Package Leaflet: Information for the User

Kivexa 600 mg/300 mg film-coated tablets

abacavir/lamivudine
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 give it to other people, even if they have the same symptoms as yours, because it could be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist immediately. See section 4.

IMPORTANT — Hypersensitivity Reactions
Kivexa contains abacavir (which is also the active substance in medicines such as Trizivir,
Triumeq, and Ziagen). Some people taking abacavir may develop a hypersensitivity reaction
(a severe allergic reaction), which can be life-threatening if they continue to take medicines containing abacavir.
Read carefully all the information under 'Hypersensitivity Reactions' in the box in section 4.
The Kivexa package includes a Warning Card to remind you and healthcare professionals about abacavir hypersensitivity. Remove this card and always carry it with you.

Contents of this leaflet:

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

1. What Kivexa is and what it is used for

Kivexa is used to treat HIV (Human Immunodeficiency Virus) infection in adults,
adolescents, and children weighing at least 25 kg.
Kivexa contains two active substances used in the treatment of HIV infection:
abacavir and lamivudina. These medicines belong to a class of antiretroviral drugs
known as nucleoside reverse transcriptase inhibitors (NRTIs).
Kivexa does not completely cure HIV infection; it reduces the amount of virus in the body and keeps it at low levels. In addition, it increases the number of CD4 cells in the blood. CD4 cells are a type of white blood cell important in helping the body fight infection.
Not all people respond to treatment with Kivexa in the same way. Your doctor will monitor how well the treatment is working.

2. What you should know before taking Kivexa

Do not take Kivexa:

if you are allergic ( hypersensitive ) to abacavir (or to any other medicine containing abacavir –
such as Trizivir, Triumeq or Ziagen ), lamivudine, or to any of the other ingredients of this
medicine (listed in section 6).
Read carefully all the information about hypersensitivity reactions in section 4.
Consult your doctor if you think this applies to you. Do not take Kivexa.

Be especially careful with Kivexa
Some people taking Kivexa or other combination therapies for the treatment of HIV are at higher risk of serious side effects. You should be aware of these additional risks:

if you have moderate or severe liver disease
if you have had liver disease, including hepatitis B or C (if you have hepatitis B infection, do not stop taking Kivexa without consulting your doctor, as hepatitis may reappear)
if you are severely overweight (particularly if you are a woman)
if you have kidney problems

Tell your doctor if any of these situations apply to you before using Kivexa.
You may need additional monitoring, including blood tests, while taking this medicine. See section 4 for further information.

Hypersensitivity reactions to abacavir
Even patients who do not have the HLA-B*5701 gene may still develop a hypersensitivity reaction (a severe allergic reaction).
Read carefully all the information about hypersensitivity reactions in section 4 of this leaflet.

Risk of cardiovascular events
It cannot be ruled out that abacavir may be associated with an increased risk of cardiovascular events.
Inform your doctor if you have cardiovascular problems, are a smoker, or have conditions that increase the risk of cardiovascular disease such as high blood pressure or diabetes.
Do not stop taking Kivexa unless your doctor advises you to do so.

Pay attention to important symptoms
Some people taking medicines for HIV infection develop other conditions that may be serious. You should be informed about important signs and symptoms so you can remain vigilant while taking Kivexa.
Read the information under ‘Other possible side effects of combination therapy for HIV’ in section 4 of this leaflet.

Other medicines and Kivexa
Tell your doctor or pharmacist if you are taking any other medicines, or have recently taken any, including herbal remedies or other medicines purchased without a prescription.
Remember to inform your doctor or pharmacist if you start taking a new medicine during treatment with Kivexa.

The following medicines must not be taken with Kivexa:

emtricitabine for the treatment of HIV infection
other medicines containing lamivudine used to treat HIV infection or hepatitis B virus infection
high doses of trimethoprim/sulfamethoxazole, an antibiotic
cladribine, used to treat hairy cell leukemia.

Inform your doctor if you are being treated with any of these medicines.

Some medicines interact with Kivexa
These include:

phenytoin, used to treat epilepsy. Inform your doctor if you are taking phenytoin. Your doctor may need to monitor you while you are taking Kivexa.
methadone, used as a heroin substitute. Abacavir increases the rate at which methadone is eliminated from the body. If you are taking methadone, you will be monitored for any withdrawal symptoms. It may be necessary to adjust the dose of methadone. Inform your doctor if you are taking methadone.
medicines (usually liquids) containing sorbitol and other sweeteners (such as xylitol, mannitol, lactitol or maltitol), if taken regularly. Inform your doctor or pharmacist if you are taking any of these.
riociguat, for the treatment of high blood pressure in the blood vessels (pulmonary arteries) carrying blood from the heart to the lungs. Your doctor may need to reduce the dose of riociguat, as abacavir may increase blood levels of riociguat.

Pregnancy
The use of Kivexa during pregnancy is not recommended. Kivexa and similar medicines may cause unwanted effects in unborn children.
If you have already taken Kivexa during pregnancy, your doctor may regularly perform blood tests and other diagnostic examinations to monitor the child's development. In children whose mothers took NRTIs during pregnancy, the benefit of protection against HIV has outweighed the risk of side effects.

Breast-feeding
Breast-feeding is not recommended for HIV-positive women, as HIV infection can be transmitted to the child through breast milk. A small amount of the components of Kivexa may also pass into breast milk.
If you are breast-feeding or considering breast-feeding, you must discuss this with your doctor as soon as possible.

Driving and using machines
Kivexa may cause side effects that could affect your ability to drive and use machinery.
Talk to your doctor about your ability to drive and use machinery while taking Kivexa.

Important information about some of the excipients in Kivexa tablets
Kivexa contains a colouring agent called sunset yellow (E110) which may cause allergic reactions in some individuals.
This medicine contains less than 1 mmol (23 mg) of sodium per dosage unit, i.e. it is essentially ‘sodium-free’.

3. How to take Kivexa

Always take this medicine exactly as your doctor has told you. Check with your
doctor or pharmacist if you are unsure.
The recommended dose of Kivexa in adults, adolescents, and children weighing 25 kg or more is one tablet once daily.
Swallow the tablets whole with water. Kivexa may be taken with or without food.
Stay in regular contact with your doctor
Kivexa helps to control your condition. You must take it every day to prevent your condition from worsening.
You may still develop other infections and illnesses related to HIV infection.
Keep in contact with your doctor, and do not stop taking Kivexa without your doctor's advice.
If you take more Kivexa than you should
If you accidentally take more Kivexa, inform your doctor or pharmacist or contact the Emergency Department of the nearest hospital for further advice.
If you forget to take Kivexa
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before. Do not take a double dose to make up for the forgotten dose.
It is important to take Kivexa regularly, as taking it at irregular intervals may increase the risk of developing a hypersensitivity reaction.
If you have stopped taking Kivexa
If you have stopped taking Kivexa for any reason – particularly because you thought you were experiencing side effects or because you had other illnesses:
talk to your doctor before starting to take it again. Your doctor will assess whether your symptoms were related to a hypersensitivity reaction. If your doctor thinks that your symptoms may have been due to a hypersensitivity reaction, you will be told never to take Kivexa or any other medicine containing abacavir again (e.g. Trizivir, Triumeq or Ziagen). It is important that you follow this advice.
If your doctor advises restarting Kivexa, you will be asked to take the first doses in a place where you can receive immediate medical assistance if needed.

4. Possible side effects

During HIV therapy, increases in body weight and blood levels of lipids and glucose may occur.
This is partly related to the recovery of health status and lifestyle, and in the case of blood lipids, sometimes to the HIV medicines themselves. Your doctor will monitor these changes.
Like all medicines, this medicine can cause side effects, although not everyone gets them.
During HIV treatment, it may be difficult to determine whether a symptom is an unwanted effect of Kivexa or of other medicines you are taking, or an effect of HIV disease itself. For this reason, it is very important to inform your doctor of any changes in your health status.
Even patients who do not have the HLA-B*5701 gene may still develop a hypersensitivity reaction (a severe allergic reaction), described in this leaflet in a section titled 'Hypersensitivity reactions'.
It is very important to read and understand the information about this serious reaction.
During combination therapy for HIV, both the side effects listed below for Kivexa and other illnesses may occur.
It is important to read the information in another section of this leaflet under 'Other possible side effects of combination therapy for HIV'.

Hypersensitivity reactions
Kivexa contains abacavir (which is also the active substance in medicines such as Trizivir, Triumeq, and Ziagen). Abacavir can cause a severe allergic reaction known as a hypersensitivity reaction. These hypersensitivity reactions have been observed more frequently in people taking medicines containing abacavir.

Who is at risk of these reactions?
Any person taking Kivexa could develop a hypersensitivity reaction to abacavir, which could be life-threatening if Kivexa is continued.
You are more likely to have this reaction if you carry a gene called HLA-B*5701 (but you may still have this reaction even if you do not have this gene). You will be tested for the presence of this gene before Kivexa is prescribed. If you know you have this gene, inform your doctor before taking Kivexa.
In a clinical study, among 100 patients treated with abacavir who did not have the HLA-B*5701 gene, approximately 3 to 4 patients experienced a hypersensitivity reaction.

What are the symptoms?
The most common symptoms are:

fever and rash.

Other common symptoms are:

nausea, vomiting, diarrhoea, abdominal (stomach) pain, severe fatigue.

Other symptoms include:
muscle or joint pain, swelling of the neck, shortness of breath, sore throat, cough, occasional headache, eye inflammation (conjunctivitis), mouth ulcers, low blood pressure, tingling or numbness in hands or feet.

When do these reactions occur?
Hypersensitivity reactions may occur at any time during treatment with Kivexa, but are more likely during the first 6 weeks of treatment.

Contact your doctor immediately:
1 if you develop a rash, OR
2 if you develop symptoms from at least 2 of the following groups:

fever
shortness of breath, sore throat, or cough
nausea or vomiting, diarrhoea, or abdominal pain
severe fatigue or body aches, or a general feeling of being unwell.

Your doctor may advise you to stop taking Kivexa.

If you have stopped taking Kivexa
If you have stopped taking Kivexa due to a hypersensitivity reaction, YOU MUST NEVER TAKE KIVEXA AGAIN, OR ANY OTHER MEDICINE CONTAINING ABACAVIR (e.g., Trizivir, Triumeq, or Ziagen). If you do, your blood pressure could drop dangerously within a few hours, which could lead to death.
If you have stopped taking Kivexa for any reason—especially because you thought you were experiencing side effects or other illnesses:
talk to your doctor before restarting it. Your doctor will assess whether your symptoms were related to a hypersensitivity reaction. If your doctor believes your symptoms may have been due to a hypersensitivity reaction, you will be told never to take Kivexa or any other medicine containing abacavir (e.g., Trizivir, Triumeq, or Ziagen) again. It is important to follow this advice.
Sometimes, hypersensitivity reactions have occurred in patients who restarted abacavir-containing medicines after having experienced even one of the symptoms listed on the Warning Card prior to stopping the medicine.
Very rarely, patients who previously took abacavir-containing medicines without any hypersensitivity symptoms have later developed a hypersensitivity reaction when restarting these medicines.
If your doctor advises restarting Kivexa, you will be asked to take the first doses in a place where you can receive immediate medical assistance if needed.
If you are hypersensitive to Kivexa, you must return all unused Kivexa tablets for safe disposal. Ask your doctor or pharmacist for advice.
The Kivexa package includes a Warning Card to remind you and healthcare professionals about hypersensitivity reactions. Detach this card and keep it with you at all times.

Common side effects
These may affect up to 1 in 10 patients:

hypersensitivity reaction
headache
vomiting
nausea
diarrhoea
stomach pain
loss of appetite
fatigue, lack of energy
fever (elevated temperature)
general feeling of being unwell
sleep disturbances (insomnia)
muscle discomfort and pain
joint pain
cough
irritation of nasal mucous membranes or runny nose
rash
hair loss

Uncommon side effects
These may affect up to 1 in 100 patients and may be detected by blood tests:

low red blood cell count (anaemia) or low white blood cell count (neutropenia)
increased liver enzymes
reduced number of cells involved in blood clotting (thrombocytopenia)

Rare side effects
These may affect up to 1 in 1,000 patients:

liver problems such as jaundice, enlarged liver, or fatty liver, inflammation (hepatitis)
inflammation of the pancreas (pancreatitis)
muscle tissue breakdown

Rare side effects that may be detected by blood tests include:

increased levels of an enzyme called amylase

Very rare side effects
These may affect up to 1 in 10,000 patients:

sensation of numbness or tingling in the skin (pins and needles)
feeling of weakness in arms and legs
rash with blister-like spots resembling small targets (a dark spot in the centre surrounded by a clear area with a dark ring around the edge) (erythema multiforme)
widespread rash with blisters and skin peeling, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome), and a more severe form causing skin peeling over more than 30% of the body surface (toxic epidermal necrolysis)
lactic acidosis (excess lactic acid in the blood)

If you notice any of these symptoms, contact your doctor urgently.
A very rare side effect that may be detected by blood tests is:

failure of the bone marrow to produce new red blood cells (pure red cell aplasia).

If you experience side effects
Tell your doctor or pharmacist if any of the side effects become severe or troublesome, or if you notice any side effect not listed in this leaflet.

Other possible side effects of combination therapy for HIV
Combination therapy such as Kivexa may cause the development of other illnesses during HIV treatment.

Symptoms of infection and inflammation
Old infections may flare up again
People with advanced HIV infection (AIDS) have a weakened immune system and are more likely to develop serious infections (opportunistic infections). These infections may be "silent" and not detected by the weakened immune system before treatment begins. After starting treatment, the immune system becomes stronger and may react against these infections, causing symptoms of infection or inflammation. Symptoms generally include fever, along with some of the following:

headache
stomach pain
difficulty breathing

In rare cases, as the immune system strengthens, it may also attack healthy body tissues (autoimmune disorders). Symptoms of autoimmune disorders may develop many months after starting HIV treatment. Symptoms may include:

palpitations (rapid or irregular heartbeat) or tremor
hyperactivity (excessive agitation and movement)
weakness starting in the hands and feet and spreading toward the body trunk. If you experience any symptoms of infection and inflammation or notice any of the symptoms listed above: inform your doctor immediately. Do not take any other medicines for infection without consulting your doctor.

You may have bone problems
Some people receiving combination antiretroviral therapy for HIV infection develop a condition called osteonecrosis. As a result of this disease, part of the bone tissue dies due to reduced blood supply to the bone. People may be more likely to develop this condition:

if they have been on combination therapy for a long time
if they are also taking anti-inflammatory medicines called corticosteroids
if they consume alcohol
if their immune system is very weak
if they are overweight.

Signs of osteonecrosis include:

stiffness in the joints
pain (especially in the hip, knee, or shoulder)
difficulty moving. If you notice any of these symptoms: inform your doctor.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly through 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 Kivexa

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton. The expiry date refers to the last day of that month.
Do not store above 30°C.
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 Kivexa contains
The active substances in each film-coated tablet of Kivexa are 600 mg of abacavir (as sulfate) and 300 mg of lamivudine.
The excipients are microcrystalline cellulose, sodium starch glycolate, and magnesium stearate in the tablet core. The tablet coating contains Opadry Orange YS-1-13065-A, which in turn consists of hypromellose, titanium dioxide, macrogol 400, polysorbate 80, and the yellow sunset FCF colourant (E110).

Description of the appearance of Kivexa and contents of the pack
The film-coated tablets of Kivexa are imprinted with 'GS FC2' on one side. They are orange, capsule-shaped tablets supplied in blister packs containing 30 tablets and in multiple blister packs containing 90 (3x30) tablets.

Marketing Authorisation Holder
ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, The Netherlands.

Manufacturer
Glaxo Wellcome S.A., Avenida de Extremadura 3, 09400 Aranda de Duero Burgos, Spain.

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

België/Belgique/Belgien Lietuva
ViiV Healthcare srl/bv ViiV Healthcare BV
Tél/Tel: + 32 (0) 10 85 65 00 Tel: + 370 80000334

България Luxembourg/Luxemburg
ViiV Healthcare BV ViiV Healthcare srl/bv
Teл.: + 359 80018205 Belgique/Belgien
Tél/Tel: + 32 (0) 10 85 65 00

Česká republika Magyarország
GlaxoSmithKline s.r.o. ViiV Healthcare BV
Tel: + 420 222 001 111 Tel.: + 36 80088309
[email protected]

Danmark Malta
GlaxoSmithKline Pharma A/S ViiV Healthcare BV
Tlf: + 45 36 35 91 00 Tel: + 356 80065004
[email protected]

Deutschland Nederland
ViiV Healthcare GmbH ViiV Healthcare BV
Tel.: + 49 (0)89 203 0038-10 Tel: + 31 (0) 33 2081199
[email protected]

Eesti Norge
ViiV Healthcare BV GlaxoSmithKline AS
Tel: + 372 8002640 Tlf: + 47 22 70 20 00

Ελλάδα Österreich
GlaxoSmithKline Μονοπρόσωπη A.E.B.E. GlaxoSmithKline Pharma GmbH
Τηλ: + 30 210 68 82 100 Tel: + 43 (0)1 97075 0
[email protected]

España Polska
Laboratorios ViiV Healthcare, S.L. GSK Services Sp. z o.o.
Tel: +34 900 923 501 Tel.: + 48 (0)22 576 9000
[email protected]

France Portugal
ViiV Healthcare SAS VIIVHIV HEALTHCARE,
Tél.: + 33 (0)1 39 17 6969 UNIPESSOAL, LDA
[email protected] Tel: + 351 21 094 08 01
[email protected]

Hrvatska România
ViiV Healthcare BV ViiV Healthcare BV
Tel: + 385 800787089 Tel: + 40800672524

Ireland Slovenija
GlaxoSmithKline (Ireland) Limited ViiV Healthcare BV
Tel: + 353 (0)1 4955000 Tel: + 40800672524

Ísland Slovenská republika
Vistor hf. ViiV Healthcare BV
Sími: +354 535 7000 Tel: + 421 800500589

Italia Suomi/Finland
ViiV Healthcare S.r.l GlaxoSmithKline Oy
Tel: + 39 (0)45 7741600 Puh/Tel: + 358 (0)10 30 30 30

Κύπρος Sverige
ViiV Healthcare BV GlaxoSmithKline AB
Τηλ: + 357 80070017 Tel: + 46 (0)8 638 93 00
[email protected]

Latvija United Kingdom (Northern Ireland)
ViiV Healthcare BV ViiV Healthcare BV
Tel: + 371 80205045 Tel: + 44 (0)800 221441
[email protected]

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

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for abacavir/lamivudina, the PRAC's scientific conclusions are as follows:
In light of the available literature data on cardiovascular events associated with abacavir, including a plausible mechanism of action, the PRAC considers that the warnings and precautions for use of medicinal products containing abacavir should be revised to adequately reflect the current level of information on cardiovascular events. Furthermore, in line with current therapeutic guidelines, a recommendation should be included in the product information advising against the use of medicinal products containing abacavir in patients with high cardiovascular risk. The PRAC concluded that the product information for medicinal products containing abacavir/lamivudine should therefore be amended accordingly.

Following review of the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and reasoning of the PRAC's recommendation.

Grounds for the variation to the terms of the marketing authorisation
Based on the scientific conclusions regarding abacavir/lamivudine, the CHMP considers that the benefit-risk balance of medicinal products containing abacavir/lamivudine remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.