103N), remained sensitive to emtricitabine.
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.

Clinical trials.

Adult patients.

Study 301A: Emtriva once daily + didanosine once daily + efavirenz once daily compared to d4T twice daily + didanosine once daily + efavirenz once daily.

Study 301A was a 48 week double blind, active controlled multicentre study comparing Emtriva (200 mg once daily) administered in combination with didanosine and efavirenz versus d4T, didanosine and efavirenz in 571 antiretroviral naïve adult patients. Patients had a mean age of 36 years (range 18 to 69), 85% were male, 52% Caucasian, 16% African American and 26% Hispanic. Patients had a mean baseline CD4 cell count of 318 cells/mm3 (range 5-1317) and a median baseline plasma HIV RNA of 4.9 log10 copies/mL (range 2.6-7.0). Thirty-eight percent of patients had baseline viral loads > 100,000 copies/mL and 31% had CD4 cell counts < 200 cells/mL. Treatment outcomes are presented in Table 6.
The mean increase from baseline in CD4 cell count was 168 cells/mm3 for the Emtriva arm and 134 cells/mm3 for the d4T arm.
Through 48 weeks in the Emtriva group, 5 patients (1.7%) experienced a new CDC class C event, compared to 7 patients (2.5%) in the d4T group.

Study 303: Emtriva once daily + stable background therapy (SBT) compared to lamivudine BID + SBT.

Study 303 was a 48 week, open label, active controlled multicentre study comparing Emtriva (200 mg once daily) to lamivudine, in combination with d4T or zidovudine and a protease inhibitor or NNRTI in 440 adult patients who were on a lamivudine containing triple antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV-1 RNA ≤ 400 copies/mL.
Patients were randomised 1:2 to continue therapy with lamivudine (150 mg BID) or to switch to Emtriva (200 mg once daily). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22-80), 86% were male, 64% Caucasian, 21% African American and 13% Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm3 (range 37-1909), and a median baseline plasma HIV RNA of 1.7 log10 copies/mL (range 1.7-4.0).
The median duration of prior antiretroviral therapy was 27.6 months. (See Table 7.)
The mean increase from baseline in CD4 cell count was 29 cells/mm3 for the Emtriva arm and 61 cells/mm3 for the lamivudine arm.
Through 48 weeks, in the Emtriva group 2 patients (0.7%) experienced a new CDC class C event, compared to 2 patients (1.4%) in the lamivudine group.

Study 934: Emtriva + Viread + efavirenz compared with Combivir (lamivudine/ zidovudine) + efavirenz.

Study 934 is a randomized, open label, active controlled multicentre study comparing two different dosing regimens in 511 antiretroviral naïve HIV-1 infected adult patients. Patients were randomised to receive either Emtriva + Viread administered in combination with efavirenz or Combivir (lamivudine/ zidovudine) administered in combination with efavirenz. For patients randomised to receive Emtriva + Viread the two drugs were administered individually for the first 96 weeks and then switched to Truvada (fixed dose combination of tenofovir DF 300 mg/ emtricitabine 200 mg) during weeks 96 to 144, without regard to food.
For inclusion in the study, antiretroviral treatment naïve adult patients (≥ 18 years) with plasma HIV RNA greater than 10,000 copies/mL must have an estimated glomerular filtration rate as measured by Cockroft-Gault method of ≥ 50 mL/min, adequate haematologic function, hepatic transaminases and alanine aminotransferases ≤ 3 x ULN, total bilirubin ≤ 1.5 mg/dL, serum amylase ≤ 1.5 x ULN and serum phosphorus ≥ 2.2 mg/dL. Exclusion criteria included: a new AIDS defining condition diagnosed within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents that interacted with efavirenz, pregnancy/ lactation, a history of clinically significant renal/ bone disease or malignant disease other than Kaposi's sarcoma or basal cell carcinoma, or a life expectancy of less than one year. If efavirenz associated central nervous system toxicities occurred, nevirapine could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment regimen after week 48 or 96 and during the 30 day extension study window were not eligible to continue to weeks 96 or 144, respectively.
Patients had a mean age of 38 years (range 18 to 80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm3 (range 2 to 1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56 to 6.54). Patients were stratified by baseline CD4 count (< or ≥ 200 cells/mm3); 41% had CD4 cell counts < 200 cells/mm3 and 51% of patients had baseline viral loads > 100,000 copies/mL. Treatment outcomes at 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 8.
In this study, Emtriva + Viread in combination with efavirenz was statistically significantly superior to Combivir in combination with efavirenz with regards to the primary and secondary endpoints: achieving and maintaining HIV-1 RNA < 400 copies/mL through 48 and 144 weeks (Table 6). The difference in the proportions of responders between the Emtriva + Viread group and the Combivir group was 11.4%, and the 95% CI was 4.3% to 18.6% (p = 0.002) at week 48 and a difference of 12.9% (95% CI was 4.2% to 21.6%, p = 0.004) at week 144.
Through 48 weeks of therapy, 80% and 70% of patients in the Emtriva + Viread and the Combivir arms, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL. The difference in the proportions of responders between the Emtriva + Viread group and the Combivir group was 9.1%, and the 95% CI was 1.6% to 16.6% (p = 0.021) at week 48. The proportion of patients responding at 144 weeks of therapy was higher in the Truvada group (64%) compared with the Combivir group (56%); p = 0.082, a difference of 8.1% and the 95% CI was -0.8% to 17.0%.
The mean increase from baseline in CD4 cell count was 190 cells/mm3 and 312 cells/mm3 for the Emtriva + Viread + efavirenz arm, and 158 cells/mm3 and 271 cells/mm3 for the Combivir + efavirenz arm (p = 0.002 and p = 0.088) at weeks 48 and 144, respectively.
Resistance analysis was performed on HIV isolates from all patients with > 400 copies/mL of HIV-1 RNA at week 144 while on study drug or after treatment switch. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed in both treatment arms. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the Truvada group and in 72% (21/29) analysed patients in the Combivir group. The M184V mutation, associated with resistance to emtricitabine and lamivudine developed significantly less in the analysed patients in the Truvada group 11% (2/19) compared with the analysed patients in the Combivir group, 34% (10/29). Two patients in the Combivir group developed thymidine analog mutations, specifically D67N or K70R mutations in the reverse transcriptase gene.

Paediatric patients.

Studies FTC-202, FTC-203 and FTC-211.

In three open label, nonrandomized clinical studies (studies FTC-202, FTC-203, and FTC-211), Emtriva was administered to 169 HIV-1 infected treatment naïve and experienced (defined as virologically suppressed on a lamivudine containing regimen for which Emtriva was substituted for lamivudine) patients in the following age groups: 3 to 24 months, 25 months to 6 years (FTC-203 only), 7 to 12 years, 13 to 17 years and 18 to 21 years.
Through 48 weeks of therapy, the overall proportion of patients who achieved and sustained an HIV-1 RNA < 400 copies/mL was 86%, and < 50 copies/mL was 73%. The mean increase from baseline in CD4 cell count was 232 cells/mm3 (-945, +1512).

5.2 Pharmacokinetic Properties

The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV infected individuals. Emtricitabine pharmacokinetics are similar between these populations.
Figure 1 shows the mean steady-state plasma emtricitabine concentration time profile in 20 HIV infected subjects receiving Emtriva.

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, steady-state plasma emtricitabine peak concentrations (Cmax), trough concentrations (Cmin) and area under the plasma concentration time curve over a 24 hour dosing interval (AUC) were 1.8 ± 0.7 microgram/mL, 0.09 ± 0.7 microgram/mL and 10.0 ± 3.1 hour.microgram/mL, respectively. The mean steady-state plasma trough concentration at 24 hours postdose was equal to or greater than the mean in vitro IC90 value for anti-HIV activity (IC90 0.09 microgram/mL).
The absolute bioavailability of Emtriva 200 mg capsules was estimated to be 93%.

Effects of food on oral absorption.

Administration of emtricitabine 200 mg hard capsules with a high fat meal did not affect systemic exposure (AUC0-∞) whilst Cmax decreased by 29%. Therefore Emtriva 200 mg hard capsules may be administered with or without food.

Distribution.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02-200 microgram/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0. Distribution of emtricitabine to central nervous system has not been studied.
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.

Metabolism.

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following oral administration of 14C-emtricitabine, complete recovery of the dose was achieved in urine (~ 86%) and faeces (~ 14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~ 4% of dose). No other metabolites were identifiable.

Excretion.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (~ 86%) and faeces (~ 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/minute (4.03 mL/min/kg). Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours. The renal clearance of emtricitabine is greater than the estimated creatinine clearance, which suggests elimination by both glomerular filtration and active tubular secretion.

Linearity/ nonlinearity.

The pharmacokinetics of emtricitabine are proportional to dose over a dose range of 25 to 200 mg following single or repeated administration.

Age and gender.

In general, emtricitabine pharmacokinetics in children (aged 12 to 18 years of age) are similar to those seen in adults. The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly. No clinically important differences have been identified due to gender or ethnicity.

Renal impairment.

The pharmacokinetics of emtricitabine are altered in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use). In patients with creatinine clearance < 50 mL/min or with endstage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to a reduction in renal clearance (see Table 9). It is required that the dosing interval for Emtriva be modified in patients with creatinine clearance < 50 mL/min or in patients with ESRD who require dialysis (see Section 4.2 Dose and Method of Administration).
In patients with ESRD requiring haemodialysis approximately 30% of the emtricitabine dose was recovered in dialysate over a 3 hour dialysis period started within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of approximately 600 mL/min).

Hepatic impairment.

Pharmacokinetics of emtricitabine have not been fully elucidated in persons with hepatic impairment.

Pharmacokinetic/ pharmacodynamic relationship.

The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25 to 400 mg a day of Emtriva as monotherapy for 10 to 14 days. A dose related antiviral effect was observed, with a median decrease from baseline in plasma HIV RNA of 1.3 log10 at a dose of 25 mg once daily and 1.7 log10 to 1.9 log10 at a dose of 200 mg once daily.

Intracellular pharmacokinetics.

In a clinical study the intracellular half-life of emtricitabine triphosphate in peripheral blood mononuclear cells (PBMCs) was 39 hours and intracellular triphosphate levels increased with dose, but reached a plateau at doses of 200 mg or greater.

Pharmacokinetic drug interactions.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit uridine-5-diphosphoglucuronyl transferase, 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.
Emtriva has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), indinavir, famciclovir, zidovudine and d4T. Table 10 and Table 11 summarise the pharmacokinetic effects of coadministered drugs on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.
There are no clinically significant interactions when emtricitabine is coadministered with either indinavir, zidovudine, d4T, famciclovir or tenofovir disoproxil fumarate.
There is no clinical experience of coadministration of emtricitabine with other cytidine analogues. Use of emtricitabine in combination with lamivudine or zalcitabine is not recommended.
Emtricitabine is primarily excreted renally via glomerular filtration and active tubular secretion. Apart from famciclovir and tenofovir disoproxil fumarate, the effect of coadministration of 200 mg emtricitabine with medicinal products that are excreted renally, or other medicinal products known to affect renal function has not been evaluated. Coadministration of 200 mg 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.

5.3 Preclinical Safety Data

Genotoxicity.

Emtricitabine is not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.

Carcinogenicity.

There was no evidence of tumourigenesis in mice or rats given emtricitabine for 2 years at oral doses up to 750 mg/kg/day and 600 mg/kg/day, (30-33 and 34-42 times the clinical exposure based on AUC, respectively).

4 Clinical Particulars

4.1 Therapeutic Indications

Emtriva is indicated for the treatment of HIV in combination with other antiretroviral agents in adults and paediatric patients 12 years of age and older, weighing more than 33 kg.
Evidence to support this claim is based on surrogate markers (plasma HIV RNA and CD4 count) in antiretroviral naïve individuals and in antiretroviral experienced individuals with virological suppression (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Emtriva is contraindicated in patients with known hypersensitivity to emtricitabine or any other components of the capsule.
Emtriva should not be administered concomitantly with other products containing emtricitabine or products containing lamivudine.

4.4 Special Warnings and Precautions for Use

General.

Emtricitabine is not recommended for use in monotherapy for the treatment of HIV infection.
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.
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. There is no experience of using emtricitabine in patients who are failing their current regimen or who have failed multiple regimens.

Lactic acidosis/ severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, in the treatment of HIV infection. A majority of cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Patients at increased risk should be followed closely and dosing suspended in any patient who develops clinical/ laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
All patients, with or without identifiable risk factors, may develop this adverse event.

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.

Post-treatment exacerbation of hepatitis.

The safety and efficacy of emtricitabine in patients coinfected with HIV and HBV has not been fully established. Exacerbations of hepatitis B have been reported after discontinuation of emtricitabine treatment. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. In some of these patients, HBV reactivation was associated with more severe liver disease, including decompensation and liver failure.
Therefore, it is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy. Coinfected patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine. There is insufficient evidence to determine whether reinitiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis.

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, 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 antiretroviral therapy. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.

Use in hepatic impairment.

Emtricitabine has not been evaluated in non-HBV infected patients with hepatic impairment.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.

Use in renal impairment.

Emtricitabine is principally eliminated by the kidney via glomerular filtration and active tubular secretion. Coadministration of 200 mg 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 of this elimination pathway. Reduction of dosage is recommended for patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

Clinical studies of Emtriva did not contain sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety and efficacy of Emtriva in patients between 12 to 17 years of age is supported by data from three open label, nonrandomised clinical studies FTC-203, FTC-202 and FTC-211 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The potential for drug interactions with Emtriva has been studied in combination with indinavir, zidovudine, d4T, famciclovir and tenofovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic drug interactions).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Emtricitabine did not affect fertility in female and male mice or in male rats at oral doses up to 1000 mg/kg/day and 3000 mg/kg/day (52-77 and 132 times the clinical exposure based on AUC, respectively). No fertility effects were observed in the offspring of mice given up to 1000 mg/kg/day oral emtricitabine (52 times the clinical exposure based on AUC) from gestation through lactation.
(Category B1)
Studies in mice and rabbits have shown that emtricitabine readily crosses the placenta.
No evidence of embryofoetal toxicity or teratogenicity was observed in pregnant mice or rabbits given oral doses of emtricitabine up to 1000 mg/kg/day (52 and 130 times the clinical exposure based on AUC, respectively). Impaired weight gain observed in pregnant rabbits at doses ≥ 300 mg/kg/day was not associated with any adverse foetal effects (at least 33 times the clinical exposure based on AUC).
There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Emtriva should be used during pregnancy only if clearly needed.
No developmental toxicity was noted postnatally in the offspring of mice given oral emtricitabine up to 1000 mg/kg/day (52 times the clinical exposure based on AUC) from gestation through lactation. Impaired weight gain observed in lactating mice at the 1000 mg/kg/day dose was not associated with any adverse events on pup survival, developmental or reproductive parameters.
Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the emtricitabine IC50 (50% maximal inhibitory concentration) but 3 to 12 times lower than the Cmin (minimal expected trough concentrations in adults) achieved from oral administration of emtricitabine. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Because of the potential for HIV transmission and the potential for serious adverse reactions in nursing infants mothers should be instructed not to breastfeed if they are receiving Emtriva.

Cytotoxicity.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been rare reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. There was no evidence of toxicity to mitochondria in vitro with emtricitabine and no causal associate between emtricitabine and mitochondrial toxicity has been established.

Teratology and reproductive toxicity.

Emtricitabine showed no evidence of teratogenicity and did not adversely affect reproduction or embryofetal development. A moderate reduction in weight gain was observed in pregnant rabbits at exposures (AUC0-24) that were at least 30-fold greater than the anticipated human exposure following the recommended dose of 200 mg once daily.

4.8 Adverse Effects (Undesirable Effects)

More than 2000 adult patients with HIV infection have been treated with Emtriva alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in phase I-III clinical trials.
Assessment of adverse reactions is based on data from studies 301A and 303 in which 571 treatment naïve (301A) and 440 treatment experienced (303) adult patients received Emtriva 200 mg (n = 580) or comparator drug (n = 431) for 48 weeks.
The most common adverse events that occurred in patients receiving Emtriva with other antiretroviral agents in clinical trials were headache, diarrhoea, nausea and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in Emtriva and control treatment groups with the exception of skin discoloration, which was reported with higher frequency in the Emtriva treated group.
Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
In addition to the adverse reactions reported in adults, anaemia has been reported commonly and hyperpigmentation very commonly, in paediatric patients (study FTC-203).
A summary of Emtriva treatment emergent clinical adverse events in studies 301A and 303 is provided in Table 2.

Laboratory abnormalities.

Very common (≥ 10%): creatine kinase elevation.
Common (≥ 1% and < 10%): hypertriglyceridaemia, neutropenia, elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT), amylase elevation including pancreatic amylase elevation, hyperglycaemia, serum lipase elevation, hyperbilirubinaemia.
The adverse reaction profile in patients coinfected with HBV is similar to that seen in patients infected with HIV virus 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.
Laboratory abnormalities in these studies occurred with similar frequency in the Emtriva and comparator groups. A summary of grade 3 and 4 laboratory abnormalities is provided in Table 3.

Study 934 - treatment emergent adverse events.

Study 934 was an open label active controlled study in which 511 antiretroviral naïve patients received either Emtriva + Viread administered in combination with efavirenz (n = 257) or Combivir (lamivudine/ zidovudine) administered in combination with efavirenz (n = 254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment experienced or treatment naïve patients (see Table 4). Adverse events leading to study drug discontinuation occurred in significantly smaller number of patients in the Truvada (tenofovir DF/ emtricitabine) group compared to the Combivir group (5% vs 11%, p = 0.010). The most frequently occurring adverse event leading to study drug discontinuation was anaemia (including decreased haemoglobin), no patient in the Truvada group and 6% of patients in the Combivir group.

Laboratory abnormalities.

Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (see Table 5).

From postmarketing surveillance.

In addition to adverse reactions from clinical studies, the following adverse reactions were identified during postapproval use of emtricitabine (FTC). Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Immune system disorders.

Autoimmune hepatitis (see Section 4.4 Special Warnings and Precautions for Use).

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to infectious pathogens (active or inactive) may arise (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults.

The recommended dose of Emtriva is one 200 mg hard capsule, taken orally once daily.

Paediatric patients (12 to 17 years inclusive).

The recommended dose of Emtriva for paediatrics weighing more than 33 kg, is one 200 mg hard capsule, taken orally once daily.
Emtriva may be taken with or without food.

Elderly.

No data are available on which to make a dose recommendation for patients over the age of 65 years.

Renal insufficiency.

Emtricitabine is eliminated by renal excretion and exposure to emtricitabine was significantly increased in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties). Dosing interval adjustment is required in all patients with creatinine clearance < 50 mL/min (see Table 1).
The safety and efficacy of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
No data are available on which to make a dosage recommendation in paediatric patients with renal impairment.

Hepatic impairment.

Based upon minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for Emtriva in patients with hepatic impairment. No data are available on which to make a dose recommendation for patients with hepatic impairment.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on ability to drive or use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with emtricitabine, which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.9 Overdose

There is no known antidote for Emtriva. Limited clinical experience is available at doses higher than the therapeutic dose of Emtriva. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.
The effects of higher doses are not known. If overdose occurs the patient should be monitored for signs of toxicity and standard supportive treatment applied as necessary.
Haemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Emtriva hard capsules contain the following ingredients as excipients: microcrystalline cellulose, crospovidone, magnesium stearate, povidone, Capsugel Part #GIHCSRR0334 empty hard gelatin capsule PI (11024), TekPrint SW-9008 Black Ink PI (2328), TekPrint SW-9009 Black Ink PI (2343).
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Hard capsules are packaged in white high density polyethylene (HDPE) bottle containing 30 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes