Trizivir

Package Leaflet: Information for the User

Trizivir 300 mg/150 mg/300 mg film-coated tablets

abacavir/lamivudine/zidovudine
Please read this leaflet carefully before 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 others, even if they have the same symptoms as you, because it may be harmful to them.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist immediately. See section 4.

IMPORTANT — Hypersensitivity Reactions
Trizivir contains abacavir (which is also the active substance in medicines such as Kivexa,
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.
You must read carefully all the information under ‘Hypersensitivity Reactions’ in the box in section 4.
The Trizivir package includes an Alert Card to remind you and healthcare professionals about abacavir hypersensitivity. Remove this card and always carry it with you.

Contents of this leaflet

1. What Trizivir is and what it is used for
2. What you need to know before taking Trizivir
3. How to take Trizivir
4. Possible side effects
5. How to store Trizivir
6. Contents of the pack and other information

1. What Trizivir is and what it is used for

Trizivir is used to treat HIV (Human Immunodeficiency Virus) infection in adults.
Trizivir contains three active substances used in the treatment of HIV infection: abacavir,
lamivudine and zidovudine. All of these medicines belong to a group of antiretroviral drugs
called nucleoside analogue reverse transcriptase inhibitors (NRTIs).
Trizivir helps control your condition. Trizivir does not cure HIV infection; it reduces the viral load in the body and keeps it low. This helps the body increase the CD4 cell count in the blood. CD4 cells are a type of white blood cell that play an important role in helping the body fight infection.
Not all people respond to treatment with Trizivir in the same way. Your doctor will monitor the effectiveness of your treatment.

2. What you should know before taking Trizivir

Do not take Trizivir:

• if you are allergic ( hypersensitive ) to abacavir (or any other medicine containing abacavir – Kivexa, Triumeq or Ziagen ), lamivudine or zidovudine, 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.
• if you have severe kidney problems
• if you have very low red blood cell count ( anaemia ) or very low white blood cell count ( neutropenia ). Consult your doctor if any of these conditions applies to you.

Take special care with Trizivir
Some people taking Trizivir 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 Trizivir without consulting your doctor, as hepatitis may worsen)
• if you are severely overweight (especially if you are a woman) Inform your doctor if any of these conditions apply to you before using Trizivir. 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 carry 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 suffer from conditions that increase the risk of cardiovascular disease, such as high blood pressure or diabetes. Do not stop taking Trizivir unless advised by your doctor.

Be alert to important symptoms
Some people taking Trizivir develop other conditions that may be serious. It is important that you are aware of key signs and symptoms so that you can monitor yourself while taking Trizivir.
Read the information under 'Other possible side effects of Trizivir' in section 4 of this leaflet.

Other medicines and Trizivir
Inform your doctor or pharmacist if you are taking any other medicine, or have recently taken any, including herbal preparations or other medicines purchased without prescription.
Remember to inform your doctor or pharmacist if you start taking a new medicine while being treated with Trizivir.

The following medicines must not be taken with Trizivir:

• stavudine or emtricitabine to treat HIV infection
• other medicines containing lamivudine, used to treat HIV infection or hepatitis B
• ribavirin or intravenous ganciclovir to treat viral infections
• high doses of co-trimoxazole, an antibiotic
• cladribine, used to treat hairy cell leukaemia. Inform your doctor if you are being treated with any of these medicines.

Some medicines may increase the likelihood of side effects or make them worse.
These include:

• sodium valproate, to treat epilepsy
• interferon, to treat viral infections
• pyrimethamine, to treat malaria and other parasitic infections
• dapsone, to prevent pneumonia and to treat skin infections
• fluconazole or flucytosine, to treat fungal infections such as candidiasis
• pentamidine or atovaquone, to treat parasitic infections such as Pneumocystis jirovecii pneumonia (often referred to as PCP)
• amphotericin or co-trimoxazole, to treat fungal and bacterial infections
• probenecid, to treat gout and similar conditions, and administered with other antibiotics to enhance their effectiveness
• methadone, used as heroin substitute
• vincristine, vinblastine or doxorubicin, to treat cancer. Inform your doctor if you are taking any of these medicines.

Some medicines interact with Trizivir
These include:

• clarithromycin, an antibiotic. If you are taking clarithromycin, take your dose at least 2 hours before or after taking Trizivir.
• phenytoin, to treat epilepsy. Inform your doctor if you are taking phenytoin. Your doctor may need to monitor you while you are taking Trizivir.
• 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, to treat 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.

Methadone and Trizivir
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. The dose of methadone may need to be adjusted.

Pregnancy
If you are pregnant, become pregnant, or are planning a pregnancy, talk to your doctor about the risks and benefits of taking Trizivir during pregnancy for you and your baby.
Trizivir and similar medicines may cause side effects in unborn children.
If you have already taken Trizivir during pregnancy, your doctor may request regular blood tests and other diagnostic examinations to monitor your baby'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 Trizivir 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
Trizivir may cause dizziness and other side effects that may reduce attention.
Do not drive or operate machinery unless you feel well.

Important information about some of the other ingredients in Trizivir tablets
This medicine contains less than 1 mmol (23 mg) of sodium per dosage unit, i.e. essentially ‘sodium-free’.

3. How to take Trizivir

Always take this medicine exactly as your doctor has told you. Check with your
doctor or pharmacist if you are unsure.
Stay in contact with your doctor and do not stop taking Trizivir without your doctor's advice.
Dosage
The usual dose of Trizivir in adults is one tablet twice daily.
Take the tablets at regular intervals of approximately 12 hours between doses.
Swallow the tablets whole with water. Trizivir can be taken with or without food.
If you take more Trizivir than you should
If you accidentally take more Trizivir, inform your doctor or pharmacist or contact the Emergency Department
of your nearest hospital for further advice.
If you forget to take Trizivir
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 missed dose.
It is important to take Trizivir regularly, as taking it at irregular intervals may result in it no longer working effectively against HIV infection and you may be more likely to develop a hypersensitivity reaction.
If you have stopped taking Trizivir
If you have stopped taking Trizivir for any reason – particularly because you thought you were experiencing side effects or 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
Trizivir or any other medicine containing abacavir (Kivexa, Triumeq or Ziagen) again.
It is important that you follow this advice.
If your doctor advises restarting Trizivir, you will be asked to take the first doses in a setting where you can receive immediate medical attention if needed.

4. Possible side effects

During HIV therapy, an increase in weight and in 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.
Treatment with Trizivir often causes loss of fat from the legs, arms, and face (lipoatrophy). This loss of body fat has been shown not to be completely reversible after discontinuation of zidovudine. Your doctor should monitor for signs of lipoatrophy. Inform your doctor if you notice any fat loss from your legs, arms, or face. If these signs occur, Trizivir must be stopped and HIV treatment changed.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
During HIV treatment, it may be difficult to determine whether a symptom is an unwanted effect of Trizivir, of other medicines you are taking, or an effect of the HIV infection itself. For this reason, it is very important to inform your doctor about 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 treatment, both the side effects listed below for Trizivir and other conditions may occur.
It is important to read the information in another section of this leaflet under 'Other possible side effects of Trizivir'.

Hypersensitivity reactions
Trizivir contains abacavir (which is also the active substance in Kivexa, Triumeq, and Ziagen).
Abacavir can cause a serious allergic reaction known as a hypersensitivity reaction.
Such hypersensitivity reactions have been observed more frequently in people taking medicines containing abacavir.
Who is at risk of these reactions?
Any person taking Trizivir could develop a hypersensitivity reaction to abacavir, which could be life-threatening if Trizivir 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 should be tested for the presence of this gene before Trizivir is prescribed. If you know you have this gene, inform your doctor before taking Trizivir.
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 (high temperature) and rash.

Other common symptoms include:

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

Additional symptoms include:
muscle or joint pain, neck swelling, 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 can start at any time during treatment with Trizivir, but are most 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 discomfort, or general feeling of being unwell.

Your doctor may advise you to stop taking Trizivir.
If you have stopped taking Trizivir
If you have stopped taking Trizivir due to a hypersensitivity reaction, you must NEVER take Trizivir again, or any other medicine containing abacavir (Kivexa, Triumeq, or Ziagen). If you do, within a few hours your blood pressure could drop dangerously, which could lead to death.
If you have stopped taking Trizivir for any reason – particularly 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 suspects that your symptoms may have been due to a hypersensitivity reaction, you will be told never to take Trizivir or any other medicine containing abacavir (Kivexa, Triumeq, or Ziagen) again. It is important that you follow this advice.
Sometimes, hypersensitivity reactions have occurred in patients who restarted abacavir-containing medicines, even if they had only one of the symptoms described on the Warning Card before 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 Trizivir, you will be asked to take the first doses in a setting where you can receive immediate medical care if needed.
If you are hypersensitive to Trizivir, you must return all unused Trizivir tablets for safe disposal. Ask your doctor or pharmacist for advice.
The Trizivir 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.

Very common side effects
These may affect more than 1 in 10 people:

• headache
• nausea

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

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

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

• low red blood cell count (anaemia) or low white blood cell count (neutropenia or leucopenia)
• increased liver enzymes
• increased blood levels of bilirubin (a substance produced by the liver), which may cause yellowing of the skin.

Uncommon side effects
These may affect up to 1 in 100 people:

• shortness of breath
• flatulence
• itching
• muscle weakness

An uncommon side effect that may be detected by blood tests is:

• reduced number of platelets involved in blood clotting (thrombocytopenia) or reduced numbers of all types of blood cells (pancytopenia).

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

• liver disorders such as jaundice, enlarged liver, or fatty liver, inflammation (hepatitis)
• lactic acidosis (excess lactic acid in the blood; see next section ‘Other possible side effects of Trizivir’)
• inflammation of the pancreas (pancreatitis)
• chest pain; heart muscle disease (cardiomyopathy)
• seizures
• anxiety or depression, difficulty concentrating, drowsiness
• indigestion, taste disturbances
• changes in the colour of nails, skin, or the mucous membrane inside the mouth
• flu-like feeling – chills and sweating
• skin tingling sensation (pins and needles)
• feeling of limb weakness
• muscle tissue breakdown
• paraesthesia (altered sensation to touch)
• more frequent urination
• increased breast gland volume in male patients

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

• increased levels of an enzyme called amylase
• failure of the bone marrow to produce new red blood cells (pure red cell aplasia).

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

• skin rash with blister-like spots resembling small targets (a dark spot in the centre surrounded by a pale area with a black 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). 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 or white blood cells (aplastic anaemia).

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

Other possible side effects of Trizivir
Trizivir may cause the development of other conditions 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 (opportunistic) infections. When these people start treatment, previously hidden infections may flare up, causing signs and symptoms of inflammation. These symptoms are likely due to immune reconstitution, whereby the body starts fighting these infections. Symptoms usually include fever plus one or more of the following:

• headache
• stomach pain
• difficulty breathing

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

• palpitations (fast or irregular heartbeat) or tremor
• hyperactivity (agitation and excessive movement)
• weakness starting in the hands and feet and spreading towards the trunk of the body. If you notice any signs of infection while taking Trizivir: inform your doctor immediately. Do not take any other medicines for infection without consulting your doctor.

Lactic acidosis is a rare but serious side effect
Some people taking Trizivir develop a condition called lactic acidosis, together with liver enlargement.
Lactic acidosis is caused by a build-up of lactic acid in the body. It is a rare side effect and, if it occurs, usually develops after several months of treatment. It can be life-threatening and may lead to organ failure.
Lactic acidosis is more likely to occur in people with liver disease or in obese individuals (very overweight), especially women.
Signs of lactic acidosis include:

• nausea, vomiting
• stomach pain
• general feeling of being unwell
• loss of appetite, weight loss
• difficult, deep, and rapid breathing
• weakness or numbness in the limbs

During treatment, your doctor will monitor for signs of lactic acidosis. If you experience any of the symptoms listed above or any other symptom that concerns you:
contact your doctor as soon as possible.

You may have bone problems
Some people receiving combination antiretroviral therapy for HIV infection develop a condition called osteonecrosis. As a result of this condition, 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
• are also taking anti-inflammatory medicines called corticosteroids
• consume alcohol
• have a very weak immune system
• are overweight.

Signs of osteonecrosis include:

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

Other effects may be detected by blood tests
Trizivir may also cause:

• increased levels of lactic acid in the blood, which in rare cases may lead to lactic acidosis

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 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 Trizivir

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 Trizivir contains
The active substances in each film-coated tablet of Trizivir are 300 mg of abacavir (as sulfate), 150 mg of lamivudine and 300 mg of zidovudine.
The excipients are: microcrystalline cellulose, sodium starch glycolate and magnesium stearate contained in the tablet core. The tablet coating contains hypromellose, titanium dioxide, polyethylene glycol, indigo carmine aluminium lake, yellow iron oxide.

Description of the appearance of Trizivir and package contents
The film-coated tablets of Trizivir are blue/green, capsule-shaped and marked with 'GX LL1' on one side. They are supplied in packs containing 60 tablets in blisters or in bottles containing 60 tablets with child-resistant closures.

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

Manufacturer
Delpharm Poznań Spółka Akcyjna, ul. Grunwaldzka 189, 60-322 Poznan, Poland

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

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

България (Bulgaria)
ViiV Healthcare BV
Teл.: + 359 80018205

Česká republika (Czech Republic)
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
[email protected]

Danmark (Denmark)
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
[email protected]

Deutschland (Germany)
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
[email protected]

Eesti (Estonia)
ViiV Healthcare BV
Tel: + 372 8002640

Ελλάδα (Greece)
GlaxoSmithKline Μονοπρόσωπη A.E.B.E.
Τηλ: + 30 210 68 82 100

España (Spain)
Laboratorios ViiV Healthcare, S.L.
Tel: +34 900 923 501
[email protected]

France
ViiV Healthcare SAS
Tél.: + 33 (0)1 39 17 6969
[email protected]
[email protected]

Hrvatska (Croatia)
ViiV Healthcare BV
Tel: + 385 800787089

Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000

Ísland (Iceland)
Vistor hf.
Sími: +354 535 7000

Italia (Italy)
ViiV Healthcare S.r.l
Tel: + 39 (0)45 7741600

Κύπρος (Cyprus)
ViiV Healthcare BV
Τηλ: + 357 80070017
[email protected]

Latvija (Latvia)
ViiV Healthcare BV
Tel: + 371 80205045

Lietuva (Lithuania)
ViiV Healthcare BV
Tel: + 370 80000334

Luxembourg/Luxemburg
ViiV Healthcare srl/bv
Belgique/Belgien
Tél/Tel: + 32 (0) 10 85 65 00

Magyarország (Hungary)
ViiV Healthcare BV Ltd
Tel.: + 36 80088309

Malta
ViiV Healthcare BV
Tel: + 356 80065004

Nederland (Netherlands)
ViiV Healthcare BV
Tel: + 31 (0) 33 2081199

Norge (Norway)
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00

Österreich (Austria)
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
[email protected]

Polska (Poland)
GSK Services Sp. z o.o.
Tel.: + 48 (0)22 576 9000

Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL, LDA
Tel: + 351 21 094 08 01
[email protected]

România (Romania)
ViiV Healthcare BV
Tel: + 40800672524

Slovenija (Slovenia)
ViiV Healthcare BV
Tel: + 386 80688869

Slovenská republika (Slovakia)
ViiV Healthcare BV
Tel: + 421 800500589

Suomi/Finland (Finland)
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30

Sverige (Sweden)
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00

United Kingdom (Northern Ireland)
ViiV Healthcare BV
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 REASONS FOR THE CHANGE IN THE TERMS OF THE MARKETING AUTHORISATION

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for abacavir / lamivudine / zidovudine, 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 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, the product information should also include a recommendation advising against the use of abacavir-containing medicinal products in patients at high cardiovascular risk. The PRAC concluded that the product information for medicinal products containing abacavir / lamivudine / zidovudine should therefore be amended accordingly.

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

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