EPIVIR ORAL SOLUTION

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
LAMIVUDINE
Available from:
GLAXO SMITH KLINE (ISRAEL) LTD
ATC code:
J05AF05
Pharmaceutical form:
SOLUTION (ORAL)
Composition:
LAMIVUDINE 10 MG/ML
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
GLAXO SMITH KLINE INC., CANADA
Therapeutic group:
LAMIVUDINE
Therapeutic area:
LAMIVUDINE
Therapeutic indications:
Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children. 28/10/2018 בקשה לשינוי משטר מינון.
Authorization number:
124 08 28843 21
Authorization date:
2014-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

25-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

12-09-2019

Patient leaflet in accordance with the

Pharmacists' Regulations (Preparations) – 1986

The medicine is dispensed according to a physician's prescription

only.

Epivir Oral Solution

Each ml of oral solution contains Lamivudine 10 mg.

For the list of the inactive and allergenic ingredients, see section

2 - “Important information about some of the ingredients of Epivir” and

section 6 - “Additional information”.

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 you or for your child. Do not

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

illness is similar.

1. What is the medicine intended for?

Epivir is used to treat HIV infection (human immunodeficiency virus)

in adults and children.

Therapeutic group: Epivir is a type of medicine known as an

anti-retroviral. It belongs to a group of medicines called nucleoside

analogue reverse transcriptase inhibitors (NRTIs).

Epivir 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 Epivir 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 lamivudine or to any of the additional

ingredients contained in the medicine (listed in section 6).

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

Special warnings regarding the use of the medicine

Some people taking Epivir 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 ever had liver disease, including hepatitis B or C (if you

have hepatitis B infection, do not stop using Epivir without your

physician’s advice, as your hepatitis may come back)

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

if you or your child has a kidney problem, your dose may be

altered.

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.

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 Epivir.

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 anti-retroviral therapy.

Discuss with your physician the precautions needed to avoid infecting

other people.

Other medicines and Epivir

If you are taking, or have recently taken, other medicines including

non -prescription medicines and food supplements, tell the physician

or the pharmacist.

Remember to inform your physician or pharmacist if you begin taking

a new medicine while you are taking Epivir.

These medicines should not be used with Epivir:

medicines (usually liquids) containing sorbitol and other sugar alcohols

(such as xylitol, mannitol, lactitol or maltitol), if taken regularly

other medicines containing lamivudine (used to treat HIV infection

or hepatitis B infection)

emtricitabine (used to treat HIV infection)

high doses of co-trimoxazole, an antibiotic

cladribine (used to treat hairy cell leukaemia)

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

Pregnancy, Breast-feeding and fertility

Pregnancy

If you are pregnant, become pregnant, or are planning to become

pregnant, talk to your physician about the risks and benefits to you

and your baby of taking Epivir.

Epivir and similar medicines may cause side effects in unborn babies.

If you have taken Epivir 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 of 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 Epivir 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

Epivir is unlikely to affect your ability to drive or use machines.

Important information about some of the ingredients of Epivir

If you are a diabetic, please note that each dose (150 mg = 15 ml)

contains 3 g sugar.

Epivir contains sucrose. If you have been told by your physician that

you have an intolerance to some sugars, contact your physician before

taking Epivir. Sucrose may be harmful to the teeth.

Epivir also contains preservatives (parahydroxybenzoates) which may

cause allergic reactions (possibly delayed).

This medicine contains 300 mg propylene glycol in every 15 ml of

medicine.

This medicine contains less than 1 mmol sodium (23 mg) for ml, so it

is essentially sodium-free.

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.

Do not exceed the recommended dose

Epivir can be taken with or without food.

Stay in regular contact with your physician

Epivir 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 physician and do not stop taking Epivir

without your physician’s advice.

The dosage and treatment regimen will be determined only by the

physician. The recommended dosage is usually:

Adults, adolescents and children weighing at least 25 kg

The recommended dosage of Epivir is usually 30 ml a day (300 mg)

to be taken as 15 ml (150 mg) twice a day (at intervals of approximately

12 hours between each dose) or as approximately 30 ml (300 mg)

once a day.

Children from 3 months of age, weighing less than 25 kg

The dosage depends on the child’s weight.

The recommended dosage of Epivir is usually 0.5 ml/kg (5 mg/kg)

twice daily (at intervals of approximately 12 hours between each dose)

or 1 ml/kg (10 mg/kg) once daily.

Use the oral dosing syringe supplied with the pack to measure your

dose accurately.

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

remove the cap, press down, while simultaneously twisting to the

left (turning counterclockwise).

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

the bottle.

Insert the syringe firmly into the adapter.

Turn the bottle upside down.

Pull out the syringe plunger until the syringe contains the first part

of your full dose.

Turn the bottle the correct way up. Remove the syringe from the

adapter.

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, to avoid choking.

Repeat steps 3 to 7 in the same way until you have taken your

whole dose. For example, if your dose is 15 ml, you need to take

one and a half syringes of medicine.

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.

If you or your child has a kidney problem, the dose may be altered.

Talk to your physician if this applies to you or your child.

If you accidentally have taken a higher dosage

Accidentally taking too much Epivir is unlikely to cause any serious

problems. If you have taken an overdose 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

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.

Adhere to the treatment as recommended by the physician.

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 Epivir 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 Epivir 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.

As well as the side effects listed below for Epivir, 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”.

Common side effects

These may affect up to 1 in 10 people:

headache

nausea

vomiting

diarrhoea

stomach pains

tiredness, lack of energy

fever

general feeling of being unwell

muscle pain and discomfort

joint pain

difficulty in sleeping (insomnia)

cough

irritated or runny nose

rash

hair loss (alopecia).

Uncommon side effects

These may affect up to 1 in 100 people:

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

a decrease in the number of cells involved in blood clotting

(thrombocytopenia)

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

(neutropenia)

an increase in the level of liver enzymes.

Rare side effects

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

serious allergic reaction causing swelling of the face, tongue or throat

which may cause difficulty in swallowing or breathing

inflammation of the pancreas (pancreatitis)

breakdown of muscle tissue

liver disorders, such as jaundice, enlarged liver or fatty liver,

inflammation (hepatitis).

A rare side effect that may show up in blood tests is:

increase in an enzyme called amylase.

Very rare side effects

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

lactic acidosis (excess lactic acid in the blood)

tingling or numbness of the arms, legs, hands or feet.

A very rare side effect that may show up in blood tests is:

a failure of the bone marrow to produce new red blood cells (pure

red cell aplasia).

Other possible side effects of combination therapy for HIV

Combination therapy such as Epivir may cause other conditions to

develop during HIV treatment.

Old infections may flare up

People with advanced HIV infection (AIDS) have a weak immune

system 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.

In addition to the opportunistic infections, autoimmune disorders

(a condition that occurs when the immune system attacks healthy body

tissue) may also occur after you start taking medicines for the treatment

of your HIV infection. Autoimmune disorders may occur many months

after the start of treatment. If you notice any symptoms of infection

or other symptoms such as muscle weakness, weakness beginning

in the hands and feet and moving up towards the trunk of the body,

palpitations, tremor or hyperactivity, please inform your physician

immediately to receive the necessary treatment.

If you get any symptoms of infection while you are taking Epivir:

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. 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 system is 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 physician.

If a side effect has appeared, if any of the side effects get worse or

when you suffer from a side effect that has not been mentioned in

the leaflet, you should 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://sideeffects.health.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.

Discard one month after first opening.

Do not store above 25°C.

6. Additional information

In addition to the active ingredient the medicine also contains:

Sucrose 20%, propylene glycol, sodium citrate, methyl

parahydroxybenzoate, citric acid (Anhydrous), artificial strawberry

flavour, artificial banana flavour, propyl parahydroxybenzoate, purified

water.

What does the medicine look like and what is the content of the

package:

Epivir oral solution is supplied in a white polyethylene bottle

containing 240 ml of solution. An oral dosing syringe and a plastic

adapter for the bottle are included in the pack. The bottle is closed

with a child-resistant cap.

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

July 2019.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health: 124-08-28843.

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

of companies.

©2019 ViiV Healthcare group of companies or its licensor.

EpiOS PT v7.1A 20394

EpiOS PT v7.1A 20394

Page 1 of 16

The format of this leaflet was determined by the Ministry of Health and its content was

checked and approved in July 2019

Epivir Oral Solution

1.

NAME OF THE MEDICINAL PRODUCT

Epivir oral solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 10 mg of lamivudine.

Excipient(s) with known effect:

Each 15 ml dose contains 3 g sucrose (20% w/v).

Methyl parahydroxybenzoate

Propyl parahydroxybenzoate

Each 15 ml dose contains 300 mg propylene glycol.

Each 15 ml dose contains 44.1 mg sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Oral solution

Clear, colourless to pale yellow solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infected adults and children.

4.2

Posology and method of administration

The therapy should be initiated by a physician experienced in the management of HIV

infection.

Epivir may be administered with or without food.

Epivir is also available as a tablet formulation for patients who weigh at least 14 kg (see

section 4.4).

Patients changing between lamivudine tablets and lamivudine oral solution should follow the

dosing recommendations that are specific for the formulation (see section 5.2).

Page 2 of 16

For patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a

small amount of semi-solid food or liquid, all of which should be consumed immediately (see

section 5.2).

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

The recommended dose of Epivir is 300 mg daily. This may be administered as either 150 mg

(15 ml) twice daily or 300 mg (30 ml) once daily (see section 4.4).

Children (weighing less than 25 kg):

Children from one year of age:

The recommended dose is 0.5 mL/kg (5 mg/kg) twice daily,

or 1 mL/kg (10 mg/kg) once daily (see sections 4.4 and 4.5).

Children from three months to one year of age:

The recommended dose is 0.5 mL/kg (5

mg/kg) twice daily. If a twice daily regimen is not feasible, a once daily regimen (10

mg/kg/day) could be considered. It should be taken into account that data for the once daily

regimen are very limited in this population (see sections 4.4, 5.1 and 5.2).

Children less than three months of age:

The limited data available are insufficient to propose

specific dosage recommendations (see section 5.2).

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

should take the recommended once daily dose (as described above) approximately 12 hours

after the last twice daily dose, and then continue to take the recommended 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:

Older people:

No specific data are available; however, 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:

Lamivudine concentrations are increased in patients with

moderate - severe renal impairment due to decreased clearance. The dose should therefore be

adjusted (see tables).

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

Creatinine clearance

(ml/min)

First dose

Maintenance dose

300 mg (30 ml)

150 mg (15 ml)

300 mg (30 ml) once daily

150 mg (15 ml) twice daily

30 to<50

150 mg (15 ml)

150 mg (15 ml) once daily

15 to <30

150 mg (15 ml)

100 mg (10 ml) once daily

5 to <15

150 mg (15 ml)

50 mg (5 ml) once daily

<5

50 mg (5 ml)

25 mg (2.5 ml) once daily

Page 3 of 16

There are no data available on the use of lamivudine in children with renal impairment.

Based on the assumption that creatinine clearance and lamivudine clearance are correlated

similarly in children as in adults; it is recommended that the dosage in children with renal

impairment be reduced according to their creatinine clearance by the same proportion as in

adults. The Epivir 10 mg/mL oral solution may be the most appropriate formulation to

achieve the recommended dose in children with renal impairment aged at least 3 months and

weighing less than 25kg.

Dosing recommendations – Children aged at least 3 months and weighing less than 25 kg:

Creatinine clearance

(ml/min)

First dose

Maintenance dose

10 mg/kg

5 mg/kg

10 mg/kg once daily

5 mg/kg twice daily

30 to<50

5 mg/kg

5 mg/kg once daily

15 to <30

5 mg/kg

3.3 mg/kg once daily

5 to <15

5 mg/kg

1.6 mg/kg once daily

<5

1.6 mg/kg

0.9 mg/kg once daily

Hepatic impairment:

Data obtained in patients with moderate to severe hepatic impairment

shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.

Based on these data, no dose adjustment is necessary in patients with moderate or severe

hepatic impairment unless accompanied by renal impairment.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

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.

Epivir is not recommended for use as monotherapy.

Renal impairment:

In patients with moderate –to- severe renal impairment, the terminal

plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose

should be adjusted (see section 4.2).

Triple nucleoside therapy:

There have been reports of a high rate of virological failure and of

emergence of resistance at an early stage when lamivudine was combined with tenofovir

disoproxil fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine

as a once daily regimen.

Opportunistic infections:

Patients receiving Epivir or any other antiretroviral therapy may

continue to develop opportunistic infections and other complications of HIV infection, and

therefore should remain under close clinical observation by physicians experienced in the

treatment of patients with associated HIV diseases.

Pancreatitis

: Cases of pancreatitis have occurred rarely. However it is not clear whether

these cases were due to the antiretroviral treatment or to the underlying HIV disease.

Page 4 of 16

Treatment with Epivir should be stopped immediately if clinical signs, symptoms or

laboratory abnormalities suggestive of pancreatitis occur.

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 nucleoside

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.

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.

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, and

Pneumocystis jirovecii

pneumonia (often referred to as PCP). 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.

Liver disease:

If lamivudine is being used concomitantly for the treatment of HIV and HBV,

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

infection is available in the Zeffix physician leaflet.

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 events. In case of

concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product

information for these medicinal products.

If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of

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

lamivudine may result in an acute exacerbation of hepatitis (see Zeffix physician leaflet).

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

(see section 4.8).

Page 5 of 16

Excipients:

Diabetic patients should be advised that each dose (150 mg = 15 ml) contains 3 g

of sucrose.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose

malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Epivir contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. These may

cause allergic reactions (possibly delayed).

Paediatric Population:

In a study performed in paediatric patients (see section 5.1 ARROW

study), lower rates of virologic suppression and more frequent viral resistance were reported

in children receiving the oral solution of Epivir as compared to those receiving the tablet

formulation.

Whenever possible in children, an all-tablet regimen should preferably be used. Epivir oral

solution given concomitantly with sorbitol-containing medicines should be used only when an

all-tablet regimen cannot be used and the benefits of treatment outweigh possible risks

including lower virological suppression. Consider more frequent monitoring of HIV-1 viral

load when Epivir is used with chronically-administered, sorbitol-containing medicines [e.g.

Ziagen oral solution]. Although not studied, the same effect would be expected with other

osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol,

maltitol (see section 4.5)).

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 combination antiretroviral therapy (CART). Patients

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

stiffness or difficulty in movement.

Drug Interactions:

Epivir should not be taken with any other medicinal products containing

lamivudine or medicinal products containing emtricitabine (see section 4.5).

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

4.5

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein

binding and almost complete renal clearance.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase

in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole

component did not interact. However, unless the patient has renal impairment, no dosage

adjustment of lamivudine is necessary (see section 4.2). Lamivudine has no effect on the

pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is

warranted, patients should be monitored clinically. Co-administration of lamivudine with high

doses of co-trimoxazole for the treatment of

Pneumocystis jirovecii

pneumonia (PCP) and

toxoplasmosis should be avoided.

The possibility of interactions with other medicinal products administered concurrently

should be considered, particularly when the main route of elimination is active renal secretion

via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g.

Page 6 of 16

ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to

interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not

eliminated by this mechanism and are unlikely to interact with lamivudine.

A modest increase in C

(28 %) was observed for zidovudine when administered with

lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no

effect on the pharmacokinetics of lamivudine (see section 5.2).

Due to similarities, Epivir should not be administered concomitantly with other cytidine

analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other

medicinal products containing lamivudine (see section 4.4).

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).

Lamivudine metabolism does not involve CYP3A, making interactions with medicinal

products metabolised by this system (e.g. PIs) unlikely.

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of

lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in

lamivudine exposure (AUC

) and 28%, 52%, and 55% in the C

of lamivudine in adults.

When possible, avoid chronic coadministration of Epivir with medicinal products containing

sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol,

mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when

chronic coadministration cannot be avoided (see section 4.4).

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 lamivudine showed an increase in early embryonic deaths in rabbits but

not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in

humans.

More than 1000 outcomes from first trimester and more than 1000 outcomes from second and

third trimester exposure in pregnant women indicate no malformative and foeto/neonatal

effect. Epivir can be used during pregnancy if clinically needed. The malformative risk is

unlikely in humans based on those data.

For patients co-infected with hepatitis who are being treated with 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

in vivo

to cause a variable degree of mitochondrial damage. There have been reports

of mitochondrial dysfunction in infants exposed

in utero

and/or post-natally to nucleoside

analogues (see section 4.4).

Page 7 of 16

Breast-feeding

Following oral administration lamivudine was excreted in breast milk at similar

concentrations to those found in serum. 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 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 lamivudine 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 the ability to drive and use machines have been performed.

4.8

Undesirable effects

The following adverse reactions have been reported during therapy for HIV disease with

Epivir.

The adverse reactions considered at least possibly related to the treatment are listed below by

body system, organ class and absolute frequency. Frequencies are defined as 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). Within each frequency grouping, undesirable effects are

presented in order of decreasing seriousness.

Blood and lymphatic systems disorders

Uncommon

: Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare

: Pure red cell aplasia

Metabolism and nutrition disorders

Very rare:

Lactic acidosis

Nervous system disorders

Common:

Headache, insomnia

Very rare:

Peripheral neuropathy (or paraesthesia)

Respiratory, Thoracic and mediastinal disorders

Common:

Cough, nasal symptoms

Gastrointestinal disorders

Common:

Nausea, vomiting, abdominal pain or cramps, diarrhoea

Rare:

Pancreatitis, elevations in serum amylase

Hepatobiliary disorders

Uncommon:

Transient elevations in liver enzymes (AST, ALT)

Rare:

Hepatitis

Skin and subcutaneous tissue disorders

Common:

Rash, alopecia

Rare:

Angioedema

Page 8 of 16

Musculoskeletal and connective tissue disorders

Common:

Arthralgia,

muscle disorders

Rare:

Rhabdomyolysis

General disorders and administration site conditions

Common:

Fatigue, malaise, fever

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see

section 4.4)

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).

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

acknowledged risk factors, advanced HIV disease or long-term combined antiretroviral

exposure (CART). The frequency of which is unknown (see section 4.4).

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://sideeffects.health.gov.il

4.9

Overdose

Administration of lamivudine at very high dose levels in acute animal studies did not result in

any organ toxicity. Limited data are available on the consequences of ingestion of acute

overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or

symptoms have been identified following such overdose.

If overdosage occurs the patient should be monitored, and standard supportive treatment

applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used

in the treatment of overdosage, although this has not been studied.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.

Mechanism of action

Page 9 of 16

Lamivudine is a nucleoside analogue which has activity against human immunodeficiency

virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active

moiety, lamivudine 5’- triphosphate. Its main mode of action is as a chain terminator of viral

reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and

HIV-2 replication

in vitro

it is also active against zidovudine-resistant clinical isolates of

HIV. No antagonistic effects

in vitro

were seen with lamivudine and other anti retrovirals

(tested agents: abacavir, didanosine, nevirapine and zidovudine).

Resistance

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change

close to the active site of the viral reverse transcriptase (RT). This variant arises both

in vitro

and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy.

M184V mutants display greatly reduced susceptibility to lamivudine and show diminished

viral replicative capacity

in vitro

In vitro

studies indicate that zidovudine-resistant virus

isolates can become zidovudine sensitive when they simultaneously acquire resistance to

lamivudine. The clinical relevance of such findings remains, however, not well defined.

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 NRTI’s 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 NRTI’s are

available.

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class

of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities

against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against

lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant

shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these

findings is unknown.

In vitro

susceptibility testing has not been standardised and results may

vary according to methodological factors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established

lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor

cells

in vitro

Clinical efficacy and safety

In clinical trials, lamivudine in combination with zidovudine

has been shown to reduce HIV-1

viral load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in

combination with zidovudine, results in a significant reduction in the risk of disease

progression and mortality.

Evidence from clinical studies shows that lamivudine plus zidovudine

delays the emergence

of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.

Lamivudine has been widely used as a component of antiretroviral combination therapy with

other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside

reverse transcriptase inhibitors).

Page 10 of 16

Clinical trial evidence from paediatric patients receiving lamivudine with other antiretroviral

drugs (abacavir, nevirapine/efavirenz or zidovudine) has shown that the resistance profile

observed in paediatric patients is similar to that observed in adults, in terms of the genotypic

substitutions detected and their relative frequency.

Children receiving lamivudine oral solution concomitantly with other antiretroviral oral

solutions in clinical trials developed viral resistance more frequently than children receiving

tablets (see the description of the clinical experience in paediatric population (ARROW

study) and section 5.2).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in

antiretrovirally-naive patients as well as in patients presenting with viruses containing the

M184V mutations.

The relationship between

in vitro

susceptibility of HIV to lamivudine and clinical response to

lamivudine-containing therapy remains under investigation.

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the

treatment of adult patients with chronic HBV infection (for details of clinical studies, see the

prescribing information for Zeffix). However, for the treatment of HIV infection, only a

300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been

shown to be efficacious.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.

Once daily dosing (300 mg once a day):

a clinical study has demonstrated the non inferiority

between Epivir once a day and Epivir twice a day containing regimens. These results were

obtained in an antiretroviral naïve-population, primarily consisting of asymptomatic HIV

infected patients (CDC stage A).

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:

Page 11 of 16

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

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.

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 vs twice daily

demonstrated no significant effect of sex, age, or viral load at randomisation. Conclusions

supported non-inferiority regardless of analysis method.

At the time of randomization to once daily vs twice daily dosing (Week 0), those patients who

had received tablet formulations had a higher rate of viral load suppression than those who

had received any solution formulations at any time. These differences were observed in each

different age group studied. This difference in suppression rates between tablets and solutions

remained through Week 96 with once daily dosing.

Proportions of Subjects in the Once Daily versus Twice Daily Abacavir+Lamivudine

Randomisation of ARROW with Plasma HIV-1 RNA <80 copies/ml: Subgroup Analysis

by Formulation

Twice Daily

Plasma HIV-1 RNA

<80 c/ml:

n/N (%)

Once Daily

Plasma HIV-1 RNA

<80 c/ml:

n/N (%)

Week 0 (after 36 weeks on Treatment)

Any solution regimen at any time

14/26 (54)

15/30 (50)

All tablet based regimen throughouts

236/305 (77)

222/305 (73)

Week 96

Any solution regimen at any time

13/26 (50)

17/30 (57)

Page 12 of 16

All tablet based regimen throughouts

221/300 (74)

213/301 (71)

Genotypic resistance analyses were conducted on samples with plasma HIV-1 RNA >1000

copies/ml. More cases of resistance were detected among patients who had received

lamivudine solution, in combination with other antiretroviral solutions, compared with those

who received similar doses of tablet formulation. This is consistent with the lower rates of

antiviral suppression observed in these patients.

5.2

Pharmacokinetic properties

Absorption

Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral

lamivudine in adults is normally between 80 and 85%. Following oral administration, the

mean time (t

) to maximal serum concentrations (C

) is about an hour. Based on data

derived from a study in healthy volunteers, at a therapeutic dose of 150 mg twice daily, mean

(CV) steady-state C

and C

of lamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml

(27%), respectively. The mean (CV) AUC over a dosing interval of 12 hours is 4.7 µg.h/ml

(18%). At a therapeutic dose of 300 mg once daily, the mean (CV) steady-state C

24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and 8.9 µg.h/ml (21%), respectively.

Co-administration of lamivudine with food results in a delay of t

and a lower C

(decreased by 47 %). However, the extent (based on the AUC) of lamivudine absorbed is not

influenced.

Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28%

increase in peak plasma levels. This is not considered to be of significance to patient safety

and therefore no dosage adjustments are necessary.

Distribution

From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed half-life

of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately

0.32 l/h/kg, with predominantly renal clearance (>70 %) via the organic cationic transport

system.

Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays

limited binding to the major plasma protein albumin (< 16% - 36% to serum albumin in

in

vitro

studies).

Limited data show that lamivudine penetrates the central nervous system and reaches the

cerebro-spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours

after oral administration was approximately 0.12. The true extent of penetration or

relationship with any clinical efficacy is unknown.

Biotransformation

The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in

the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60

healthy adult volunteers, Epivir 300 mg once daily has been demonstrated to be

pharmacokinetically equivalent at steady-state to Epivir 150 mg twice daily with respect to

intracellular triphosphate AUC

and C

Page 13 of 16

Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of

metabolic interactions of lamivudine with other medicinal products is low due to the small

extent of hepatic metabolism (5-10%) and low plasma protein binding.

Elimination

Studies in patients with renal impairment show lamivudine elimination is affected by renal

dysfunction. A recommended dosage regimen for patients with creatinine clearance below

50 ml/min is shown in the dosage section (see section 4.2).

An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in

lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the

patient also has renal impairment (see sections 4.5 and 4.2). Administration of co-

trimoxazole with lamivudine in patients with renal impairment should be carefully assessed.

Special populations

Children:

The absolute bioavailability of lamivudine (approximately 58-66%) was reduced in

paediatric patients below 12 years of age. In children, administration of tablets given

concomitantly with other antiretroviral tablets delivered higher plasma lamivudine AUC

than oral solution given concomitantly with other antiretroviral oral solutions. Children

receiving lamivudine oral solution according to the recommended dosage regimen achieve

plasma lamivudine exposure within the range of values observed in adults. Children

receiving lamivudine oral tablets according to the recommended dosage regimen achieve

higher plasma lamivudine exposure than children receiving oral solution because higher

mg/kg doses are administered with the tablet formulation and the tablet formulation has

higher bioavailability (see section 4.2). Paediatric pharmacokinetic studies with both oral

solution and tablet formulations have demonstrated that once daily dosing provides equivalent

0-24

to twice daily dosing of the same total daily dose.

There are limited pharmacokinetic data for patients less than three months of age. In neonates

one week of age, lamivudine oral clearance was reduced when compared to paediatric

patients and is likely to be due to immature renal function and variable absorption. Therefore

to achieve similar adult and paediatric exposure, an appropriate dose for neonates is

4 mg/kg/day. Glomerular filtration estimates suggests that to achieve similar adult and

paediatric exposure, an appropriate dose for children aged six weeks and older could be

8 mg/kg/day.

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 Lamivudine AUC (0-24) (µg.h/ml) and Statistical

Page 14 of 16

Comparisons for Once and Twice-Daily Oral Administration Across Studies

Study

Age Group

Lamivudine

8mg/kg Once-

Daily Dosing

Geometric

Mean (95% Cl)

Lamivudine

4 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=35)

13.0

(11.4,14.9)

12.0

(10.7, 13.4)

1.09

(0.979, 1.20)

PENTA 13

2 to 12 years

(N=19)

9.80

(8.64, 11.1)

8.88

(7.67, 10.3)

1.12

(1.03, 1.21)

PENTA 15

3 to 36 months

(N=17)

8.66

(7.46, 10.1)

9.48

(7.89, 11.40)

0.91

(0.79, 1.06)

In PENTA 15 study, the geometric mean plasma lamivudine 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 10.31 (6.26, 17.0) µg.h/ml in the once-daily dosing and 9.24 (4.66, 18.3)

µg.h/mL in the twice-daily dosing.

Pregnancy:

Following oral administration, lamivudine pharmacokinetics in late-pregnancy

were similar to non-pregnant women.

5.3

Preclinical safety data

Administration of lamivudine in animal toxicity studies at high doses was not associated with

any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver

and kidney function were seen together with occasional reductions in liver weight. The

clinically relevant effects noted were a reduction in red blood cell count and neutropenia.

Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed

activity in an

in vitro

cytogenetic assay and the mouse lymphoma assay. Lamivudine was not

genotoxic

in vivo

at doses that gave plasma concentrations around 40-50 times higher than the

anticipated clinical plasma levels. As the

in vitro

mutagenic activity of lamivudine could not

be confirmed in

in vivo

tests, it is concluded that

lamivudine should not represent a genotoxic

hazard to patients undergoing treatment.

A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with

the combination of zidovudine and lamivudine at human-equivalent exposures. The study

demonstrated that foetuses exposed

in utero

to the combination sustained a higher level of

nucleoside analogue-DNA incorporation into multiple foetal organs, and showed evidence of

more telomere shortening than in those exposed to zidovudine alone. The clinical significance

of these findings is unknown.

The results of long-term carcinogenicity studies in rats and mice did not show any

carcinogenic potential relevant for humans.

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

Page 15 of 16

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sucrose 20 % w/v

Propylene glycol

Sodium citrate

Methyl parahydroxybenzoate

Citric acid (Anhydrous)

Artificial strawberry flavour

Artificial banana flavour

Propyl parahydroxybenzoate

Purified water

6.2

Incompatibilities

Not applicable

6.3

Shelf life

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

Discard the oral solution one month after first opening.

6.4

Special precautions for storage

Do not store above 25°C.

6.5

Nature and contents of container

Cartons containing 240 ml oral solution in a white high density polyethylene (HDPE) bottle,

with a child resistant closure. 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.

The oral dosing syringe is provided for accurate measurement of the prescribed dose of the

oral solution. Instructions for use are included in the pack.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

MANUFACTURER

GlaxoSmithKline Inc., Mississauga, Canada.

8.

LICENSE HOLDER AND IMPORTER

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

9.

LICENSE NUMBER

124-08-28843

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

Page 16 of 16

©2019 ViiV Healthcare group of companies or its licensor.

EpiOS DR v6.1

ילוי

2019

:ןודנה ריביפא היתשל הסימת

Oral Solution

Epivir

ה/דבכנ ה/אפור

,ה/דבכנ ת/חקור

( מ"עב לארשי ןיילקתימסוסקלג תרבח

ולעה ןוכדע לע עידוהל תשקבמ ) םינ

אפורל ןכרצלו לש

רישכתה

:

Epivir Oral

Solution

ה

םינוכדע רישכתה לש ןונימה רטשמב יוניש וללכ םינולעב .ןויעב םינולעה תא אורקל םיצילממ ונא ןכ לע .

וז העדוהב ולעב םייתוהמה םייונישה םילולכ םינ

אפורל

ןכרצלו

:םקזוחו םיליעפ םיביכרמ

Lamivudine – 10 mg/ml

:לארשיב רישכתל המושרה היוותה

Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency

Virus (HIV) infected adults and children.

ע

וכד

נ

םיאבה םיפיעסב ושענ םייתוהמ םי

ב

: אפורל ןולע

4.2 Posology and method of administration

The therapy should be initiated by a physician experienced in the management of HIV infection.

Epivir may be administered with or without food.

Epivir is also available as a tablet formulation for patients who weigh at least 14 kg (see section 4.4).

Patients changing between lamivudine tablets and lamivudine oral solution should follow the dosing recommendations that

are specific for the formulation (see section 5.2).

For patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid

food or liquid, all of which should be consumed immediately (see section 5.2).

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

The recommended dose of Epivir is 300 mg daily. This may be administered as either 150 mg (15 ml) twice daily or 300 mg

(30 ml) once daily (see section 4.4).

Children (weighing less than 25 kg):

Children from one year of age: The recommended dose is 0.5 mL/kg (5 mg/kg) twice daily, or 1 mL/kg (10 mg/kg) once daily

up to a maximum total daily dose of 300 mg (30 ml) (see sections 4.4 and 4.5).

Children from three months to one year of age: The recommended dose is 0.5 mL/kg (5 mg/kg) twice daily. If a twice daily

regimen is not feasible, a once daily regimen (10 mg/kg/day) could be considered. It should be taken into account that data

for the once daily regimen are very limited in this population (see sections 4.4, 5.1 and 5.2).

Children less than three months of age: The limited data available are insufficient to propose specific dosage

recommendations (see section 5.2).

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

daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the

recommended 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:

Older people: No specific data are available; however, 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: Lamivudine concentrations are increased in patients with moderate - severe renal impairment due to

decreased clearance. The dose should therefore be adjusted (see tables).

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

Creatinine clearance

(ml/min)

First dose

Maintenance dose

300 mg (30 ml)

150 mg (15 ml)

300 mg (30 ml) once daily

150 mg (15 ml) twice daily

30 to<50

150 mg (15 ml)

150 mg (15 ml) once daily

15 to <30

150 mg (15 ml)

100 mg (10 ml) once daily

5 to <15

150 mg (15 ml)

50 mg (5 ml) once daily

<5

50 mg (5 ml)

25 mg (2.5 ml) once daily

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that

creatinine clearance and lamivudine clearance are correlated similarly in children as in adults; it is recommended that the

dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in

adults. The Epivir 10 mg/mL oral solution may be the most appropriate formulation to achieve the recommended dose in

children with renal impairment aged at least 3 months and weighing less than 25kg.

Dosing recommendations – Children aged at least 3 months and weighing less than 25 kg:

Creatinine clearance

(ml/min)

First dose

Maintenance dose

810 mg/kg

45 mg/kg

810 mg/kg once daily

5 mg/kg twice daily

30 to<50

45 mg/kg

45 mg/kg once daily

15 to <30

45 mg/kg

2.63.3 mg/kg once daily

5 to <15

45 mg/kg

1.36 mg/kg once daily

<5

1.36 mg/kg

0.79 mg/kg once daily

Hepatic impairment: Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine

pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is

necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

ע

ל ןולעב םיאבה םיפיעסב ושענ םייתוהמ םינוכד

צ

ןכר

:

3

.

?הפורתב שמתשת דציכ

םידלי ליגמ

3

םישדוח מ תוחפ םילקושה

-

25

ג"ק

.דליה לש ףוגה לקשמב יולת ןונימה

לבוקמה ןונימה ללכ ךרדב ריביפא לש וניה

0.5

( ג"ק/ל"מ

5

ג"ק / ג"מ

)

םויב םיימעפ

(

כ לש םישרפהב

ןיב תועש הנמ לכ

וא

1

ג"ק/ל"מ

(

10

ג"ק/ג"מ

)

םויב םעפ לש יברימ ןונימל דע

300

םויל ג"מ

.

: םינמוסמה םינוכדעל ארקמ

רסוהש עדימ

הצוח םודא וקב ןמוסמ

תפסות

בתכ לוחכ

הרמחה תפסות

בתכ לוחכ

רקרמ בוהצב ןמוסמ

ולעה םינ אפורל

ןכרצל

וחלשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

https://data.health.gov.il/drugs/index.html#/byDrug

ןתינו םיספדומ םלבקל

לע

לזב 'חר ןיילקתימסוסקלג תרבחל הינפ ידי

:ןופלטב הוקת חתפ

03-9297100

,הכרבב

ןבוקשר הינט

הנוממ תחקור

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