Lamivudine 300mg tablets

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

Buy It Now

Active ingredient:
Lamivudine
Available from:
Mylan
ATC code:
J05AF05
INN (International Name):
Lamivudine
Dosage:
300mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05030100; GTIN: 5016695004785
Authorization number:
PL 04569/1174

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Page 1 of 6

Package leaflet: Information for the patient

Lamivudine 150 mg Film-coated Tablets

Lamivudine 300 mg Film-coated Tablets

lamivudine

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

important information for you.

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

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

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

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

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

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Lamivudine is and what it is used for

What you need to know before you take Lamivudine

How to take Lamivudine

Possible side effects

How to store Lamivudine

Contents of the pack and other information

1.

What Lamivudine is and what it is used for

Lamivudine is used to treat HIV (human immunodeficiency virus) infection in adults and children.

Lamivudine belongs to a group of antiviral medicines, also known as antiretrovirals, called nucleoside

analogue reverse transcriptase inhibitors (NRTIs).

Lamivudine does not completely cure HIV infection; it reduces the amount of virus in your body, and

keeps it at a low level. It also increases CD4 cell count in your blood. CD4 cells are a type of white

blood cell that are important in maintaining a healthy immune system to help fight infection.

Response to treatment with lamivudine varies between patients. Your doctor will be monitoring the

effectiveness of your treatment.

2.

What you need to know before you take Lamivudine

Do not take Lamivudine:

if you are allergic to lamivudine or any of the other ingredients of this medicine (listed in section

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

Warnings and precautions

Talk to your doctor or pharmacist before taking Lamivudine:

if you are currently being treated for HIV with tenofovir and abacavir or tenofovir and didanosine

(other NRTIs)

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

not stop taking Lamivudine without your doctor’s advice, as your hepatitis may come back)

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

Page 2 of 6

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

Talk to your doctor 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 Lamivudine.

Read the information ‘Other possible side effects of combination therapy for HIV’ in section 4 of

this leaflet.

Protect other people

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

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

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

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

Other medicines and Lamivudine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including herbal medicines or other medicines you bought without a prescription.

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

Lamivudine.

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

other medicines containing lamivudine (used to treat HIV infection or hepatitis B infection)

a group of medicines called cytidine analogues used to treat HIV such as emtricitabine

co-trimoxazole (an antibiotic medicine used to treat infections)

cladribine (used to treat cancer of the blood (leukaemia))

Pregnancy and breast-feeding

Pregnancy

If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor or

pharmacist for advice before taking this medicine.

Lamivudine and similar medicines may cause side effects in unborn babies. If you have taken

Lamivudine during your pregnancy, your doctor may request regular blood tests and other diagnostic

tests to monitor the development of your child. In children whose mothers took NRTIs during

pregnancy, the benefit from the protection against HIV outweighed the risk of side effects.

Breast-feeding

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

baby in breast milk.

A small amount of the ingredients in this medicine can also pass into your breast milk.

If you are breast-feeding or thinking of breast-feeding talk to your doctor immediately.

Driving and using machines

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

Page 3 of 6

3.

How to take Lamivudine

Always take this medicine exactly as your doctor has told you to. You should check with your doctor

or pharmacist if you are not sure.

Swallow the tablets with some water. Lamivudine can be taken with or without food.

If you cannot swallow the tablets whole, you may crush and combine them with a small amount of

food or drink, and take all the dose immediately. Alternatively other forms of the medicine may be

available, ask your doctor or pharmacist

[For 150 mg] The tablet can be divided into equal doses.

Stay in regular contact with your doctor.

Lamivudine helps to control your condition. You need to keep taking it every day to stop your illness

getting worse. You may still develop other infections and illnesses linked to HIV infection.

Keep in touch with your doctor, and do not stop taking Lamivudine without your doctor’s advice.

How much to take

[For 150 mg only]

Use in adults, adolescents and children who weigh at least 25 kg:

The recommended dose of Lamivudine is 300 mg a day. This may be taken as either:

one 150 mg tablet twice a day, leaving approximately 12 hours between each dose, or

two 150 mg tablets once a day as advised by your doctor

Use in children weighing at least 20 kg and less than 25 kg:

The recommended dose is 225 mg a day. This can be given as either:

75 mg (half a Lamivudine 150 mg tablet in the morning, and

one whole Lamivudine tablet (150 mg) in the evening, or

225 mg (one and a half 150 mg tablets) once a day as advised by your doctor

Use in children weighing at least 14 kg and less than 20 kg:

The recommended dose is 150 mg a day. This can be given as either:

75 mg (half a Lamivudine 150 mg tablet twice a day, leaving approximately 12 hours between

each dose, or

150 mg (one 150 mg tablet) once a day as advised by your doctor

[For 300 mg only]

The usual dose of Lamivudine for adults, adolescents and children who weigh at least 25 kg is:

one 300 mg tablet once a day

Other forms of this medicine may be more suitable for children or for people who need a lower dose

than normal, or those who cannot take the tablets; ask your doctor or pharmacist.

If you or your child has a kidney problem, your dose may be altered. Talk to your doctor if this applies

to you or your child.

If you take more Lamivudine than you should

Accidentally taking too much Lamivudine is unlikely to cause any serious problems. However, you

should tell your doctor or your pharmacist, or contact your nearest hospital emergency department for

further advice.

Page 4 of 6

If you forget to take Lamivudine

If you forget to take a dose of Lamivudine, take it as soon as you remember and then continue as

before. Do not take a double dose to make up for a forgotten dose.

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

4.

Possible side effects

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

is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV

medicines themselves. Your doctor will test for these changes.

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

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

lamivudine or other medicines you are taking, or an effect of the HIV disease itself. For this reason it

is very important that you inform your doctor about any changes in your health.

As well as the side effects listed below for Lamivudine, other conditions can develop during

combination therapy for HIV.

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

combination therapy for HIV’.

If you notice any of the following serious side effects contact your doctor immediately:

Uncommon (may affect up to 1 in 100 people):

an increase in the number of infections you get which causes fever, severe chills, sore throat or

mouth ulcers. This may be signs you have a low number of white blood cells in your blood

(neutropenia).

unexplained bruising or bleeding for longer than usual. These may be signs of a decrease in the

number of cells involved in blood clotting (thrombocytopenia).

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

swelling in the face, mouth, lips, tongue or throat causing difficulty breathing or swallowing

(angioedema).

severe stomach pain which may radiate to your back. This may be signs of problems with your

pancreas (pancreatitis).

yellowing of your skin or whites of your eyes, dark urine, pale stools, tiredness, fever, feeling sick

(nausea), weakness, drowsiness and abdominal pain. These may be signs you have serious

problems with your liver (hepatitis).

dark coloured urine with muscle weakness or tiredness. These may be signs of muscle breakdown

(rhabdomyolysis).

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

tiredness, weakness, pale coloured skin, shortness of breath. These may be signs of a disorder

where you are not producing red blood cells (pure red cell aplasia).

numbness and tingling (commonly known as pins and needles), burning, stabbing or shooting

pain in the feet or hands leading to loss of balance and co-ordination. These may be signs of nerve

damage (peripheral neuropathy).

deep, rapid, difficult breathing, drowsiness, numbness or weakness in the limbs, feeling sick

(nausea), being sick (vomiting) and stomach pain. These may be signs of excess lactic acid in the

blood (lactic acidosis).

Other possible side effects include:

Page 5 of 6

Common (may affect up to 1 in 10 people):

feeling sick (nausea)

being sick (vomiting)

stomach pains

diarrhoea

headache

joint pain

muscle pain and discomfort

cough

irritated or runny nose

fever (high temperature)

tiredness, lack of energy

general feeling of being unwell

skin rash

hair loss (alopecia)

difficulty in sleeping (insomnia)

Uncommon (may affect up to 1 in 100 people):

a low red blood cell count (anaemia)

an increase in the level of liver enzymes

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

increase in an enzyme called amylase that can be seen in a blood test

Other possible side effects of combination therapy for HIV

Combination therapy including Lamivudine may cause other conditions to develop during HIV

treatment.

Old infections may flare up

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

develop serious infections (opportunistic infections). When these people start treatment, they may find

that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are

probably caused by the body’s immune system becoming stronger, so that the body starts to fight these

infections.

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 doctor immediately to seek necessary treatment.

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

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

advice.

You may have problems with your bones

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

condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be

more likely to get this condition:

if they have been taking combination therapy for a long time

if they are also taking anti-inflammatory medicines called corticosteroids

if they drink alcohol

if their immune systems are very weak

if they are overweight

Page 6 of 6

Signs of osteonecrosis include:

stiffness in the joints

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

difficulty moving

If you notice any of these symptoms tell your doctor.

Reporting of side effects

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

not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme, Website:

www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Lamivudine

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle or blister or carton after

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

This medicine does not require any special storage conditions.

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

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

6.

Contents of the pack and other information

What Lamivudine film-coated tablets contain

The active substance is lamivudine. Each 150 mg film-coated tablet contains 150 mg of lamivudine.

Each 300 mg film-coated tablet contains 300 mg of lamivudine.

The other ingredients are:

Tablet core: microcrystalline cellulose, sodium starch glycolate, magnesium stearate.

Tablet coating: hypromellose, titanium dioxide, propylene glycol.

What Lamivudine film-coated tablets look like and contents of the pack

Lamivudine 150 mg film-coated tablets are white to off-white,

capsule shaped with two sides that

curve out, marked with “M105” on one side and a functional scoreline on the other.

Lamivudine 300 mg film-coated tablets are white to off-white, oval shaped with two sides that curve

out, marked with “M300” on one side and plain on the other.

Lamivudine is available in blisters of 30, 60, 90, 120 tablets and in bottles of 30 and 60 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

Manufacturer

Generics [UK] Limited, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road, Dublin 13, Ireland.

This leaflet was last revised in August 2016.

Read the complete document

Object 1

Lamivudine Mylan 300 mg Film-coated Tablets

Summary of Product Characteristics Updated 17-Jul-2017 | Generics UK T/A Mylan

1. Name of the medicinal product

Lamivudine Mylan 300 mg Film-coated Tablets

2. Qualitative and quantitative composition

Each 300 mg film-coated tablet contains 300 mg of lamivudine.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

White to off-white, oval shaped, biconvex film-coated tablet, debossed with “M300” on one side and

plain on the other.

4. Clinical particulars

4.1 Therapeutic indications

Lamivudine Mylan 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.

Posology

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

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

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

The 300 mg tablet is only suitable for the once a day regimen.

Children (weighing less than 25 kg)

Children from three months of age

As an accurate dosage cannot be achieved with the 300 mg non-scored tablet formulation in this patient

population, it is recommended that the Lamivudine Mylan 150 mg scored tablet formulation is used and

the corresponding recommended dosage instructions are followed.

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

Elderly

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 to severe renal impairment due to

decreased clearance. The dose should therefore be adjusted, using oral solution presentation of

lamivudine for patients whose creatinine clearance falls below 30 ml/min (see tables).

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

Creatinine clearance (ml/min)

First dose

Maintenance dose

≥50

300 mg

150 mg

300 mg once daily

150 mg twice daily

30 to <50

150 mg

150 mg once daily

<30

As doses below 150 mg are needed, the use of the oral solution is

recommended

15 to <30

150 mg

100 mg once daily

5 to <15

150 mg

50 mg once daily

<5

50 mg

25 mg 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. Lamivudine oral solution may be the most

appropriate formulation to achieve the recommended maintenance dose in paediatric patients with renal

impairment.

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

Creatinine clearance (ml/min)

First dose

Maintenance dose

≥50

8 mg/kg

8 mg/kg once daily

4 mg/kg

4 mg/kg twice daily

30 to <50

4 mg/kg

4 mg/kg once daily

15 to <30

4 mg/kg

2.6 mg/kg once daily

5 to <15

4 mg/kg

1.3 mg/kg once daily

<5

1.3 mg/kg

0.7 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.

Method of administration

For oral use.

Lamivudine Mylan may be administered with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.

Lamivudine is available as an oral solution for children over three months of age and who weigh less than

14 kg or for patients who are unable to swallow tablets.

Alternatively, for patients who are unable to swallow the tablets, the tablets 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).

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.

Lamivudine 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 lamivudine 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. Treatment with Lamivudine Mylan 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, 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 (hyperlactataemia,

hyperlipasemia). These reactions have often been transitory. Late-onset neurological disorders have been

reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are

transient or permanent is currently unknown. These findings should be considered for any child exposed

in utero to nucleoside and nucleotide analogues, who present with severe clinical findings of unknown

aetiology, 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 carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment

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

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

these events can occur many months after initiation of treatment.

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 corresponding

SPC.

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 Lamivudine Mylan 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 corresponding SPC).

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).

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

lamivudine as compared to those receiving the tablet formulation. Whenever possible in children,

lamivudine as tablet formulation should preferably be used.

Osteonecrosis

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

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

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

Lamivudine Mylan 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 carinii 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. 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, lamivudine should not be administered concomitantly with other cytidine analogues,

such as emtricitabine. Moreover, Lamivudine Mylan 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.

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 1,000 outcomes from the first trimester and more than 1,000 outcomes from the second and

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

Lamivudine 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 and 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).

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 breast-fed infants of mothers treated for HIV are very low (< 4% of maternal serum

concentrations) and progressively decrease to undetectable levels when breast-fed 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 lamivudine.

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) or very rare

(<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing

seriousness.

Blood and lymphatic system 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

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) 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 of suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website:

www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

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.

Treatment

If overdose 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

overdose, although this has not been studied.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; nucleoside and nucleotide reverse transcriptase

inhibitors, ATC Code: J05AF05.

Mechanism of action

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 antiretrovirals (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 NRTIs

should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine

therapy, despite emergence of M184V mutation, should only be considered in cases where no other active

NRTIs are available.

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).

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-naïve 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 in the

corresponding SPC). 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

lamivudine once a day and lamivudine twice a day containing regimens. These results were obtained in an

antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC stage

Paediatric population

A randomised comparison of a regimen including once daily vs twice daily dosing of abacavir and

lamivudine was undertaken within a randomised, multicentre, controlled study of HIV-infected,

paediatric patients. 1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial

(COL105677) and were dosed according to the weight - band dosing recommendations in the World

Health Organisation treatment guidelines (Antiretroviral therapy of HIV infection in infants and children,

2006). After 36 weeks on a regimen including twice daily abacavir and lamivudine, 669 eligible subjects

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

for at least 96 weeks. Of note, from this study clinical data were not available for children under one year

old. The results are summarised in the table below:

Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week 48 and Week 96 in

the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW (Observed

Analysis)

Twice daily

N (%)

Once daily

N (%)

Week 0 (After ≥36 weeks in 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%), 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)

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

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

respectively.

The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC

, and t

Administration of a tablet formulation has been shown to be bioequivalent to an oral solution with respect

to AUC

and C

in adults.

Absorption differences have been observed between adult and paediatric populations (see Special

populations).

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.

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected

to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical

effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the

patient crushes and transfers 100% of the tablet and ingests immediately.

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 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,

lamivudine 300 mg once daily has been demonstrated to be pharmacokinetically equivalent at steady-state

to lamivudine 150 mg twice daily with respect to intracellular triphosphate AUC

and C

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

Paediatric population

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

and C

than oral solution given concomitantly with

other antiretroviral 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 AUC

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 Comparisons for

Once and Twice-Daily Oral Administration Across Studies

Study

Age group

Lamivudine

8 mg/kg Once-daily

dosing geometric

mean (95% CI)

Lamivudine

4 mg/kg Twice-daily

dosing geometric

mean (95% CI)

Once versus twice-

daily comparison

GLS mean ratio

(90% CI)

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.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Cellulose, microcrystalline

Sodium starch glycolate (Type A)

Magnesium stearate

Film coat

Hypromellose

Titanium dioxide

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Pack sizes (HDPE bottles with PP screw cap): 30 and 60 film-coated tablets

Pack sizes (PVC/PVdC - Al unit dose blisters):30 and 60 film-coated tablets

Pack sizes (PVC/PVdC – Al blister): 30, 60, 90, & 120 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close, Potters Bar

Hertfordshire EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 04569/1174

9. Date of first authorisation/renewal of the authorisation

24/11/2011

10. Date of revision of the text

12/04/2017

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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