Patient Information Leaflet

Eviplera 200 mg/25 mg/245 mg film-coated tablets

emtricitabine/rilpivirine/tenofovir disoproxil
Please read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms seem identical to yours, as it may be harmful to them.
If you experience any side effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Eviplera is and what it is used for
What you need to know before taking Eviplera
How to take Eviplera
Possible side effects
How to store Eviplera
Contents of the pack and other information

1. What Eviplera is and what it is used for

Eviplera contains three active substances used to treat infection with the human immunodeficiency
virus (HIV):

emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI).
rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI).
tenofovir disoproxil, a nucleotide reverse transcriptase inhibitor (NtRTI).

Each of these active substances, also known as antiretroviral medicines, works by interfering with an
enzyme (a protein called "reverse transcriptase") that is essential for the virus to replicate.
Eviplera reduces the amount of HIV in the body. In this way, it improves the immune system and
reduces the risk of developing HIV-related illnesses.
Eviplera is a treatment for human immunodeficiency virus (HIV) infection in adults aged 18 years
and older.

2. What you need to know before taking Eviplera

Do not take Eviplera

If you are allergic to emtricitabine, rilpivirine, tenofovir disoproxil, or any of the other ingredients of this medicine (listed in section 6).

If any of the following apply to you, inform your doctor immediately.

If you are currently taking any of the following medicines:
carbamazepine, oxcarbazepine, phenobarbital, and phenytoin (medicines used to treat epilepsy and prevent seizures)
rifampicin and rifapentine (used to treat certain bacterial infections such as tuberculosis)
omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole (proton pump inhibitors used to prevent and treat stomach ulcers, heartburn, and acid reflux)
dexamethasone (a corticosteroid used to treat inflammation and suppress the immune system) taken orally or by injection (except for a single-dose treatment)
products containing St. John’s wort (Hypericum perforatum) (a herbal remedy used for depression and anxiety)

Warnings and precautions
While taking Eviplera, you must continue to be monitored by your doctor.

This medicine is not a cure for HIV infection. While taking Eviplera, you may still develop infections or other diseases associated with HIV infection.
Inform your doctor if you have had kidney disease or if blood tests have shown kidney problems. Eviplera may have effects on the kidneys. Before starting treatment and during treatment, your doctor may order blood tests to monitor kidney function. Eviplera is not recommended if you have moderate to severe kidney disease.

Eviplera should not be taken with other medicines that may damage the kidneys (see
Other medicines and Eviplera). If this is unavoidable, your doctor will monitor your kidney function
once a week.

Inform your doctor if you have osteoporosis, have previously had bone fractures, or have bone problems.
Inform your doctor if you have a history of liver disease, including hepatitis. HIV patients with liver disease (including chronic hepatitis B or C) who are treated with antiretrovirals have a higher risk of severe and potentially fatal liver complications. If you have hepatitis B, your doctor will carefully evaluate the most appropriate treatment regimen for you. Two of the active substances in Eviplera (tenofovir disoproxil and emtricitabine) have some activity against the hepatitis B virus. If you have a history of liver disease or chronic hepatitis B infection, your doctor may request blood tests to monitor liver function.

If you have hepatitis B, liver problems may worsen after stopping
Eviplera. It is important not to interrupt treatment with Eviplera without speaking to your doctor:
see section 3, Do not stop treatment with Eviplera.

Inform your doctor immediately and stop taking Eviplera if you develop a skin rash accompanied by any of the following symptoms: fever, blisters, red or swollen eyes, swelling of the face, mouth, or body. This reaction may become severe or potentially life-threatening.
Inform your doctor if you are over 65 years of age. Eviplera has not been studied in a sufficient number of patients over 65 years of age. If you are over 65 and have been prescribed Eviplera, your doctor will monitor you closely.

While taking Eviplera
When starting Eviplera, be alert for:

any signs of inflammation or infection
bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in fractures) which may occur due to kidney tubular cell damage

(see section 4, Possible side effects). Inform your doctor if you experience bone pain or
fractures.
Tenofovir disoproxil (a component of Eviplera) may also cause loss of bone mass. In
general, the long-term effects of tenofovir disoproxil on bone health and the risk of future fractures in adult patients are uncertain.
If you notice any of these symptoms, inform your doctor immediately.
Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age.
Other medicines and Eviplera
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including over-the-counter and herbal medicines.
Inform your doctor if you are taking any of the following medicines:

Any other medicine containing:
emtricitabine
rilpivirine
tenofovir disoproxil
tenofovir alafenamide
any other antiviral medicine containing lamivudine or adefovir dipivoxil

Eviplera may interact with other medicines. As a result, the blood levels of Eviplera or the other medicines may be altered. This may prevent the medicines from working properly or may worsen their side effects. In some cases, your doctor may need to adjust the dose or monitor blood levels.

Medicines that may damage the kidneys, such as:
aminoglycosides (such as streptomycin, neomycin, and gentamicin), vancomycin (for bacterial infections)
foscarnet, ganciclovir, cidofovir (for viral infections)
amphotericin B, pentamidine (for fungal infections)
interleukin-2, also known as aldesleukin (for treating cancer)
non-steroidal anti-inflammatory drugs (NSAIDs, used to relieve bone or muscle pain)
Medicines containing didanosine (for HIV infection): taking Eviplera with other antiviral medicines containing didanosine may increase the level of didanosine in the blood and may reduce CD4+ cell count. When medicines containing tenofovir disoproxil and didanosine have been taken together, rare cases of pancreatitis and lactic acidosis (excess lactic acid in the blood) have been reported, which have sometimes led to death. Your doctor will need to consider carefully whether to treat you with other medicines used for HIV infection (see Other medicines used for HIV infection).
Other medicines used for HIV infection: non-nucleoside reverse transcriptase inhibitors (NNRTIs). Eviplera contains an NNRTI (rilpivirine) and therefore should not be combined with other medicines of this class. Your doctor will evaluate whether a different medicine should be used, if necessary.
Rifabutin, a medicine used to treat certain bacterial infections. This medicine may reduce the amount of rilpivirine (a component of Eviplera) in the blood. Your doctor may need to prescribe an additional dose of rilpivirine to treat HIV infection (see section 3, How to take Eviplera).
Antibiotics used to treat bacterial infections, including tuberculosis, containing:
clarithromycin
erythromycin These medicines may increase the amount of rilpivirine (a component of Eviplera) in the blood. Your doctor may need to change the dose of the antibiotic or prescribe a different antibiotic.
Medicines for stomach ulcers, heartburn, or acid reflux, such as:
antacids (aluminum/magnesium hydroxide or calcium carbonate)
H₂-antagonists (famotidine, cimetidine, nizatidine, or ranitidine) These medicines may reduce the amount of rilpivirine (a component of Eviplera) in the blood. If you are taking one of these medicines, your doctor will prescribe a different medicine for stomach ulcers, heartburn, or acid reflux, or will advise you on how and when to take the medicine.
If you are taking an antacid (such as medicines containing magnesium or potassium), take it at least 2 hours before or at least 4 hours after Eviplera (see section 3, How to take Eviplera).
If you are taking an H₂-antagonist (also used to treat stomach acidity or acid reflux disease), take it at least 12 hours before or at least 4 hours after Eviplera. H₂-antagonists may be taken only once daily with Eviplera. H₂-antagonists should not be taken twice daily. Speak with your doctor about an alternative dosing schedule (see section 3, How to take Eviplera).
Methadone, a medicine used to treat opioid dependence, as your doctor may need to adjust the methadone dose.
Dabigatran etexilate, a medicine used to treat heart problems, as your doctor may need to monitor blood levels of this medicine.

Inform your doctor if you are taking any of these medicines. Do not stop treatment without
contacting your doctor.
Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Use an effective method of contraception while taking Eviplera.
Inform your doctor immediately if you become pregnant or are planning a pregnancy. Pregnant women should discuss the use of Eviplera with their doctor. Your doctor will discuss with you the potential benefits and risks of taking Eviplera for both you and your baby.
If you have taken Eviplera during pregnancy, your doctor may request regular blood tests and other diagnostic tests to monitor your baby’s development. In babies whose mothers took NRTIs during pregnancy, the benefit of protection against HIV has outweighed the risk of side effects.

Do not breastfeed while being treated with Eviplera. The reason is that the active substance of
this medicine is excreted in breast milk.
Breastfeeding is not recommended for HIV-positive women because HIV infection can be
transmitted to the baby through breast milk.
If you are breastfeeding or considering breastfeeding, you must speak to your doctor as soon as possible.
Driving and using machines
Do not drive or operate machinery if you feel tired, sleepy, or dizzy after taking this medicine.
Eviplera contains lactose, aluminium orange yellow lake (E110), and sodium

If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.
Inform your doctor if you are allergic to aluminium orange yellow lake (E110). Eviplera contains aluminium orange yellow lake, also known as “E110”, which may cause allergic reactions.
This medicine contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially “sodium-free”.

3. How to take Eviplera

Take this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor or pharmacist.
The usual dose is one tablet daily, taken by mouth. The tablet must be taken with food. This is important to achieve the correct levels of active substance in the body.
A nutritional drink alone does not replace food.
Swallow the tablet whole with some water.
Do not chew, crush, or split the tablet, as this would affect how the medicine is released in the body.
If your doctor decides to discontinue one of the components of Eviplera or to change the dose of Eviplera, you may be given emtricitabine, rilpivirine and/or tenofovir disoproxil separately, or other medicines for the treatment of HIV infection.
If you are taking an antacid such as medicines containing magnesium or potassium, take it at least 2 hours before or at least 4 hours after taking Eviplera.
If you are taking an H*-antagonist such as famotidine, cimetidine, nizatidine or ranitidine, take it at least 12 hours before or at least 4 hours after taking Eviplera. H*-antagonists may be taken only once daily together with Eviplera. H*-antagonists must not be taken twice daily.
Talk to your doctor about an alternative dosing schedule.
If you are taking rifabutin, your doctor may need to prescribe an additional dose of rilpivirine. Take the rilpivirine tablet at the same time as you take Eviplera. If you have any doubts, consult your doctor or pharmacist.
If you take more Eviplera than you should
If you accidentally take more Eviplera than recommended, you may have an increased risk of experiencing possible side effects of this medicine (see section 4, Possible side effects).
Contact your doctor or the nearest emergency department immediately. Take the bottle of tablets with you so that you can easily describe what has been taken.
If you forget to take Eviplera
It is important not to miss any dose of Eviplera.
If you forget a dose:

If you remember within 12 hours of your usual dosing time, take the tablet as soon as possible. Always take the tablet with food. Then take your next dose at the usual time.
If you remember 12 hours or more after your usual dosing time, do not take the missed dose. Wait and take the next dose with food at your usual time.

If you vomit within 4 hours of taking Eviplera, take another tablet with food. If you vomit more than 4 hours after taking Eviplera, do not take another tablet until your next regularly scheduled dose.
Do not stop treatment with Eviplera
Do not stop treatment with Eviplera without first talking to your doctor. Stopping treatment with Eviplera may seriously affect your response to future treatment. If treatment with Eviplera is stopped for any reason, discuss this with your doctor before restarting the tablets. Your doctor may give you the components of Eviplera separately, or adjust the dose, if necessary.
When your supply of Eviplera is running low, get a new supply from your doctor or pharmacist. This is very important because the amount of virus in your body may start to increase if the medicine is stopped, even for a short time. The virus may then become more difficult to treat.
If you have both HIV and hepatitis B infection, it is especially important not to stop treatment with Eviplera without first contacting your doctor. Some patients have experienced worsening of their hepatitis, as shown by symptoms or blood tests, after stopping emtricitabine or tenofovir disoproxil (two of the three active substances in Eviplera). If Eviplera is stopped, your doctor may advise you to restart treatment for hepatitis B. Blood tests may be needed for up to 4 months after stopping treatment to monitor liver function. In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended, as it may lead to worsening of hepatitis, which could be potentially fatal.
Tell your doctor immediately about any new or unusual symptoms you notice after stopping treatment, particularly symptoms normally associated with hepatitis B infection.
If you have any questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Possible side effects: tell your doctor immediately

Lactic acidosis (excess lactic acid in the blood) is a rare, but potentially life-threatening side effect of some HIV medicines. Lactic acidosis occurs more frequently in women, especially if overweight, and in people with liver disease. The following may be signs of lactic acidosis:
deep, rapid breathing
tiredness or drowsiness
nausea, vomiting
stomach pain If you think you may have lactic acidosis, tell your doctor immediately.

Signs of inflammation or infection. In some patients with advanced HIV infection (AIDS) and
a history of opportunistic infections (infections that occur in people with a weakened immune
system), signs and symptoms of inflammation from previous infections may occur shortly after
starting anti-HIV treatment. These symptoms are thought to be due to an improved immune response
by the body, allowing it to fight infections that may have been present without obvious symptoms.
In addition to opportunistic infections, autoimmune disorders (a condition in which the immune
system attacks the body's healthy tissues) may also occur after starting medicines for the treatment
of HIV infection. Autoimmune disorders may occur many months after starting treatment. If you
notice any symptoms of infection or other symptoms such as muscle weakness, initial weakness in
hands and feet spreading upwards towards the trunk, palpitations, tremor, or hyperactivity, tell your
doctor immediately to receive necessary treatment.
If you notice symptoms of inflammation or infection, tell your doctor immediately.
Very common side effects
(Effects occurring in more than 1 in 10 patients)

diarrhoea, vomiting, nausea
difficulty sleeping (insomnia)
dizziness, headache
rash
feeling weak

Blood tests may also show:

reduced phosphate levels in the blood
increased creatine kinase levels in the blood, which may cause muscle pain and weakness
increased cholesterol and/or pancreatic amylase levels in the blood
increased liver enzyme levels in the blood If any of these side effects worsen, tell your doctor.

Common side effects
(Effects occurring in fewer than 1 in 10 patients)

reduced appetite
depression and depressed mood
tiredness, drowsiness
drowsiness
pain, discomfort or pain in the stomach, bloating sensation, dry mouth
abnormal dreams, sleep disturbances
digestive problems resulting from discomfort after meals, intestinal gas (flatulence)
skin rashes (including red spots or pustules, sometimes with blisters and skin swelling), which may be allergic reactions, itching, skin colour changes with appearance of dark patches
other allergic reactions, such as shortness of breath, swelling, or feeling light-headed
loss of bone mass

Blood tests may also show:

decreased white blood cell count (this may make you more susceptible to infection)
decreased platelet count (a type of blood cell involved in blood clotting)
decreased haemoglobin in the blood (low red blood cell count)
increased fatty acids (triglycerides), bilirubin or blood sugar levels
pancreas problems If any of these side effects worsen, tell your doctor.

Uncommon side effects
(Effects occurring in fewer than 1 in 100 patients)

anaemia (low red blood cell count)
abdominal pain caused by inflammation of the pancreas
muscle breakdown, muscle pain or muscle weakness
swelling of the face, lips, tongue or throat
signs or symptoms of inflammation or infection
severe skin reactions including rash accompanied by fever, swelling and liver problems
damage to renal tubular cells

Blood tests may also show:

reduced potassium in the blood
increased creatinine in the blood
changes in urine If any of these side effects worsen, tell your doctor.

Rare side effects
(These effects occur in fewer than 1 in 1,000 patients)

lactic acidosis (see Possible side effects; inform a doctor immediately)
back pain caused by kidney problems, including kidney failure. Your doctor may order blood tests to assess whether your kidneys are functioning properly
fatty liver
yellowing of the skin and eyes, itching or abdominal pain caused by liver inflammation
kidney inflammation, excessive urination and thirst
softening of the bones (with bone pain and sometimes fractures)

Muscle breakdown, softening of the bones (with bone pain and sometimes fractures), muscle pain,
muscle weakness, and decreased potassium or phosphate in the blood may occur due to damage to
renal tubular cells.
If any of these side effects worsen, tell your doctor.
Other effects that may occur during HIV treatment
The frequency of the following side effects is unknown (the frequency cannot be determined from the
available data).

Bone problems. Some patients taking combination antiretroviral medicines such as Eviplera may develop a bone disease called osteonecrosis (death of bone tissue caused by reduced blood supply to the bone). Taking this type of medicine for a prolonged period, taking corticosteroids, alcohol consumption, having a weakened immune system, and being overweight may be some of the many risk factors for developing this condition. Signs of osteonecrosis include:
joint stiffness
joint discomfort and pain (especially in hips, knees and shoulders)
difficulty moving If you notice any of these symptoms, tell your doctor.

During HIV treatment, an increase in body weight and in blood lipid and glucose levels may occur. This
is partly related to improved health and lifestyle, and in the case of blood lipids, sometimes to the
HIV medicines themselves. Your doctor will monitor these changes.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please tell your doctor or
pharmacist. You can also report side effects directly via the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Eviplera

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the bottle and carton after {Exp.}. The expiry date refers to the last day of that month.
Store in the original packaging to protect the medicine from moisture. Keep the bottle tightly closed.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Eviplera contains

The active substances are emtricitabine, rilpivirine, and tenofovir disoproxil. Each Eviplera film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride), and 245 mg of tenofovir disoproxil (as fumarate).
The other components are: Tablet core: microcrystalline cellulose, monohydrate lactose, pregelatinized maize starch, povidone, polysorbate 20, sodium croscarmellose, and magnesium stearate.

Film coating:
hypromellose, aluminium lacquer indigo carmine, monohydrate lactose, polyethylene glycol, red iron oxide, orange-yellow aluminium lake (E110), titanium dioxide, and triacetin.

Description of the appearance of Eviplera and package contents
Eviplera film-coated tablets are pink-purple, capsule-shaped, marked on one side with “GSI” and smooth on the other side. Eviplera is supplied in bottles of 30 tablets and in packs consisting of 3 bottles, each containing 30 tablets. Each bottle contains silica gel as a desiccant, which must remain in the bottle to protect the tablets. The silica gel is contained in a separate sachet or container and must not be swallowed.

It is possible that not all pack sizes are marketed.

Marketing Authorisation Holder
Gilead Sciences Ireland UC
Carrigtohill
County Cork, T45 DP77
Ireland

Manufacturer:
Gilead Sciences Ireland UC
IDA Business & Technology Park
Carrigtohill
County Cork
Ireland

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Gilead Sciences Belgium SRL-BV Gilead Sciences Ireland UC
Tél/Tel: + 32 (0) 24 01 35 50 Tel: + 353 (0) 1 686 1888

България Luxembourg/Luxemburg
Gilead Sciences Ireland UC Gilead Sciences Belgium SRL-BV
Тел.: + 353 (0) 1 686 1888 Tél/Tel: + 32 (0) 24 01 35 50

Česká republika Magyarország
Gilead Sciences s.r.o. Gilead Sciences Ireland UC
Tel: + 420 910 871 986 Tel: + 353 (0) 1 686 1888

Danmark Malta
Gilead Sciences Sweden AB Gilead Sciences Ireland UC
Tlf: + 46 (0) 8 5057 1849 Tel: + 353 (0) 1 686 1888

Deutschland Nederland
Gilead Sciences GmbH Gilead Sciences Netherlands B.V.
Tel: + 49 (0) 89 899890-0 Tel: + 31 (0) 20 718 36 98

Eesti Norge
Gilead Sciences Ireland UC Gilead Sciences Sweden AB
Tel: + 353 (0) 1 686 1888 Tlf: + 46 (0) 8 5057 1849

Ελλάδα Österreich
Gilead Sciences Ελλάς Μ.ΕΠΕ. Gilead Sciences GesmbH
Τηλ: + 30 210 8930 100 Tel: + 43 1 260 830

España Polska
Gilead Sciences, S.L. Gilead Sciences Poland Sp. z o.o.
Tel: + 34 91 378 98 30 Tel.: + 48 22 262 8702

France Portugal
Gilead Sciences Gilead Sciences, Lda.
Tél: + 33 (0) 1 46 09 41 00 Tel: + 351 21 7928790

Hrvatska România
Gilead Sciences Ireland UC Gilead Sciences (GSR) S.R.L.
Tel: + 353 (0) 1 686 1888 Tel: + 40 31 631 18 00

Ireland Slovenija
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 214 825 999 Tel: + 353 (0) 1 686 1888

Ísland Slovenská republika
Gilead Sciences Sweden AB Gilead Sciences Slovakia s.r.o.
Sími: + 46 (0) 8 5057 1849 Tel: + 421 232 121 210

Italia Suomi/Finland
Gilead Sciences S.r.l. Gilead Sciences Sweden AB
Tel: + 39 02 439201 Puh/Tel: + 46 (0) 8 5057 1849

Κύπρος Sverige
Gilead Sciences Ελλάς Μ.ΕΠΕ. Gilead Sciences Sweden AB
Τηλ: + 30 210 8930 100 Tel: + 46 (0) 8 5057 1849

Latvija United Kingdom (Northern Ireland)
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 1 686 1888 Tel: + 44 (0) 8000 113 700

More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for emtricitabine/rilpivirine/tenofovir disoproxil, the PRAC's scientific conclusions are as follows:
In light of the available data on reduced bone mineral density from clinical studies, literature, and spontaneous reports, and considering the plausible mechanism of action, the PRAC considers that a causal relationship between emtricitabine/rilpivirine/tenofovir disoproxil and reduced bone mineral density is at least a reasonable possibility. The PRAC also considers that the current warning/precaution regarding bone effects should be further strengthened. The PRAC concluded that the product information for medicinal products containing emtricitabine/rilpivirine/tenofovir disoproxil should be modified accordingly.
Following review of the PRAC recommendation, the Committee for Medicinal Products for Human Use (CHMP) agrees with the general conclusions and the rationale for the recommendation.

Grounds for the variation to the terms of the marketing authorisation(s)
Based on the scientific conclusions for emtricitabine/rilpivirine/tenofovir disoproxil, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing emtricitabine/rilpivirine/tenofovir disoproxil remains favourable, subject to the proposed changes to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation(s).