12-09-2019
23-09-2019
23-07-2019
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
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