Consumer medicine information

Abacavir/Lamivudine Viatris

Abacavir; Lamivudine

BRAND INFORMATION

Brand name

Abacavir/Lamivudine Viatris

Active ingredient

Abacavir; Lamivudine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Abacavir/Lamivudine Viatris.

SUMMARY CMI

ABACAVIR/LAMIVUDINE VIATRIS

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using ABACAVIR/LAMIVUDINE VIATRIS?

ABACAVIR/LAMIVUDINE VIATRIS contains the active ingredients abacavir and lamivudine. ABACAVIR/LAMIVUDINE VIATRIS is used together with other antiretrovirals to slow down the progression of human immunodeficiency virus (HIV) infection, which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (e.g. AIDS-related Complex or ARC).
For more information, see Section 1. Why am I using ABACAVIR/LAMIVUDINE VIATRIS? in the full CMI.

2. What should I know before I use ABACAVIR/LAMIVUDINE VIATRIS?

Do not use if you have ever had an allergic reaction to abacavir or lamivudine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ABACAVIR/LAMIVUDINE VIATRIS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ABACAVIR/LAMIVUDINE VIATRIS and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ABACAVIR/LAMIVUDINE VIATRIS?

  • The normal dose for adults and adolescents is one tablet once a day.
  • ABACAVIR/LAMIVUDINE VIATRIS tablets should be swallowed whole with water and do not have to be taken with food.

More instructions can be found in Section 4. How do I use ABACAVIR/LAMIVUDINE VIATRIS? in the full CMI.

5. What should I know while using ABACAVIR/LAMIVUDINE VIATRIS?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ABACAVIR/LAMIVUDINE VIATRIS.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • For as long as you're taking ABACAVIR/LAMIVUDINE VIATRIS, your doctor will arrange regular blood tests to check for side effects.
  • Keep in contact with your doctor, and don't stop taking KIVEXA without your doctor's advice.
Things you should not do
  • Do not take ABACAVIR/LAMIVUDINE VIATRIS to treat any other complaints unless your doctor tells you to.
  • Do not stop taking ABACAVIR/LAMIVUDINE VIATRIS tablets or change the dose without first talking to your doctor.
Driving or using machines
  • Don't drive or operate machinery unless you are sure you are not affected.
Looking after your medicine
  • Keep your tablets in cool, dry place where it stays below 25°C
  • Keep your ABACAVIR/LAMIVUDINE VIATRIS tablets in their pack until you take them.

For more information, see Section 5. What should I know while using ABACAVIR/LAMIVUDINE VIATRIS? in the full CMI.

6. Are there any side effects?

The most common side effects are feeling sick (nausea), diarrhoea, being sick (vomiting), stomach pain (abdominal pain), headache and rash. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

PATIENTS TAKING ABACAVIR/LAMIVUDINE VIATRIS, WHICH CONTAINS ABACAVIR, MAY DEVELOP A HYPERSENSITIVITY REACTION (SERIOUS ALLERGIC REACTION) WHICH CAN BE LIFE-THREATENING IF TREATMENT WITH ABACAVIR/LAMIVUDINE VIATRIS IS CONTINUED. CONTACT YOUR DOCTOR IMMEDIATELY FOR ADVICE ON WHETHER YOU SHOULD STOP TAKING ABACAVIR/LAMIVUDINE VIATRIS IF:

1) YOU GET A SKIN RASH OR

2) YOU GET ONE OR MORE SYMPTOMS FROM AT LEAST TWO OF THE FOLLOWING GROUPS:
• FEVER
• SHORTNESS OF BREATH, SORE THROAT OR COUGH
• NAUSEA OR VOMITING OR DIARRHOEA OR ABDOMINAL PAIN
• SEVERE TIREDNESS OR ACHINESS OR GENERALLY ILL FEELING

IF YOU HAVE HAD A HYPERSENSITIVITY (ALLERGIC) REACTION TO ABACAVIR/LAMIVUDINE VIATRIS TABLETS, NEVER TAKE ABACAVIR/LAMIVUDINE VIATRIS, OR ANY OTHER MEDICINAL PRODUCT CONTAINING ABACAVIR AGAIN AS YOU MAY DEVELOP A LIFE THREATENING REACTION WHICH CAN BE FATAL.

THERE IS AN ALERT CARD INCLUDED IN THE ABACAVIR/LAMIVUDINE VIATRIS PACK, TO REMIND YOU AND MEDICAL STAFF ABOUT ABACAVIR HYPERSENSITIVITY. THIS CARD SHOULD BE REMOVED FROM THE PACK AND KEPT WITH YOU AT ALL TIMES. SEE MORE DETAILS UNDER BEFORE YOU TAKE ABACAVIR/LAMIVUDINE VIATRIS.



FULL CMI

ABACAVIR/LAMIVUDINE VIATRIS

Active ingredient(s): abacavir (as sulfate) and lamivudine

Consumer Medicine Information (CMI)

This leaflet provides important information about using ABACAVIR/LAMIVUDINE VIATRIS. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ABACAVIR/LAMIVUDINE VIATRIS.

Where to find information in this leaflet:

1. Why am I using ABACAVIR/LAMIVUDINE VIATRIS?
2. What should I know before I use ABACAVIR/LAMIVUDINE VIATRIS?
3. What if I am taking other medicines?
4. How do I use ABACAVIR/LAMIVUDINE VIATRIS?
5. What should I know while using ABACAVIR/LAMIVUDINE VIATRIS?
6. Are there any side effects?
7. Product details

1. Why am I using ABACAVIR/LAMIVUDINE VIATRIS?

ABACAVIR/LAMIVUDINE VIATRIS contains the active ingredients abacavir and lamivudine. ABACAVIR/LAMIVUDINE VIATRIS belong to a group of medicines called antiretrovirals.

These are also available as separate medicinal products.

ABACAVIR/LAMIVUDINE VIATRIS is used to treat human immunodeficiency virus (HIV) infection.

ABACAVIR/LAMIVUDINE VIATRIS tablets do not cure AIDS or kill the HIV virus, but delays further damage to the immune system by stopping production of new viruses.

You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. You will still be able to pass on the HIV virus by sexual activity or by contamination with infected blood. You should still use proper precautions to prevent this. Discuss with your doctor the precautions needed to avoid infecting other people.

ABACAVIR/LAMIVUDINE VIATRIS tablets are used together with other antiretrovirals to slow down the progression of human immunodeficiency virus (HIV) infection, which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (e.g. AIDS-related Complex or ARC).

2. What should I know before I use ABACAVIR/LAMIVUDINE VIATRIS?

Warnings

Do not use ABACAVIR/LAMIVUDINE VIATRIS if:

  • you have ever had an allergic reaction to abacavir.
  • you are allergic to the active ingredient lamivudine, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have a serious liver disease ABACAVIR/LAMIVUDINE VIATRIS may not be suitable for you.
  • you have severe kidney disease.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You must not take ABACAVIR/LAMIVUDINE VIATRIS tablets if you are pregnant, think you may be pregnant or are breastfeeding, unless your doctor tells you to.

Symptoms of infection and inflammation

People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to develop serious infections (opportunistic infections). When these people start treatment, the immune system becomes stronger, so that the body starts to fight these infections.

Symptoms of infection and inflammation may develop, caused by either:

  • old, hidden infections flaring up against as the body fights them
  • the immune system attacking healthy body tissue (autoimmune disorders).

The symptoms of autoimmune disorders may develop many months after you start taking medicine to treat your HIV infection.

Symptoms may include:

  • muscle weakness and/or muscle pain
  • joint pain or swelling
  • weakness beginning in the hands feet and moving towards the trunk of the body
  • palpitations or tremor
  • hyperactivity (excessive restlessness and movement).

If you get any symptoms of infection or if you notice any of the symptoms above tell your doctor immediately. Don't take other medicines for the infection without your doctors' advice.

3. What if I am taking other medicines?

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

Abacavir or lamivudine in ABACAVIR/LAMIVUDINE VIATRIS tablets may interact with certain other medicines. ABACAVIR/LAMIVUDINE VIATRIS tablets should not be taken with emtricitabine.

Some medicines may interfere with ABACAVIR/LAMIVUDINE VIATRIS and affect how it works.

  • sorbitol-containing medicines (usually liquids) used regularly
  • trimethoprim-sulphamethoxazole (also known as co-trimoxazole), (an antibiotic used to treat PCP - Pneumocystis jiroveci pneumonia (often referred to as PCP) or toxoplasmosis).

If you are taking methadone, your doctor may need to adjust your methadone dose, as abacavir increases the rate at which methadone leaves your body. This is unlikely to affect most methadone users.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ABACAVIR/LAMIVUDINE VIATRIS.

4. How do I use ABACAVIR/LAMIVUDINE VIATRIS?

How much to take

  • The normal dose for adults and adolescents is one tablet once a day.
  • Follow the instructions provided and use ABACAVIR/LAMIVUDINE VIATRIS until your doctor tells you to stop.

When to take ABACAVIR/LAMIVUDINE VIATRIS

  • ABACAVIR/LAMIVUDINE VIATRIS should be used swallowed whole with water. ABACAVIR/LAMIVUDINE VIATRIS tablets do not have to be taken with food.

If you forget to take ABACAVIR/LAMIVUDINE VIATRIS

ABACAVIR/LAMIVUDINE VIATRIS should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then continue as before.

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

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

If you take too much ABACAVIR/LAMIVUDINE VIATRIS

If you think that you have used too much ABACAVIR/LAMIVUDINE VIATRIS, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ABACAVIR/LAMIVUDINE VIATRIS?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ABACAVIR/LAMIVUDINE VIATRIS tablets.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

If you have stopped taking ABACAVIR/LAMIVUDINE VIATRIS tablets for any reason, it is important that you contact your doctor before restarting. This is especially so if you think you are having side-effects or have another illness. In some cases your doctor will ask you to restart ABACAVIR/LAMIVUDINE VIATRIS tablets where medical care can be readily accessed by yourself or others.

You will need regular blood tests

For as long as you're taking ABACAVIR/LAMIVUDINE VIATRIS, your doctor will arrange regular blood tests to check for side effects.

Stay in regular contact with your doctor

  • ABACAVIR/LAMIVUDINE VIATRIS helps to control your condition, but does not cure HIV infection, you will need to take the tablets every day to stop your illness from getting worse. While taking ABACAVIR/LAMIVUDINE VIATRIS tablets and/or any other therapy for HIV disease, you may continue to develop other infections and other complications of HIV infection.
  • You should keep in regular contact with the doctor who is looking after you.
  • Do not stop taking ABACAVIR/LAMIVUDINE VIATRIS tablets or change the dose without first talking to your doctor.

Things you should not do

  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use ABACAVIR/LAMIVUDINE VIATRIS tablets to treat any other complaints unless your doctor tells you to.
  • If you have hepatitis B infection, you should not stop ABACAVIR/LAMIVUDINE VIATRIS tablets without instructions from your doctor, as you may have a recurrence of your hepatitis. This may occur due to you suddenly stopping lamivudine.

Hypersensitivity reaction

  • ABACAVIR/LAMIVUDINE VIATRIS contains abacavir. Abacavir can cause a serious allergic reaction known as a hypersensitivity reaction, which can be life-threatening if treatment with abacavir containing products is not stopped.
  • Research has found that people with a gene called HLA-B (type 5701) are more likely to have a hypersensitivity reaction to abacavir. However, even if you do not have this gene type it is still possible for you to get this reaction. If you know you have this gene type, be sure to tell your doctor before you take abacavir.
  • The most common symptoms of this reaction include high temperature (fever) and a skin rash. Other most frequently seen symptoms include nausea, vomiting, diarrhoea or abdominal pain; severe tiredness or body aches or generally feeling ill; headache; shortness of breath, sore throat or cough. If you develop any of these symptoms call your doctor IMMEDIATELY WHO WILL ADVISE YOU WHETHER YOU SHOULD STOP TAKING ABACAVIR/LAMIVUDINE VIATRIS tablets. If your doctor is not available you must urgently seek other medical advice (e.g. the Accident and Emergency unit of the nearest hospital) before taking the next dose.
  • Other symptoms may include joint or muscle pain, swelling of the neck or itchy skin. Occasionally inflammation of the eye (conjunctivitis), ulcers in the mouth, tingling or numbness of the hands or feet or low blood pressure may occur. The symptoms of this allergic reaction can occur at any time during treatment with ABACAVIR/LAMIVUDINE VIATRIS tablets. However they usually occur in the first six weeks of treatment, and get worse with continued treatment.
  • If you have had this serious reaction to ABACAVIR/LAMIVUDINE VIATRIS tablets, NEVER take ABACAVIR/LAMIVUDINE VIATRIS or any other medicinal product containing abacavir again as within hours you may experience a life-threatening lowering of your blood pressure or death.
  • Occasionally life threatening hypersensitivity reactions have occurred when ABACAVIR/LAMIVUDINE VIATRIS tablets was restarted in patients who reported only one of the symptoms on the Alert Card before stopping.
  • On very rare occasions, hypersensitivity has been reported when ABACAVIR/LAMIVUDINE VIATRIS tablets were restarted in patients who had no symptoms of hypersensitivity before stopping.
  • If you have stopped taking ABACAVIR/LAMIVUDINE VIATRIS tablets for any reason it is important that you contact your doctor before restarting. This is especially so if you think you are having side-effects from other medicines or have another illness. Your doctor will check whether any symptoms you had before stopping may be related to this hypersensitivity reaction. If your doctor thinks there is a possibility that they were related, you may be told never to take ABACAVIR/LAMIVUDINE VIATRIS tablets again. It is important that you follow this advice.
  • If you are hypersensitive to ABACAVIR/LAMIVUDINE VIATRIS tablets you should return all of your unused ABACAVIR/LAMIVUDINE VIATRIS tablets to your doctor or pharmacist for proper disposal.

Kidney disease

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ABACAVIR/LAMIVUDINE VIATRIS affects you.

No studies on the effects of ABACAVIR/LAMIVUDINE VIATRIS tablets on the ability to drive and use machines have been performed. However, you should take into account the state of your health and the possible side effects of ABACAVIR/LAMIVUDINE VIATRIS tablets before considering driving or using machines.

Looking after your medicine

  • Keep your ABACAVIR/LAMIVUDINE VIATRIS tablets in their pack until you take them.
  • Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it, such as a locked cupboard.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Check with your doctor as soon as possible if you think you are experiencing any side-effects or allergic reactions while taking ABACAVIR/LAMIVUDINE VIATRIS tablets, even if the problem is not listed in this leaflet.

Hypersensitivity Reaction

ABACAVIR/LAMIVUDINE VIATRIS contains abacavir. Abacavir can cause a serious allergic reaction known as a hypersensitivity reaction, which can be life-threatening if treatment with abacavir containing products is not stopped. This is described in the section 5. What should I know while using ABACAVIR/LAMIVUDINE VIATRIS?.

It is important that you read and understand the information about this serious reaction.

As ABACAVIR/LAMIVUDINE VIATRIS tablets contains both abacavir and lamivudine, the side effects reported for each of these have been combined.

Less serious side effects

Less serious side effectsWhat to do
Very common side-effects

These may affect at least one to ten in every 100 people:

Gastrointestinal:
  • feeling sick (nausea)
  • being sick (vomiting)
  • diarrhoea
  • stomach pain (abdominal pain)
General:
  • lethargy, fatigue, loss of appetite
Nervous system:
  • headache
  • high temperature
Musculoskeletal:
  • joint and muscle pain
Skin related:
  • abacavir hypersensitivity
  • skin rash (without any other illness)
  • hair loss
Uncommon side effects

These may affect less than one in every 100 people:

From blood tests:
  • increases in enzymes produced by the liver
  • anaemia (low red blood cell count)
  • neutropenia (low white blood cell count)
  • reduction in the number of platelets (blood cells important for blood clotting).

If the production of red blood cells is reduced, you may have symptoms of tiredness or breathlessness.

A reduction in your white blood cell count can make you more prone to infection. If you have a low platelet count, you may notice that you bruise more easily.

Rare side-effects

These may affect less than one in every 1,000 people):

General:
  • inflammation of the pancreas (pancreatitis).
Musculoskeletal:
  • breakdown of muscle tissue, increases of an enzyme called amylase
Very rare side-effects

These may affect less than one in every 10,000 people):

General:
  • severe anaemia
Skin related:
  • serious skin reactions
Other observations:
  • Fat gain and loss
  • Changes in the amounts of fatty substances and glucose in the blood.

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions (e.g. pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV. If you become concerned about any new symptoms, or any changes in your health after starting HIV treatment, please discuss with your doctor immediately.

In babies and infants exposed to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) during pregnancy or labour small temporary increases in blood levels of a substance called lactate have been observed.
Additionally there have been very rare reports of diseases that affect the nervous system such as a delayed development and seizures. Overall, in children whose mothers took NRTIs during pregnancy, the benefit from the reduced chance of being infected with HIV is likely to be greater than the risk of suffering from side effects.

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Lactic Acidosis:
  • Some people taking ABACAVIR/LAMIVUDINE VIATRIS, or other medicines like it (NRTIs), develop a condition called lactic acidosis, together with an enlarged liver.
  • Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually develops after a few months of treatment. It can be life-threatening, causing failure of internal organs.
  • Lactic acidosis is more likely to develop in people who have liver disease, especially in women.
  • Signs of lactic acidosis include:
    - deep, rapid, difficult breathing
    - drowsiness
    - numbness or weakness in the limbs
    - feeling sick (nausea), being sick (vomiting)
    - stomach pain.
Allergic (anaphylactic) reaction
  • The symptoms of an allergic (anaphylactic) reaction which may occur soon after starting ABACAVIR/LAMIVUDINE VIATRIS include wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ABACAVIR/LAMIVUDINE VIATRIS contains

Active ingredient
(main ingredient)		600 mg of abacavir as the sulfate salt and 300 mg of lamivudine
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • crospovidone
  • magnesium stearate
  • silicified microcrystalline cellulose
  • colloidal
  • anhydrous silica
  • talc
  • OPADRY II complete film coating system 13B58894 White (ARTG PI No: 13119) containing: hypromellose, titanium dioxide, macrogol 400 and polysorbate 80.
Potential allergensABACAVIR/LAMIVUDINE VIATRIS tablets contain sorbates and sulfites.

Do not take this medicine if you are allergic to any of these ingredients.

What ABACAVIR/LAMIVUDINE VIATRIS looks like

ABACAVIR/LAMIVUDINE VIATRIS is white, film-coated, modified capsule shaped, biconvex tablet debossed with AL12 on one side of the tablet and M on the other side (AUST R 266516).

ABACAVIR/LAMIVUDINE VIATRIS tablets are supplied in blister packs containing 30 tablets.

Who distributes ABACAVIR/LAMIVUDINE VIATRIS

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you the individual advice you need. You may also be able to find out more information about your disease from books, for example in public libraries.

Counselling is also available from your local AIDS council.

This leaflet was prepared in Jan 2023.

ABACAVIR/LAMIVUDINE VIATRIS_cmi\Jan23/00

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Abacavir/Lamivudine Viatris

Active ingredient

Abacavir; Lamivudine

Schedule

S4

 

1 Name of Medicine

Abacavir sulfate and lamivudine.

2 Qualitative and Quantitative Composition

Abacavir/Lamivudine Viatris is supplied as film-coated tablets each containing 600 mg of abacavir as abacavir sulfate and 300 mg lamivudine.

Excipients with known effect.

Sorbates and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Abacavir/Lamivudine Viatris is a white, film-coated, modified capsule shaped, biconvex tablet debossed with AL12 on one side of the tablet and M on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Abacavir/Lamivudine Viatris tablets are a combination of two nucleoside analogues (abacavir and lamivudine). Abacavir/Lamivudine Viatris is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age.

4.2 Dose and Method of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection.
Abacavir/Lamivudine Viatris tablets should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.
Abacavir/Lamivudine Viatris tablets can be taken with or without food.
Abacavir/Lamivudine Viatris tablets should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance < 30 mL/min. Separate preparations of abacavir or lamivudine should be administered in cases where discontinuation or dose adjustment is indicated. In these cases the physician should refer to the individual product information for these medicinal products.

Adults and adolescents.

The recommended dose of Abacavir/Lamivudine Viatris tablets in adults and adolescents is one tablet once daily.

Elderly.

The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age. When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicinal products or disease.

Children.

Abacavir/Lamivudine Viatris tablets are not recommended for treatment of children less than 12 years of age as the necessary dose adjustment cannot be made. Physicians should refer to the individual product information for lamivudine and abacavir.

Renal impairment.

Whilst no dosage adjustment of abacavir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore, abacavir/lamivudine fixed dose combination tablets are not recommended for use in patients with a creatinine clearance < 30 mL/min (see Section 5.2 Pharmacokinetic Properties, Special populations).

Administration in subjects with moderate renal impairment.

Patients with a creatinine clearance between 30 and 49 mL/min receiving abacavir/lamivudine fixed dose combination tablets may experience a 1.6 to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥ 50 mL/min (see Section 5.2 Pharmacokinetic Properties, Special populations). There are no safety data from randomised, controlled trials comparing abacavir/lamivudine fixed dose combination tablets to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in < 1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.
Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive abacavir/lamivudine fixed dose combination tablets should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with abacavir/lamivudine fixed dose combination tablets. Abacavir/lamivudine fixed dose combination tablets should be discontinued and the individual components should be used to construct the treatment regimen.
Risks and benefits of using abacavir/lamivudine fixed dose combination tablets in patients with renal impairment should be assessed by a physician experienced in the management of HIV infection and discussed with the patient.

Hepatic impairment.

A dose reduction of abacavir may be required for patients with mild hepatic impairment (Child-Pugh grade A). As dose reduction is not possible with Abacavir/Lamivudine Viatris tablets, the separate preparations of abacavir and lamivudine should be used when this is judged to be necessary. Abacavir/Lamivudine Viatris is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see Section 5.2 Pharmacokinetic Properties, Special populations).

4.3 Contraindications

Abacavir/Lamivudine Viatris tablets are contra-indicated in patients with known hypersensitivity to abacavir or lamivudine, or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Hypersensitivity - special warning.

The special warnings and precautions relevant to both abacavir and lamivudine are included in this section. There are no additional precautions and warnings relevant to abacavir/lamivudine fixed dose combination tablets.

Hypersensitivity to abacavir.

(See Section 4.8 Adverse Effects (Undesirable Effects).)
Hypersensitivity to abacavir is a multi-organ clinical syndrome which can occur at any time during treatment, but most often occurs within the first 6 weeks of therapy. Signs or symptom usually present in 2 or more of the following groups although hypersensitivity following the presentation of a single sign or symptom has been reported infrequently: fever; rash; gastrointestinal, including nausea, vomiting, diarrhoea, or abdominal pain; constitutional, including generalized malaise, fatigue, or achiness; respiratory, including dyspnoea, cough, or pharyngitis.
Hypersensitivity reactions may present similarly to pneumonia, bronchitis or pharyngitis, influenza-like illness or gastroenteritis.
Discontinue abacavir/lamivudine combination tablet as soon as a hypersensitivity reaction is suspected.
If hypersensitivity reaction cannot be ruled out, abacavir/lamivudine combination tablet or any other medicinal product containing abacavir must not be restarted.
The risk is significantly increased for patients who test positive for the HLA-B*5701 allele. However, abacavir hypersensitivity reactions have been reported at a lower frequency in patients who do not carry this allele.
Abacavir/lamivudine fixed dose combination tablet is not recommended for use in patients with the HLA-B*5701 allele or in patients who have had a suspected abacavir HSR while taking any medicinal product containing abacavir.
Testing for HLA-B*5701 status is recommended before initiating abacavir treatment and also before re-starting abacavir treatment in patients of unknown HLA-B*5701 status who have previously tolerated abacavir.
The diagnosis of hypersensitivity reaction is based on clinical judgment. If a hypersensitivity reaction is suspected, abacavir/lamivudine fixed dose combination tablet must be stopped without delay, even in the absence of the HLA-B*5701 allele. Delay in stopping treatment with abacavir after the onset of hypersensitivity may result in a life-threatening hypotension and death.
Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity reaction have also experienced life-threatening reactions within hours of re-initiating abacavir therapy. Therefore, if a hypersensitivity reaction is ruled out, the reintroduction of abacavir/lamivudine fixed dose combination or any other abacavir-containing product is recommended only if medical care can be readily accessed.
Each patient should be reminded to read the Consumer Medicine Information. They should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.
Patients who have experienced a hypersensitivity reaction should be instructed to dispose of their remaining abacavir/lamivudine fixed dose combination tablets in order to avoid restarting abacavir.

Lactic acidosis/severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir and lamivudine in the treatment of HIV infection. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).
Caution should be exercised when administering abacavir/lamivudine fixed dose combination tablets, particularly to those with known risk factors for liver disease. Treatment with abacavir/lamivudine fixed dose combination tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Fat loss or fat gain.

Fat loss or fat gain has been reported during combination antiretroviral therapy. The long term consequences of these events are currently unknown. A causal relationship has not been established.

Serum lipids and blood glucose.

Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and lifestyle changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome.

In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jirovecii pneumonia (often referred to as PCP). Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Post-treatment exacerbations of hepatitis B.

Clinical study and marketed use of lamivudine, have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If abacavir/lamivudine fixed dose combination tablets are discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

Opportunistic infections.

Patients receiving abacavir/lamivudine fixed dose combination tablets or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Transmission of infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Mitochondrial dysfunction.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Myocardial infarction.

Several observational, epidemiological studies have reported an association with abacavir use and the risk of myocardial infarction. Meta-analyses of randomised controlled trials have observed no excess risk of myocardial infarction with abacavir use. To date there is no established biological mechanism to explain a potential increase in risk. In totality the available data from observational studies and from controlled clinical trials show inconsistency and therefore the evidence for a causal relationship between abacavir treatment and the risk of myocardial infarction is inconclusive.
As a precaution the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).

General.

Abacavir/Lamivudine Viatris should not be taken with any other abacavir or lamivudine containing product.
As part of a triple-drug regimen, abacavir/lamivudine fixed dose combination tablet is generally recommended for use with antiretroviral agents from different pharmacological classes and not solely with other nucleoside/nucleotide reverse transcriptase inhibitors. This is based on results from randomised, double-blind, controlled studies in which the proportion of subjects with early virological failure (for example tenofovir, lamivudine and abacavir or tenofovir, lamivudine and didanosine) was higher in the triple nucleoside groups than in groups who received regimens involving two nucleosides in combination with an agent from a different pharmacological class. However, consideration needs to be given to a number of factors, including compliance, safety, toxicity and preservation of future treatment options, which also remain important when selecting an appropriate antiretroviral combination for a patient.

Therapy experienced patients.

In clinical trials patients with prolonged prior NRTI exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir or lamivudine and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients with prolonged prior NRTI exposure, or who have HIV-1 isolates containing multiple mutations conferring resistance to NRTIs (see Section 5.1 Pharmacodynamic Properties, Cross-resistance).

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Abacavir/Lamivudine Viatris is a fixed combination product not suitable for use in children aged < 12 years who weigh less than 40 kg, for whom dosage recommendations vary based on body weight.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Table 2.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As Abacavir/Lamivudine Viatris tablets contain abacavir and lamivudine, any interactions that have been identified with these agents individually may occur with Abacavir/Lamivudine Viatris tablets. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine. Abacavir and lamivudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Lamivudine does not inhibit cytochrome P450 enzymes. Abacavir shows limited potential to inhibit metabolism mediated by CYP3A4 and has been shown in vitro not to inhibit CYP2C9 or CYP2D6 enzymes. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P450 enzymes.
The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein binding, and almost complete renal clearance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is renal.

Effect of abacavir on the pharmacokinetics of other agents.

In vitro, abacavir demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp) and minimal inhibition of organic cation transporter 1 (OCT1), OCT2 and multidrug and toxin extrusion protein 2-K (MATE2-K). Abacavir is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.
Abacavir is an inhibitor of MATE1 in vitro, however abacavir has low potential to affect the plasma concentrations of MATE1 substrates at therapeutic drug exposures (up to 600 mg).

Effect of other agents on the pharmacokinetics of abacavir.

In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, Multidrug resistance-associated protein 2 (MRP2) or MRP4, therefore drugs that modulate these transporters are not expected to affect abacavir plasma concentrations.
Although abacavir is a substrate of BCRP and Pgp in vitro, clinical studies demonstrate no clinically significant changes in abacavir pharmacokinetics when co-administered with lopinavir/ritonavir (Pgp and BCRP inhibitors).

Interactions relevant to abacavir.

Ethanol.

The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. Given the safety profile of abacavir, these findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.

Methadone.

In a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax, but AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study, abacavir increased the mean methadone systemic clearance by 22%. This change is not considered clinically relevant for the majority of patients, however occasionally methadone dose re-titration may be required.

Riociguat.

In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine (600/50/300 mg once daily) led to an approximately three-fold higher riociguat AUC (0-∞) when compared to historical riociguat AUC (0-∞) reported in healthy subjects. Riociguat dose may need to be reduced, consult the riociguat product labeling for dosing recommendations and for interactions observed in patients receiving highly active antiretroviral therapy.

Retinoids.

Retinoid compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.

Effect of lamivudine on the pharmacokinetics of other agents.

In vitro, lamivudine demonstrates no or weak inhibition of the drug transporters OATP1B1, OATP1B3, BCRP or Pgp, MATE1, MATE2-K or OCT3. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.
Lamivudine is an inhibitor of OCT1 and OCT2 in vitro with IC50 values of 17 and 33 microM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).

Effect of other agents on the pharmacokinetics of lamivudine.

Lamivudine is a substrate of MATE1, MATE2-K and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.
Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.
Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

Interactions relevant to lamivudine.

Sorbitol.

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14% (9 - 20%), 32% (28 - 37%), and 36% (32 - 41%) in lamivudine exposure (AUC∞) and 28% (20 - 34%), 52% (47 - 57%), and 55% (50 - 59%) in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of sorbitol-containing medicines with lamivudine. Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Trimethoprim.

Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see Section 4.2 Dose and Method of Administration). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. Administration of lamivudine in patients with renal impairment should be assessed carefully. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis has not been studied.

Emtricitabine.

Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Abacavir had no adverse effects on the mating performance or fertility of male and female rats at oral doses of up to 427 mg/kg per day, a dose expected to produce exposures approximately 30 fold higher than that in humans at the therapeutic dose based on AUC. Orally administered lamivudine (up to 70 times anticipated clinical exposure based on Cmax) have shown evidence of impairment of fertility in male and female rats.
There are no data on the effect of abacavir or lamivudine on human female fertility.
(Category B3)
There are no adequate and well-controlled studies in pregnant women and the safe use of abacavir, lamivudine or abacavir/lamivudine fixed dose combination tablet in human pregnancy has not been established. Therefore administration of Abacavir/Lamivudine Viatris in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the foetus.
Abacavir has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for abacavir compared to the background rate. The Antiretroviral Pregnancy Registry has received prospective reports of over 2,000 exposures to abacavir during pregnancy resulting in live birth. These consist of over 800 exposures during the first trimester, over 1,100 exposures during the second/third trimester and included 27 and 32 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.1% (2.0, 4.4%) and in the second/third trimester, 2.7% (1.9, 3.9%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. There was no association between abacavir and overall birth defects observed in the Antiretroviral Pregnancy Registry.
Lamivudine has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for lamivudine compared to the background rate. The Antiretroviral Pregnancy Registry has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,200 exposures during the first trimester, over 6,900 exposures during the second/third trimester and included 135 and 198 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.6, 3.7%) and in the second/third trimester, 2.8% (2.4, 3.2%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine compared to the background rate.
There is no data available on the treatment with a combination of abacavir, and lamivudine in animals. In reproductive studies in animals, abacavir and lamivudine were shown to cross the placenta.
Studies in pregnant rats showed that abacavir is transferred to the foetus through the placenta. Developmental toxicity (depressed foetal body weight and reduced crown-rump length) and increased incidences of foetal anasarca and skeletal malformations were observed when rats were treated with abacavir at doses of 648 mg/kg during organogenesis (approximately 35 times the human exposure at the recommended dose, based on AUC). In a fertility study, evidence of toxicity to the developing embryo and foetuses (increased resorptions, decreased foetal body weights) occurred only at 427 mg/kg per day. The offspring of female rats treated with abacavir at 427 mg/kg (beginning at embryo implantation and ending at weaning) showed increased incidence of stillbirth and lower body weights throughout life. In the rabbit, there was no evidence of drug-related developmental toxicity and no increases in foetal malformations at doses up to 453 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC).
Lamivudine caused an increase in early embryonic deaths in the rabbit at exposures (based on Cmax and AUC) less than the maximum anticipated clinical exposure. Lamivudine was not teratogenic in rats and rabbits with exposure (based on Cmax) up to 40 and 36 times respectively those observed in humans at the clinical dosage.
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
 No studies have been carried out to determine the effects of the combination of abacavir and lamivudine in lactating animals.
Abacavir and its metabolites are excreted into the milk of lactating rats. A study in lactating rats showed that the concentration of lamivudine in milk was more than four times higher than that in maternal plasma.
Excretion of abacavir and lamivudine in breast milk has been reported in clinical studies, resulting in sub-therapeutic infant plasma levels.
There is no data available on the safety of abacavir and/or lamivudine administered to babies less than three months old.
Breast feeding is not advised because of the potential for HIV transmission from mother to child, and the potential risk of adverse events due to antiretroviral drug excretion in breast milk.
In settings where formula feeding is unsafe or unavailable, the World Health Organisation has provided Guidelines.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of abacavir or lamivudine, on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of these medicinal products. The clinical status of the patient and the adverse event profile of abacavir/lamivudine fixed dose combination tablets should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Abacavir/Lamivudine Viatris tablets contain abacavir and lamivudine, therefore adverse events would be expected to be similar to those experienced by patients on separate preparations of lamivudine and abacavir. For many of the adverse events listed it is unclear whether they are related to specific antiretroviral agents, or the wide range of other medications taken by HIV-infected patients, or whether they are a result of the underlying disease process.

Description of selected adverse effects.

Hypersensitivity to abacavir. (See Section 4.4 Special Warnings and Precautions for Use.)
Abacavir hypersensitivity reaction (HSR) has been identified as a common adverse reaction with abacavir therapy. The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are marked with an asterisk.
Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however, reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.

Skin.

Rash* (usually maculopapular or urticarial).

Gastrointestinal tract.

Nausea*, vomiting*, diarrhoea*, abdominal pain*, mouth ulceration.

Respiratory tract.

Dyspnoea*, cough*, sore throat, adult respiratory distress syndrome, respiratory failure.

Miscellaneous.

Fever*, fatigue*, malaise*, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis.

Neurological/psychiatry.

Headache*, paraesthesia.

Haematological.

Lymphopenia.

Liver/pancreas.

Elevated liver function tests*, hepatic failure.

Musculoskeletal.

Myalgia*, rarely myolysis, arthralgia, elevated creatine phosphokinase.

Urology.

Elevated creatinine, renal failure.
Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e. patients previously considered to be abacavir tolerant).
For details of clinical management in the event of a suspected abacavir HSR, see Section 4.4 Special Warnings and Precautions for Use.

Clinical trial data.

Table 1 lists the most common adverse events, occurring at an incidence of 5% or more, reported in the controlled pivotal clinical trial CNA30021, irrespective of the investigator's assessment of possible relationship to the study drug.
Many of the adverse events listed occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If abacavir/lamivudine fixed dose combination tablets have been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart abacavir, this must be done only under direct medical supervision (for Special considerations following an interruption of abacavir/lamivudine combination therapy, see Section 4.4 Special Warnings and Precautions for Use).
See Table 2.

Post-marketing data.

In addition to the adverse events included from clinical trial data, the following adverse events listed in Table 3 have been identified during post-approval use of abacavir and lamivudine. These events have been chosen for inclusion due to a potential causal connection to abacavir and/or lamivudine.

Reporting suspected adverse effects.

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

4.9 Overdose

Symptoms and signs.

No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as Adverse Effects.

Treatment.

If overdose occurs the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Abacavir and lamivudine are NRTIs, and are potent, selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. Similar intracellular kinetics are expected from abacavir 600 mg once daily. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16 to 19 hours, compared to the plasma lamivudine half-life of 5 to 7 hours. These data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021, see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Resistance.

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. Studies in vitro indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.
Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that reverse transcriptase amino acid residue 184 was consistently the most frequent position for NRTI resistance-associated mutations (M184V or M184I). The second most frequent mutation was L74V. Mutations Y115F and K65R were uncommon. Viral resistance to abacavir develops relatively slowly in vitro and in vivo, requiring multiple mutations to reach an eight-fold increase in IC50 over wild-type virus, which may be a clinically relevant level.
In a study of therapy-naive adults receiving abacavir 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), there was a low overall incidence of virologic failure at 48 weeks in both the once and twice daily treatment groups (10% and 8% respectively). Additionally, for technical reasons genotyping was restricted to samples with plasma HIV-1 RNA > 500 copies/mL. This resulted in a small sample size. Therefore, no firm conclusions could be drawn regarding differences in treatment emergent mutations between the two treatment groups. Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20). L74V, Y115F and K65R were the other RT mutations observed in the study.
Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a > 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a > 2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to > 116) and 1.1 (range 0.68 to > 116) in the once-daily and twice-daily abacavir arms, respectively.

Cross-resistance.

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing abacavir and lamivudine resistance-associated mutations, namely, M184V, L74V, Y115F and K65R, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in vitro and in patients. The M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine and the K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the L74V plus the M184V/I mutation, viruses with K65R with or without the M184V/I mutation, and viruses with thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

Clinical trials.

Abacavir and lamivudine have been used as components of antiretroviral combination therapy in naïve and experienced patients. Combination therapy has included other antiretroviral agents of the same class or different classes, such as PIs and NNRTIs. Abacavir and lamivudine from abacavir/lamivudine fixed dose combination tablets have been shown to be bioequivalent to abacavir and lamivudine when given separately (see Section 5.2 Pharmacokinetic Properties). The clinical efficacy of antiretroviral combination therapy containing abacavir plus lamivudine, administered once or twice daily has been confirmed in the studies described below.
A once daily regimen of abacavir and lamivudine was investigated in a multicentre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The duration of double-blind treatment was at least 48 weeks. The results are summarised in Table 4.
The abacavir once daily group was demonstrated to be non-inferior when compared to the twice daily group in the overall and base-line viral load sub-groups. The incidence of adverse events reported were similar in the two treatment groups.
In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg once daily. The duration of double-blind treatment was at least 48 weeks.
In the intent-to-treat (ITT) population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine group, achieved a virologic response of plasma HIV-1 RNA ≤ 50 copies/mL by Week 48. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The abacavir group was demonstrated to be non-inferior when compared to the zidovudine group in the overall and base-line viral load sub-groups. This study confirms the non-inferiority of a regimen containing abacavir plus lamivudine, compared to a more widely used regimen of zidovudine plus lamivudine.

5.2 Pharmacokinetic Properties

Abacavir/lamivudine fixed dose combination tablets have been shown to be bioequivalent to abacavir and lamivudine administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study (CAL10001) of abacavir/lamivudine fixed dose combination tablets (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine tablets (fasted) versus abacavir/lamivudine fixed dose combination tablets administered with a high fat meal, in healthy volunteers (n = 30).
In the fasted state there was no significant difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component. Food did not alter the extent of systemic exposure to abacavir based on AUC, but Cmax was decreased by approximately 24% compared to fasted conditions. These results indicate that abacavir/lamivudine fixed dose combination tablets can be taken with or without food.
The pharmacokinetic properties of lamivudine and abacavir are described below.

Absorption.

Abacavir and lamivudine are rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine respectively. Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4.26 microgram/mL and the mean AUC∞ is 11.95 microgram.h/mL. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days the mean steady-state Cmax is 2.04 microgram/mL and the mean AUC24 is 8.87 microgram.h/mL.

Distribution.

Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 L/kg respectively. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (< 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.
Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 microgram/mL or 0.26 microM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

Metabolism.

Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (< 10%).

Excretion.

The mean plasma half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day, there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.
The observed lamivudine half-life of elimination is 18 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system.

Special populations.

Impaired hepatic function.

Pharmacokinetic data has been obtained for abacavir and lamivudine separately. Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6). The results showed that there was a mean increase of 1.89 fold in the abacavir AUC and 1.58 fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased.
Dosage reduction of abacavir is likely to be required in patients with mild hepatic impairment. The separate preparation of abacavir should therefore be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. Abacavir is therefore not recommended in patients with moderate to severe impairment of hepatic function and abacavir/lamivudine fixed dose combination tablets are therefore also not recommended in such patients.
Data obtained for lamivudine in patients with moderate to severe hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction.

Impaired renal function.

Pharmacokinetic data have been obtained for abacavir and lamivudine separately. Abacavir is primarily metabolised by the liver, with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Lamivudine requires dose adjustment in patients with creatinine clearance of < 30 mL/min; as abacavir/lamivudine fixed dose combination tablets cannot be dose adjusted it is not recommended in these patients and the separate preparation of lamivudine should be used. For patients with creatinine clearance 30-49 mL/min taking 300 mg lamivudine daily, an approximately two-fold (range 1.6-3.3) increase in exposure of lamivudine was predicted in pharmacokinetic modelling studies. (See Section 4.2 Dose and Method of Administration.)

5.3 Preclinical Safety Data

Genotoxicity.

Abacavir was inactive in in vitro tests for gene mutation in bacteria but it showed clastogenic activity against human lymphocytes in vitro and in an in vivo mouse micronucleus test. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was not mutagenic in bacterial mutagenicity assays.
Lamivudine was not active in a microbial mutagenicity screen but did induce mutations at the thymidine kinase locus of mouse lymphoma L5178Y cells without metabolic activation. Lamivudine was clastogenic in human peripheral blood lymphocytes in vitro, with or without metabolic activation. In rats, lamivudine did not cause chromosomal damage in bone marrow cells in vivo or cause DNA damage in primary hepatocytes.

Carcinogenicity.

There are no data available on the effects of the combination of abacavir and lamivudine in animals.
Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver, urinary bladder, lymph nodes and the subcutis of female rats. Nonmalignant tumours occurred in the liver of mice and rats, Harderian gland of female mice, and thyroid gland of rats. In rats, there were also increased incidences of urothelial hyperplasia and urinary bladder tumours, associated with increased urinary calculi.
The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24 to 33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to six times the expected human systemic exposure.
Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
When lamivudine was administered orally to separate groups of rodents at doses up to 2000 times (mice and male rats) and 3000 (female rats) mg/kg/day, there was no evidence of a carcinogenic effect due to lamivudine in the mouse study. In the rat study there was an increased incidence of endometrial tumours at the highest dose (approximately 70 times the estimated human exposure at the recommended therapeutic dose of one tablet twice daily, based on AUC). However, the relationship of this increase to treatment is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Abacavir/Lamivudine Viatris tablets contain: microcrystalline cellulose, crospovidone, magnesium stearate, silicified microcrystalline cellulose, colloidal anhydrous silica and purified talc.
The tablet coating Opadry II complete film coating system 13B58894 White (ARTG PI No. 13119) contains: hypromellose, titanium dioxide, macrogol 400 and polysorbate 80.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Available in blister packs (PVC/PVdC/Al) or plastic HDPE bottles with a child-resistant closure. Each pack type contains 30 tablets.
Some pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 266516 - Abacavir/Lamivudine Viatris abacavir (as sulfate)/lamivudine 600 mg/300 mg film-coated tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Abacavir sulfate.

Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring.
Chemical name: Bis[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-enyl]methanol] sulphate.
Structural formula:
Molecular formula: (C14H18N6O)2.H2SO4.
Molecular weight: 670.76.
Abacavir sulfate has a solubility of approximately 77 mg/mL in water at 25°C. Abacavir sulfate is a white to off-white crystalline powder.

Lamivudine.

Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2', 3'-dideoxy, 3'-thiacytidine.
Chemical name: 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2(1H)-one.
Structural formula:
Molecular formula: C8H11N3O3S.
Molecular weight: 229.3.
Lamivudine is highly soluble in water. Lamivudine is a white to off-white crystalline solid.

CAS number.

Abacavir sulfate.

188062-50-2.

Lamivudine.

134678-17-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes