Abacavir 600mg / Lamivudine 300mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Lamivudine; Abacavir
Available from:
Dr Reddy's Laboratories (UK) Ltd
ATC code:
J05AR02
INN (International Name):
Lamivudine; Abacavir
Dosage:
300mg ; 600mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05030100; GTIN: 05036072006799
Authorization number:
PL 08553/0589

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Package leaflet: Information for the user

Abacavir/Lamivudine 600 mg/300 mg Film-Coated Tablets

abacavir/lamivudine

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may

harm them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible

side effects not listed in this leaflet. See section 4.

IMPORTANT — Hypersensitivity reactions

Abacavir/Lamivudine contains abacavir (which is also an active substance in other related

medicines). Some people who take abacavir may develop a hypersensitivity reaction (a

serious allergic reaction), which can be life-threatening if they continue to take abacavir

containing products.

You must carefully read all the information under ‘Hypersensitivity reactions’ in the

panel in Section 4.

The Abacavir/Lamivudine pack includes an Alert Card, to remind you and medical staff

about abacavir hypersensitivity. Detach this card and keep it with you at all times.

What is in this leaflet

What Abacavir/Lamivudine is and what it is used for

What you need to know before you take Abacavir/Lamivudine

How to take Abacavir/Lamivudine

Possible side effects

How to store Abacavir/Lamivudine

Contents of the pack and other information

1.

What Abacavir/Lamivudine is and what it is used for

Abacavir/Lamivudine is used to treat HIV (human immunodeficiency virus) infection in

adults, adolescents and in children weighing at least 25 kg.

Abacavir/Lamivudine contains two active ingredients that are used to treat HIV infection:

abacavir and lamivudine. These belong to a group of anti-retroviral medicines called

nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Abacavir/Lamivudine does not completely cure HIV infection; it reduces the amount of virus

in your body, and keeps it at a low level. It also increases the CD4 cell count in your blood.

CD4 cells are a type of white blood cells that are important in helping your body to fight

infection.

Not everyone responds to treatment with Abacavir/Lamivudine in the same way. Your doctor

will monitor the effectiveness of your treatment.

2.

What you need to know before you take Abacavir/Lamivudine

Do not take Abacavir/Lamivudine:

if you are allergic (hypersensitive) to abacavir (or any other medicine containing

abacavir), lamivudine or any of the other ingredients of this medicine (listed in section 6).

Carefully read all the information about hypersensitivity reactions in Section 4.

Check with your doctor if you think this applies to you. Do not take

Abacavir/Lamivudine.

Take special care with Abacavir/Lamivudine

Some people taking Abacavir/Lamivudine or other combination treatments for HIV are more

at risk of serious side effects. You need to be aware of the extra risks:

if you have moderate or severe liver disease

if you have ever had liver disease, including hepatitis B or C (if you have hepatitis B

infection, do not stop Abacavir/Lamivudine without your doctor’s advice, as your

hepatitis may come back)

if you are seriously overweight (especially if you are a woman)

if you have a kidney problem

Talk to your doctor if any of these apply to you before using

Abacavir/Lamivudine. You may need extra check-ups, including blood tests, while

you are taking your medicine. See Section 4 for more information.

Abacavir hypersensitivity reactions

Even patients who don’t have the HLA-B*5701 gene may still develop a hypersensitivity

reaction (a serious allergic reaction).

Carefully read all the information about hypersensitivity reactions in Section 4

of this leaflet.

Risk of heart attack

It cannot be excluded that abacavir may increase the risk of having a heart attack.

Tell your doctor if you have heart problems, if you smoke, or have other illnesses

that may increase your risk of heart disease such as high blood pressure, or diabetes.

Do not stop taking Abacavir/Lamivudine unless your doctor advises you to do so.

Look out for important symptoms

Some people taking medicines for HIV infection develop other conditions, which can be

serious. You need to know about important signs and symptoms to look out for while you are

taking Abacavir/Lamivudine.

Read the information ‘Other possible side effects of combination therapy for

HIV’ in Section 4 of this leaflet.

Protect other people

HIV infection is spread by sexual contact with someone who has the infection, or by transfer

of infected blood (for example, by sharing injection needles). You can still pass on HIV when

taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss

with your doctor the precautions needed to avoid infecting other people.

Other medicines and Abacavir/Lamivudine

Tell your doctor or pharmacist if you are taking any other medicines, or if you have

taken any recently, including herbal medicines or other medicines you bought without a

prescription.

Remember to tell your doctor or pharmacist if you begin taking a new medicine while you are

taking Abacavir/Lamivudine.

These medicines should not be used with Abacavir/Lamivudine:

Emtricitabine, to treat HIV infection

other medicinal products containing lamivudine, used to treat HIV infection or

hepatitis B infection

high doses of trimethoprim/sulfamethoxazole, an antibiotic

cladribine, used to treat hairy cell leukaemia

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

Some medicines interact with Abacavir/Lamivudine

These include:

phenytoin, for treating epilepsy.

Tell your doctor if you are taking phenytoin. Your doctor may need to

monitor you while you are taking Abacavir/Lamivudine.

methadone, used as a heroin substitute. Abacavir increases the rate at which

methadone is removed from the body. If you are taking methadone, you will be

checked for any withdrawal symptoms. Your methadone dose may need to be

changed.

Tell your doctor if you are taking methadone.

Pregnancy

Abacavir/Lamivudine is not recommended for use during pregnancy.

Abacavir/Lamivudine and similar medicines may cause side effects in unborn babies.

If you have taken Abacavir/Lamivudine during your pregnancy, your doctor may request

regular blood tests and other diagnostic tests to monitor the development of your child. In

children whose mothers took NRTIs during pregnancy, the benefit from the protection against

HIV outweighed the risk of side effects.

Breast-feeding

Women who are HIV-positive must not breast-feed, because HIV infection can be passed

on to the baby in breast milk. A small amount of the ingredients in Abacavir/Lamivudine can

also pass into your breast milk.

If you are breast-feeding, or thinking about breast-feeding:

Talk to your doctor immediately.

Driving and using machines

Abacavir/Lamivudine may cause side effects which could affect your ability to drive or use

machines.

Talk to your doctor about your ability to drive or operate machines while taking

Abacavir/Lamivudine.

Important information about some of the other ingredients of Abacavir/Lamivudine

tablets

Abacavir/Lamivudine contains a colouring called sunset yellow Aluminium Lake (E110), this

may cause allergic reactions in some people.

3.

How to take Abacavir/Lamivudine

Always take this medicine exactly as your doctor has told you. Check with your doctor or

pharmacist if you are not sure.

The recommended dose of Abacavir/Lamivudine for adults, adolescents and children

weighing 25 kg or more is one tablet once a day.

Swallow the tablets whole, with some water. Abacavir/Lamivudine can be taken with or

without food.

Stay in regular contact with your doctor

Abacavir/Lamivudine helps to control your condition. You need to keep taking it every day to

stop your illness getting worse. You may still develop other infections and illnesses linked to

HIV infection.

Keep in touch with your doctor, and do not stop taking Abacavir/Lamivudine

without your doctor’s advice.

If you take more Abacavir/Lamivudine than you should

If you accidentally take too much Abacavir/Lamivudine, tell your doctor or your pharmacist,

or contact your nearest hospital emergency department for further advice.

If you forget to take Abacavir/Lamivudine

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 a forgotten dose.

It is important to take Abacavir/Lamivudine regularly, because if you take it at irregular

intervals, you may be more likely to have a hypersensitivity reaction.

If you have stopped taking Abacavir/Lamivudine

If you have stopped taking Abacavir/Lamivudine for any reason – especially because you

think you are having side effects, or because you have other illness:

Talk to your doctor before you start taking it again. Your doctor will check

whether your symptoms were related to a hypersensitivity reaction. If the doctor

thinks they may have been related, you will be told never again to take

Abacavir/Lamivudine, or any other medicine containing abacavir. It is important

that you follow this advice.

If your doctor advises that you can start taking Abacavir/Lamivudine again, you may be asked

to take your first doses in a place where you will have ready access to medical care if you

need it.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or

nurse.

4.

Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and

glucose. This is partly linked to restored health and life style, and in the case of blood lipids

sometimes to the HIV medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everyone gets them.

When you are being treated for HIV, it can be hard to tell whether a symptom is a side effect

of Abacavir/Lamivudine or other medicines you are taking, or an effect of the HIV disease

itself. So it is very important to talk to your doctor about any changes in your health.

Even patients who don’t have the HLA-B*5701 gene may still develop a

hypersensitivity reaction (a serious allergic reaction), described in this leaflet in the

panel headed ‘Hypersensitivity reactions’.

It is very important that you read and understand the information about this

serious reaction.

As well as the side effects listed below for Abacavir/Lamivudine, other conditions can

develop during combination therapy for HIV.

It is important to read the information later in this section under ‘Other possible side

effects of combination therapy for HIV’.

Hypersensitivity reactions

Abacavir/Lamivudine contains abacavir (which is also an active substance in other related

medicines). Abacavir can cause a serious allergic reaction known as a hypersensitivity

reaction. These hypersensitivity reactions have been seen more frequently in people taking

medicines that contain abacavir.

Who gets these reactions?

Anyone taking Abacavir/Lamivudine could develop a hypersensitivity reaction to abacavir,

which could be life threatening if they continue to take Abacavir/Lamivudine.

You are more likely to develop this reaction if you have a gene called HLA-B*5701 (but you

can get a reaction even if you do not have this gene). You should have been tested for this

gene before Abacavir/Lamivudine was prescribed for you. If you know you have this gene,

tell your doctor before you take Abacavir/Lamivudine.

About 3 to 4 in every 100 patients treated with abacavir in a clinical trial who did not have the

HLA-B*5701 gene developed a hypersensitivity reaction.

What are the symptoms?

The most common symptoms are:

fever (high temperature) and skin rash.

Other common symptoms are:

nausea (feeling sick), vomiting (being sick), diarrhoea, abdominal (stomach) pain,

severe tiredness.

Other symptoms include:

Pains in the joints or muscles, swelling of the neck, shortness of breath, sore throat, cough,

occasional headaches, inflammation of the eye (conjunctivitis), mouth ulcers, low blood

pressure, tingling or numbness of the hands or feet.

When do these reactions happen?

Hypersensitivity reactions can start at any time during treatment with Abacavir/Lamivudine,

but are more likely during the first 6 weeks of treatment.

Contact your doctor immediately:

1.

if you get a skin rash, OR

2.

if you get 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 tiredness or achiness, or generally feeling ill.

Your doctor may advise you to stop taking Abacavir/Lamivudine.

If you have stopped taking Abacavir/Lamivudine

If you have stopped taking Abacavir/Lamivudine because of a hypersensitivity reaction, you

must NEVER AGAIN take Abacavir/Lamivudine, or any other medicine containing

abacavir. If you do, within hours, your blood pressure could fall dangerously low, which

could result in death.

If you have stopped taking Abacavir/Lamivudine for any reason – especially because you

think you are having side effects, or because you have other illness:

Talk to your doctor before you start again. Your doctor will check whether your symptoms

were related to a hypersensitivity reaction. If the doctor thinks they may have been, you will

then be told never again to take Abacavir/Lamivudine, or any other medicine containing

abacavir. It is important that you follow this advice.

Occasionally hypersensitivity reactions have developed in people who start taking abacavir

containing products again, but who had only one symptom on the Alert Card before they

stopped taking it.

Very rarely patients who have taken medicines containing abacavir in the past without any

symptoms of hypersensitivity have developed a hypersensitivity reaction when they start

taking these medicines again.

If your doctor advises that you can start taking Abacavir/Lamivudine again, you may be asked

to take your first doses in a place where you will have ready access to medical care if you

need it.

If you are hypersensitive to Abacavir/Lamivudine, return all your unused

Abacavir/Lamivudine tablets for safe disposal. Ask your doctor or pharmacist for advice.

The Abacavir/Lamivudine pack includes an Alert Card, to remind you and medical staff

about hypersensitivity reactions. Detach this card and keep it with you at all times.

Common side effects

These may affect up to 1 in 10 people:

hypersensitivity reaction

headache

being sick (vomiting)

feeling sick (nausea)

diarrhoea

stomach pains

loss of appetite

tiredness, lack of energy

fever (high temperature)

general feeling of being unwell

difficulty in sleeping (insomnia)

muscle pain and discomfort

joint pain

cough

irritated or runny nose

skin rash

hair loss.

Uncommon side effects

These may affect up to 1 in 100 people and may show up in blood tests:

a low red blood cell count (anaemia) or low white blood cell count (neutropenia)

an increase in the level of liver enzymes

a decrease in the number of cells involved in blood clotting (thrombocytopenia).

Rare side effects

These may affect up to 1 in 1000 people:

liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (hepatitis)

inflammation of the pancreas (pancreatitis)

breakdown of muscle tissue.

Rare side effects that may show up in blood tests are:

increase in an enzyme called amylase

Very rare side effects

These may affect up to 1 in 10,000 people:

numbness, tingly feelings in the skin (pins and needles)

sensation of weakness in the limbs

skin rash, which may form blisters and looks like small targets (central dark spots

surrounded by a paler area, with a dark ring around the edge) (erythema multiforme)

a widespread rash with blisters and peeling skin, particularly around the mouth, nose,

eyes and genitals (Stevens–Johnson syndrome), and a more severe form causing skin

peeling in more than 30% of the body surface (toxic epidermal necrolysis).

lactic acidosis (excess lactic acid in the blood)

If you notice any of these symptoms contact a doctor urgently.

Very rare side effects that may show up in blood tests are:

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

If you get side effects

Tell your doctor or pharmacist if any of the side effects gets severe or troublesome,

or if you notice any side effects not listed in this leaflet.

Other possible side effects of combination therapy for HIV

Combination therapy such as Abacavir/Lamivudine may cause other conditions to develop

during HIV treatment.

Symptoms of infection and inflammation

Old infections may flare up

People with advanced HIV infection (AIDS) have weak immune systems, and are more likely

to develop serious infections (opportunistic infections). Such infections may have been

“silent” and not detected by the weak immune system before treatment was started. After

starting treatment, the immune system becomes stronger, and may attack the infections, which

can cause symptoms of infection or inflammation. Symptoms usually include fever, plus

some of the following:

headache

stomach ache

difficulty breathing

In rare cases, as the immune system becomes stronger, it can also attack 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:

palpitations (rapid or irregular heartbeat) or tremor

hyperactivity (excessive restlessness and movement)

weakness beginning in the hands and feet and moving up towards the trunk of the

body.

If you get any symptoms of infection and inflammation or if you notice any of the

symptoms above:

Tell your doctor immediately. Do not take other medicines for the infection without

your doctor’s advice.

You may have problems with your bones

Some people taking combination therapy for HIV develop a condition called osteonecrosis.

With this condition, parts of the bone tissue die because of reduced blood supply to the bone.

People may be more likely to get this condition:

if they have been taking combination therapy for a long time

if they are also taking anti-inflammatory medicines called corticosteroids

if they drink alcohol

if their immune systems are very weak

if they are overweight.

Signs of osteonecrosis include:

stiffness in the joints

aches and pains (especially in the hip, knee or shoulder)

difficulty moving.

If you notice any of these symptoms:

Tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the Yellow Card

Scheme, website www.mhra.gov.uk/yellowcard. By reporting side effects you can help

provide more information on the safety of this medicine.

5.

How to store Abacavir/Lamivudine

Keep this medicine out of the sight and reach of children.

Do not take this medicine after the expiry date shown on the carton and blister after <EXP>.

The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6.

Contents of the pack and other information

What Abacavir/Lamivudine contains

The active substances in each Abacavir/Lamivudine film-coated tablet are 600 mg of

abacavir and 300 mg of lamivudine.

The other ingredients are Cellulose, Microcrystalline PH 102 (E460), Cellulose,

Microcrystalline PH 200 (E460), sodium starch glycolate (Type A), povidone K 90

(E1201), magnesium stearate (E470b), hypromellose 5 (E464), macrogol 400 (E1521),

titanium dioxide (E171), sunset yellow FCF aluminium lake (E110)

What Abacavir/Lamivudine looks like and contents of the pack

Abacavir/Lamivudine film-coated tablets are orange, film-coated, modified capsule shaped

tablets. The dimensions of the tablets are 19.4 mm x 10.4 mm.

Abacavir/Lamivudine is available in Aluminium-PVC/PE/PVDC white opaque blisters

containing 30 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Dr. Reddy’s Laboratories (UK) Ltd., 6 Riverview Road, Beverley, East Yorkshire,

HU17 0LD, United Kingdom

Manufacturer

Remedica Ltd, Aharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus

This leaflet was last revised in 09/2016

Read the complete document

Object 1

Abacavir/Lamivudine Dr. Reddys 600 mg/300 mg

Film-Coated Tablets

Summary of Product Characteristics Updated 01-Dec-2016 | Dr. Reddy's Laboratories (UK) Ltd

1. Name of the medicinal product

Abacavir/Lamivudine Dr. Reddy's 600 mg/300 mg Film-Coated Tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 600 mg abacavir and 300 mg lamivudine.

Excipient with known effect:

Sunset Yellow FCF Aluminium Lake (E110) 1.86 mg per tablet.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Orange, film-coated, modified capsule shaped tablets. The dimensions of the tablets are 19.4 mm x 10.4

4. Clinical particulars

4.1 Therapeutic indications

Abacavir/Lamivudine is indicated in antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infection in adults, adolescents and children weighing at least 25 kg (see

sections 4.4 and 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be

performed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir should not

be used in patients known to carry the HLA-B*5701 allele.

4.2 Posology and method of administration

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Posology

Adults, adolescents and children weighing at least 25 kg:

The recommended dose of Abacavir/Lamivudine is one tablet once daily.

Children Under 25 kg:

Abacavir/Lamivudine should not be administered to children who weigh less than 25 kg because it is a

fixed-dose tablet that cannot be dose reduced.

Abacavir/Lamivudine is a fixed-dose tablet and should not be prescribed for patients requiring dose

adjustments. Separate preparations of abacavir or lamivudine are available in cases where discontinuation

or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to

the individual product information for these medicinal products.

Special Populations

Elderly:

No pharmacokinetic data are currently available in patients over 65 years of age. Special care is advised

in this age group due to age associated changes such as the decrease in renal function and alteration of

haematological parameters.

Renal impairment:

Abacavir/Lamivudine is not recommended for use in patients with a creatinine clearance < 50 ml/min as

necessary dose adjustment cannot be made (see section 5.2).

Hepatic impairment:

Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderate or

severe hepatic impairment, therefore the use of Abacavir/Lamivudine is not recommended unless judged

necessary. In patients with mild hepatic impairment (Child-Pugh score 5-6) close monitoring is required,

including monitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).

Paediatric population:

The safety and efficacy of Abacavir/Lamivudine in children weighing less than 25 kg has not been

established.

Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on posology can

be made.

Method of administration

Oral use

Abacavir/Lamivudine can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. See sections 4.4

and 4.8.

4.4 Special warnings and precautions for use

The special warnings and precautions relevant to abacavir and lamivudine are included in this section.

There are no additional precautions and warnings relevant to Abacavir/Lamivudine.

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.

Hypersensitivity reactions (see also section 4.8)

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section 4.8) characterised by

fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with

abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed

appropriately.

The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele.

However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this allele.

Therefore the following should be adhered to:

- HLA-B*5701 status must always be documented prior to initiating therapy.

- Abacavir/Lamivudine should never be initiated in patients with a positive HLA-B*5701 status, nor in

patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-

containing regimen.

- Abacavir/Lamivudine must be stopped without delay, even in the absence of the HLA-B*5701 allele,

if an HSR is suspected. Delay in stopping treatment with Abacavir/Lamivudine after the onset of

hypersensitivity may result in a life-threatening reaction.

- After stopping treatment with Abacavir/Lamivudine for reasons of a suspected HSR,

Abacavir/Lamivudine or any other medicinal product containing abacavir must never be re-initiated.

- Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return

of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may

include life-threatening hypotension and death.

- In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be

instructed to dispose of their remaining Abacavir/Lamivudine tablets.

Clinical Description

of abacavir HSR

Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of

treatment with abacavir, although these reactions may occur at any time during therapy.

Almost all HSR to abacavir include fever and/or rash. Other signs and symptoms that have been observed

as part of abacavir HSR are described in detail in section 4.8 (Description of selected adverse reactions),

including respiratory and gastrointestinal symptoms. Importantly, such symptoms may lead to

misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis.

The symptoms related to HSR worsen with continued therapy and can be life-threatening. These symptoms

usually resolve upon discontinuation of abacavir.

Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also

experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8

Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting

where medical assistance is readily available.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.

Such changes may in part be linked to disease control and life style. For lipids, there is in some cases

evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any

particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV

treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis

Pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.

Risk of virological failure

- Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of

emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir

disoproxil fumarate as a once daily regimen.

- The risk of virological failure with Abacavir/Lamivudine might be higher than with other therapeutic

options (see section 5.1).

Liver disease

The safety and efficacy of Abacavir/Lamivudine has not been established in patients with significant

underlying liver disorders. Abacavir/Lamivudine is not recommended in patients with moderate or severe

hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased

frequency of liver function abnormalities during combination antiretroviral therapy, and should be

monitored according to standard practice. If there is evidence of worsening liver disease in such patients,

interruption or discontinuation of treatment must be considered.

Patients co-infected with chronic hepatitis B or C virus

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an

increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral

therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal

products.

If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV),

additional information relating to the use of lamivudine in the treatment of hepatitis B infection can be

found in the Summary of Product Characteristics for products containing lamivudine that are indicated for

the treatment of HBV.

If Abacavir/Lamivudine is discontinued in patients co-infected with HBV, periodic monitoring of both

liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may

result in an acute exacerbation of hepatitis (see the Summary of Product Characteristics for products

containing lamivudine that are indicated for the treatment of HBV).

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is

most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial

dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues: these

have predominantly concerned treatment with regimens containing zidovudine. The main adverse

reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders

(hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Late onset neurological

disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such

neurological disorders are transient or permanent is currently unknown. These findings should be

considered for any child exposed in utero to nucleotide and nucleotide analogues, who presents with

severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not

affect current national recommendations to use antiretroviral therapy in pregnant women to prevent

vertical transmission of HIV.

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination

antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic

pathogens 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 CART. Relevant

examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and

Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment

instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to

occur in the setting of immune reactivation; however, the reported time to onset is more variable and

these events can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol

consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been

reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. Patients

should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or

difficulty in movement.

Opportunistic infections

Patients should be advised that Abacavir/Lamivudine or any other antiretroviral therapy does not cure

HIV infection and that they 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.

Myocardial infarction

Observational studies have shown an association between myocardial infarction and the use of abacavir.

Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited

numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available

data from observational cohorts and from randomised trials show some inconsistency so can neither

confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction.

To date, there is no established biological mechanism to explain a potential increase in risk. When

prescribing Abacavir/Lamivudine, action should be taken to try to minimize all modifiable risk factors

(e.g. smoking, hypertension, and hyperlipidaemia).

Drug Interactions:

Abacavir/Lamivudine should not be taken with any other medicinal products containing lamivudine or

medicinal products containing emtricitabine.

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

Excipients

Abacavir/Lamivudine contains the azo colouring agent sunset yellow (E110), which may cause allergic

reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Abacavir/Lamivudine contains abacavir and lamivudine, therefore any interactions identified for these

individually are relevant to Abacavir/Lamivudine. Clinical studies have shown that there are no clinically

significant interactions between abacavir and lamivudine.

Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase; co-

administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol

dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of

lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of

lamivudine with OCT inhibitors may increase lamivudine exposure.

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. Therefore, there is little

potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal

products metabolised by major P450 enzymes.

Abacavir/Lamivudine should not be taken with any other medicinal products containing lamivudine (see

section 4.4).

The list below should not be considered exhaustive but is representative of the classes studied.

Drugs by Therapeutic Area

Interaction Geometric mean

change (%)

(Possible mechanism)

Recommendation concerning

co-administration

ANTIRETROVIRAL MEDICINAL PRODUCTS

Didanosine /Abacavir

Interaction not studied.

No dosage adjustment

necessary.

Didanosine/Lamivudine

Interaction not studied.

Zidovudine/Abacavir

Interaction not studied.

Zidovudine/Lamivudine

Zidovudine 300 mg single dose

Lamivudine 150 mg single dose

Lamivudine: AUC ↔

Zidovudine : AUC ↔

Emtricitabine/Lamivudine

Due to similarities,

Abacavir/Lamivudine should

not be administered

concomitantly with other

cytidine analogues, such as

emtricitabine.

ANTI-INFECTIVE PRODUCTS

Trimethoprim/sulfamethoxazole (Co-

trimoxazole)/Abacavir

Interaction not studied.

No Abacavir/Lamivudine

dosage adjustment necessary.

When concomitant

administration with co-

trimoxazole is warranted,

patients should be monitored

clinically. High doses of

trimethoprim/ sulfamethoxazole

for the treatment of

Trimethoprim/sulfamethoxazole (Co-

trimoxazole)/Lamivudine

(160 mg/800 mg once daily for 5

days/300 mg single dose)

Lamivudine: AUC ↑40%

Trimethoprim: AUC ↔

Sulfamethoxazole: AUC ↔

(organic cation transporter

inhibition)

Pneumocystis jirovecii

pneumonia (PCP) and

toxoplasmosis have not been

studied and should be avoided

ANTIMYCOBACTERIALS

Rifampicin/Abacavir

Interaction not studied.

Potential to slightly decrease

abacavir plasma concentrations

through UGT induction.

Insufficient data to recommend

dosage adjustment.

Rifampicin/Lamivudine

Interaction not studied.

ANTICONVULSANTS

Phenobarbital/Abacavir

Interaction not studied.

Potential to slightly decrease

abacavir plasma concentrations

through UGT induction.

Insufficient data to recommend

dosage adjustment.

Phenobarbital/Lamivudine

Interaction not studied.

Phenytoin/Abacavir

Interaction not studied.

Potential to slightly decrease

abacavir plasma concentrations

through UGT induction.

Insufficient data to recommend

dosage adjustment.

Monitor phenytoin

concentrations.

Phenytoin/Lamivudine

Interaction not studied.

ANTIHISTAMINES (HISTAMINE H2 RECEPTOR ANTAGONISTS)

Ranitidine/Abacavir

Interaction not studied.

No dosage adjustment

necessary.

Ranitidine/Lamivudine

Interaction not studied.

Clinically significant interaction

unlikely. Ranitidine eliminated

only in part by renal organic

cation transport system.

Cimetidine/Abacavir

Interaction not studied.

No dosage adjustment

necessary.

Cimetidine/Lamivudine

Interaction not studied.

Clinically significant interaction

unlikely. Cimetidine eliminated

only in part by renal organic

cation transport system.

CYTOTOXICS

Cladribine/Lamivudine

Interaction not studied.

In vitro lamivudine inhibits the

intracellular phosphorylation of

cladribine leading to a potential

risk of cladribine loss of efficacy

in case of combination in the

clinical setting. Some clinical

findings also support a possible

interaction between lamivudine

and cladribine

Therefore, the concomitant use

of lamivudine with cladribine is

not recommended (see section

4.4).

OPIOIDS

Methadone/Abacavir

(40 to 90mg once daily for 14

days/600mg single dose, then 600mg

twice daily for 14 days)

Abacavir: AUC ↔

↓35%

Methadone: CL/F ↑22%

No Abacavir/Lamivudine

dosage adjustment necessary.

Methadone dosage adjustment

unlikely in majority of patients;

occasionally methadone re-

titration may be required.

Methadone/Lamivudine

Interaction not studied.

RETINOIDS

Retinoid compounds (e.g.

isotretinoin)/Abacavir

Interaction not studied.

Possible interaction given

common pathway of elimination

via alcohol dehydrogenase.

Insufficient data to recommend

dosage adjustment.

Retinoid compounds (e.g.

isotretinoin)/Lamivudine

No drug interaction studies

Interaction not studied.

MISCELLANEOUS

Ethanol/Abacavir

0.7 g/kg single dose/600 mg single

dose)

Abacavir: AUC ↑41%

Ethanol: AUC ↔

(Inhibition of alcohol

dehydrogenase)

No dosage adjustment

necessary.

Ethanol/Lamivudine

Interaction not studied.

Abbreviations: ↑ = Increase; ↓ = decrease; ↔ = no significant change; AUC = area under the

concentration versus time curve; C

= maximum observed concentration; CL/F = apparent oral

clearance

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in

pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the

animal data as well as the clinical experience in pregnant women should be taken into account.

Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but not in

rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not

in rats (see section 5.3). The active ingredients of Abacavir/Lamivudine may inhibit cellular DNA

replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The

clinical relevance of these findings is unknown. Placental transfer of abacavir and lamivudine has been

shown to occur in humans.

In pregnant women treated with abacavir, more than 800 outcomes after first trimester exposure and more

than 1000 outcomes after second and third trimester exposure indicate no malformative and

foetal/neonatal effect. In pregnant women treated with lamivudine, more than 1000 outcomes from first

trimester and more than 1000 outcomes from second and third trimester exposure indicate no

malformative and foeto/neonatal effect. There are no data on the use of Abacavir/Lamivudine in

pregnancy, however the malformative risk is unlikely in humans based on those data.

For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal

product such as Abacavir/Lamivudine and subsequently become pregnant, consideration should be given

to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

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 (see section 4.4).

Breast-feeding

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into

human milk.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in

breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and

progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no

data available on the safety of abacavir and lamivudine when administered to babies less than three

months old.

It is recommended that HIV infected women do not breast-feed their infants under any circumstances in

order to avoid transmission of HIV.

Fertility

Studies in animals showed that neither abacavir nor lamivudine had any effect on fertility (see section

5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on ability to drive and use machines have been performed. The clinical status of

the patient and the adverse reaction profile of Abacavir/Lamivudine should be borne in mind when

considering the patient's ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety profile

The adverse reactions reported for abacavir/lamivudine were consistent with the known safety profiles of

abacavir and lamivudine when given as separate medicinal products. For many of these adverse reactions

it is unclear whether they are related to the active substance, the wide range of other medicinal products

used in the management of HIV infection, or whether they are a result of the underlying disease process.

Many of the adverse reactions listed in the table below 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 (see section 4.4). Very

rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been

reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products

containing abacavir should be permanently discontinued.

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body

system, organ class and absolute frequency. Frequencies are defined as very common (> 1/10), common

(> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (<

1/10,000), not known (cannot be estimated from the available data).

Body system

Abacavir

Lamivudine

Blood and lymphatic systems

disorders

Uncommon: Neutropenia and

anaemia (both occasionally severe),

thrombocytopenia

Very rare: Pure red cell aplasia

Immune system disorders

Common: hypersensitivity

Metabolism and nutrition

disorders

Common: anorexia

Very rare: lactic acidosis

Very rare: lactic acidosis

Nervous system disorders

Common: headache

Common: Headache, insomnia.

Very rare: Cases of peripheral

neuropathy (or paraesthesia) have

been reported

Respiratory, thoracic and

mediastinal disorders

Common: Cough, nasal symptoms

Gastrointestinal disorders

Common: nausea, vomiting,

diarrhoea

Rare: pancreatitis has been

reported, but a causal relationship

to abacavir treatment is uncertain

Common: Nausea, vomiting,

abdominal pain or cramps,

diarrhoea

Rare: Rises in serum amylase.

Cases of pancreatitis have been

reported

Hepatobiliary disorders

Uncommon: Transient rises in liver

enzymes (AST, ALT),

Rare: Hepatitis

Skin and subcutaneous tissue

disorders

Common: rash (without systemic

symptoms)

Very rare: erythema multiforme,

Stevens-Johnson syndrome and

toxic epidermal necrolysis

Common: Rash, alopecia

Rare: Angioedema

Musculoskeletal and connective

tissue disorders

Common: Arthralgia, muscle

disorders

Rare: Rhabdomyolysis

General disorders and

administration site conditions

Common: fever, lethargy, fatigue.

Common: fatigue, malaise, fever.

Description of selected adverse reactions

Abacavir hypersensitivity

The signs and symptoms of this HSR 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 in bold text.

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, lethargy, malaise, oedema, lymphadenopathy, hypotension,

conjunctivitis, anaphylaxis

Neurological/Psychiatry

Headache, paraesthesia

Haematological

Lymphopenia

Liver/pancreas

Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal

Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase

Urology

Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in rare

instance, have been fatal.

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. Similar 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).

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination

antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may

arise. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of

immune reconstitution; however, the reported time to onset is more variable and these events can occur

many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see

section 4.4).

Paediatric population

The safety database to support once daily dosing in paediatric patients comes from the ARROW Trial

(COL105677) in which 669 HIV-1 infected paediatric subjects (from 12 months to ≤17 years old)

received abacavir and lamivudine either once or twice daily (see section 5.1). Within this population, 104

HIV-1 infected paediatric subjects weighing at least 25 kg received abacavir and lamivudine as fixed

combination once daily. No additional safety issues have been identified in paediatric subjects receiving

either once or twice daily dosing compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at

www.mhra.gov.uk/yellowcard.

4.9 Overdose

No specific symptoms or signs have been identified following acute overdose with abacavir or

lamivudine, apart from those listed as undesirable effects.

If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections,

combinations. ATC code: J05AR02.

Mechanism of action: Abacavir and lamivudine are NRTIs, and are potent selective inhibitors of HIV-1

and HIV-2 (LAV2 and EHO) replication. Both abacavir and lamivudine are metabolised sequentially by

intracellular kinases to the respective 5'-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.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents:

didanosine, nevirapine and zidovudine). The antiviral activity of abacavir in cell culture was not

antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine,

emtricitabine, stavudine, tenofovir or zidovudine, the non-nucleoside reverse transcriptase inhibitor

(NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

Antiviral Activity in vitro

Both abacavir and lamivudine have been shown to inhibit replication of laboratory strains and clinical

isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage

derived lines and primary cultures of activated peripheral blood lymphocytes (PBLs) and

monocyte/macrophages. The concentration of drug necessary to effect viral replication by 50% (EC

) or

50% inhibitory concentration (IC

) varied according to virus and host cell type.

The mean EC

for abacavir against laboratory strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to

5.8 μM. The median or mean EC

values for lamivudine against laboratory strains of HIV-1 ranged from

0.007 to 2.3 μM. The mean EC

against laboratory strains of HIV-2 (LAV2 and EHO) ranged from 1.57

to 7.5 μM for abacavir and from 0.16 to 0.51 μM for lamivudine.

The EC

values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 μM,

against Group O from 0.022 to 1.21 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. For

lamivudine, the EC

values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 μM, against

Group O from 0.030 to 0.160 μM and against HIV-2 isolates from 0.002 to 0.120 μM in peripheral blood

mononuclear cells.

Baseline HIV-1 samples from therapy-naive subjects with no amino acid substitutions associated with

resistance have been evaluated using either the multi-cycle Virco Antivirogram™ assay (n=92 from

COL40263) or the the single cycle Monogram Biosciences PhenoSense™ assay (n=138 from ESS30009).

These resulted in median EC

values of 0.912 μM (range: 0.493 to 5.017 μM) and 1.26 μM (range 0.72

to 1.91 μM) respectively for abacavir, and median EC

values of 0.429 μM (range: 0.200 to 2.007 μM)

and 2.38 μM (1.37 to 3.68 μM) respectively for lamivudine.

Phenotypic susceptibility analyses of clinical isolates from antiretroviral-naïve patients with HIV-1 Group

M non-B subtypes in three studies have each reported that all viruses were fully susceptible to both

abacavir and lamivudine; one study of 104 isolates that included subtypes A and A1 (n=26), C (n=1), D

(n=66), and the circulating recombinant forms (CRFs) AD (n=9), CD (n=1), and a complex inter-subtype

recombinant_cpx (n=1), a second study of 18 isolates including subtype G (n=14) and CRF_AG (n=4)

from Nigeria, and a third study of six isolates (n=4 CRF_AG, n=1 A and n=1 undetermined) from

Abidjan (Côte d'Ivoire).

HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37

untreated patients in Africa and Asia were susceptible to abacavir (IC

fold changes <2.5), and

lamivudine (IC

fold changes<3.0), except for two CRF02_AG isolates with fold-changes of 2.9 and 3.4

for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly

sensitive.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against

non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates.

Resistance

In vivo resistance

Abacavir-resistant isolates of HIV-1 have been selected in-vitro in wild-type strain HIV-1 (HXB2) and

are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and

Y115). Selection for the M184V mutation occurred first and resulted in a two fold increase in IC

Continued passage in increasing concentrations of drug resulted in selection for double RT mutants

65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-fold

change in abacavir susceptibility and combinations of three mutations were required to confer more than

an 8-fold change in susceptibility. Passage with a zidovudine resistant clinical isolate RTMC also selected

for the 184V mutation.

HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184V amino

acid change close to the active site of the viral RT. Passage of HIV-1 (HXB2) in the presence of

increasing 3TC concentrations results in high-level (>100 to >500-fold) lamivudine-resistant viruses and

the RT M184I or V mutation is rapidly selected. The IC

for wild-type HXB2 is 0.24 to 0.6 μM, while

the IC

for M184V containing HXB2 is >100 to 500 μM.

Antiviral therapy According to Genotypic/Phenotypic Resistance

In vivo resistance (Therapy-naïve patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing

antiretroviral therapy.

Isolates from most patients experiencing virological failure with a regimen containing abacavir in pivotal

clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or M184I

selection (45%). The overall selection frequency for M184V or M184I was high (54%), and less common

was the selection of L74V (5%), K65R (1%) and Y115F (1%) (see table below). The inclusion of

zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the

presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).

Therapy

Abacavir +

Combivir

1

Abacavir +

lamivudine +

NNRTI

Abacavir +

lamivudine + PI (or

PI/ritonavir)

Total

Number of

Subjects

1094

2285

Number of

Virological

Failures

Number of On-

Therapy

Genotypes

40 (100%)

51 (100%)

141 (100%)

232 (100%)

K65R

1 (2%)

2 (1%)

3 (1%)

L74V

9 (18%)

3 (2%)

12 (5%)

Y115F

2 (4%)

2 (1%)

M184V/I

34 (85%)

22 (43%)

70 (50%)

126 (54%)

TAMs

3

3 (8%)

2 (4%)

4 (3%)

9 (4%)

1. Combivir is a fixed dose combination of lamivudine and zidovudine

2. Includes three non-virological failures and four unconfirmed virological failures.

3. Number of subjects with ≥1 Thymidine Analogue Mutations (TAMs).

TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of six

clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine (0/127), but

were selected by regimens containing abacavir and the thymidine analogue zidovudine (22/86, 26%).

In vivo resistance (Therapy experienced patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing

antiretroviral therapy and confer high-level resistance to lamivudine. In vitro data tend to suggest that the

continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide

residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these

findings is not established. Indeed, the available clinical data are very limited and preclude any reliable

conclusion in the field. In any case, initiation of susceptible NRTIs should always be preferred to

maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of

M184V mutation should only be considered in cases where no other active NRTIs are available.

Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates of

patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other

nucleoside inhibitors. In a meta-analysis of five clinical trials where ABC was added to intensify therapy,

of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had M41L, 30 (18%) had

K70R and 25 (15%) had D67N. K65R was absent and L74V and Y115F were uncommon (≤3%). Logistic

regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1RNA

[vRNA], CD4+ cell count, number and duration of prior antiretroviral therapies) showed that the presence

of 3 or more NRTI resistance-associated mutations was associated with reduced response at Week 4

(p=0.015) or 4 or more mutations at median Week 24 (p≤0.012). In addition, the 69 insertion complex or

the Q151M mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high

level of resistance to abacavir.

Baseline Reverse

Transcriptase Mutation

Week 4

(n = 166)

n

Median Change vRNA

(log

10

c/mL)

Percent with <400 copies/mL

vRNA

None

-0.96

M184V alone

-0.74

Any one NRTI mutation

-0.72

Any two NRTI-

associated mutations

-0.82

Any three NRTI-

associated mutations

-0.30

Four or more NRTI-

associated mutations

-0.07

Phenotypic resistance and cross-resistance

Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, or

M184V with multiple TAMs. Phenotypic cross-resistance to other NRTIs with M184V or M184I

mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral

activities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-

resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise to

cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F gives

rise to cross-resistance between abacavir and lamivudine. Readily available genotypic drug resistance

interpretation algorithms and commercially available susceptibility tests have established clinical cut offs

for reduced activity for abacavir and lamivudine as separate drug entities that predict susceptibility,

partial susceptibility or resistance based upon either direct measurement of susceptibility or by calculation

of the HIV-1 resistance phenotype from the viral genotype. Appropriate use of abacavir and lamivudine

can be guided using these currently recommended resistance algorithms.

Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or

NNRTIs is unlikely.

Clinical experience

Clinical experience with the combination of abacavir and lamivudine as a once daily regimen is mainly

based on four studies in treatment-naïve subjects, CNA30021, EPZ104057 (HEAT study), ACTG5202,

and CNA109586 (ASSERT study) and two studies in treatment-experienced subjects, CAL30001 and

ESS30008.

Therapy-naïve patients

The combination of abacavir and lamivudine as a once daily regimen is supported by a 48 weeks multi-

centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These

were primarily asymptomatic HIV infected patients (CDC stage A). They were randomised to receive

either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination with lamivudine 300 mg

once daily and efavirenz 600 mg once daily. The results are summarised by subgroup in the table below:

Efficacy Outcome at Week 48 in CNA30021 by baseline HIV-1 RNA and CD4 Categories (ITTe

TLOVR ART naïve subjects).

ABC QD +3TC+EFV

(n=384)

ABC BID +3TC+EFV

(n=386)

ITT-E Population

TLOVR analysis

Proportion with HIV-1 RNA <50 copies/ml

All Subjects

253/384 (66%)

261/386 (68%)

Baseline RNA category <100,000

copies/mL

141/217 (65%)

145/217 (67%)

Baseline RNA category >=100,000

copies/mL

112/167 (67%)

116/169 (69%)

Baseline CD4 category <50

3/ 6 (50%)

4/6 (67%)

Baseline CD4 category 50-100

21/40 (53%)

23/37 (62%)

Baseline CD4 category 101-200

57/ 85 (67%)

43/67 (64%)

Baseline CD4 category 201-350

101/143 (71%)

114/170 (67%)

Baseline CD4 category >350

71/109 (65%)

76/105 (72%)

>1 log reduction in HIV RNA or <50

cp/mL

All Patients

372/384 (97%)

373/386 (97%)

Similar clinical success (point estimate for treatment difference: -1.7, 95% CI –8.4, 4.9) was observed for

both regimens. From these results, it can be concluded with 95% confidence that the true difference is no

greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently small to

draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.

There was a low, similar overall incidence of virologic failure (viral load > 50 copies/ml) in both the once

and twice daily treatment groups (10% and 8% respectively). In the small sample size for genotypic

analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once daily versus the

twice daily abacavir regimens. No firm conclusion could be drawn due to the limited data derived from

this study.

There are conflicting data in some comparative studies with abacavir/lamivudine i.e. HEAT, ACTG5202

and ASSERT:

EPZ104057 (HEAT study) was a randomised, double-blind, placebo-matched, 96 week, multi-centre

study with the primary objective of evaluating the relative efficacy of abacavir/lamivudine (ABC/3TC,

600mg/300mg) and tenofovir /emtricitabine (TDF/FTC, 300mg/200mg), each given once-daily in

combination with lopinavir/ritonavir (LPV/r, 800mg/200mg) in HIV-infected, therapy-naive adults. The

primary efficacy analysis was performed at week 48 with study continuation to week 96 and

demonstrated non-inferiority. The results are summarised below:

Virologic Response Based on Plasma HIV-1 RNA < 50 copies/ml

ITT-Exposed Population M=F switch included

Virologic Response

ABC/3TC +LPV/r

(N = 343)

TDF/FTC + LPV/r

(N = 345)

Week 48

Week 96

Week 48

Week 96

Overall response (stratified by

baseline HIV-1 RNA)

231/343 (68%)

205/343 (60%)

232/345 (67%)

200/345

(58%)

Response by Baseline HIV-1 RNA

<100,000 c/ml

134/188 (71%)

118/188 (63%)

141/205 (69%)

119/205

(58%)

Response by Baseline HIV-1 RNA

≥100,000 c/ml

97/155 (63%)

87/155 (56%)

91/140 (65%)

81/140 (58%)

A similar virologic response was observed for both regimens (point estimate for treatment difference at

week 48: 0.39%, 95% CI: -6.63, 7.40).

ACTG 5202 study was a, multi-centre, comparative, randomised study of double-blind

abacavir/lamivudine or emtricitabine/tenofovir in combination with open-label efavirenz or

atazanavir/ritonavir in treatment-naïve HIV-1 infected patients. Patients were stratified at screening based

on plasma HIV-1 RNA levels < 100,000 and ≥ 100,000 copies/mL.

An interim analysis from ACTG 5202 revealed that abacavir/lamivudine was associated with a

statistically significantly higher risk of virological failure as compared to emtricitabine/tenofovir (defined

as viral load >1000 copies/mL at or after 16 weeks and before 24 weeks or HIV-RNA level >200

copies/mL at or after 24 weeks) in subjects with a screening viral load ≥100,000 copies/mL (estimated

hazard ratio: 2.33, 95% CI: 1.46, 3.72, p=0.0003). The Data Safety Monitoring Board (DSMB)

recommended that consideration be given to change in the therapeutic management of all subjects in the

high viral load stratum due to the efficacy differences observed. The subjects in the low viral load stratum

remained blinded and on-study.

Analysis of the data from subjects in the low viral load stratum showed no demonstrable difference

between the nucleoside backbones in the proportion of patients free of virological failure at week 96. The

results are presented below:

- 88.3% with ABC/3TC vs 90.3% with TDF/FTC when taken with atazanavir/ritonovir as third drug,

treatment difference -2.0% (95% CI -7.5%, 3.4%),

- 87.4% with ABC/3TC vs 89.2% with TDF/FTC, when taken with efavirenz as third drug, treatment

difference -1.8% (95% CI -7.5%, 3.9%).

CNA109586 (ASSERT study), a multi-centre, open label, randomised study of abacavir/lamivudine

(ABC/3TC, 600mg/300mg) and tenofovir/emtricitabine (TDF/FTC, 300mg/200mg), each given once

daily with efavirenz (EFV, 600mg) in ART naïve, HLA-B*5701 negative, HIV-1 infected adults.The

virologic results are summarised in the table below:

Virologic Response at Week 48 ITT-Exposed Population < 50 copies/ml TLOVR

ABC/3TC + EFV

(N =192)

TDF/FTC + EFV

(N =193)

Overall response

114/192

(59%)

137/193

(71%)

Response by Baseline HIV-1 RNA

<100,000 c/mL

61/95

(64%)

62/83

(75%)

Response by Baseline HIV-1 RNA

≥100,000 c/mL

53/97

(55%)

75/110

(68%)

At week 48, a lower rate of virologic response was observed for ABC/3TC compared to TDF/FTC (point

estimate for the treatment difference: 11.6%, 95% CI: 2.2, 21.1).

Therapy-experienced patients

Data from two studies, CAL30001 and ESS30008 demonstrated that abacavir/lamivudine once daily has

similar virological efficacy to abacavir 300 mg twice daily plus lamivudine 300 mg once daily or 150 mg

twice daily in therapy-experienced patients.

In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and

received treatment with either abacavir/lamivudine once daily or abacavir 300 mg twice daily plus

lamivudine 300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks.

Similar reductions in HIV-1 RNA as measured by average area under the curve minus baseline were

observed, indicating that the abacavir/lamivudine group was non-inferior to the abacavir plus lamivudine

twice daily group (AAUCMB, -1.65 log

copies/ml versus -1.83 log

copies/ml respectively, 95% CI

-0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) and < 400 copies/ml (54%

versus 57%) at week 48 were also similar in each group (ITT population). However, as there were only

moderately experienced patients included in this study with an imbalance in baseline viral load between

the arms, these results should be interpreted with caution.

In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing

abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomised to

continue this regimen or switch to abacavir/lamivudine plus a PI or NNRTI for 48 weeks. Results at 48

weeks indicated that the abacavir/lamivudine group was associated with a similar virologic outcome (non-

inferior) compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-1

RNA < 50 copies/ml (90% and 85% respectively, 95% CI -2.7, 13.5).

A genotypic sensitivity score (GSS) has not been established by the MAH for the abacavir/lamivudine

combination. The proportion of treatment-experienced patients in the CAL30001 study with HIV-RNA

<50 copies/mL at Week 48 by genotypic sensitivity score in optimized background therapy (OBT) are

tabulated The impact of major IAS-USA defined mutations to abacavir or lamivudine and multi-NRTI

resistance associated mutations to the number of baseline mutations on response was also evaluated. The

GSS was obtained from the Monogram reports with susceptible virus ascribed the values '1-4' based upon

the numbers of drugs in the regimen and with virus with reduced susceptibility ascribed the value '0'.

Genotypic sensitivity scores were not obtained for all patients at baseline. Similar proportions of patients

in the once-daily and twice-daily abacavir arms of CAL30001 had GSS scores of <2 or ≥2 and

successfully suppressed to <50 copies/mL by Week 48.

Proportion of Patients in CAL30001 with <50 copies/mL at Week 48 by Genotypic Sensitivity Score

in OBT and Number of Baseline Mutations

ABC/3TC FDC QD

(n=94)

Number of Baseline Mutations

1

ABC BID +3TC

QD

(n=88)

Genotypic

SS

in

OBT

2

10/24 (42%)

3/24 (13%)

7/24 (29%)

12/26 (46%)

>2

29/56 (52%)

21/56 (38%)

8/56 (14%)

27/56 (48%)

Unknown

8/14 (57%)

6/14 (43%)

2/14 (14%)

2/6 (33%)

All

47/94 (50%)

30/94 (32%)

17/94 (18%)

41/88 (47%)

Major IAS-USA defined mutations to Abacavir or Lamivudine and multi-NRTI resistance associated

mutations

For the CNA109586 (ASSERT) and CNA30021 studies in treatment-naïve patients, genotype data was

obtained for only a subset of patients at screening or at baseline, as well as for those patients who met

virologic failure criteria. The partial patient subset of data available for CNA30021 is tabulated below,

but must be interpreted with caution. Drug susceptibility scores were assigned for each patient's viral

genotype utilising the ANRS 2009 HIV-1 genotypic drug resistance algorithm. Each susceptible drug in

the regimen received a score of 1 and drugs for which the ANRS algorithm predicts resistance were

ascribed the value '0'.

Proportion of Patients in CNA30021with <50 cps/mL at Week 48 by Genotypic Sensitivity Score in

OBT and Number of Baseline Mutations

ABC QD + 3TC QD + EFV QD

(N=384)

Number of Baseline Mutations

1

ABC BID+ 3TC

QD + EFV QD

(N=386)

Genotypic SS in

OBT

2

2/6 (33%)

2/6 (33%)

3/6 (50%)

>2

58/119 (49%)

57/119 (48%)

1/119 (<1%)

57/114 (50%)

All

60/125 (48%)

59/125 (47%)

1/125 (<1%)

60/120 (50%)

Major IAS-USA (Dec 2009) defined mutations for Abacavir or Lamivudine

Paediatric population

A comparison of a regimen including once daily versus twice daily dosing of abacavir and lamivudine

was undertaken within a randomised, multicentre, controlled study of HIV-infected, paediatric patients.

1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial (COL105677) and were

dosed according to the weight - band dosing recommendations in the World Health Organisation

treatment guidelines (Antiretroviral therapy of HIV infection in infants and children, 2006). After 36

weeks on a regimen including twice daily abacavir and lamivudine, 669 eligible subjects were

randomised to either continue twice daily dosing or switch to once daily abacavir and lamivudine for at

least an additional 96 weeks. Within this population, 104 patients, weighing at least 25 kg, received 600

mg abacavir and 300 mg lamivudine as fixed combination once daily, with a median duration of exposure

of 596 days.

Among the 669 subjects randomized in this study (from 12 months to 17 years old), the

abacavir/lamivudine once daily dosing group was demonstrated to be non-inferior to the twice daily

group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of <80

c/mL at Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested (<200c/mL,

<400c/mL, <1000c/mL), which all fell well within this non-inferiority margin. Subgroup analyses testing

for heterogeneity of once versus twice daily demonstrated no significant effect of sex, age, or viral load at

randomisation. Conclusions supported non-inferiority regardless of analysis method.

Among the 104 patients who received abacavir/lamivudine, including the ones who were between 40 kg

and 25 kg, the viral suppression was similar.

5.2 Pharmacokinetic properties

The fixed-dose combination tablet of abacavir/lamivudine (FDC) has been shown to be bioequivalent to

lamivudine and abacavir administered separately. This was demonstrated in a single dose, 3-way

crossover bioequivalence study of FDC (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg

lamivudine tablets (fasted) versus FDC 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 (C

), of each

component. There was also no clinically significant food effect observed between administration of FDC

in the fasted or fed state. These results indicate that FDC 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 from the gastro-intestinal tract following oral

administration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and

80-85% respectively. The mean time to maximal serum concentrations (t

) is about 1.5 hours and 1.0

hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, the mean

(CV) C

is 4.26 μg/ml (28%) and the mean (CV) AUC

is 11.95 μg.h/ml (21%). Following multiple-

dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state

is 2.04 μg/ml (26%) and the mean (CV) AUC

is 8.87 μg.h/ml (21%).

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 limited plasma protein binding in

vitro (< 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 IC

of abacavir of

0.08 μg/ml or 0.26 μM 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.

Biotransformation

Abacavir is primarily metabolised by the liver with approximately 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 by renal

excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low

due to the small extent of hepatic metabolism (5-10%).

Elimination

The mean 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 5 to 7 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. Studies in patients with renal impairment show lamivudine elimination is

affected by renal dysfunction. Abacavir/Lamivudine is not recommended for use in patients with a

creatinine clearance < 50 ml/min as necessary dose adjustment cannot be made (see section 4.2).

Intracellular pharmacokinetics

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. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were

higher for the abacavir 600 mg once daily regimen (AUC

24,ss

+ 32%, C

max24,ss

+ 99% and C

trough

+ 18%)

compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the

terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma

lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy volunteers, intracellular lamivudine-

TP pharmacokinetic parameters were similar (AUC

24,ss

and C

max24,ss

) or lower (C

trough

– 24%) for the

lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen. Overall,

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 and safety of this combination given once daily has been

demonstrated in a pivotal clinical study (CNA30021- See Clinical experience).

Special patient populations

Hepatic impairment

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) receiving a single 600 mg dose; the median

(range) AUC value was 24.1 (10.4 to 54.8) ug.h/ml. The results showed that there was a mean (90%CI)

increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-

life. No definitive recommendation on dose reduction is possible in patients with mild hepatic impairment

due to substantial variability of abacavir exposure.

Data obtained in patients with moderate to severe hepatic impairment show that lamivudine

pharmacokinetics are not significantly affected by hepatic dysfunction.

Based on data obtained for abacavir, Abacavir/Lamivudine is not recommended in patients with moderate

or severe hepatic impairment.

Renal impairment

Pharmacokinetic data have been obtained for lamivudine and abacavir alone. 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. Abacavir/Lamivudine is not recommended for use in

patients with a creatinine clearance < 50 ml/min as necessary dose adjustment cannot be made.

Elderly

No pharmacokinetic data are available in patients over 65 years of age.

Children

Abacavir is rapidly and well absorbed from oral formulations when administered to children. Paediatric

pharmacokinetic studies have demonstrated that once daily dosing provides equivalent AUC

to twice

daily dosing of the same total daily dose for both oral solution and tablet formulations.

The absolute bioavailability of lamivudine (approximately 58 to 66%) was lower and more variable in

paediatric patients under 12 years of age. However, paediatric pharmacokinetic studies with tablet

formulations have demonstrated that once daily dosing provides equivalent AUC

to twice daily dosing

of the same total daily dose.

5.3 Preclinical safety data

With the exception of a negative in vivo rat micronucleus test, there are no data available on the effects of

the combination of abacavir and lamivudine in animals.

Mutagenicity and carcinogenicity

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside

analogues, they inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma

assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were

negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma

concentrations up to 40-50 times higher than clinical plasma concentrations. Abacavir has a weak

potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.

The carcinogenic potential of a combination of abacavir and lamivudine has not been tested. In long-term

oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.

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 rats in the thyroid gland of males and in the

liver, urinary bladder, lymph nodes and the subcutis of females.

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. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg

in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the

human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these

data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.

Repeat-dose toxicity

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical

relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic.

Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal

products hepatically metabolised has not been observed in man.

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.

Reproductive toxicology

In reproductive toxicity studies in animals, lamivudine and abacavir were shown to cross the placenta.

Lamivudine was not teratogenic in animal studies but there were indications of an increase in early

embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in

humans. A similar effect was not seen in rats even at very high systemic exposure.

Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These

findings included decreased foetal body weight, foetal oedema, and an increase in skeletal

variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with

regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.

A fertility study in rats has shown that abacavir and lamivudine had no effect on male or female fertility

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Cellulose, Microcrystalline PH 102 (E460)

Cellulose, Microcrystalline PH 200 (E460)

Sodium Starch Glycolate (Type A)

Povidone K 90 (E 1201)

Magnesium Stearate (E470b)

Tablet coating

Hypromellose 5 (E464)

Macrogol 400 (E1521)

Titanium Dioxide (E171)

Sunset Yellow FCF Aluminium Lake (E110)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium- PVC/PE/PVDC white opaque blisters containing 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. Marketing authorisation holder

Dr. Reddy's Laboratories (UK) Ltd.

6 Riverview Road

Beverley

East Yorkshire

HU17 0LD

United Kingdom

8. Marketing authorisation number(s)

PL 08553/0589

9. Date of first authorisation/renewal of the authorisation

29/11/2016

10. Date of revision of the text

29/11/2016

Company Contact Details

Dr. Reddy's Laboratories (UK) Ltd

Address

6 Riverview Road, Beverley, Hull, HU17 0LD

Telephone

+44 (0)1482 860228

Medical Information Direct Line

+44 (0)1748 828873

Customer Care direct line

+44 (0)1482 389858

http://www.drreddys.com/united-kingdom

+44 (0)1482 860204

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1748 828801

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