ZIAGEN ORAL SOLUTION

Patient leaflet in accordance with the

Pharmacists' Regulations (Preparations) - 1986

The medicine is dispensed according to a physician's prescription only

ZIAGEN ORAL SOLUTION

Each ml of Ziagen Oral Solution contains:

abacavir (as sulfate) 20 mg.

List of the additional ingredients is detailed in Section 6.

Read the entire leaflet carefully before using the medicine. This leaflet

contains concise information about the medicine. If you have any other

questions, refer to the physician or the pharmacist.

This medicine has been prescribed for the treatment of your illness. Do not

pass it on to others. It may harm them even if it seems to you that their illness

is similar.

IMPORTANT

- Hypersensitivity reactions

Ziagen contains abacavir (which is also an active substance in medicines

such as Kivexa, Triumeq and Trizivir). 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 Ziagen pack includes an Alert Card, to remind you and the medical staff

about abacavir hypersensitivity.

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

This card contains important safety information that you must know and

abide by before starting treatment and during the course of treatment with

Ziagen. Read the Alert Card and patient leaflet before starting to use the

preparation.

1.

What is the medicine intended for?

Ziagen is used to treat HIV (Human Immunodeficiency Virus) infection.

Therapeutic group: Ziagen contains the active ingredient abacavir. Abacavir

belongs to a group of anti-retroviral medicines called

nucleoside analogue

reverse transcriptase inhibitors (NRTIs)

Ziagen 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 Ziagen in the same way. Your

physician will monitor the effectiveness of your treatment.

2.

Before using the medicine

Do not use the medicine if:

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

abacavir, such as Trizivir, Triumeq or Kivexa) or any of the additional

ingredients of this medicine (listed in Section 6).

Carefully read all the information about hypersensitivity reactions in

Section 4.

Check with your physician if you think this applies to you.

Special warnings regarding the use of the medicine

Some people taking Ziagen 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 are seriously overweight (especially if you are a woman)

if you have severe kidney disease.

Talk to your physician if any of these apply to you. 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 do not 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 physician 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 Ziagen unless your physician 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 Ziagen.

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 infection when taking this medicine, although the

risk is lowered by effective anti-retroviral therapy. Discuss with your physician

the precautions needed to avoid infecting other people.

If you are taking or have recently taken other medicines including

non­prescription medicines and food supplements, tell the physician or

the pharmacist. Remember to tell your physician or pharmacist if you begin

taking a new medicine while you are taking Ziagen.

There are medicines that interact with Ziagen, these include:

phenytoin, for treating epilepsy.

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

monitor your condition while you are taking Ziagen.

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 withdrawal symptoms. Your methadone dose may

need to be changed.

Tell your physician if you are taking methadone.

Pregnancy, breast-feeding and fertility

Pregnancy

Ziagen is not recommended for use during pregnancy. Ziagen and similar

medicines may cause side effects in unborn babies.

If you have taken Ziagen during your pregnancy, your physician 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

passed

baby

breast

milk.

small

amount

ingredients in Ziagen can also pass into your breast milk.

If you are breast-feeding, or thinking about breast-feeding: Talk to your

physician immediately.

Driving and using machines

Do not drive or operate machines unless you are feeling well.

Important

information

about

some

of

the

additional

ingredients

of

Ziagen Oral Solution

This medicine contains the sweetener sorbitol (approximately 5 grams in each

15 ml dose), which may have a mild laxative effect. Do not take medicines

containing sorbitol if you have hereditary fructose intolerance. The calorific

value of sorbitol is 2.6 kcal/g.

Ziagen also contains preservatives (

parahydroxybenzoates

) which may cause

allergic reactions (possibly delayed reaction).

3.

How should you use the medicine?

Always use according to the physician's instructions. You should check with

the physician or the pharmacist if you are unsure about the preparation

dosage and treatment regimen.

The dosage and treatment will be determined only by the physician.

Ziagen can be taken with or without food.

Stay in regular contact with your physician

Ziagen helps to control your condition. You need to keep taking it every day to

stop your illness from getting worse. You may still develop illnesses and other

infections linked to HIV infection.

Keep in touch with your physician, and do not stop taking Ziagen without

consulting your physician.

The usual dosage is:

Adults, adolescents and children weighing at least 25 kg

The usual dosage of Ziagen is 600 mg (30 ml) a day. Can be taken either

as 300 mg (15 ml) twice a day or 600 mg (30 ml) once a day.

Children from three months of age weighing less than 25 kg

The dosage depends on the child’s body weight. The usual dosage is 8 mg/kg

twice a day or 16 mg/kg once a day, up to a maximum of 600 mg daily.

How to measure the dose and take the medicine

Use the measuring syringe supplied with the pack to measure your dose

accurately. When the syringe is full, it contains 10 ml of solution.

1. Remove the bottle cap. Keep it safely. Opening instructions - to remove

the cap, press down, while simultaneously twisting to the left (turning

counterclockwise).

2. Hold the bottle firmly. Push the plastic adapter into the neck of the

bottle.

3. Insert the syringe firmly into the adapter.

4. Turn the bottle upside down.

5. Pull out the syringe plunger until the syringe contains the first part of the

full dose.

6. Turn the bottle the right way up. Remove the syringe from the adapter.

7. Put the syringe into your mouth, placing the tip of the syringe against the

inside of your cheek. Slowly push the plunger in, allowing time to

swallow. Do not push too hard and squirt the liquid into the back of your

throat, or you may choke.

8. Repeat steps 3 to 7 in the same way until you have taken the whole dose.

For example, if the dose is 30 ml, you need to take 3 syringe-fulls of

medicine.

9. Take the syringe out of the bottle and wash it thoroughly in clean water.

Let it dry completely before you use it again.

10. Close the bottle tightly with the cap, leaving the adapter in place. Closing

instructions - replace cap on top of open end of the bottle and twist to the

right (turning clockwise) until it locks tight enough.

Do not exceed the recommended dose.

If you accidentally have taken a higher dosage or if a child has accidentally

swallowed the medicine, refer immediately to a physician or to a hospital

emergency room and bring the package of the medicine with you.

If you forgot to take the medicine at the scheduled time take it as soon as

you remember. Then continue your treatment as usual. Do not take a double

dose to make up for a forgotten dose.

Adhere to the treatment as recommended by the physician.

Even if there is an improvement in your health, do not stop the treatment with

the medicine without consulting the physician or the pharmacist.

It is important to take Ziagen regularly, because if you take it at irregular

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

If you stop taking the medicine

If you have stopped taking Ziagen for any reason - especially because you

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

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

check whether your symptoms were related to a hypersensitivity reaction. If

the physician thinks they may have been related, you will be told never

again to take Ziagen, or any other medicine containing abacavir (e.g.

Trizivir, Triumeq or Kivexa). It is important that you follow this advice.

If your physician advises that you can start taking Ziagen 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.

Do not take medicines in the dark! Check the label and the dose

each time you take a medicine. Wear glasses if you need them.

If you have any other questions regarding the use of the medicine,

consult the physician or the pharmacist.

4.

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 health and life style, and in the case

of blood lipids sometimes to the HIV medicines themselves. Your physician

will test for these changes.

As with any medicine, use of Ziagen Oral Solution may cause side effects in

some of the users. Do not be alarmed by reading the list of side effects. You

may not experience any of them.

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

is a side effect of Ziagen or other medicines you are taking, or an effect of the

HIV disease itself. So it is very important to talk to your physician about

any changes in your health.

Even patients who do not 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.

In addition to the side effects listed below for Ziagen, 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

Ziagen contains abacavir (which is also an active substance in Kivexa,

Triumeq and Trizivir). 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 Ziagen could develop a hypersensitivity reaction to abacavir,

which could be life-threatening if they continue to take Ziagen.

You are more likely to develop such a reaction if you have the HLA-B*5701

gene (but you can get a reaction even if you do not have this gene). You

should have been tested for this gene before Ziagen was prescribed for you.

If you know you have this gene, tell your physician before you take

Ziagen.

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, vomiting, 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 headache, inflammation of the eye

(conjunctivitis)

mouth ulcers, low blood pressure, tingling or numbness of the feet or palms

of your hands.

When do these reactions happen?

Hypersensitivity reactions can start at any time during treatment with Ziagen,

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

If you are caring for a child who is being treated with Ziagen, it is

important

that

you

understand

the

information

about

this

hypersensitivity reaction. If your child gets the symptoms described

below it is essential that you follow the instructions given.

Talk to your physician immediately:

1. if you have a skin rash, OR

2. if you have 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 physician may advise you to stop taking Ziagen.

If you have stopped taking Ziagen

If you have stopped taking Ziagen because of a hypersensitivity reaction,

you must NEVER AGAIN take Ziagen, or any other medicine containing

abacavir (e.g. Trizivir, Triumeq or Kivexa). If you take, within hours, your

blood pressure could fall dangerously low, which could result in death.

If you have stopped taking Ziagen for any reason - especially because you

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

Talk to your physician before you start again. Your physician will check

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

physician thinks they may have been related, you will then be told never

again to take Ziagen, or any other medicine containing abacavir (e.g.

Trizivir, Triumeq or Kivexa). 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 them.

Very rarely, patients who have taken medicines containing abacavir in the

past

without

symptoms

hypersensitivity

have

developed

hypersensitivity reaction when they start taking these medicines again.

If your physician advises that you can start taking Ziagen 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 Ziagen, return all your remaining unused

Ziagen

Oral

Solution

for

safe

disposal.

Consult

your

physician

pharmacist.

The Ziagen pack includes an Alert Card, to remind you and the 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

nausea

headache

vomiting

(being sick)

diarrhoea

loss of appetite

tiredness, lack of energy

fever (high temperature)

skin rash.

Rare side effects

(These may affect up to 1 in 1,000 people):

inflammation of the pancreas

(pancreatitis)

Very rare side effects

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

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 talk to a physician urgently.

Other possible side effects of combination therapy for HIV

Combination therapy including Ziagen may cause other medical 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)

. When

these people start treatment, they may find that old, hidden infections flare up,

causing signs and symptoms of inflammation. These symptoms are probably

caused by the body’s immune system becoming stronger, so that the body

starts to fight these infections. 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 while you are taking Ziagen:

Tell your physician immediately. Do not take other medicines for the

infection without your physician’s advice.

You may have problems with your bones

Some people taking combination therapy for HIV develop a condition called

osteonecrosis

(necrosis of the bone). 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

they are also taking anti-inflammatory medicines called corticosteroids

they drink alcohol

their immune systems are very weak

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 physician.

If a side effect occurs, if one of the side effects worsens or when you

suffer from a side effect not mentioned in the leaflet, consult the

physician.

Side effects can be reported to the Ministry of Health by clicking on the link

“Report Side Effects of Drug Treatment” found on the Ministry of Health

homepage (www.health.gov.il) that directs you to the online form for reporting

side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?form

Type=Adve

rsEffectMedic@moh.gov.il

5.

How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be kept in a

closed place out of the sight and reach of children and/or infants in order to

avoid poisoning. Do not induce vomiting without an explicit instruction from

the physician.

Do not use the medicine after the expiry date (exp. date) appearing on the

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

Do not store above 30ºC.

Use within 60 days after first opening.

6.

Additional information

In addition to the active ingredient the medicine also contains -

sorbitol 70% (E420), propylene glycol (E1520), sodium citrate, citric acid

anhydrous, artificial strawberry and banana flavour, methyl

parahydroxybenzoate (E218), saccharin sodium, propyl

parahydroxybenzoate (E216), maltodextrin, lactic acid, glyceryl triacetate,

purified water, sodium hydroxide and/or hydrochloric acid for pH adjustment.

What the medicine looks like and the contents of the package -

Ziagen Oral Solution is clear to yellowish in colour with strawberry/banana

flavouring. It is supplied in cartons containing a white polyethylene bottle,

with a child resistant cap. The bottle contains 240 ml (20 mg abacavir/ml) of

solution. A 10 ml oral dosing syringe and a plastic adapter for the bottle are

included in the pack.

License Holder: GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

Manufacturer: GlaxoSmithKline Inc., Mississauga, Canada.

This leaflet was checked and approved by the Ministry of Health in January

2019.

Registration number of the medicine in the National Drug Registry of the

Ministry of Health: 112-98-29543.

Trade marks are owned by or licensed to the ViiV Healthcare group of

companies.

©2019 ViiV Healthcare group of companies or its licensor.

Zia OS PT v6.2A

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in January

2019

ZIAGEN ORAL SOLUTION

1.

NAME OF THE MEDICINAL PRODUCT

Ziagen oral solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 20 mg of abacavir (as sulfate).

Excipients with known effect:

Sorbitol (E420) 340 mg/ml

Methyl parahydroxybenzoate (E218) 1.5 mg/ml

Propyl parahydroxybenzoate (E216) 0.18 mg/ml

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Oral solution

The oral solution is clear to slightly opalescent yellowish, aqueous solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infection.

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in

treatment-naïve adult patients on combination therapy with a twice daily regimen (see section 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

Ziagen should be prescribed by physicians experienced in the management of HIV infection.

Ziagen can be taken with or without food.

Ziagen is also available as a tablet formulation.

Adults, adolescents and children (weighing at least 25 kg):

The recommended dose of Ziagen is 600 mg daily (30 ml). This may be administered as either 300 mg

(15 ml) twice daily or 600 mg (30 ml) once daily (see sections 4.4 and 5.1).

Children (weighing less than 25 kg):

Children from one year of age

: The recommended dose is 8 mg/kg twice daily or 16 mg/kg once daily,

up to a maximum total daily dose of 600 mg (30 ml).

Children from three months to one year of age

: The recommended dose is 8 mg/kg twice daily. If a

twice daily regimen is not feasible, a once daily regimen (16 mg/kg/day) could be considered.

should be taken into account that data for the once daily regimen are very limited in this population

(see sections 5.1 and 5.2).

Children less than three months of age:

the experience in children aged less than three months is

limited (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take

the recomended once daily dose (as described above) approximately 12 hours after the last twice daily

dose, and then continue to take the recomended once daily dose (as described above) approximately

every 24 hours. When changing back to a twice daily regimen, patients should take the recommended

twice daily dose approximately 24 hours after the last once daily dose.

Special populations

Renal impairment

No dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is

not recommended for patients with end-stage renal disease (see section 5.2).

Hepatic impairment

Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in

patients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severe

hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended

unless judged necessary. If abacavir is used in patients with mild hepatic impairment, then close

monitoring is required, including monitoring of abacavir plasma levels if feasible (see sections 4.4

and 5.2).

Elderly

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

4.3

Contraindications

Hypersensitivity to abacavir 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

Hypersensitivity reactions (see also section 4.8):

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) 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.

Ziagen 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. (e.g. Kivexa, Trizivir, Triumeq)

Ziagen 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 Ziagen after the onset of hypersensitivity

may result in a life-threatening reaction.

After stopping treatment with Ziagen for reasons of a suspected HSR,

Ziagen or any other

medicinal product containing abacavir

(e.g. Kivexa, Trizivir, Triumeq)

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 Ziagen Oral Solution

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.

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 events 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

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.

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 abacavir treatment is uncertain.

Triple nucleoside therapy

In patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir,

lamivudine and zidovudine needs special consideration (see section 5.1).

There have been reports of a high rate of virological failure and of emergence of resistance at an early

stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily

regimen.

Liver disease

The safety and efficacy of Ziagen has not been established in patients with significant underlying liver

disorders. Ziagen 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.

Renal disease

Ziagen should not be administered to patients with end-stage renal disease (see section 5.2).

Excipients

Ziagen oral solution contains 340 mg/ml of sorbitol. When taken according to the dosage

recommendations each 15 ml dose contains approximately 5 g of sorbitol. Patients with rare hereditary

problems of fructose intolerance should not take this medicine. Sorbitol can have a mild laxative

effect. The calorific value of sorbitol is 2.6 kcal/g.

Ziagen oral solution also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate

which may cause allergic reactions (possibly delayed).

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 mycobacterium infections,

Pneumocystis carinii

pneumonia. Any inflammatory symptoms should be evaluated and treatment

instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis)

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 aetiology 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 receiving Ziagen 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

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.

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 Ziagen, action should be taken to try to minimize all

modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

4.5

Interaction with other medicinal products and other forms of interaction

Based on the results of

in vitro

experiments and the known major metabolic pathways of abacavir, the

potential for P450 mediated interactions with other medicinal products involving abacavir is low.

P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit

metabolism mediated by CYP 3A4. Abacavir has also been shown

in vitro

not to inhibit CYP 3A4,

CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism

has not been observed in clinical studies. Therefore, there is little potential for interactions with

antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies

have shown that there are no clinically significant interactions between abacavir, zidovudine, and

lamivudine.

Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on

UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.

Ethanol:

the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC

of abacavir of about 41%. 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 C

and a one hour delay in t

but the 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%. The induction of drug

metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and

abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as

occasionally methadone re-titration may be required.

Retinoids:

retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is

possible but has not been studied.

4.6

Fertility, pregnancy and lactation

Pregnancy

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

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

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

Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see

section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical

relevance in human of these data is unknown. Placental transfer of abacavir and/or its related

metabolites has been shown to occur in human.

In pregnant women, 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 of abacavir. The malformative risk is unlikely in humans based on those data.

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. There are no data available on the safety of abacavir 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 abacavir had no 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.

4.8

Undesirable effects

For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide

range of medicinal products used in the management of HIV infection or as a result of the disease

process.

Many of the adverse reactions listed 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.

Many of the adverse reactions have not been treatment limiting. The following convention has been

used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000

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

Metabolism and nutrition disorders

Common:

anorexia

Very rare:

lactic acidosis

Nervous system disorders

Common:

headache

Gastrointestinal disorders

Common:

nausea, vomiting, diarrhoea

Rare:

pancreatitis

Skin and subcutaneous tissue disorders

Common

: rash (without systemic symptoms)

Very rare:

erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

General disorders and administration site conditions

Common:

fever, lethargy, fatigue

Description of Selected Adverse Reactions

Abacavir hypersensitivity reactions

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 (CART) an inflammatory reaction to asymptomatic or residual opportunistic

infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 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 (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).

Changes in laboratory chemistries

In controlled clinical studies laboratory abnormalities related to Ziagen treatment were uncommon,

with no differences in incidence observed between Ziagen treated patients and the control arms.

Paediatric population

1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial

(COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section

5.1). 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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

Additionally, you should also report to GSK Israel, (

il.safety@gsk.com

4.9

Overdose

Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to

patients in clinical studies. No additional adverse reactions to those reported for normal doses were

reported. The effects of higher doses are not known. If overdose occurs the patient should be

monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as

necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06

Mechanism of action

Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2. Abacavir is metabolised

intracellularly to the active moiety, carbovir 5’- triphosphate (TP).

In vitro

studies have demonstrated

that its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme,

an event which results in chain termination and interruption of the viral replication cycle. 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 or

zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease

inhibitor (PI) amprenavir.

Resistance

In vitro resistance

Abacavir-resistant isolates of HIV-1 have been selected

in vitro

and are associated with specific

genotypic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V and

Y115F). Viral resistance to abacavir develops relatively slowly

in vitro,

requiring multiple mutations

for a clinically relevant increase in EC

over wild-type virus.

In vivo resistance (Therapy naïve patients)

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%). 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)

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 abacavir 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-1 RNA [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

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. Appropriate use of abacavir can be

guided using currently recommended resistance algorithms.

Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) is

unlikely.

Clinical efficacy and safety

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult

treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with

zidovudine and lamivudine.

Twice daily (300 mg) administration:

Therapy naïve adults

In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of

patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat

analysis at 48 weeks) with corresponding rise in CD4 cells.

One randomised, double blind, placebo controlled clinical study in adults has compared the

combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and

zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued

randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence

between the treatment regimens at week 48. Although a similar antiviral effect was observed between

the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable

viral load (

400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT),

86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir

combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline;

ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively).

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 (point

estimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the difference

between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to

95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -

11.8; -1.7). However, both analyses were compatible with a conclusion of non-inferiority between

both treatment arms.

ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147

antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine

(3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median

follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be

virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml)

with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4

drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the

proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the

ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety

Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of

patients with virologic failure. The remaining arms were continued in a blinded fashion. After a

median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the

ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant

difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study,

addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.

ZDV/3TC/ABC

ZDV/3TC/EFV

ZDV/3TC/ABC/EFV

Virologic failure (HIV

RNA >200 copies/ml)

32 weeks

144 weeks

Virologic success (48

weeks HIV RNA < 50

copies/ml)

Therapy experienced adults

In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination

antiretroviral therapy provided modest benefits in reducing viral load (median change

0.44 log

copies/ml at 16 weeks).

In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit as part

of a new combination regimen will depend on the nature and duration of prior therapy which may

have selected for HIV-1 variants with cross-resistance to abacavir.

Once daily (600 mg) administration:

Therapy naïve adults

The once daily regimen of abacavir 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 - Centre for Disease Control and Prevention (CDC) stage A. They were

randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination with

efavirenz and lamivudine given once daily. 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. Long term data with abacavir used as a once daily regimen (beyond 48

weeks) are currently limited.

Therapy experienced adults

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

received treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) 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. Results indicate that the FDC group was non-inferior to the

abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area

under the curve minus baseline (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%) 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 FDC plus a PI or NNRTI for 48

weeks. Results indicate that the FDC 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).

Additional information:

The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still not

completely assessed (particularly in combination with NNRTIs).

Abacavir penetrates the cerebrospinal fluid (CSF) (see section 5.2), and has been shown to reduce

HIV-1 RNA levels in the CSF. However, no effects on neuropsychological performance were seen

when it was administered to patients with AIDS dementia complex.

Paediatric population:

A randomised comparison of a regimen including once daily vs 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 96 weeks. Of note, from this study clinical data were not available

for children under one year old. The results are summarised in the table below:

Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week 48 and Week

96 in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW

(Observed Analysis)

Twice Daily

N (%)

Once Daily

N (%)

Week 0 (After ≥36 Weeks on Treatment)

Plasma HIV-1 RNA

<80 c/ml

250/331 (76)

237/335 (71)

Risk difference (once

daily-twice daily)

-4.8% (95% CI -11.5% to +1.9%), p=0.16

Week 48

Plasma HIV-1 RNA

<80 c/ml

242/331 (73)

236/330 (72)

Risk difference (once

daily-twice daily)

-1.6% (95% CI -8.4% to +5.2%), p=0.65

Week 96

Plasma HIV-1 RNA

<80 c/ml

234/326 (72)

230/331 (69)

Risk difference (once

daily-twice daily)

-2.3% (95% CI -9.3% to +4.7%), p=0.52

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/mlat 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 vs twice daily demonstrated no significant effect of sex, age,

or viral load at randomisation. Conclusions supported non-inferiority regardless of analysis method.

In a separate study comparing the unblinded NRTI combinations (with or without blinded nelfinavir)

in children, a greater proportion treated with abacavir and lamivudine (71%) or abacavir and

zidovudine (60%) had HIV-1 RNA

400 copies/ml at 48 weeks, compared with those treated with

lamivudine and zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportions

of children treated with the abacavir containing combinations had HIV-1 RNA

50 copies/ml at 48

weeks (53%, 42% and 28% respectively, p=0.07).

In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months of

age switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Three

subjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48.

No safety concerns were observed in these subjects.

5.2

Pharmacokinetic properties

Absorption

Abacavir is rapidly and well absorbed following oral administration. The absolute bioavailability of

oral abacavir in adults is about 83%. Following oral administration, the mean time (t

) to maximal

serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for

the solution formulation.

There are no differences observed between the AUC for the tablet or solution. At therapeutic dosages

a dosage of 300 mg twice daily, the mean (CV) steady state C

and C

of abacavir are

approximately 3.00

g/ml (30%) and 0.01 µg/ml(99%), respectively. The mean (CV) AUC over a

dosing interval of 12 hours was 6.02

g.h/ml (29%), equivalent to a daily AUC of approximately

12.0

g.h/ml. The C

value for the oral solution is slightly higher than the tablet. After a 600 mg

abacavir tablet dose, the mean (CV) abacavir C

was approximately 4.26

g/ml (28%) and the mean

(CV) AUC

was 11.95

g.h/ml (21%).

Food delayed absorption and decreased C

but did not affect overall plasma concentrations (AUC).

Therefore Ziagen can be taken with or without food.

Distribution

Following intravenous administration, the apparent volume of distribution was about 0.8 l/kg,

indicating that abacavir penetrates freely into body tissues.

Studies in HIV infected patients have shown good penetration of abacavir into the CSF, with 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

.

Plasma protein binding studies

in vitro

indicate that abacavir binds only low to moderately (~49%) to

human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions

with other medicinal products through plasma protein binding displacement.

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. The metabolites are excreted in the urine.

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.

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. Overall, these data support the use

of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy

and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021-

See section 5.1 Clinical experience).

Special patient populations

Hepatic impairment

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 values 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 dosage reduction is possible in patients

with mild hepatic impairment due to the substantial variability of abacavir exposure.

Abacavir is not recommended in patients with moderate or severe hepatic impairment.

Renal impairment

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. Therefore no dosage reduction is required in patients with renal

impairment. Based on limited experience Ziagen should be avoided in patients with end-stage renal

disease.

Paediatric population

According to clinical trials performed in children abacavir is rapidly and well absorbed from oral

solution and tablet formulations administered to children. Plasma abacavir exposure has been shown to

be the same for both formulations when administered at the same dose. Children receiving abacavir

oral solution according to the recommended dosage regimen achieve plasma abacavir exposure similar

to adults. Children receiving abacavir oral tablets according to the recommended dosage regimen

achieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kg

doses are administered with the tablet formulation.

There are insufficient safety data to recommend the use of Ziagen in infants less than three months

old. The limited data available indicate that an oral solution dose of 2 mg/kg in neonates less than 30

days old provides similar or greater AUCs, compared to the 8 mg/kg oral solution dose administered

to older children.

Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and

ARROW PK substudy) enrolling children under 12 years of age. The data are displayed in the table

below:

Summary of Stead-State Plasma Abacavir AUC (0-24) (µg.h/ml) and Statistical Comparisons for

Once and Twice-Daily Oral Administration Across Studies

Study

Age Group

Abacavir

16 mg/kg Once-

Daily Dosing

Geometric Mean

(95% Cl)

Abacavir

8 mg/kg Twice-

Daily Dosing

Geometric Mean

(95% Cl)

Once-Versus

Twice-Daily

Comparison

GLS Mean Ratio

(90% Cl)

ARROW PK

Substudy

Part 1

3 to 12 years

(N=36)

15.3

(13.3-17.5)

15.6

(13.7-17.8)

0.98

(0.89, 1.08)

PENTA 13

2 to 12 years

(N=14)

13.4

(11.8-15.2)

9.91

(8.3-11.9)

1.35

(1.19-1.54)

PENTA 15

3 to 36 months

(N=18)

11.6

(9.89-13.5)

10.9

(8.9-13.2)

1.07

(0.92-1.23)

In PENTA 15 study, the geometric mean plasma abacavir AUC(0-24) (95% CI) of the four subjects

under 12 months of age who switch from a twice daily to a once daily regimen (see section 5.1) are

15.9 (8.86, 28.5) µg.h/ml in the once-daily dosing and 12.7 (6.52, 24.6) µg.h/ml in the twice-daily

dosing.

Elderly

The pharmacokinetics of abacavir has not been studied in patients over 65 years of age.

5.3

Preclinical safety data

Abacavir was not mutagenic in bacterial tests but showed activity

in vitro

in the human lymphocyte

chromosome aberration assay, the mouse lymphoma assay, and the

in vivo

micronucleus test. This is

consistent with the known activity of other nucleoside analogues. These results indicate that abacavir

has a weak potential to cause chromosomal damage both

in vitro

in vivo

at high test

concentrations.

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

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 carcinogenic potential in humans

is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential

clinical benefit.

In pre-clinical toxicology studies, abacavir treatment 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.

In reproductive toxicity studies, embryo and foetal toxicity have been observed 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 the rat has shown that abacavir had no effect on male or female fertility.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sorbitol 70% (E420)

Propylene glycol (E1520)

Sodium citrate

Citric acid anhydrous

Artificial strawberry and banana flavours

Methyl parahydroxybenzoate (E218)

Saccharin sodium

Propyl parahydroxybenzoate (E216)

Maltodextrin

Lactic acid

Glyceryl triacetate

Sodium hydroxide and/or hydrochloric acid for pH adjustment.

Purified water

6.2

Incompatibilities

Not applicable

6.3

Shelf-life

The expiry date of the product is indicated on the packaging materials.

After first opening the container: 60 days

6.4

Special precautions for storage

Do not store above 30

6.5

Nature and contents of container

Ziagen oral solution is supplied in high density polyethylene bottles with child-resistant closures,

containing 240 ml of oral solution.

The pack also includes a polyethylene syringe-adapter and a 10 ml oral dosing syringe comprised of a

polypropylene barrel (with ml graduations) and a polyethylene plunger.

6.6

Special precautions for disposal

A plastic adapter and oral dosing syringe are provided for accurate measurement of the prescribed

dose of oral solution. The adapter is placed in the neck of the bottle and the syringe attached to this.

The bottle is inverted and the correct volume withdrawn.

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

7. MANUFACTURER

GlaxoSmithKline INC., Mississauga,Canada.

8.

LICENSE HOLDER AND IMPORTER

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

9.

LICENSE NUMBER

112-98-29543

Trade marks are owned by or licensed to the ViiV Healthcare group of companies.

©2018 ViiV Healthcare group of companies or its licensor.

Zia OS DR v7.2