Patient leaflet - Emtricitabine/tenofovir Disoproxil Krka D.D. 200 mg / 245 mg film-coated tablets

1. What Emtricitabine/Tenofovir disoproxil Krka d.d. is and what it is used for

Emtricitabine/Tenofovir disoproxil Krka d.d. contains two active substances, emtricitabine and tenofovir disoproxil. Both of these active substances are antiretroviral medicines which are used to treat HIV infection. Emtricitabine is a nucleoside reverse transcriptase inhibitor and tenofovir is a nucleotide reverse transcriptase inhibitor. However, both are generally known as NRTIs and they work by interfering with the normal working of an enzyme (reverse transcriptase) that is essential for the virus to reproduce itself.

Emtricitabine/Tenofovir disoproxil Krka d.d. is used to treat Human Immunodeficiency Virus 1 (HIV-1) infection in adults.
It is also used to treat HIV in adolescents aged 12 to less than 18 years who weigh at least 35 kg, and who have already been treated with other HIV medicines that are no longer effective or have caused side effects. - Emtricitabine/Tenofovir disoproxil Krka d.d. should always be used combined with other medicines to treat HIV infection.
- Emtricitabine/Tenofovir disoproxil Krka d.d. can be administered in place of emtricitabine and tenofovir disoproxil used separately at the same doses. This medicine is not a cure for HIV infection. While taking Emtricitabine/Tenofovir disoproxil Krka d.d. you may still develop infections or other illnesses associated with HIV infection.

2. What you need to know before you take

Emtricitabine/Tenofovir disoproxil Krka d.d. Do not take Emtricitabine/Tenofovir disoproxil Krka d.d.if you are allergic to emtricitabine, tenofovir, tenofovir disoproxil, or any of the other ingredients of this medicine (listed in section 6).

→ If this applies to you, tell your doctor immediately. Warnings and precautions

While taking Emtricitabine/Tenofovir disoproxil Krka d.d. to treat HIV

Emtricitabine/Tenofovir disoproxil Krka d.d. may affect your kidneys. Before and during treatment, your doctor may order blood tests to measure kidney function. Tell your doctor if you have had kidney disease, or if tests have shown kidney problems. Emtricitabine/Tenofovir disoproxil Krka d.d. should not be given to adolescents with existing kidney problems. If you have kidney problems, your doctor may advise you to stop taking Emtricitabine/Tenofovir disoproxil Krka d.d. or, if you already have HIV, to take Emtricitabine/Tenofovir disoproxil Krka d.d. less frequently. Emtricitabine/ Tenofovir disoproxil Krka d.d. is not recommended if you have severe kidney disease or are on dialysis.
Talk to your doctor if you suffer from osteoporosis, have a history of bone fracture or if you have problems with your bones.
Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in fractures) may also occur due to damage to kidney tubule cells (see section 4, Possible side effects). Tell your doctor if you have bone pain or fractures.
Tenofovir disoproxil may also cause loss of bone mass. The most pronounced bone loss was seen in clinical studies when patients were treated for HIV with tenofovir disoproxil in combination with a boosted protease inhibitor.
Overall, the effects of tenofovir disoproxil on long term bone health and future fracture risk in adult and paediatric patients are uncertain.
- Talk to your doctor if you have a history of liver disease, including hepatitis. Patients infected with HIV who also have 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 or C, your doctor will carefully consider the best treatment regimen for you.
- Know your hepatitis B virus (HBV) infection status
  before starting Emtricitabine/Tenofovir disoproxil Krka d.d.. If you have HBV, there is a serious risk of liver problems when you stop taking Emtricitabine/Tenofovir disoproxil Krka d.d., whether or not you also have HIV. It is important not to stop taking Emtricitabine/Tenofovir disoproxil Krka d.d. without talking to your doctor: see section 3, Do not stop taking Emtricitabine/Tenofovir disoproxil Krka d.d..
- Talk to your doctor if you are over 65. Emtricitabine/ Tenofovir disoproxil Krka d.d. has not been studied in patients over 65 years of age.
- Talk to your doctor if you are intolerant to lactose
  (see Emtricitabine/Tenofovir disoproxil Krka d.d. contains lactose later in this section).
  Children and adolescents
  Emtricitabine/Tenofovir disoproxil Krka d.d. is not for use in children under 12 years of age.
  Other medicines and Emtricitabine/Tenofovir disoproxil Krka d.d.
  Do not take Emtricitabine/Tenofovir disoproxil Krka d.d. if you are already taking other medicines that contain the components of Emtricitabine/Tenofovir disoproxil Krka d.d. (emtricitabine and tenofovir disoproxil) or any other antiviral medicines that contain tenofovir alafenamide, lamivudine or adefovir dipivoxil.
  Taking Emtricitabine/Tenofovir disoproxil Krka d.d. with other medicines that can damage your kidneys: it is especially important to tell your doctor if you are taking any of these medicines, including
  - aminoglycosides (for bacterial infection)
  - amphotericin B (for fungal infection)
  - foscarnet (for viral infection)
  - ganciclovir (for viral infection)
  - pentamidine (for infections)
  - vancomycin (for bacterial infection)
  - interleukin-2 (to treat cancer)
  - cidofovir (for viral infection)
  - non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains)

If you are taking another antiviral medicine called a protease inhibitor to treat HIV, your doctor may order blood tests to closely monitor your kidney function. It is also important to tell your doctor if you are taking ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/ velpatasvir/voxilaprevir to treat hepatitis C infection.

Taking Emtricitabine/Tenofovir disoproxil Krka d.d. with other medicines containing didanosine (for treatment of HIV infection): Taking Emtricitabine/ Tenofovir disoproxil Krka d.d. with other antiviral medicines that contain didanosine can raise the levels of didanosine in your blood and may reduce CD4 cell counts. Rarely, inflammation of the pancreas and lactic acidosis (excess lactic acid in the blood), which sometimes causes death, have been reported when medicines containing tenofovir disoproxil and didanosine were taken together. Your doctor will carefully consider whether to treat you with combinations of tenofovir and didanosine.

→ Tell your doctor if you are taking any of these medicines. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Emtricitabine/Tenofovir disoproxil Krka d.d. with food and drink

Whenever possible, Emtricitabine/Tenofovir disoproxil Krka d.d. should be taken with food.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

If you have taken Emtricitabine/Tenofovir disoproxil Krka d.d. during your pregnancy, your doctor may request regular blood tests and other diagnostic tests to monitor the development of your child. In children whose mothers took NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk of side effects.

Do not breast-feed during treatment with Emtricitabine/Tenofovir disoproxil Krka d.d.. This is because the active substances in this medicine pass into human breast milk.
Breast-feeding is not recommended in women living with HIV because HIV infection can be passed on to the baby in breast milk.
If you are breast-feeding, or thinking about breast-feeding, you should discuss it with your doctor as soon as possible.

Driving and using machines

Emtricitabine/Tenofovir disoproxil Krka d.d. can cause dizziness. If you feel dizzy while taking Emtricitabine/ Tenofovir disoproxil Krka d.d., do not drive and do not use any tools or machines.

Emtricitabine/Tenofovir disoproxil Krka d.d. contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Emtricitabine/Tenofovir disoproxil Krka d.d. contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

3. How to take Emtricitabine/Tenofovir disoproxil Krka d.d.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
The recommended dose of Emtricitabine/Tenofovir disoproxil Krka d.d. is:
- Adults: one tablet each day, where possible, with food.
- Adolescents aged 12 to less than 18 years who weigh at least 35 kg: one tablet each day, whenever possible with food.

If you have difficulty swallowing, you can use the tip of a spoon to crush the tablet. Then mix the powder with about 100 mL (half a glass) of water, orange juice or grape juice, and drink immediately.

Always take the dose recommended by your doctor. This is to make sure that your medicine is fully effective, and to reduce the risk of developing resistance to the treatment. Do not change the dose unless your doctor tells you to.
Your doctor will prescribe Emtricitabine/Tenofovir disoproxil Krka d.d. with other antiretroviral medicines. Please refer to the patient information leaflets of the other antiretrovirals for guidance on how to take those medicines.

Ask your doctor if you have any questions about how to prevent getting HIV or prevent spreading HIV to other people.

If you take more Emtricitabine/Tenofovir disoproxil Krka d.d. than you should

If you accidentally take more than the recommended dose of Emtricitabine/Tenofovir disoproxil Krka d.d., contact your doctor or nearest emergency department for advice. Keep the tablet bottle with you so that you can easily describe what you have taken.

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If you forget to take Emtricitabine/Tenofovir disoproxil Krka d.d.

It is important not to miss a dose of Emtricitabine/Tenofovir disoproxil Krka d.d..

If you notice within 12 hours of the time you usually take Emtricitabine/Tenofovir disoproxil Krka d.d., take the tablet preferably with food as soon as possible. Then take the next dose at your usual time.
If you notice 12 hours or more after the time you usually take Emtricitabine/Tenofovir disoproxil Krka d.d., forget about the missed dose. Wait and take the next dose, preferably with food, at your usual time. If you vomit less than 1 hour after taking Emtricitabine/ Tenofovir disoproxil Krka d.d., take another tablet. You do not need to take another tablet if you were sick more than 1 hour after taking Emtricitabine/Tenofovir disoproxil Krka d.d..

If you stop taking Emtricitabine/Tenofovir disoproxil Krka d.d.

Stopping tablets may reduce the effectiveness of the anti-HIV therapy recommended by your doctor. → Do not stop taking Emtricitabine/Tenofovir disoproxil Krka d.d. without contacting your doctor. If you have hepatitis B, it is especially important not to stop your Emtricitabine/Tenofovir disoproxil Krka d.d. treatment without talking to your doctor first. You may require blood tests for several months after stopping treatment. In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of your hepatitis, which may be life-threatening.
→ Tell your doctor immediately about new or unusual symptoms after you stop treatment, particularly symptoms you associate with hepatitis B infection
If you have any further questions on the use of this 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 serious side effects:

Lactic acidosis (excess lactic acid in the blood) is a rare but potentially life-threatening side effect. Lactic acidosis occurs more often in women, particularly if they are overweight, and in people with liver disease. The following may be signs of lactic acidosis:
- deep rapid breathing
- drowsiness
- feeling sick (nausea), being sick (vomiting) - stomach pain

→ If you think you may have lactic acidosis, get medical help immediately.

Any 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 weak immune system), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is thought that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms.
- Autoimmune disorders, when the immune system attacks healthy body tissue, may also occur after you start taking medicines to treat HIV infection. Autoimmune disorders may occur many months after the start of treatment. Look out for any symptoms of infection or other symptoms such as:
  - muscle weakness
  - weakness beginning in the hands and feet and moving up towards the trunk of the body
  - palpitations, tremor or hyperactivity

→ If you notice these or any symptoms of inflammation or infection, get medical help immediately. Possible side effects:

Very common side effects

(may affect more than 1 in 10 people)

diarrhoea, being sick (vomiting), feeling sick (nausea)
dizziness, headache
rash
feeling weak

Tests may also show:

decreases in phosphate in the blood
increased creatine kinase

Common side effects

(may affect up to 1 in 10 people)

pain, stomach pain
difficulty sleeping, abnormal dreams
problems with digestion resulting in discomfort after meals, feeling bloated, flatulence
rashes (including red spots or blotches sometimes with blistering and swelling of the skin), which may be allergic reactions, itching, changes in skin colour including darkening of the skin in patches
- other allergic reactions, such as wheezing, swelling or feeling light-headed
- loss of bone mass

Tests may also show:

low white blood cell count (a reduced white blood cell count can make you more prone to infection)
increased triglycerides (fatty acids), bile or sugar in the blood
liver and pancreas problems

Uncommon side effects

(may affect up to 1 in 100 people)

pain in the abdomen (tummy) caused by inflammation of the pancreas
swelling of the face, lips, tongue or throat
anaemia (low red blood cell count)
breakdown of muscle, muscle pain or weakness which may occur due to damage to the kidney tubule cells Tests may also show:
decreases in potassium in the blood
increased creatinine in your blood
changes to your urine

Rare side effects

(may affect up to 1 in 1 000 people)

Lactic acidosis (see Possible serious side effects)
fatty liver
yellow skin or eyes, itching, or pain in the abdomen (tummy) caused by inflammation of the liver
inflammation of the kidney, passing a lot of urine and feeling thirsty, kidney failure, damage to kidney tubule cells
softening of the bones (with bone pain and sometimes resulting in fractures)
back pain caused by kidney problems
Damage to kidney tubule cells may be associated with breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood.
→ If you notice any of the side effects listed above or if any of the side effects get serious, talk to your doctor or pharmacist.
The frequency of the following side effects is not known.
- Bone problems. Some patients taking combination antiretroviral medicines such as emtricitabine/tenofovir disoproxil may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). Taking this type of medicine for a long time, taking corticosteroids, drinking alcohol, having a very weak immune system, and being overweight, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are: - joint stiffness
  - joint aches and pains (especially of the hip, knee and shoulder)
  - difficulty with movement

→ If you notice any of these symptoms tell your doctor.

During treatment for HIV there may be an increase in weight and in levels of blood lipids and glucose. This is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV medicines themselves. Your doctor will test for these changes. Other effects in children

Children given emtricitabine very commonly experienced changes in skin colour including
- darkening of the skin in patches
  - Children commonly experienced low red blood cell count (anaemia).
    - This may cause the child to be tired or breathless → If you notice any of these symptoms tell your doctor. Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme, Website: yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Emtricitabine/Tenofovir disoproxil Krka d.d.

Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry date refers to the last day of that month.

Blisters

Do not store above 30°C.

Store in the original blister in order to protect from moisture and light.

Bottle

Do not store above 30°C.

Keep the bottle tightly closed in order to protect from moisture and light.

Shelf life after first opening of the bottle: 2 months.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Emtricitabine/Tenofovir disoproxil Krka d.d. contains

The active substances are emtricitabine and tenofovir disoproxil.
Each tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300.7 mg of tenofovir disoproxil succinate or 136 mg of tenofovir).
The other ingredients are:
Tablet core: pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, stearic acid.
Film coating: hypromellose 5 cP, titanium dioxide (E171), macrogol, indigo carmine aluminium lake (E132). See section 2 “Emtricitabine/Tenofovir disoproxil Krka d.d. contains lactose”, “Emtricitabine/Tenofovir disoproxil Krka d.d. contains sodium”.

What Emtricitabine/Tenofovir disoproxil Krka d.d. looks like and contents of the pack

Emtricitabine/Tenofovir disoproxil Krka d.d. film-coated tablets (tablets) are blue, oval, biconvex tablets, of dimensions 20 mm x 10 mm.

Emtricitabine/Tenofovir disoproxil Krka d.d. is available in carton boxes of 28 x 1 and 84 film-coated tablets in blisters.

Emtricitabine/Tenofovir disoproxil Krka d.d. is available also in bottles of 30 tablets, with a child-resistant tamper evident plastic closure with integrated a silica gel desiccant, which helps to protect your tablets. The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer